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Koksal BT, Barıs Z, Sencelikel T, Ozcay F, Ozbek OY. Food protein-induced allergic proctocolitis in infants is associated with low serum levels of macrophage inflammatory protein-3a. J Pediatr Gastroenterol Nutr 2024; 78:211-216. [PMID: 38374573 DOI: 10.1002/jpn3.12069] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/08/2023] [Revised: 10/06/2023] [Accepted: 10/15/2023] [Indexed: 02/21/2024]
Abstract
BACKGROUND Food protein-induced allergic proctocolitis (FPIAP) is a nonimmunoglobulin (IgE)-mediated food hypersensitivity and the exact mechanisms that cause FPIAP are unknown. Chemokines play crucial roles in the development of allergic diseases. OBJECTIVE To examine serum levels of a group of chemokines in infants with FPIAP. METHODS In 67 infants with FPIAP and 65 healthy infants, we measured serum levels of mucosa-associated epithelial chemokine (MEC/CCL28), thymus-expressed chemokine (TECK/CCL25), CX3CL1 and macrophage inflammatory protein (MIP)-3a/CCL20. RESULTS Infants with FPIAP had a lower median value of MIP3a/CCL20 than healthy infants [0.7 (0-222) vs. 4 (0-249) pg/mL, respectively] (p < 0.001). Infants with MIP3a/CCL20 levels ≤0.95 pg/mL have 13.93 times more risk of developing FPIAP than infants with MIP3a/CCL20 levels >0.95 pg/mL. Serum MEC/CCL28, TECK/CCL25, and CX3CL1 levels were similar between the infants with FPIAP and the control group. CONCLUSION MIP3a/CCL20 serum levels were reduced in infants with FPIAP compared with healthy controls. Whether this finding has a role in pathogenesis remains to be determined.
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Affiliation(s)
- Burcu Tahire Koksal
- Department of Pediatric Allergy, Baskent University Faculty of Medicine, Ankara, Turkey
| | - Zeren Barıs
- Department of Pediatric Gastroenterology and Hepatology, Eskisehir Osmangazi University Faculty of Medicine, Eskisehir, Turkey
| | - Tugce Sencelikel
- Department of Biostatistics, Ankara Medipol University, Ankara, Turkey
| | - Figen Ozcay
- Department of Pediatric Gastroenterology and Hepatology, Baskent University Faculty of Medicine, Ankara, Turkey
| | - Ozlem Yılmaz Ozbek
- Department of Pediatric Allergy, Baskent University Faculty of Medicine, Ankara, Turkey
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2
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Kelly AJ, Long A. Targeting T-cell integrins in autoimmune and inflammatory diseases. Clin Exp Immunol 2024; 215:15-26. [PMID: 37556361 PMCID: PMC10776250 DOI: 10.1093/cei/uxad093] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Revised: 07/28/2023] [Accepted: 08/08/2023] [Indexed: 08/11/2023] Open
Abstract
The recruitment of T cells to tissues and their retention there are essential processes in the pathogenesis of many autoimmune and inflammatory diseases. The mechanisms regulating these processes have become better understood over the past three decades and are now recognized to involve temporally and spatially specific interactions between cell-adhesion molecules. These include integrins, which are heterodimeric molecules that mediate in-to-out and out-to-in signalling in T cells, other leukocytes, and most other cells of the body. Integrin signalling contributes to T-cell circulation through peripheral lymph nodes, immunological synapse stability and function, extravasation at the sites of inflammation, and T-cell retention at these sites. Greater understanding of the contribution of integrin signalling to the role of T cells in autoimmune and inflammatory diseases has focused much attention on the development of therapeutics that target T-cell integrins. This literature review describes the structure, activation, and function of integrins with respect to T cells, then discusses the use of integrin-targeting therapeutics in inflammatory bowel disease, multiple sclerosis, and psoriasis. Efficacy and safety data from clinical trials and post-marketing surveillance are presented for currently approved therapeutics, therapeutics that have been withdrawn from the market, and novel therapeutics currently in clinical trials. This literature review will inform the reader of the current means of targeting T-cell integrins in autoimmune and inflammatory diseases, as well as recent developments in the field.
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Affiliation(s)
- Aidan J Kelly
- Trinity Translational Medicine Institute, Trinity College Dublin, Trinity Centre for Health Sciences, St James's Hospital, Dublin D08 NHY1, Ireland
| | - Aideen Long
- Trinity Translational Medicine Institute, Trinity College Dublin, Trinity Centre for Health Sciences, St James's Hospital, Dublin D08 NHY1, Ireland
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3
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Okamoto Y, Shikano S. Emerging roles of a chemoattractant receptor GPR15 and ligands in pathophysiology. Front Immunol 2023; 14:1179456. [PMID: 37457732 PMCID: PMC10348422 DOI: 10.3389/fimmu.2023.1179456] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2023] [Accepted: 06/19/2023] [Indexed: 07/18/2023] Open
Abstract
Chemokine receptors play a central role in the maintenance of immune homeostasis and development of inflammation by directing leukocyte migration to tissues. GPR15 is a G protein-coupled receptor (GPCR) that was initially known as a co-receptor for human immunodeficiency virus (HIV) and simian immunodeficiency virus (SIV), with structural similarity to other members of the chemoattractant receptor family. Since the discovery of its novel function as a colon-homing receptor of T cells in mice a decade ago, GPR15 has been rapidly gaining attention for its involvement in a variety of inflammatory and immune disorders. The recent identification of its natural ligand C10orf99, a chemokine-like polypeptide strongly expressed in gastrointestinal tissues, has established that GPR15-C10orf99 is a novel signaling axis that controls intestinal homeostasis and inflammation through the migration of immune cells. In addition, it has been demonstrated that C10orf99-independent functions of GPR15 and GPR15-independent activities of C10orf99 also play significant roles in the pathophysiology. Therefore, GPR15 and its ligands are potential therapeutic targets. To provide a basis for the future development of GPR15- or GPR15 ligand-targeted therapeutics, we have summarized the latest advances in the role of GPR15 and its ligands in human diseases as well as the molecular mechanisms that regulate GPR15 expression and functions.
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Affiliation(s)
| | - Sojin Shikano
- Department of Biochemistry and Molecular Genetics, University of Illinois at Chicago, Chicago, IL, United States
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4
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Aghaallaei N, Agarwal R, Benjaminsen J, Lust K, Bajoghli B, Wittbrodt J, Feijoo CG. Antigen-Presenting Cells and T Cells Interact in a Specific Area of the Intestinal Mucosa Defined by the Ccl25-Ccr9 Axis in Medaka. Front Immunol 2022; 13:812899. [PMID: 35185906 PMCID: PMC8853713 DOI: 10.3389/fimmu.2022.812899] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2021] [Accepted: 01/10/2022] [Indexed: 11/21/2022] Open
Abstract
Organized intestinal mucosal immune response appears to be restricted to tetrapods. In teleost fish, there is no evidence for the existence of a particular intestinal region that facilitates the interaction of antigen-presenting cells (APCs) and T cells, such as secondary lymphoid organs. Indeed, despite their importance in the defense against pathogens, the location and manner of APC-T cell interaction within the fish gut is unknown. Here, using non-invasive live imaging of newly developed transgenic reporter lines, we addressed the spatial organization and behavior of APCs and T cells in the intestine of medaka fish both during homeostasis and inflammation. We report that Ccr9a+ T cells are recruited to a band in the lamina propria next to the muscularis mucosa in which Ccl25-expressing cells are present. Ccr9a+ T cells contact APCs for several minutes, in a process mediated by connexin 43. This type of interaction was observed in homeostasis and inflammation, with the interaction being longer and more frequent during inflammation. Thus, our results demonstrate that the mucosal immune response in the intestine of medaka is organized and endowed with a specific region with specialized microenvironment and function.
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Affiliation(s)
- Narges Aghaallaei
- Centre for Organismal Studies (COS), Heidelberg University, Heidelberg, Germany
| | - Rashi Agarwal
- Centre for Organismal Studies (COS), Heidelberg University, Heidelberg, Germany
| | - Joergen Benjaminsen
- Centre for Organismal Studies (COS), Heidelberg University, Heidelberg, Germany
| | - Katharina Lust
- Centre for Organismal Studies (COS), Heidelberg University, Heidelberg, Germany
| | - Baubak Bajoghli
- Directors' Research Unit, European Molecular Biology Laboratory (EMBL), Heidelberg, Germany
| | - Joachim Wittbrodt
- Centre for Organismal Studies (COS), Heidelberg University, Heidelberg, Germany
| | - Carmen G Feijoo
- Centre for Organismal Studies (COS), Heidelberg University, Heidelberg, Germany.,Departamento de Ciencias Biologicas, Facultad de Ciencias de la Vida, Universidad Andres Bello, Santiago, Chile
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Paiva IA, Familiar-Macedo D, Badolato-Corrêa J, Carvalho FR, Dias HG, Pauvolid-Corrêa A, dos Santos CF, Silva AA, de Azeredo EL, Vianna RADO, Cardoso CAA, Grifoni A, Sette A, Weiskopf D, de-Oliveira-Pinto LM. Involvement of Th1Th17 Cell Subpopulations in the Immune Responses of Mothers Who Gave Birth to Children with Congenital Zika Syndrome (CZS). Viruses 2022; 14:v14020250. [PMID: 35215843 PMCID: PMC8879837 DOI: 10.3390/v14020250] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Revised: 01/11/2022] [Accepted: 01/20/2022] [Indexed: 11/16/2022] Open
Abstract
High levels of T helper 17 cell (Th17)-related cytokines have been shown in acute Zika virus (ZIKV) infection. We hypothesized that the high levels of Th17-related cytokines, associated with a regulatory environment during pregnancy, create a favorable milieu for the differentiation of CD4+Th17 cells. We present data from a cross-sectional study on mothers who confirmed ZIKV infection by qRT-PCR and their children. We also recruited non-pregnant women infected with ZIKV in the same period. ZIKV infection occurred between 2015 and 2017. We collected samples for this study between 2018 and 2019, years after the initial infection. We highlight that, after in vitro stimulation with ZIKV CD4 megapool (ZIKV MP), we found a lower frequency of IL-17-producing CD4+ T cells (Th17), especially in the mothers, confirmed by the decrease in IL-17 production in the supernatant. However, a higher frequency of CD4+ IL-17+ IFN-γ+ T cells (Th1Th17) responding to the ZIKV MP was observed in the cells of the mothers and children but not in those of the non-pregnant women. Our data indicate that the priming of CD4 T cells of the Th1Th17 phenotype occurred preferentially in the mothers who gave birth to children with CZS and in the children.
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Affiliation(s)
- Iury Amancio Paiva
- Laboratory of Viral Immunology, Fundação Oswaldo Cruz, Rio de Janeiro 21040-360, Brazil; (I.A.P.); (D.F.-M.); (J.B.-C.); (H.G.D.); (C.F.d.S.); (E.L.d.A.)
| | - Débora Familiar-Macedo
- Laboratory of Viral Immunology, Fundação Oswaldo Cruz, Rio de Janeiro 21040-360, Brazil; (I.A.P.); (D.F.-M.); (J.B.-C.); (H.G.D.); (C.F.d.S.); (E.L.d.A.)
| | - Jéssica Badolato-Corrêa
- Laboratory of Viral Immunology, Fundação Oswaldo Cruz, Rio de Janeiro 21040-360, Brazil; (I.A.P.); (D.F.-M.); (J.B.-C.); (H.G.D.); (C.F.d.S.); (E.L.d.A.)
| | - Fabiana Rabe Carvalho
- Multiuser Laboratory for Research in Nephrology and Medical Science, School of Medicine, Universidade Federal Fluminense, Niterói 24033-900, Brazil; (F.R.C.); (A.A.S.); (C.A.A.C.)
| | - Helver Gonçalves Dias
- Laboratory of Viral Immunology, Fundação Oswaldo Cruz, Rio de Janeiro 21040-360, Brazil; (I.A.P.); (D.F.-M.); (J.B.-C.); (H.G.D.); (C.F.d.S.); (E.L.d.A.)
| | - Alex Pauvolid-Corrêa
- Department of Veterinary Integrative Biosciences, Texas A&M University, College Station, TX 77843-4458, USA;
- Laboratory of Respiratory Viruses and Measles, Fiocruz, Rio de Janeiro 21040-360, Brazil
| | - Caroline Fernandes dos Santos
- Laboratory of Viral Immunology, Fundação Oswaldo Cruz, Rio de Janeiro 21040-360, Brazil; (I.A.P.); (D.F.-M.); (J.B.-C.); (H.G.D.); (C.F.d.S.); (E.L.d.A.)
| | - Andréa Alice Silva
- Multiuser Laboratory for Research in Nephrology and Medical Science, School of Medicine, Universidade Federal Fluminense, Niterói 24033-900, Brazil; (F.R.C.); (A.A.S.); (C.A.A.C.)
| | - Elzinandes Leal de Azeredo
- Laboratory of Viral Immunology, Fundação Oswaldo Cruz, Rio de Janeiro 21040-360, Brazil; (I.A.P.); (D.F.-M.); (J.B.-C.); (H.G.D.); (C.F.d.S.); (E.L.d.A.)
| | | | - Claudete Aparecida Araújo Cardoso
- Multiuser Laboratory for Research in Nephrology and Medical Science, School of Medicine, Universidade Federal Fluminense, Niterói 24033-900, Brazil; (F.R.C.); (A.A.S.); (C.A.A.C.)
- Department of Maternal and Child, School of Medicine, Universidade Federal Fluminense, Niterói 24033-900, Brazil;
| | - Alba Grifoni
- Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology (LJI), San Diego, CA 92037, USA; (A.G.); (A.S.); (D.W.)
| | - Alessandro Sette
- Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology (LJI), San Diego, CA 92037, USA; (A.G.); (A.S.); (D.W.)
- Division of Infectious Diseases and Global Public Health, Department of Medicine, University of California San Diego, San Diego, CA 92093, USA
| | - Daniela Weiskopf
- Center for Infectious Disease and Vaccine Research, La Jolla Institute for Immunology (LJI), San Diego, CA 92037, USA; (A.G.); (A.S.); (D.W.)
| | - Luzia Maria de-Oliveira-Pinto
- Laboratory of Viral Immunology, Fundação Oswaldo Cruz, Rio de Janeiro 21040-360, Brazil; (I.A.P.); (D.F.-M.); (J.B.-C.); (H.G.D.); (C.F.d.S.); (E.L.d.A.)
- Correspondence:
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6
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Hinrichs AC, Blokland SLM, Lopes AP, Wichers CGK, Kruize AA, Pandit A, Radstake TRDJ, van Roon JAG. Transcriptome Analysis of CCR9+ T Helper Cells From Primary Sjögren's Syndrome Patients Identifies CCL5 as a Novel Effector Molecule. Front Immunol 2021; 12:702733. [PMID: 34386009 PMCID: PMC8354142 DOI: 10.3389/fimmu.2021.702733] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2021] [Accepted: 07/09/2021] [Indexed: 12/27/2022] Open
Abstract
Introduction CCR9+ Tfh-like pathogenic T helper (Th) cells are elevated in patients with primary Sjögren’s syndrome (pSS) and indicated to play a role in pSS immunopathology. Here we delineate the CCR9+ Th cell-specific transcriptome to study the molecular dysregulation of these cells in pSS patients. Methods CCR9+, CXCR5+ and CCR9-CXCR5- Th cells from blood of 7 healthy controls (HC) and 7 pSS patients were FACS sorted and RNA sequencing was performed. Computational analysis was used to identify differentially expressed genes (DEGs), coherent gene expression networks and differentially regulated pathways. Target genes were replicated in additional cohorts. Results 5131 genes were differentially expressed between CCR9+ and CXCR5+ Th cells; 6493 and 4783 between CCR9+ and CCR9-CXCR5- and between CXCR5+ and CCR9-CXCR5-, respectively. In the CCR9+ Th cell subset 2777 DEGs were identified between HC and pSS patients, 1416 and 1077 in the CXCR5+ and CCR9-CXCR5- subsets, respectively. One gene network was selected based on eigengene expression differences between the Th cell subsets and pathways enriched for genes involved in migration and adhesion, cytokine and chemokine production. Selected DEGs of interest (HOPX, SOX4, ITGAE, ITGA1, NCR3, ABCB1, C3AR1, NT5E, CCR5 and CCL5) from this module were validated and found upregulated in blood CCR9+ Th cells, but were similarly expressed in HC and pSS patients. Increased frequencies of CCR9+ Th cells were shown to express higher levels of CCL5 than CXCR5+ and CCR9-CXCR5- Th cells, with the highest expression confined to effector CCR9+ Th cells. Antigenic triggering and stimulation with IL-7 of the Th cell subsets co-cultured with monocytes strongly induced CCL5 secretion in CCR9+ Th cell cocultures. Additionally, effector CCR9+ Th cells rapidly released CCL5 and secreted the highest CCL5 levels upon stimulation. Conclusion Transcriptomic analysis of circulating CCR9+ Th cells reveals CCR9-specific pathways involved in effector T cell function equally expressed in pSS patients and HC. Given the increased numbers of CCR9+ Th cells in the blood and inflamed glands of pSS patients and presence of inflammatory stimuli to activate these cells this suggests that CCR9-specific functions, such as cell recruitment upon CCL5 secretion, could significantly contribute to immunopathology in pSS.
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Affiliation(s)
- Anneline C Hinrichs
- Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.,Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
| | - Sofie L M Blokland
- Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.,Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
| | - Ana P Lopes
- Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.,Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
| | - Catharina G K Wichers
- Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.,Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
| | - Aike A Kruize
- Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
| | - Aridaman Pandit
- Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.,Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
| | - Timothy R D J Radstake
- Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.,Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
| | - Joel A G van Roon
- Department of Rheumatology & Clinical Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands.,Center for Translational Immunology, University Medical Center Utrecht, Utrecht University, Utrecht, Netherlands
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7
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Paiva IA, Badolato-Corrêa J, Familiar-Macedo D, de-Oliveira-Pinto LM. Th17 Cells in Viral Infections-Friend or Foe? Cells 2021; 10:cells10051159. [PMID: 34064728 PMCID: PMC8151546 DOI: 10.3390/cells10051159] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2021] [Revised: 04/20/2021] [Accepted: 04/28/2021] [Indexed: 12/12/2022] Open
Abstract
Th17 cells are recognized as indispensable in inducing protective immunity against bacteria and fungi, as they promote the integrity of mucosal epithelial barriers. It is believed that Th17 cells also play a central role in the induction of autoimmune diseases. Recent advances have evaluated Th17 effector functions during viral infections, including their critical role in the production and induction of pro-inflammatory cytokines and in the recruitment and activation of other immune cells. Thus, Th17 is involved in the induction both of pathogenicity and immunoprotective mechanisms seen in the host's immune response against viruses. However, certain Th17 cells can also modulate immune responses, since they can secrete immunosuppressive factors, such as IL-10; these cells are called non-pathogenic Th17 cells. Here, we present a brief review of Th17 cells and highlight their involvement in some virus infections. We cover these notions by highlighting the role of Th17 cells in regulating the protective and pathogenic immune response in the context of viral infections. In addition, we will be describing myocarditis and multiple sclerosis as examples of immune diseases triggered by viral infections, in which we will discuss further the roles of Th17 cells in the induction of tissue damage.
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8
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Umar S, Palasiewicz K, Van Raemdonck K, Volin MV, Romay B, Ahmad I, Tetali C, Sweiss N, Amin MA, Zomorrodi RK, Shahrara S. CCL25 and CCR9 is a unique pathway that potentiates pannus formation by remodeling RA macrophages into mature osteoclasts. Eur J Immunol 2021; 51:903-914. [PMID: 33347617 PMCID: PMC10041658 DOI: 10.1002/eji.202048681] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2020] [Revised: 10/26/2020] [Accepted: 12/18/2020] [Indexed: 12/18/2022]
Abstract
This study elucidates the mechanism of CCL25 and CCR9 in rheumatoid arthritis (RA). RA synovial fluid (SF) expresses elevated levels of CCL25 compared to OA SF and plasma from RA and normal. CCL25 was released into RA SF by fibroblasts (FLS) and macrophages (MΦs) stimulated with IL-1β and IL-6. CCR9 is also presented on IL-1β and IL-6 activated RA FLS and differentiated MΦs. Conversely, in RA PBMCs neither CCL25 nor CCR9 are impacted by 3-month longitudinal TNF inhibitor therapy. CCL25 amplifies RA FLS and monocyte infiltration via p38 and ERK phosphorylation. CCL25-stimulated RA FLS secrete potentiated levels of IL-8 which is disrupted by p38 and ERK inhibitors. CCL25 polarizes RA monocytes into nontraditional M1 MΦs that produce IL-8 and CCL2. Activation of p38 and ERK cascades are also responsible for the CCL25-induced M1 MΦ development. Unexpectedly, CCL25 was unable to polarize RA PBMCs into effector Th1/Th17 cells. Consistently, lymphokine like RANKL was uninvolved in CCL25-induced osteoclastogenesis; however, this manifestation was regulated by osteoclastic factors such as RANK, cathepsin K (CTSK), and TNF-α. In short, we reveal that CCL25/CCR9 manipulates RA FLS and MΦ migration and inflammatory phenotype in addition to osteoclast formation via p38 and ERK activation.
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Affiliation(s)
- Sadiq Umar
- Jesse Brown VA Medical Center, Chicago, IL
- Department of Medicine, Division of Rheumatology, the University of Illinois at Chicago, IL
| | - Karol Palasiewicz
- Jesse Brown VA Medical Center, Chicago, IL
- Department of Medicine, Division of Rheumatology, the University of Illinois at Chicago, IL
| | - Katrien Van Raemdonck
- Jesse Brown VA Medical Center, Chicago, IL
- Department of Medicine, Division of Rheumatology, the University of Illinois at Chicago, IL
| | - Michael V. Volin
- Department of Microbiology and Immunology, Midwestern University, Downers Grove, IL
| | - Bianca Romay
- Department of Medicine, Division of Rheumatology, the University of Illinois at Chicago, IL
| | - Imran Ahmad
- Department of Medicine, Division of Rheumatology, the University of Illinois at Chicago, IL
| | - Chandana Tetali
- Department of Medicine, Division of Rheumatology, the University of Illinois at Chicago, IL
| | - Nadera Sweiss
- Department of Medicine, Division of Rheumatology, the University of Illinois at Chicago, IL
| | - M Asif Amin
- Division of Rheumatology and Clinical Autoimmunity Center of Excellence, University of Michigan, Ann Arbor, MI 481096
| | - Ryan K Zomorrodi
- Department of Medicine, Division of Rheumatology, the University of Illinois at Chicago, IL
| | - Shiva Shahrara
- Jesse Brown VA Medical Center, Chicago, IL
- Department of Medicine, Division of Rheumatology, the University of Illinois at Chicago, IL
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9
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Fischer MA, Golovchenko NB, Edelblum KL. γδ T cell migration: Separating trafficking from surveillance behaviors at barrier surfaces. Immunol Rev 2020; 298:165-180. [PMID: 32845516 PMCID: PMC7968450 DOI: 10.1111/imr.12915] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2020] [Revised: 07/22/2020] [Accepted: 07/23/2020] [Indexed: 12/23/2022]
Abstract
γδ T cells are found in highest numbers at barrier surfaces throughout the body, including the skin, intestine, lung, gingiva, and uterus. Under homeostatic conditions, γδ T cells provide immune surveillance of the epidermis, intestinal, and oral mucosa, whereas the presence of pathogenic microorganisms in the dermis or lungs elicits a robust γδ17 response to clear the infection. Although T cell migration is most frequently defined in the context of trafficking, analysis of specific migratory behaviors of lymphocytes within the tissue microenvironment can provide valuable insight into their function. Intravital imaging and computational analyses have been used to define "search" behavior associated with conventional αβ T cells; however, based on the known role of γδ T cells as immune sentinels at barrier surfaces and their TCR-independent functions, we put forth the need to classify distinct migratory patterns that reflect the surveillance capacity of these unconventional lymphocytes. This review will focus on how γδ T cells traffic to various barrier surfaces and how recent investigation into their migratory behavior has provided unique insight into the contribution of γδ T cells to barrier immunity.
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Affiliation(s)
- Matthew A. Fischer
- Center for Immunity and Inflammation, Department of Pathology, Immunology & Laboratory Medicine, Rutgers New Jersey Medical School, Newark, NJ
| | - Natasha B. Golovchenko
- Center for Immunity and Inflammation, Department of Pathology, Immunology & Laboratory Medicine, Rutgers New Jersey Medical School, Newark, NJ
| | - Karen L. Edelblum
- Center for Immunity and Inflammation, Department of Pathology, Immunology & Laboratory Medicine, Rutgers New Jersey Medical School, Newark, NJ
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Yan H, Shao D, Lao Y, Li M, Hu H, Leong KW. Engineering Cell Membrane-Based Nanotherapeutics to Target Inflammation. ADVANCED SCIENCE (WEINHEIM, BADEN-WURTTEMBERG, GERMANY) 2019; 6:1900605. [PMID: 31406672 PMCID: PMC6685500 DOI: 10.1002/advs.201900605] [Citation(s) in RCA: 144] [Impact Index Per Article: 24.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 03/16/2019] [Revised: 04/28/2019] [Indexed: 05/10/2023]
Abstract
Inflammation is ubiquitous in the body, triggering desirable immune response to defend against dangerous signals or instigating undesirable damage to cells and tissues to cause disease. Nanomedicine holds exciting potential in modulating inflammation. In particular, cell membranes derived from cells involved in the inflammatory process may be used to coat nanotherapeutics for effective targeted delivery to inflammatory tissues. Herein, the recent progress of rationally engineering cell membrane-based nanotherapeutics for inflammation therapy is highlighted, and the challenges and opportunities presented in realizing the full potential of cell-membrane coating in targeting and manipulating the inflammatory microenvironment are discussed.
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Affiliation(s)
- Huize Yan
- Department of Biomedical EngineeringColumbia UniversityNew YorkNY10027USA
| | - Dan Shao
- Department of Biomedical EngineeringColumbia UniversityNew YorkNY10027USA
| | - Yeh‐Hsing Lao
- Department of Biomedical EngineeringColumbia UniversityNew YorkNY10027USA
| | - Mingqiang Li
- Department of Biomedical EngineeringColumbia UniversityNew YorkNY10027USA
- Guangdong Provincial Key Laboratory of Liver DiseaseThe Third Affiliated Hospital of Sun Yat‐sen UniversityGuangzhouGuangdong510630China
| | - Hanze Hu
- Department of Biomedical EngineeringColumbia UniversityNew YorkNY10027USA
| | - Kam W. Leong
- Department of Biomedical EngineeringColumbia UniversityNew YorkNY10027USA
- Institutes of Life SciencesSchool of Biomedical Science and Engineering and National Engineering Research Center for Tissue Restoration and ReconstructionSouth China University of TechnologyGuangzhou International CampusGuangzhouGuangdong510006China
- Department of System BiologyColumbia University Medical CenterNew YorkNY10032USA
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11
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Veazey RS. Intestinal CD4 Depletion in HIV / SIV Infection. CURRENT IMMUNOLOGY REVIEWS 2019; 15:76-91. [PMID: 31431807 PMCID: PMC6701936 DOI: 10.2174/1573395514666180605083448] [Citation(s) in RCA: 23] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/02/2018] [Revised: 04/12/2018] [Accepted: 05/18/2018] [Indexed: 12/28/2022]
Abstract
Among the most significant findings in the pathogenesis of HIV infection was the discovery that almost total depletion of intestinal CD4+ T cells occurs rapidly after SIV or HIV infection, regardless of the route of exposure, and long before CD4+ T cell losses occur in blood or lymph nodes. Since these seminal discoveries, we have learned much about mucosal and systemic CD4+ T cells, and found several key differences between the circulating and intestinal CD4+ T cell subsets, both in phenotype, relative proportions, and functional capabilities. Further, specific subsets of CD4+ T cells are selectively targeted and eliminated first, especially cells critically important for initiating primary immune responses, and for maintenance of mucosal integrity (Th1, Th17, and Th22 cells). This simultaneously results in loss of innate immune responses, and loss of mucosal integrity, resulting in mucosal, and systemic immune activation that drives proliferation and activation of new target cells throughout the course of infection. The propensity for the SIV/HIV to infect and efficiently replicate in specific cells also permits viral persistence, as the mucosal and systemic activation that ensues continues to damage mucosal barriers, resulting in continued influx of target cells to maintain viral replication. Finally, infection and elimination of recently activated and proliferating CD4+ T cells, and infection and dysregulation of Tfh and other key CD4+ T cell results in hyperactive, yet non-protective immune responses that support active viral replication and evolution, and thus persistence in host tissue reservoirs, all of which continue to challenge our efforts to design effective vaccine or cure strategies.
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Affiliation(s)
- Ronald S. Veazey
- Division of Comparative Pathology, Tulane National Primate Research Center, Covington, LA
- Department of Pathology and Laboratory Medicine, Tulane University School of Medicine, New Orleans, LA, USA
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12
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Zhang D, Ren YB, Wei K, Hong J, Yang YT, Wu LJ, Zhang J, Shi Z, Wu HG, Ma XP. Herb-partitioned moxibustion alleviates colon injuries in ulcerative colitis rats. World J Gastroenterol 2018; 24:3384-3397. [PMID: 30122878 PMCID: PMC6092579 DOI: 10.3748/wjg.v24.i30.3384] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/09/2018] [Revised: 06/22/2018] [Accepted: 06/30/2018] [Indexed: 02/06/2023] Open
Abstract
AIM To observe the effect of herb-partitioned moxibustion (HPM) on expression of colonic cytokines in ulcerative colitis (UC) rats. METHODS A UC rat model was established by protein immunization in combination with topical chemical stimulation. Rats in the HPM group (n = 8) received HPM at bilateral Tianshu (ST25) points. The gross injury and pathological scores of the colon were recorded. The expression profile of colonic cytokines was assayed using the protein microarray technique. Specific differential cytokines were selected and verified by ELISA. The corresponding UniProt Accessions of the differentially expressed cytokines were retrieved in the UniProt database. The pathways involved were analyzed with the help of the KEGG PATHWAY database. The DAVID database was used for functional cluster and pathway analysis. RESULTS HPM improved colon injuries in UC rats, manifested by accelerated repair of ulcers and alleviation of inflammation, and the gross injury and pathological scores both significantly decreased (P < 0.01). Fold change > 1.3 or < 0.77 was taken as the screening standard. There were 77 down-regulated and 9 up-regulated differentially expressed colonic cytokines in the HPM group compared with the model group, and expression of 20 differed significantly (P < 0.05). Twelve of the 20 significantly differentially expressed cytokines [β-catenin, interleukin-1 receptor 6 (IL-1R6), IL-1β, B7-1, nerve growth factor receptor, AMP-activated protein kinase-α1, neuropilin-2, orexin A, adipocyte differentiation-related protein, IL-2, Fas and FasL] were up-regulated in the model group (n = 3, compared with the normal group) but down-regulated in the HPM group (n = 3, compared with the model group). Functional cluster analysis showed that the differentially expressed colonic cytokines in the HPM group regulated apoptosis and protein phosphorylation. KEGG pathway analysis showed that 52 down-regulated and 7 up-regulated differentially expressed colonic cytokines in the HPM group had pathways. The pathways that interacted between the cytokines and their receptors accounted for the largest proportion (28 of the down-regulated and 5 of the up-regulated cytokines). CONCLUSION HPM promotes the repair of colon injuries in UC rats, which is related to the regulation of several abnormally expressed cytokines.
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Affiliation(s)
- Dan Zhang
- Laboratory of Acupuncture-moxibustion and Immunology, Shanghai Research Institute of Acupuncture and Meridian, Shanghai University of Traditional Chinese Medicine, Shanghai 200030, China
| | - Yan-Bo Ren
- Department of Integrated Traditional Chinese Medicine and Western Medicine, North Branch of Huashan Hospital, Fudan University, Shanghai 201907, China
| | - Kai Wei
- Key Laboratory of Systems Biomedicine (Ministry of Education), Shanghai Center for Systems Biomedicine, Shanghai Jiao Tong University, Shanghai 200240, China
| | - Jue Hong
- Laboratory of Acupuncture-moxibustion and Immunology, Shanghai Research Institute of Acupuncture and Meridian, Shanghai University of Traditional Chinese Medicine, Shanghai 200030, China
| | - Yan-Ting Yang
- Yueyang Clinical Medicine School, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Li-Jie Wu
- Yueyang Clinical Medicine School, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Ji Zhang
- Yueyang Clinical Medicine School, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
| | - Zheng Shi
- Laboratory of Acupuncture-moxibustion and Immunology, Shanghai Research Institute of Acupuncture and Meridian, Shanghai University of Traditional Chinese Medicine, Shanghai 200030, China
| | - Huan-Gan Wu
- Laboratory of Acupuncture-moxibustion and Immunology, Shanghai Research Institute of Acupuncture and Meridian, Shanghai University of Traditional Chinese Medicine, Shanghai 200030, China
| | - Xiao-Peng Ma
- Laboratory of Acupuncture-moxibustion and Immunology, Shanghai Research Institute of Acupuncture and Meridian, Shanghai University of Traditional Chinese Medicine, Shanghai 200030, China
- Yueyang Clinical Medicine School, Shanghai University of Traditional Chinese Medicine, Shanghai 201203, China
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13
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Lind A, Siersema PD, Kusters JG, Konijn T, Mebius RE, Koenderman L. The Microenvironment in Barrett's Esophagus Tissue Is Characterized by High FOXP3 and RALDH2 Levels. Front Immunol 2018; 9:1375. [PMID: 29967615 PMCID: PMC6015910 DOI: 10.3389/fimmu.2018.01375] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2018] [Accepted: 06/04/2018] [Indexed: 12/20/2022] Open
Abstract
Metaplasia in Barrett’s esophagus (BE) is characterized by the transition of squamous epithelium into intestinal-type columnar epithelium. The immune response in BE shares many similarities with the response found in the gut, which is different from the response found in a normal-looking esophagus. Here, we investigated the role of the genes associated with the retinoic acid (RA) pathway in BE, as RA is important not only in shaping the gut’s immune response but also in the induction of metaplasia in vitro. mRNA was isolated from esophageal and duodenal biopsies from BE (n = 14), reflux esophagitis patients (n = 9), and controls (n = 12). cDNA was made and qPCR was performed. The expression of RALDH1, CYP26A1, MAdCAM1 were similar for both the BE and duodenum, but different when compared to squamous esophageal epithelium. BE was characterized by a higher expression of RALDH2 and FOXP3, compared to the duodenum. In BE, RALDH2 correlated with expression of the myeloid dendritic cell-specific genes: CD11c and CD1c. Also, RALDH2 expression correlated with RAR-β and FOXP3. Hierarchical clustering on the expression of multiple relevant genes demonstrated that BE, duodenum, and SQ tissues are clustered as three different groups. The differential expression of RA-specific genes and dendritic cell (DC)-subsets indicates that BE resembles duodenal tissue. The higher expression of RALDH2 and FOXP3 in BE points at a mechanism associated with a possible anti-inflammatory microenvironment. This aberrant immune regulation might contribute to the altered tissue and immune responses found in BE.
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Affiliation(s)
- Alexandra Lind
- Laboratory of Translational Immunology, Department of Respiratory Medicine, University Medical Center Utrecht, Utrecht, Netherlands.,Department of Gastroenterology and Hepatology, University Medical Center Utrecht, Utrecht, Netherlands
| | - Peter D Siersema
- Department of Gastroenterology and Hepatology, University Medical Center Utrecht, Utrecht, Netherlands
| | - Johannes G Kusters
- Department of Medical Microbiology, University Medical Center Utrecht, Utrecht, Netherlands
| | - Tanja Konijn
- Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, Netherlands
| | - Reina E Mebius
- Department of Molecular Cell Biology and Immunology, VU University Medical Center, Amsterdam, Netherlands
| | - Leo Koenderman
- Laboratory of Translational Immunology, Department of Respiratory Medicine, University Medical Center Utrecht, Utrecht, Netherlands
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14
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Liu QZ, Ma WT, Yang JB, Zhao ZB, Yan K, Yao Y, Li L, Miao Q, Gershwin ME, Lian ZX. The CXC Chemokine Receptor 3 Inhibits Autoimmune Cholangitis via CD8 + T Cells but Promotes Colitis via CD4 + T Cells. Front Immunol 2018; 9:1090. [PMID: 29868034 PMCID: PMC5966573 DOI: 10.3389/fimmu.2018.01090] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2018] [Accepted: 05/01/2018] [Indexed: 11/13/2022] Open
Abstract
CXC chemokine receptor 3 (CXCR3), a receptor for the C-X-C motif chemokines (CXCL) CXCL9, CXCL10, and CXCL11, which not only plays a role in chemotaxis but also regulates differentiation and development of memory and effector T cell populations. Herein, we explored the function of CXCR3 in the modulation of different organ-specific autoimmune diseases in interleukin (IL)-2 receptor deficiency (CD25-/-) mice, a murine model for both cholangitis and colitis. We observed higher levels of CXCL9 and CXCL10 in the liver and colon and higher expression of CXCR3 on T cells of the CD25-/- mice compared with control animals. Deletion of CXCR3 resulted in enhanced liver inflammation but alleviated colitis. These changes in liver and colon pathology after CXCR3 deletion were associated with increased numbers of hepatic CD4+ and CD8+ T cells, in particular effector memory CD8+ T cells, as well as decreased T cells in mesenteric lymph nodes and colon lamina propria. In addition, increased interferon-γ response and decreased IL-17A response was observed in both liver and colon after CXCR3 deletion. CXCR3 modulated the functions of T cells involved in different autoimmune diseases, whereas the consequence of such modulation was organ-specific regarding to their effects on disease severity. Our findings emphasize the importance of extra caution in immunotherapy for organ-specific autoimmune diseases, as therapeutic interventions aiming at a target such as CXCR3 for certain disease could result in adverse effects in an unrelated organ.
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Affiliation(s)
- Qing-Zhi Liu
- Liver Immunology Laboratory, School of Life Sciences, University of Science and Technology of China, Hefei, China.,Chronic Disease Laboratory, School of Medicine, Institutes for Life Sciences, South China University of Technology, Guangzhou, China
| | - Wen-Tao Ma
- Liver Immunology Laboratory, School of Life Sciences, University of Science and Technology of China, Hefei, China.,College of Veterinary Medicine, Northwest Agriculture and Forestry University, Yangling, China
| | - Jing-Bo Yang
- Liver Immunology Laboratory, School of Life Sciences, University of Science and Technology of China, Hefei, China
| | - Zhi-Bin Zhao
- Liver Immunology Laboratory, School of Life Sciences, University of Science and Technology of China, Hefei, China.,Chronic Disease Laboratory, School of Medicine, Institutes for Life Sciences, South China University of Technology, Guangzhou, China
| | - Kai Yan
- Liver Immunology Laboratory, School of Life Sciences, University of Science and Technology of China, Hefei, China.,Chronic Disease Laboratory, School of Medicine, Institutes for Life Sciences, South China University of Technology, Guangzhou, China
| | - Yuan Yao
- Liver Immunology Laboratory, School of Life Sciences, University of Science and Technology of China, Hefei, China.,Chronic Disease Laboratory, School of Medicine, Institutes for Life Sciences, South China University of Technology, Guangzhou, China
| | - Liang Li
- Liver Immunology Laboratory, School of Life Sciences, University of Science and Technology of China, Hefei, China.,Chronic Disease Laboratory, School of Medicine, Institutes for Life Sciences, South China University of Technology, Guangzhou, China
| | - Qi Miao
- Department of Gastroenterology and Hepatology, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - M Eric Gershwin
- Division of Rheumatology, Allergy and Clinical Immunology, School of Medicine, University of California, Davis, Davis, CA, United States
| | - Zhe-Xiong Lian
- Liver Immunology Laboratory, School of Life Sciences, University of Science and Technology of China, Hefei, China.,Chronic Disease Laboratory, School of Medicine, Institutes for Life Sciences, South China University of Technology, Guangzhou, China
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15
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Archila LD, Chow IT, McGinty JW, Renand A, Jeong D, Robinson D, Farrington ML, Kwok WW. Ana o 1 and Ana o 2 cashew allergens share cross-reactive CD4(+) T cell epitopes with other tree nuts. Clin Exp Allergy 2017; 46:871-83. [PMID: 27129138 DOI: 10.1111/cea.12746] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2015] [Revised: 02/12/2016] [Accepted: 02/18/2016] [Indexed: 11/29/2022]
Abstract
BACKGROUND Allergies to cashew are increasing in prevalence, with clinical symptoms ranging from oral pruritus to fatal anaphylactic reaction. Yet, cashew-specific T cell epitopes and T cell cross-reactivity amongst cashew and other tree nut allergens in humans remain uncharacterized. OBJECTIVES In this study, we characterized cashew-specific T cell responses in cashew-allergic subjects and examined cross-reactivity of these cashew-specific cells towards other tree nut allergens. METHODS CD154 up-regulation assay was used to determine immunodominance hierarchy among cashew major allergens at the T cell level. The phenotype, magnitude and functionality of cashew-specific T cells were determined by utilizing ex vivo staining with MHC class II tetramers. Dual tetramer staining and proliferation experiments were used to determine cross-reactivity to other tree nuts. RESULTS CD4(+) T cell responses were directed towards cashew allergens Ana o 1 and Ana o 2. Multiple Ana o 1 and Ana o 2 T cell epitopes were then identified. These epitopes elicited either TH 2 or TH 2/TH 17 responses in allergic subjects, which were either cashew unique epitope or cross-reactive epitopes. For clones that recognized the cross-reactive epitope, T cell clones responded robustly to cashew, hazelnut and/or pistachio but not to walnut. CONCLUSIONS Phylogenetically diverse tree nut allergens can activate cashew-reactive T cells and elicit a TH 2-type response at an epitope-specific level. CLINICAL RELEVANCE Lack of cross-reactivity between walnut and cashew suggests that cashew peptide immunotherapy approach may not be most effective for walnut.
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Affiliation(s)
- L D Archila
- Benaroya Research Institute at Virginia Mason, Seattle, WA, USA
| | - I-T Chow
- Benaroya Research Institute at Virginia Mason, Seattle, WA, USA
| | - J W McGinty
- Benaroya Research Institute at Virginia Mason, Seattle, WA, USA
| | - A Renand
- Benaroya Research Institute at Virginia Mason, Seattle, WA, USA
| | - D Jeong
- Virginia Mason Medical center, Seattle, WA, USA.,Department of Medicine, University of Washington, Seattle, WA, USA
| | - D Robinson
- Virginia Mason Medical center, Seattle, WA, USA
| | | | - W W Kwok
- Benaroya Research Institute at Virginia Mason, Seattle, WA, USA.,Department of Medicine, University of Washington, Seattle, WA, USA
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16
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Sumida H, Lu E, Chen H, Yang Q, Mackie K, Cyster JG. GPR55 regulates intraepithelial lymphocyte migration dynamics and susceptibility to intestinal damage. Sci Immunol 2017; 2:eaao1135. [PMID: 29222090 PMCID: PMC5847323 DOI: 10.1126/sciimmunol.aao1135] [Citation(s) in RCA: 46] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2017] [Accepted: 10/27/2017] [Indexed: 12/26/2022]
Abstract
Intraepithelial lymphocytes (IELs) of the small intestine are intimately associated with the epithelial cells. Yet, the factors controlling their migration and interaction dynamics are poorly understood. We demonstrate that GPR55, a receptor that mediates migration inhibition in response to lysophosphatidylinositol (LPI), negatively regulates T cell receptor γδ (TCRγδ) IEL accumulation in the small intestine. Intravital imaging studies show that GPR55-deficient IELs migrate faster and interact more extensively with epithelial cells. GPR55 also negatively regulates T cell homing to the small intestine and γδT cell egress from Peyer's patches. GPR55 deficiency or short-term antagonist treatment protects from nonsteroidal anti-inflammatory drug-induced increases in intestinal permeability. These findings identify a migration-inhibitory receptor that restrains IEL-epithelial cell cross-talk and show that antagonism of this receptor can protect from intestinal barrier dysfunction.
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Affiliation(s)
- Hayakazu Sumida
- Department of Microbiology and Immunology and Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Erick Lu
- Department of Microbiology and Immunology and Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Hsin Chen
- Department of Microbiology and Immunology and Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Qiyun Yang
- Department of Bioengineering and Therapeutic Sciences, University of California, San Francisco, San Francisco, CA 94143, USA
| | - Ken Mackie
- Department of Psychological and Brain Sciences, Gill Center for Biomolecular Science, Indiana University, Bloomington, IN 47405, USA
| | - Jason G Cyster
- Department of Microbiology and Immunology and Howard Hughes Medical Institute, University of California, San Francisco, San Francisco, CA 94143, USA.
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17
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den Hartog G, van Osch TLJ, Vos M, Meijer B, Savelkoul HFJ, van Neerven RJJ, Brugman S. BAFF augments IgA2 and IL-10 production by TLR7/8 stimulated total peripheral blood B cells. Eur J Immunol 2017; 48:283-292. [PMID: 28921509 PMCID: PMC5836859 DOI: 10.1002/eji.201646861] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/07/2016] [Revised: 08/31/2017] [Accepted: 09/12/2017] [Indexed: 12/31/2022]
Abstract
Class‐switching of B cells to IgA can be induced via both T‐cell‐dependent and T‐cell‐independent mechanisms. IgA is most predominantly produced mucosally and is important for combating infections and allergies. In contrast to mice, humans have two forms of IgA; IgA1 and IgA2 with diverse tissue distribution. In early life, IgA levels might be sub‐optimal especially during the fall season when bacterial and viral infections are more common. Therefore, we investigated using human B cells whether T‐cell‐independent factors ‐promoting cell survival, class switching and immunoglobulin secretion‐ BAFF, APRIL, IL‐10 and retinoic acid can boost IgA production in the context of viral or bacterial infection. To this end total and naive peripheral blood B cells were stimulated with these factors for 6 days in the presence or absence of TLR7/8 agonist R848 (mimicking viral infection) or TLR9 agonist CpG‐ODN (mimicking bacterial infection). We show that BAFF significantly augments IgA2 production in TLR7/8 stimulated mature, but not naïve B cells. In addition, BAFF augments IL‐10 production and viability in TLR7/8 and TLR9 stimulated mature B cells. These data warrant further investigation of its role in immune regulation both in the periphery and mucosal tissues in early life or during disease.
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Affiliation(s)
- Gerco den Hartog
- Animal Sciences Group, Cell Biology and Immunology group, Wageningen University, the Netherlands.,Centre for Immunology of Infectious Diseases, National Institute for Public Health and the Environment, Bilthoven, the Netherlands
| | - Thijs L J van Osch
- Animal Sciences Group, Cell Biology and Immunology group, Wageningen University, the Netherlands
| | - Martijn Vos
- Animal Sciences Group, Cell Biology and Immunology group, Wageningen University, the Netherlands
| | - Ben Meijer
- Animal Sciences Group, Cell Biology and Immunology group, Wageningen University, the Netherlands
| | - Huub F J Savelkoul
- Animal Sciences Group, Cell Biology and Immunology group, Wageningen University, the Netherlands
| | - R J Joost van Neerven
- Animal Sciences Group, Cell Biology and Immunology group, Wageningen University, the Netherlands.,FrieslandCampina, Amersfoort, the Netherlands
| | - Sylvia Brugman
- Animal Sciences Group, Cell Biology and Immunology group, Wageningen University, the Netherlands
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18
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Blokland SLM, Hillen MR, Kruize AA, Meller S, Homey B, Smithson GM, Radstake TRDJ, van Roon JAG. Increased CCL25 and T Helper Cells Expressing CCR9 in the Salivary Glands of Patients With Primary Sjögren's Syndrome: Potential New Axis in Lymphoid Neogenesis. Arthritis Rheumatol 2017. [DOI: 10.1002/art.40182] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022]
Affiliation(s)
| | | | - Aike A. Kruize
- University Medical Center Utrecht; Utrecht The Netherlands
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19
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Marafini I, Monteleone I, Dinallo V, Di Fusco D, De Simone V, Laudisi F, Fantini MC, Di Sabatino A, Pallone F, Monteleone G. CCL20 Is Negatively Regulated by TGF-β1 in Intestinal Epithelial Cells and Reduced in Crohn's Disease Patients With a Successful Response to Mongersen, a Smad7 Antisense Oligonucleotide. J Crohns Colitis 2017; 11:603-609. [PMID: 28453765 DOI: 10.1093/ecco-jcc/jjw191] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/01/2016] [Accepted: 10/24/2016] [Indexed: 12/12/2022]
Abstract
BACKGROUND AND AIMS The chemokine CCL20 is over-produced in epithelium of Crohn's disease [CD] patients and contributes to recruiting immune cells to inflamed gut. Tumour necrosis factor-α [TNF-α] is a powerful inducer of CCL20 in intestinal epithelial cells. In CD, high levels of Smad7 block the activity of transforming growth factor-β1 [TGF-β1], a negative regulator of TNF signalling. We investigated whether intestinal epithelial cell-derived CCL20 is negatively regulated by TGF-β1 and whether Smad7 knock-down reduces CCL20 in CD. METHODS CCL20 was evaluated in NCM460, a normal colonic epithelial cell line, stimulated with TGF-β1 and TNF-α, and in Smad7 over-expressing NCM460 cells. CCL20 and Smad7 expression were assessed in sections of CD intestinal specimens by immunochemistry, and in CD colonic explants treated with mongersen, a Smad7 antisense oligonucleotide. CCL20 was examined in serum samples taken from 95 of 166 active CD patients receiving mongersen or placebo for 2 weeks and participating in a phase II, multicentre, double-blind, placebo-controlled study. RESULTS CCL20 expression was increased by TNF-α, and this effect was inhibited by TGF-β1 in NCM460 cells, but not in Smad7 over-expressing NCM460 cells. In CD, epithelium CCL20 and Smad7 co-localised, and treatment of CD explants with mongersen reduced CCL20 production. During follow-up, in responders to mongersen, serum CCL20 levels significantly decreased, whereas patients without response/remission to mongersen and placebo patients did not have change in CCL20. CONCLUSIONS TGF-β1 reduces intestinal epithelial cell-derived CCL20 production, an effect abrogated by Smad7. CD patients responding to mongersen demonstrated a reduction in serum CCL20.
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Affiliation(s)
- Irene Marafini
- Department of Systems Medicine, University of Rome 'Tor Vergata', Rome, Italy
| | - Ivan Monteleone
- Department of Systems Medicine, University of Rome 'Tor Vergata', Rome, Italy
| | - Vincenzo Dinallo
- Department of Systems Medicine, University of Rome 'Tor Vergata', Rome, Italy
| | - Davide Di Fusco
- Department of Systems Medicine, University of Rome 'Tor Vergata', Rome, Italy
| | - Veronica De Simone
- Department of Systems Medicine, University of Rome 'Tor Vergata', Rome, Italy
| | - Federica Laudisi
- Department of Systems Medicine, University of Rome 'Tor Vergata', Rome, Italy
| | | | - Antonio Di Sabatino
- First Department of Internal Medicine, Fondazione IRCCS Policlinico San Matteo, University of Pavia, Pavia, Italy
| | - Francesco Pallone
- Department of Systems Medicine, University of Rome 'Tor Vergata', Rome, Italy
| | - Giovanni Monteleone
- Department of Systems Medicine, University of Rome 'Tor Vergata', Rome, Italy
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20
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Richmond JM, Bangari DS, Essien KI, Currimbhoy SD, Groom JR, Pandya AG, Youd ME, Luster AD, Harris JE. Keratinocyte-Derived Chemokines Orchestrate T-Cell Positioning in the Epidermis during Vitiligo and May Serve as Biomarkers of Disease. J Invest Dermatol 2017; 137:350-358. [PMID: 27686391 PMCID: PMC5258673 DOI: 10.1016/j.jid.2016.09.016] [Citation(s) in RCA: 130] [Impact Index Per Article: 16.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/24/2016] [Revised: 08/21/2016] [Accepted: 09/08/2016] [Indexed: 12/21/2022]
Abstract
Vitiligo is an autoimmune disease of the skin that results in the destruction of melanocytes and the clinical appearance of white spots. Disease pathogenesis depends on IFN-γ and IFN-γ-induced chemokines to promote T-cell recruitment to the epidermis where melanocytes reside. The skin is a complex organ, with a variety of resident cell types. We sought to better define the microenvironment and distinct cellular contributions during autoimmunity in vitiligo, and we found that the epidermis is a chemokine-high niche in both a mouse model and human vitiligo. Analysis of chemokine expression in mouse skin showed that CXCL9 and CXCL10 expression strongly correlate with disease activity, whereas CXCL10 alone correlates with severity, supporting them as potential biomarkers for following disease progression. Further studies in both our mouse model and human patients showed that keratinocytes were the major chemokine producers throughout the course of disease, and functional studies using a conditional signal transducer and activator of transcription (STAT)-1 knockout mouse showed that IFN-γ signaling in keratinocytes was critical for disease progression and proper autoreactive T-cell homing to the epidermis. In contrast, epidermal immune cell populations including endogenous T cells, Langerhans cells, and γδ T cells were not required. These results have important clinical implications, because topical therapies that target IFN-γ signaling in keratinocytes could be safe and effective new treatments, and skin expression of these chemokines could be used to monitor disease activity and treatment responses.
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Affiliation(s)
- Jillian M Richmond
- University of Massachusetts Medical School, Department of Medicine, Division of Dermatology, Worcester, Massachusetts, USA
| | | | - Kingsley I Essien
- University of Massachusetts Medical School, Department of Medicine, Division of Dermatology, Worcester, Massachusetts, USA
| | | | - Joanna R Groom
- The Walter and Eliza Hall Institute of Medical Research, University of Melbourne, Department of Medical Biology 1G Royal Parade, Victoria, Australia
| | - Amit G Pandya
- University of Texas Southwestern Medical Center, Dallas, Texas, USA
| | | | - Andrew D Luster
- Center for Immunology and Inflammatory Diseases, Division of Rheumatology, Allergy and Immunology, Massachusetts General Hospital, Harvard Medical School, Boston, Massachusetts, USA
| | - John E Harris
- University of Massachusetts Medical School, Department of Medicine, Division of Dermatology, Worcester, Massachusetts, USA.
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21
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Toll-Like Receptor 2 Ligation Enhances HIV-1 Replication in Activated CCR6+ CD4+ T Cells by Increasing Virus Entry and Establishing a More Permissive Environment to Infection. J Virol 2017; 91:JVI.01402-16. [PMID: 27928019 DOI: 10.1128/jvi.01402-16] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2016] [Accepted: 12/01/2016] [Indexed: 12/14/2022] Open
Abstract
In this study, we investigated the effect of Toll-like receptor 2 (TLR2) ligation on the permissiveness of activated CD4+ T cells to HIV-1 infection by focusing our experiments on the relative susceptibility of cell subsets based on their expression of CCR6. Purified primary human CD4+ T cells were first subjected to a CD3/CD28 costimulation before treatment with the TLR2 agonist Pam3CSK4. Finally, cells were inoculated with R5-tropic HIV-1 particles that permit us to study the effect of TLR2 triggering on virus production at both population and single-cell levels. We report here that HIV-1 replication is augmented in CD3/CD28-costimulated CCR6+ CD4+ T cells upon engagement of the cell surface TLR2. Additional studies indicate that a higher virus entry and polymerization of the cortical actin are seen in this cell subset following TLR2 stimulation. A TLR2-mediated increase in the level of phosphorylated NF-κB p65 subunit was also detected in CD3/CD28-costimulated CCR6+ CD4+ T cells. We propose that, upon antigenic presentation, an engagement of TLR2 acts specifically on CCR6+ CD4+ T cells by promoting virus entry in an intracellular milieu more favorable for productive HIV-1 infection. IMPORTANCE Following primary infection, HIV-1 induces an immunological and structural disruption of the gut mucosa, leading to bacterial translocation and release of microbial components in the bloodstream. These pathogen-derived constituents include several agonists of Toll-like receptors that may affect gut-homing CD4+ T cells, such as those expressing the chemokine receptor CCR6, which are highly permissive to HIV-1 infection. We demonstrate that TLR2 ligation in CD3/CD28-costimulated CCR6+ CD4+ T cells leads to enhanced virus production. Our results highlight the potential impact of bacterial translocation on the overall permissiveness of CCR6+ CD4+ T cells to productive HIV-1 infection.
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Piñeros AR, Campos LW, Fonseca DM, Bertolini TB, Gembre AF, Prado RQ, Alves-Filho JC, Ramos SG, Russo M, Bonato VLD. M2 macrophages or IL-33 treatment attenuate ongoing Mycobacterium tuberculosis infection. Sci Rep 2017; 7:41240. [PMID: 28128217 PMCID: PMC5269597 DOI: 10.1038/srep41240] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2016] [Accepted: 12/19/2016] [Indexed: 11/09/2022] Open
Abstract
The protective effects of mycobacterial infections on lung allergy are well documented. However, the inverse relationship between tuberculosis and type 2 immunity is still elusive. Although type 1 immunity is essential to protection against Mycobacterium tuberculosis it might be also detrimental to the host due to the induction of extensive tissue damage. Here, we determined whether lung type 2 immunity induced by allergen sensitization and challenge could affect the outcome of M. tuberculosis infection. We used two different protocols in which sensitization and allergen challenge were performed before or after M. tuberculosis infection. We found an increased resistance to M. tuberculosis only when allergen exposure was given after, but not before infection. Infected mice exposed to allergen exhibited lower bacterial load and cellular infiltrates in the lungs. Enhanced resistance to infection after allergen challenge was associated with increased gene expression of alternatively activated macrophages (M2 macrophages) and IL-33 levels. Accordingly, either adoptive transfer of M2 macrophages or systemic IL-33 treatment was effective in attenuating M. tuberculosis infection. Notably, the enhanced resistance induced by allergen exposure was dependent on IL-33 receptor ST2. Our work indicates that IL-33 might be an alternative therapeutic treatment for severe tuberculosis.
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Affiliation(s)
- A R Piñeros
- Department of Biochemistry and Immunology, Medical School of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - L W Campos
- Department of Biochemistry and Immunology, Medical School of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - D M Fonseca
- Department of Biochemistry and Immunology, Medical School of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - T B Bertolini
- Department of Biochemistry and Immunology, Medical School of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - A F Gembre
- Department of Biochemistry and Immunology, Medical School of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - R Q Prado
- Department of Biochemistry and Immunology, Medical School of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - J C Alves-Filho
- Department of Biochemistry and Immunology, Medical School of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - S G Ramos
- Department of Pathology, Medical School of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
| | - M Russo
- Department of Biochemistry and Immunology, Medical School of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil.,Department of Immunology, Institute of Biomedical Sciences, University of São Paulo, São Paulo, Brazil
| | - V L D Bonato
- Department of Biochemistry and Immunology, Medical School of Ribeirão Preto, University of São Paulo, Ribeirão Preto, São Paulo, Brazil
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23
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Langel SN, Paim FC, Lager KM, Vlasova AN, Saif LJ. Lactogenic immunity and vaccines for porcine epidemic diarrhea virus (PEDV): Historical and current concepts. Virus Res 2016; 226:93-107. [PMID: 27212686 PMCID: PMC7111331 DOI: 10.1016/j.virusres.2016.05.016] [Citation(s) in RCA: 155] [Impact Index Per Article: 17.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2016] [Revised: 05/17/2016] [Accepted: 05/18/2016] [Indexed: 02/07/2023]
Abstract
Morbidity, mortality, and loss of productivity from enteric diseases in neonatal piglets cost swine producers millions of dollars annually. In 2013-2014, the porcine epidemic diarrhea virus (PEDV) outbreak led to $900 million to $1.8 billion in annual losses to US swine producers. Passive lactogenic immunity remains the most promising and effective way to protect neonatal suckling piglets from enteric diseases like PEDV. Protecting suckling piglets through lactogenic immunity is dependent on trafficking of pathogen-specific IgA plasmablasts to the mammary gland and accumulation of secretory IgA (sIgA) antibodies in milk, defined as the gut-mammary-sIgA axis. Due to an impermeable placenta, piglets are born agammaglobulinic, and are highly susceptible to a plethora of infectious agents. They rely solely on colostrum and milk antibodies for maternal lactogenic immunity. Previous advances in the development of live and attenuated vaccines for another devastating diarrheal virus of pigs, transmissible gastroenteritis virus (TGEV), provide insights into the mechanisms of maternal immunity and piglet protection. In this chapter, we will review previous research on TGEV-induced lactogenic immunity to provide a historical perspective on current efforts for PEDV control and vaccines in the swine industry. Identifying factors that influence lactogenic immunity and the gut-mammary-sIgA axis may lead to improved vaccine regimens for PEDV and other enteric pathogens in gestating swine and improved overall herd immunity, swine health and industry productivity.
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Affiliation(s)
- Stephanie N Langel
- Food Animal Health Research Program, Ohio Agricultural Research and Development Center, Department of Veterinary Preventive Medicine, The Ohio State University, Wooster, OH, USA
| | - Francine Chimelo Paim
- Food Animal Health Research Program, Ohio Agricultural Research and Development Center, Department of Veterinary Preventive Medicine, The Ohio State University, Wooster, OH, USA
| | - Kelly M Lager
- Virus and Prion Research Unit, National Animal Disease Center, USDA, Agricultural Research Service, Ames, IA 50010, USA
| | - Anastasia N Vlasova
- Food Animal Health Research Program, Ohio Agricultural Research and Development Center, Department of Veterinary Preventive Medicine, The Ohio State University, Wooster, OH, USA
| | - Linda J Saif
- Food Animal Health Research Program, Ohio Agricultural Research and Development Center, Department of Veterinary Preventive Medicine, The Ohio State University, Wooster, OH, USA.
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Wacleche VS, Goulet JP, Gosselin A, Monteiro P, Soudeyns H, Fromentin R, Jenabian MA, Vartanian S, Deeks SG, Chomont N, Routy JP, Ancuta P. New insights into the heterogeneity of Th17 subsets contributing to HIV-1 persistence during antiretroviral therapy. Retrovirology 2016; 13:59. [PMID: 27553844 PMCID: PMC4995622 DOI: 10.1186/s12977-016-0293-6] [Citation(s) in RCA: 78] [Impact Index Per Article: 8.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2016] [Accepted: 08/11/2016] [Indexed: 12/18/2022] Open
Abstract
BACKGROUND Th17 cells are permissive to HIV-1 infection and their depletion from the gut of infected individuals leads to microbial translocation, a major cause for non-AIDS co-morbidities. Most recent evidence supports the contribution of long-lived Th17 cells to HIV persistence during antiretroviral therapy (ART). However, the identity of long-lived Th17 cells remains unknown. RESULTS Here, we performed an in-depth transcriptional and functional characterization of four distinct Th17 subsets and investigated their contribution to HIV reservoir persistence during ART. In addition to the previously characterized CCR6(+)CCR4(+) (Th17) and CCR6(+)CXCR3(+) (Th1Th17) subsets, we reveal the existence of two novel CCR6(+) subsets, lacking (double negative, CCR6(+)DN) or co-expressing CXCR3 and CCR4 (double positive, CCR6(+)DP). The four subsets shared multiple Th17-polarization markers, a fraction of cells proliferated in response to C. albicans, and exhibited lineage commitment and plasticity when cultured under Th17 and Th1 conditions, respectively. Of note, fractions of CCR6(+)DN and Th17 demonstrated stable Th17-lineage commitment under Th1-polarization conditions. Among the four subsets, CCR6(+)DN expressed a unique transcriptional signature indicative of early Th17 development (IL-17F, STAT3), lymph-node homing (CCR7, CD62L), follicular help (CXCR5, BCL6, ASCL2), and self-renewal (LEFI, MYC, TERC). Cross sectional and longitudinal studies demonstrated that CCR6(+)DN cells were the most predominant CCR6(+) subset in the blood before and after ART initiation; high frequencies of these cells were similarly observed in inguinal lymph nodes of individuals receiving long-term ART. Importantly, replication competent HIV was isolated from CCR6(+)DN of ART-treated individuals. CONCLUSIONS Together, these results provide new insights into the functional heterogeneity of Th17-polarized CCR6(+)CD4(+) T-cells and support the major contribution of CCR6(+)DN cells to HIV persistence during ART.
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Affiliation(s)
- Vanessa Sue Wacleche
- Département of Microbiologie, Infectiologie Et immunologie, Faculté de Médecine, Université de Montréal, Montreal, QC, Canada.,Centre de recherche du CHUM, 900 rue Saint-Denis, Tour Viger, R09.416, Montreal, QC, H2X 0A9, Canada
| | | | - Annie Gosselin
- Centre de recherche du CHUM, 900 rue Saint-Denis, Tour Viger, R09.416, Montreal, QC, H2X 0A9, Canada
| | - Patricia Monteiro
- Département of Microbiologie, Infectiologie Et immunologie, Faculté de Médecine, Université de Montréal, Montreal, QC, Canada.,Centre de recherche du CHUM, 900 rue Saint-Denis, Tour Viger, R09.416, Montreal, QC, H2X 0A9, Canada
| | - Hugo Soudeyns
- Département of Microbiologie, Infectiologie Et immunologie, Faculté de Médecine, Université de Montréal, Montreal, QC, Canada.,Unité d'immunopathologie virale, Centre de recherche du CHU Sainte-Justine, Montreal, QC, Canada
| | - Rémi Fromentin
- Centre de recherche du CHUM, 900 rue Saint-Denis, Tour Viger, R09.416, Montreal, QC, H2X 0A9, Canada
| | - Mohammad-Ali Jenabian
- Département des Sciences Biologiques, Université du Québec à Montréal, Montreal, QC, Canada
| | - Shant Vartanian
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA
| | - Steven G Deeks
- Department of Medicine, University of California San Francisco, San Francisco, CA, USA
| | - Nicolas Chomont
- Département of Microbiologie, Infectiologie Et immunologie, Faculté de Médecine, Université de Montréal, Montreal, QC, Canada.,Centre de recherche du CHUM, 900 rue Saint-Denis, Tour Viger, R09.416, Montreal, QC, H2X 0A9, Canada
| | - Jean-Pierre Routy
- Chronic Viral Illness Service and Research Institute, McGill University Health Centre, Montreal, QC, Canada.,Division of Hematology, McGill University Health Centre, Montreal, QC, Canada
| | - Petronela Ancuta
- Département of Microbiologie, Infectiologie Et immunologie, Faculté de Médecine, Université de Montréal, Montreal, QC, Canada. .,Centre de recherche du CHUM, 900 rue Saint-Denis, Tour Viger, R09.416, Montreal, QC, H2X 0A9, Canada.
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25
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Fu H, Ward EJ, Marelli-Berg FM. Mechanisms of T cell organotropism. Cell Mol Life Sci 2016; 73:3009-33. [PMID: 27038487 PMCID: PMC4951510 DOI: 10.1007/s00018-016-2211-4] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2016] [Revised: 03/21/2016] [Accepted: 03/22/2016] [Indexed: 02/06/2023]
Abstract
Protective immunity relies upon T cell differentiation and subsequent migration to target tissues. Similarly, immune homeostasis requires the localization of regulatory T cells (Tregs) to the sites where immunity takes place. While naïve T lymphocytes recirculate predominantly in secondary lymphoid tissue, primed T cells and activated Tregs must traffic to the antigen rich non-lymphoid tissue to exert effector and regulatory responses, respectively. Following priming in draining lymph nodes, T cells acquire the 'homing receptors' to facilitate their access to specific tissues and organs. An additional level of topographic specificity is provided by T cells receptor recognition of antigen displayed by the endothelium. Furthermore, co-stimulatory signals (such as those induced by CD28) have been shown not only to regulate T cell activation and differentiation, but also to orchestrate the anatomy of the ensuing T cell response. We here review the molecular mechanisms supporting trafficking of both effector and regulatory T cells to specific antigen-rich tissues.
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Affiliation(s)
- Hongmei Fu
- William Harvey Research Institute, Heart Centre, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK
| | - Eleanor Jayne Ward
- William Harvey Research Institute, Heart Centre, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK
| | - Federica M Marelli-Berg
- William Harvey Research Institute, Heart Centre, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, Charterhouse Square, London, EC1M 6BQ, UK.
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26
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ANSARI AFTABA, BYRAREDDY SIDDAPPAN. The Role of Integrin Expressing Cells in Modulating Disease Susceptibility and Progression (January 2016). INTERNATIONAL TRENDS IN IMMUNITY 2016; 4:11-27. [PMID: 28770236 PMCID: PMC5536173] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Subscribe] [Scholar Register] [Indexed: 06/07/2023]
Abstract
In this review we have summarized the role of gut homing molecules with a focus on the heterodimeric integrin α4β7 since the α4β7 has been shown to be important in modulating SIV transmission, disease susceptibility and progression. This review provides an overview of integrins, their structure and function to provide a general background upon which the role of the α4β7 integrin can best be understood. We also describe integrins and their cognate receptors and their potential role in modulating disease that we hope provides some food for thought on how such knowledge can be utilized for vaccine formulation.
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Affiliation(s)
- AFTAB A. ANSARI
- Department of Pathology & Laboratory Medicine, Emory University School of Medicine, Atlanta, GA 30322
| | - SIDDAPPA N. BYRAREDDY
- Department of Pharmacology and Experimental Neurosciences, University of Nebraska Medical Center, Omaha NE 68312
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha NE 68312
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27
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Singh UP, Singh NP, Murphy EA, Price RL, Fayad R, Nagarkatti M, Nagarkatti PS. Chemokine and cytokine levels in inflammatory bowel disease patients. Cytokine 2015; 77:44-9. [PMID: 26520877 DOI: 10.1016/j.cyto.2015.10.008] [Citation(s) in RCA: 235] [Impact Index Per Article: 23.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2015] [Revised: 10/09/2015] [Accepted: 10/19/2015] [Indexed: 12/13/2022]
Abstract
Crohn's disease (CD) and ulcerative colitis (UC), two forms of inflammatory bowel disease (IBD), are chronic, relapsing, and tissue destructive lesions that are accompanied by the uncontrolled activation of effector immune cells in the mucosa. Recent estimates indicate that there are 1.3 million annual cases of IBD in the United States, 50% of which consists of CD and 50% of UC. Chemokines and cytokines play a pivotal role in the regulation of mucosal inflammation by promoting leukocyte migration to sites of inflammation ultimately leading to tissue damage and destruction. In recent years, experimental studies in rodents have led to a better understanding of the role played by these inflammatory mediators in the development and progression of colitis. However, the clinical literature on IBD remains limited. Therefore, the aim of this study was to evaluate systemic concentrations of key chemokines and cytokines in forty-two IBD patients with a range of disease activity compared to levels found in ten healthy donors. We found a significant increase in an array of chemokines including macrophage migration factor (MIF), CCL25, CCL23, CXCL5, CXCL13, CXCL10, CXCL11, MCP1, and CCL21 in IBD patients as compared to normal healthy donors (P<0.05). Further, we also report increases in the inflammatory cytokines IL-16, IFN-γ, IL-1β and TNF-α in IBD patients when compared to healthy donors (P<0.05). These data clearly indicate an increase in circulating levels of specific chemokines and cytokines that are known to modulate systemic level through immune cells results in affecting local intestinal inflammation and tissue damage in IBD patients. Blockade of these inflammatory mediators should be explored as a mechanism to alleviate or even reverse symptoms of IBD.
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Affiliation(s)
- Udai P Singh
- Department of Pathology, Microbiology and Immunology, School of Medicine, University of South Carolina, Columbia, SC 29208, USA.
| | - Narendra P Singh
- Department of Pathology, Microbiology and Immunology, School of Medicine, University of South Carolina, Columbia, SC 29208, USA
| | - E Angela Murphy
- Department of Pathology, Microbiology and Immunology, School of Medicine, University of South Carolina, Columbia, SC 29208, USA
| | - Robert L Price
- Department of Cell and Developmental Biology, University of South Carolina, Columbia, SC 29208, USA
| | - Raja Fayad
- Department of Exercise Science, Arnold School of Public Health, University of South Carolina, Columbia, SC 29208, USA
| | - Mitzi Nagarkatti
- Department of Pathology, Microbiology and Immunology, School of Medicine, University of South Carolina, Columbia, SC 29208, USA
| | - Prakash S Nagarkatti
- Department of Pathology, Microbiology and Immunology, School of Medicine, University of South Carolina, Columbia, SC 29208, USA
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28
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Rapp M, Grassmann S, Chaloupka M, Layritz P, Kruger S, Ormanns S, Rataj F, Janssen KP, Endres S, Anz D, Kobold S. C-C chemokine receptor type-4 transduction of T cells enhances interaction with dendritic cells, tumor infiltration and therapeutic efficacy of adoptive T cell transfer. Oncoimmunology 2015; 5:e1105428. [PMID: 27195186 PMCID: PMC4859768 DOI: 10.1080/2162402x.2015.1105428] [Citation(s) in RCA: 53] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/10/2015] [Revised: 10/02/2015] [Accepted: 10/03/2015] [Indexed: 12/11/2022] Open
Abstract
T cell infiltration at the tumor site has been identified as a major predictor for the efficacy of adoptive T cell therapy. The chemokine C-C motif ligand 22 (CCL22) is highly expressed by immune cells in murine and human pancreatic cancer. Expression of its corresponding receptor, C-C chemokine receptor type 4 (CCR4), is restricted to regulatory T cells (Treg). We show that transduction of cytotoxic T cells (CTL) with CCR4 enhances their immigration into a pancreatic cancer model. Further, we show that binding of CCR4 with CCL22 strengthens the binding of T cell LFA-1 to dendritic cell (DC) ICAM-1 and increases CTL activation. In vivo, in a model of subcutaneous pancreatic cancer, treatment of tumor-bearing mice with CCR4-transduced CTL led to the eradication of established tumors in 40% of the mice. In conclusion, CCR4 overexpression in CTL is a promising therapeutic strategy to enhance the efficacy of adoptive T cell transfer (ACT).
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Affiliation(s)
- Moritz Rapp
- Center of Integrated Protein Science Munich (CIPS-M) and Division of Clinical Pharmacology, Department of Internal Medicine IV, Klinikum der Ludwig-Maximilians-Universität München, Member of the German Center for Lung Research , Munich, Germany
| | - Simon Grassmann
- Center of Integrated Protein Science Munich (CIPS-M) and Division of Clinical Pharmacology, Department of Internal Medicine IV, Klinikum der Ludwig-Maximilians-Universität München, Member of the German Center for Lung Research , Munich, Germany
| | - Michael Chaloupka
- Center of Integrated Protein Science Munich (CIPS-M) and Division of Clinical Pharmacology, Department of Internal Medicine IV, Klinikum der Ludwig-Maximilians-Universität München, Member of the German Center for Lung Research , Munich, Germany
| | - Patrick Layritz
- Center of Integrated Protein Science Munich (CIPS-M) and Division of Clinical Pharmacology, Department of Internal Medicine IV, Klinikum der Ludwig-Maximilians-Universität München, Member of the German Center for Lung Research , Munich, Germany
| | - Stephan Kruger
- Department of Internal Medicine III and Comprehensive Cancer Center, Klinikum der Ludwig-Maximilians-Universität München , Munich, Germany
| | - Steffen Ormanns
- Institute of Pathology, Ludwig-Maximilians-Universität München , Munich, Germany
| | - Felicitas Rataj
- Center of Integrated Protein Science Munich (CIPS-M) and Division of Clinical Pharmacology, Department of Internal Medicine IV, Klinikum der Ludwig-Maximilians-Universität München, Member of the German Center for Lung Research , Munich, Germany
| | - Klaus-Peter Janssen
- Department of Surgery, Klinikum Rechts der Isar, Technische Universität München , Munich, Germany
| | - Stefan Endres
- Center of Integrated Protein Science Munich (CIPS-M) and Division of Clinical Pharmacology, Department of Internal Medicine IV, Klinikum der Ludwig-Maximilians-Universität München, Member of the German Center for Lung Research , Munich, Germany
| | - David Anz
- Center of Integrated Protein Science Munich (CIPS-M) and Division of Clinical Pharmacology, Department of Internal Medicine IV, Klinikum der Ludwig-Maximilians-Universität München, Member of the German Center for Lung Research, Munich, Germany; Department of Internal Medicine IV, Division of Gastroenterology, Klinikum der Ludwig-Maximilians-Universität München, Munich, Germany
| | - Sebastian Kobold
- Center of Integrated Protein Science Munich (CIPS-M) and Division of Clinical Pharmacology, Department of Internal Medicine IV, Klinikum der Ludwig-Maximilians-Universität München, Member of the German Center for Lung Research , Munich, Germany
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29
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Lima M, Leander M, Santos M, Santos AH, Lau C, Queirós ML, Gonçalves M, Fonseca S, Moura J, Teixeira MDA, Orfao A. Chemokine Receptor Expression on Normal Blood CD56(+) NK-Cells Elucidates Cell Partners That Comigrate during the Innate and Adaptive Immune Responses and Identifies a Transitional NK-Cell Population. J Immunol Res 2015; 2015:839684. [PMID: 26543875 PMCID: PMC4620293 DOI: 10.1155/2015/839684] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/24/2014] [Revised: 03/02/2015] [Accepted: 03/02/2015] [Indexed: 12/26/2022] Open
Abstract
Studies of chemokine receptors (CKR) in natural killer- (NK-) cells have already been published, but only a few gave detailed information on its differential expression on blood NK-cell subsets. We report on the expression of the inflammatory and homeostatic CKR on normal blood CD56(+low) CD16(+) and CD56(+high) CD16(-/+low) NK-cells. Conventional CD56(+low) and CD56(+high) NK-cells present in the normal PB do express CKR for inflammatory cytokines, although with different patterns CD56(+low) NK-cells are mainly CXCR1/CXCR2(+) and CXCR3/CCR5(-/+), whereas mostly CD56(+high) NK-cells are CXCR1/CXCR2(-) and CXCR3/CCR5(+). Both NK-cell subsets have variable CXCR4 expression and are CCR4(-) and CCR6(-). The CKR repertoire of the CD56(+low) NK-cells approaches to that of neutrophils, whereas the CKR repertoire of the CD56(+high) NK-cells mimics that of Th1(+) T cells, suggesting that these cells are prepared to migrate into inflamed tissues at different phases of the immune response. In addition, we describe a subpopulation of NK-cells with intermediate levels of CD56 expression, which we named CD56(+int) NK-cells. These NK-cells are CXCR3/CCR5(+), they have intermediate levels of expression of CD16, CD62L, CD94, and CD122, and they are CD57(-) and CD158a(-). In view of their phenotypic features, we hypothesize that they correspond to a transitional stage, between the well-known CD56(+high) and CD56(+low) NK-cells populations.
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Affiliation(s)
- Margarida Lima
- Laboratory of Cytometry, Service of Hematology, Hospital de Santo António (HSA), Centro Hospitalar do Porto (CHP), Rua D. Manuel II, 4050-345 Porto, Portugal
| | - Magdalena Leander
- Laboratory of Cytometry, Service of Hematology, Hospital de Santo António (HSA), Centro Hospitalar do Porto (CHP), Rua D. Manuel II, 4050-345 Porto, Portugal
| | - Marlene Santos
- Laboratory of Cytometry, Service of Hematology, Hospital de Santo António (HSA), Centro Hospitalar do Porto (CHP), Rua D. Manuel II, 4050-345 Porto, Portugal
| | - Ana Helena Santos
- Laboratory of Cytometry, Service of Hematology, Hospital de Santo António (HSA), Centro Hospitalar do Porto (CHP), Rua D. Manuel II, 4050-345 Porto, Portugal
| | - Catarina Lau
- Laboratory of Cytometry, Service of Hematology, Hospital de Santo António (HSA), Centro Hospitalar do Porto (CHP), Rua D. Manuel II, 4050-345 Porto, Portugal
| | - Maria Luís Queirós
- Laboratory of Cytometry, Service of Hematology, Hospital de Santo António (HSA), Centro Hospitalar do Porto (CHP), Rua D. Manuel II, 4050-345 Porto, Portugal
| | - Marta Gonçalves
- Laboratory of Cytometry, Service of Hematology, Hospital de Santo António (HSA), Centro Hospitalar do Porto (CHP), Rua D. Manuel II, 4050-345 Porto, Portugal
| | - Sónia Fonseca
- Laboratory of Cytometry, Service of Hematology, Hospital de Santo António (HSA), Centro Hospitalar do Porto (CHP), Rua D. Manuel II, 4050-345 Porto, Portugal
| | - João Moura
- Laboratory of Cytometry, Service of Hematology, Hospital de Santo António (HSA), Centro Hospitalar do Porto (CHP), Rua D. Manuel II, 4050-345 Porto, Portugal
| | - Maria dos Anjos Teixeira
- Laboratory of Cytometry, Service of Hematology, Hospital de Santo António (HSA), Centro Hospitalar do Porto (CHP), Rua D. Manuel II, 4050-345 Porto, Portugal
| | - Alberto Orfao
- Laboratory of Flow Cytometry, Centro de Investigación del Cancer (CIC), Campus Miguel de Unamuno, 37007 Salamanca, Spain
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30
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Jug r 2-reactive CD4(+) T cells have a dominant immune role in walnut allergy. J Allergy Clin Immunol 2015; 136:983-92.e7. [PMID: 25772597 PMCID: PMC4568181 DOI: 10.1016/j.jaci.2015.01.029] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2014] [Revised: 01/20/2015] [Accepted: 01/22/2015] [Indexed: 12/24/2022]
Abstract
Background Allergic reactions to walnut can be life threatening. While IgE epitopes of walnut have been studied, CD4+ T-cell specific epitopes for walnut remain uncharacterized. Particularly, the relationship of both phenotype and frequency of walnut specific T-cells to the disease have not been examined. Objectives We sought to provide a thorough phenotypic analysis for walnut reactive T-cells in allergic and non-allergic subjects. Particularly, the relationship of phenotypes and frequencies of walnut specific T-cells with the disease. Methods CD154 up-regulation assay was used to examine CD4+ T-cell reactivity towards walnut allergens.Jug r 1, Jug r 2 and Jug r 3. Tetramer-Guided epitope mapping approach was utilized to identify HLA-restricted CD4+ T-cells epitopes in Jug r 2. Direct ex vivo staining with peptide-major histocompatibility complex class II (pMHC-II) tetramers enabled the comparison of frequency and phenotype of Jug r 2-specific CD4+ T-cells between allergic and non-allergic subjects. Jug r 2-specific T-cell-clones were also generated and mRNA transcription factor levels were assessed by RT qPCR. Intracellular cytokine staining (ICS) assays were performed for further phenotypical analyses. Results Jug r 2 was identified as the major allergen that elicited CD4+ T-cell responses. Multiple Jug r 2 T-cell epitopes were identified. The majority of these T-cells in allergic subjects have a CCR4+ TCM (central memory) phenotype. A subset of these T-cells express CCR4+CCR6+ irrespectively of the asthmatic status of the allergic subjects. ICS confirmed these TH2, TH2/TH17 and TH17-like heterogenic profiles. Jug r 2-specific T-cell-clones from allergic subjects mainly expressed GATA3; nonetheless, a portion of T-cell clones expressed either GATA3 and RORC, or RORC, confirming the presence of TH2, TH2/TH17 and TH17 cells. Conclusions Jug r 2 specific responses dominate walnut T-cell responses in subjects with walnut allergy. Jug r 2 central memory CD4+ cells and terminal effector T-cells were detected in peripheral blood with the central memory phenotype as the most prevalent phenotype. In addition to conventional TH2-cells, TH2/TH17 and TH17 cells were also detected in non-asthmatic and asthmatic subjects with walnut allergy. Understanding this T-cell heterogeneity may render better understanding of the disease manifestation.
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Nguyen LP, Pan J, Dinh TT, Hadeiba H, O'Hara E, Ebtikar A, Hertweck A, Gökmen MR, Lord GM, Jenner RG, Butcher EC, Habtezion A. Role and species-specific expression of colon T cell homing receptor GPR15 in colitis. Nat Immunol 2015; 16:207-213. [PMID: 25531831 PMCID: PMC4338558 DOI: 10.1038/ni.3079] [Citation(s) in RCA: 122] [Impact Index Per Article: 12.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2014] [Accepted: 12/02/2014] [Indexed: 02/08/2023]
Abstract
Lymphocyte recruitment maintains intestinal immune homeostasis but also contributes to inflammation. The orphan chemoattractant receptor GPR15 mediates regulatory T cell homing and immunosuppression in the mouse colon. We show that GPR15 is also expressed by mouse TH17 and TH1 effector cells and is required for colitis in a model that depends on the trafficking of these cells to the colon. In humans GPR15 is expressed by effector cells, including pathogenic TH2 cells in ulcerative colitis, but is expressed poorly or not at all by colon regulatory T (Treg) cells. The TH2 transcriptional activator GATA-3 and the Treg-associated transcriptional repressor FOXP3 robustly bind human, but not mouse, GPR15 enhancer sequences, correlating with receptor expression. Our results highlight species differences in GPR15 regulation and suggest it as a potential therapeutic target for colitis.
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Affiliation(s)
- Linh P Nguyen
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA 94305, USA
- The Center for Molecular Biology and Medicine, Veterans Affairs Palo Alto Health Care System and The Palo Alto Veterans Institute for Research, Palo Alto, California 94304, USA
| | - Junliang Pan
- The Center for Molecular Biology and Medicine, Veterans Affairs Palo Alto Health Care System and The Palo Alto Veterans Institute for Research, Palo Alto, California 94304, USA
| | - Theresa Thanh Dinh
- Laboratory of Immunology and Vascular Biology, Department of Pathology, Stanford University School of Medicine, Stanford, California 94305, USA
| | - Husein Hadeiba
- The Center for Molecular Biology and Medicine, Veterans Affairs Palo Alto Health Care System and The Palo Alto Veterans Institute for Research, Palo Alto, California 94304, USA
| | - Edward O'Hara
- The Center for Molecular Biology and Medicine, Veterans Affairs Palo Alto Health Care System and The Palo Alto Veterans Institute for Research, Palo Alto, California 94304, USA
| | - Ahmad Ebtikar
- The Center for Molecular Biology and Medicine, Veterans Affairs Palo Alto Health Care System and The Palo Alto Veterans Institute for Research, Palo Alto, California 94304, USA
| | - Arnulf Hertweck
- UCL Cancer Institute, University College London, London, W1T 4JF, United Kingdom
| | - M Refik Gökmen
- Department of Experimental Immunobiology and NIHR Comprehensive Biomedical Research Centre, Guy's and St. Thomas' Hospital and King's College London, London, SE1 9RT, United Kingdom
| | - Graham M Lord
- Department of Experimental Immunobiology and NIHR Comprehensive Biomedical Research Centre, Guy's and St. Thomas' Hospital and King's College London, London, SE1 9RT, United Kingdom
| | - Richard G Jenner
- UCL Cancer Institute, University College London, London, W1T 4JF, United Kingdom
| | - Eugene C Butcher
- The Center for Molecular Biology and Medicine, Veterans Affairs Palo Alto Health Care System and The Palo Alto Veterans Institute for Research, Palo Alto, California 94304, USA
- Laboratory of Immunology and Vascular Biology, Department of Pathology, Stanford University School of Medicine, Stanford, California 94305, USA
| | - Aida Habtezion
- Division of Gastroenterology and Hepatology, Stanford University School of Medicine, Stanford, CA 94305, USA
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Lee J, Chang DY, Kim SW, Choi YS, Jeon SY, Racanelli V, Kim DW, Shin EC. Age-related differences in human palatine tonsillar B cell subsets and immunoglobulin isotypes. Clin Exp Med 2015; 16:81-7. [PMID: 25618165 DOI: 10.1007/s10238-015-0338-5] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2014] [Accepted: 01/08/2015] [Indexed: 11/27/2022]
Abstract
The tonsils provide defense of the upper aerodigestive tract against pathogens. Although long known to undergo functional changes with age, the precise changes occurring within tonsillar B cell populations remain undefined. In the present study, we investigated age-related changes in palatine tonsillar B cell subsets and immunoglobulin (Ig) isotypes. Palatine tonsils were obtained from forty-two tonsillectomy patients without tonsillitis who were divided into three groups: young children (4-9 years), adolescents (10-19 years), and adults (20-60 years). Tonsillar B cells were then analyzed by flow cytometry. Using expression of CD38 and IgD to define B cell subsets, we found that the frequency of germinal center (GC) B cells in the tonsils was significantly higher, and the frequency of memory B cells lower, in young children as compared to adolescents and adults. Within the GC B cell subsets, adults had a higher frequency of IgA(+) cells and a lower frequency of IgM(+) cells as compared to individuals in the younger age groups. Moreover, young children had a higher frequency of IgG(+) cells in the GC B cell subsets than did individuals in the older age groups. We also observed an abundance of IgM(+) cells among memory B cells and plasmablasts in young children and IgA(+) cells in adults. In summary, the proportion of GC B cells in palatine tonsillar B cells decreases with age, while the proportion of memory B cells increases with age. In addition, Ig isotypes in tonsils preferentially switch from IgM to IgA as individuals age.
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Affiliation(s)
- Jino Lee
- Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, KAIST, Daejeon, 305-701, Republic of Korea
| | - Dong-Yeop Chang
- Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, KAIST, Daejeon, 305-701, Republic of Korea.,Department of Otorhinolaryngology, Gyeongsang National University Hospital, Jinju, 660-702, Republic of Korea
| | - Sang-Wook Kim
- Department of Otorhinolaryngology, Gyeongsang National University Hospital, Jinju, 660-702, Republic of Korea
| | - Yoon Seok Choi
- Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, KAIST, Daejeon, 305-701, Republic of Korea
| | - Sea-Yuong Jeon
- Department of Otorhinolaryngology, Gyeongsang National University Hospital, Jinju, 660-702, Republic of Korea
| | - Vito Racanelli
- Department of Internal Medicine and Clinical Oncology, University of Bari Medical School, Bari, Italy
| | - Dae Woo Kim
- Department of Otorhinolaryngology-Head and Neck Surgery, Boramae Medical Center, Seoul National University College of Medicine, Seoul, 156-707, Republic of Korea.
| | - Eui-Cheol Shin
- Laboratory of Immunology and Infectious Diseases, Graduate School of Medical Science and Engineering, KAIST, Daejeon, 305-701, Republic of Korea.
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Wang X, Sumida H, Cyster JG. GPR18 is required for a normal CD8αα intestinal intraepithelial lymphocyte compartment. ACTA ACUST UNITED AC 2014; 211:2351-9. [PMID: 25348153 PMCID: PMC4235638 DOI: 10.1084/jem.20140646] [Citation(s) in RCA: 71] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
Intraepithelial lymphocytes (IELs) play an important role in maintaining the physiology of the small intestine. The majority of mouse IELs express CD8αα and are either γδ or αβ T cells. Although the development and homing of CD8αα IELs have been studied in some detail, the factors controlling their homeostasis and positioning are incompletely understood. Here we demonstrate that G protein-coupled receptor 18 (GPR18) is abundantly expressed in CD8αα IELs and that mice lacking this orphan receptor have reduced numbers of γδT IELs. Mixed bone marrow chimera experiments reveal a markedly reduced contribution of GPR18-deficient cells to the CD8αα IEL compartment and a reduction in the CD8αβ T cell subset. These defects could be rescued by transduction with a GPR18-expressing retrovirus. The GPR18-deficient γδT IELs that remained in mixed chimeras had elevated Thy1, and there were less granzyme B(+) and Vγ7(+) cells, indicating a greater reduction in effector-type cells. Flow cytometric analysis indicated GPR18 deficiency more strongly affected the CD8αα cells in the intraepithelial compared with the adjacent lamina propria compartment. These findings establish a requirement for GPR18 in CD8αα and CD8αβ IELs, and we suggest the receptor has a role in augmenting the accumulation of CD8 T cells in the intraepithelial versus lamina propria compartment.
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Affiliation(s)
- Xiaoming Wang
- Howard Hughes Medical Institute and Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143 Howard Hughes Medical Institute and Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143
| | - Hayakazu Sumida
- Howard Hughes Medical Institute and Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143 Howard Hughes Medical Institute and Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143
| | - Jason G Cyster
- Howard Hughes Medical Institute and Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143 Howard Hughes Medical Institute and Department of Microbiology and Immunology, University of California, San Francisco, San Francisco, CA 94143
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Kraan H, Vrieling H, Czerkinsky C, Jiskoot W, Kersten G, Amorij JP. Buccal and sublingual vaccine delivery. J Control Release 2014; 190:580-92. [PMID: 24911355 PMCID: PMC7114675 DOI: 10.1016/j.jconrel.2014.05.060] [Citation(s) in RCA: 133] [Impact Index Per Article: 12.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2014] [Revised: 05/28/2014] [Accepted: 05/29/2014] [Indexed: 11/25/2022]
Abstract
Because of their large surface area and immunological competence, mucosal tissues are attractive administration and target sites for vaccination. An important characteristic of mucosal vaccination is its ability to elicit local immune responses, which act against infection at the site of pathogen entry. However, mucosal surfaces are endowed with potent and sophisticated tolerance mechanisms to prevent the immune system from overreacting to the many environmental antigens. Hence, mucosal vaccination may suppress the immune system instead of induce a protective immune response. Therefore, mucosal adjuvants and/or special antigen delivery systems as well as appropriate dosage forms are required in order to develop potent mucosal vaccines. Whereas oral, nasal and pulmonary vaccine delivery strategies have been described extensively, the sublingual and buccal routes have received considerably less attention. In this review, the characteristics of and approaches for sublingual and buccal vaccine delivery are described and compared with other mucosal vaccine delivery sites. We discuss recent progress and highlight promising developments in the search for vaccine formulations, including adjuvants and suitable dosage forms, which are likely critical for designing a successful sublingual or buccal vaccine. Finally, we outline the challenges, hurdles to overcome and formulation issues relevant for sublingual or buccal vaccine delivery.
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Affiliation(s)
- Heleen Kraan
- Intravacc (Institute for Translational Vaccinology), Bilthoven, The Netherlands.
| | - Hilde Vrieling
- Division of Drug Delivery Technology, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden, The Netherlands
| | - Cecil Czerkinsky
- Institut de Pharmacologie Moleculaire et Cellulaire, UMR 7275 CNRS-INSERM-UNSA, Valbonne, France
| | - Wim Jiskoot
- Division of Drug Delivery Technology, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden, The Netherlands
| | - Gideon Kersten
- Intravacc (Institute for Translational Vaccinology), Bilthoven, The Netherlands; Division of Drug Delivery Technology, Leiden Academic Centre for Drug Research (LACDR), Leiden University, Leiden, The Netherlands
| | - Jean-Pierre Amorij
- Intravacc (Institute for Translational Vaccinology), Bilthoven, The Netherlands.
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Bamias G, Clark DJ, Rivera-Nieves J. Leukocyte traffic blockade as a therapeutic strategy in inflammatory bowel disease. Curr Drug Targets 2014; 14:1490-500. [PMID: 23621509 DOI: 10.2174/13894501113149990158] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2013] [Revised: 04/17/2013] [Accepted: 04/23/2013] [Indexed: 12/16/2022]
Abstract
Dysregulated recruitment of leukocytes into the intestine is a characteristic feature of IBD. Several families of molecules regulate the influx of these cells into sites of inflammation within the gastrointestinal tract. Pharmacological blockade of interactions between molecules that mediate the formation of stable bonds (integrins) and their endothelial ligands has already shown clinical efficacy. Antibodies that target participant molecules have been approved by the US Federal Drug Administration for use in Crohn's, multiple sclerosis (MS) (i.e. natalizumab) and psoriasis (i.e. efalizumab). A more recent additional family of drugs, which might also interfere with lymphocyte traffic (i.e. sphingosine-1- phosphate receptor agonists: fingolimod) is in clinical use for MS and just recently entered the clinical trial stage for ulcerative colitis. In the present review we discuss basic aspects of clinically relevant molecules and compile the clinical studies that support the targeting of specific steps of the leukocyte adhesion cascade for therapeutic purposes in IBD.
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Affiliation(s)
- Giorgos Bamias
- Inflammatory Bowel Disease Center, Division of Gastroenterology, 9500 Gilman Drive, San Diego, California 92093-0063, USA.
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Chen JP, Wu MS, Kuo SH, Liao F. IL-22 negatively regulates Helicobacter pylori-induced CCL20 expression in gastric epithelial cells. PLoS One 2014; 9:e97350. [PMID: 24824519 PMCID: PMC4019584 DOI: 10.1371/journal.pone.0097350] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2013] [Accepted: 04/18/2014] [Indexed: 12/30/2022] Open
Abstract
Helicobacter pylori is a Gram-negative bacterium that infects the human gastric mucosa and causes various gastric diseases. H. pylori infection induces the production of inflammatory chemokine CCL20 in gastric mucosa and leads to gastric inflammation. Given that the IL-22/IL-22R axis plays a critical role in the regulation of homeostasis and inflammation of epithelial cells at barrier surfaces, we investigated the effect of IL-22 on CCL20 expression induced by H. pylori. We demonstrated that H. pylori infection of the gastric epithelia-derived AGS cells significantly induced CCL20 expression and the induction was inhibited by IL-22. Functional analysis of the CCL20 promoter revealed that the H. pylori-induced CCL20 expression required the activation of NF-κB, and that IL-22 inhibited the induction by attenuating NF-κB activation. Knockdown of endogenous STAT3 by either short interfering RNAs or a short hairpin RNA significantly reduced the inhibitory effect of IL-22. Furthermore, STAT3 phosphorylation elicited by IL-22 was crucial for the inhibition of H. pylori-induced CCL20 expression. Consistent with the in vitro data showing that IL-22 negatively regulated H. pylori-induced CCL20 expression in gastric epithelial cells, studies on the tissue sections from patients with H. pylori infection also revealed an inverse association of IL-22 expression and CCL20 expression in vivo. Together, our findings suggest that IL-22 plays a role in the control of overproduction of the inflammatory chemokine and thus may protect the gastric mucosa from inflammation-mediated damage.
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Affiliation(s)
- Jia-Perng Chen
- Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan
| | - Ming-Shiang Wu
- Department of Internal Medicine, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan
| | - Sung-Hsin Kuo
- Department of Oncology, National Taiwan University Hospital, Taipei, Taiwan
- Cancer Research Center and Graduate Institute of Oncology, National Taiwan University College of Medicine, Taipei, Taiwan
| | - Fang Liao
- Institute of Microbiology and Immunology, National Yang-Ming University, Taipei, Taiwan
- Institute of Biomedical Sciences, Academia Sinica, Taipei, Taiwan
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Tiburzy B, Kulkarni U, Hauser AE, Abram M, Manz RA. Plasma cells in immunopathology: concepts and therapeutic strategies. Semin Immunopathol 2014; 36:277-88. [PMID: 24740168 DOI: 10.1007/s00281-014-0426-8] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2013] [Accepted: 04/01/2014] [Indexed: 12/12/2022]
Abstract
Plasma cells are terminally differentiated B cells that secrete antibodies, important for immune protection, but also contribute to any allergic and autoimmune disease. There is increasing evidence that plasma cell populations exhibit a considerable degree of heterogeneity with respect to their immunophenotype, migration behavior, lifetime, and susceptibility to immunosuppressive drugs. Pathogenic long-lived plasma cells are refractory to existing therapies. In contrast, short-lived plasma cells can be depleted by steroids and cytostatic drugs. Therefore, long-lived plasma cells are responsible for therapy-resistant autoantibodies and resemble a challenge for the therapy of antibody-mediated autoimmune diseases. Both lifetime and therapy resistance of plasma cells are supported by factors produced within their microenviromental niches. Current results suggest that plasma cell differentiation and survival factors such as IL-6 also signal via mammalian miRNAs within the plasma cell to modulate downstream transcription factors. Recent evidence also suggests that plasma cells and/or their immediate precursors (plasmablasts) can produce important cytokines and act as antigen-presenting cells, exhibiting so far underestimated roles in immune regulation and bone homeostasis. Here, we provide an overview on plasma cell biology and discuss exciting, experimental, and potential therapeutic approaches to eliminate pathogenic plasma cells.
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Affiliation(s)
- Benjamin Tiburzy
- Institute for Systemic Inflammation Research (ISEF), University of Lübeck, Ratzeburger Allee 160, 23538, Lübeck, Germany
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Paradis M, Mindt BC, Duerr CU, Rojas OL, Ng D, Boulianne B, McCarthy DD, Yu MD, Summers deLuca LE, Ward LA, Waldron JB, Philpott DJ, Gommerman JL, Fritz JH. A TNF-α–CCL20–CCR6 Axis Regulates Nod1-Induced B Cell Responses. THE JOURNAL OF IMMUNOLOGY 2014; 192:2787-99. [DOI: 10.4049/jimmunol.1203310] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/01/2023]
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Stoler-Barak L, Moussion C, Shezen E, Hatzav M, Sixt M, Alon R. Blood vessels pattern heparan sulfate gradients between their apical and basolateral aspects. PLoS One 2014; 9:e85699. [PMID: 24465652 PMCID: PMC3899079 DOI: 10.1371/journal.pone.0085699] [Citation(s) in RCA: 43] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2013] [Accepted: 12/05/2013] [Indexed: 01/13/2023] Open
Abstract
A hallmark of immune cell trafficking is directional guidance via gradients of soluble or surface bound chemokines. Vascular endothelial cells produce, transport and deposit either their own chemokines or chemokines produced by the underlying stroma. Endothelial heparan sulfate (HS) was suggested to be a critical scaffold for these chemokine pools, but it is unclear how steep chemokine gradients are sustained between the lumenal and ablumenal aspects of blood vessels. Addressing this question by semi-quantitative immunostaining of HS moieties around blood vessels with a pan anti-HS IgM mAb, we found a striking HS enrichment in the basal lamina of resting and inflamed post capillary skin venules, as well as in high endothelial venules (HEVs) of lymph nodes. Staining of skin vessels with a glycocalyx probe further suggested that their lumenal glycocalyx contains much lower HS density than their basolateral extracellular matrix (ECM). This polarized HS pattern was observed also in isolated resting and inflamed microvascular dermal cells. Notably, progressive skin inflammation resulted in massive ECM deposition and in further HS enrichment around skin post capillary venules and their associated pericytes. Inflammation-dependent HS enrichment was not compromised in mice deficient in the main HS degrading enzyme, heparanase. Our results suggest that the blood vasculature patterns steep gradients of HS scaffolds between their lumenal and basolateral endothelial aspects, and that inflammatory processes can further enrich the HS content nearby inflamed vessels. We propose that chemokine gradients between the lumenal and ablumenal sides of vessels could be favored by these sharp HS scaffold gradients.
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Affiliation(s)
- Liat Stoler-Barak
- Department of Immunology, the Weizmann Institute of Science, Rehovot, Israel
| | | | - Elias Shezen
- Department of Immunology, the Weizmann Institute of Science, Rehovot, Israel
| | - Miki Hatzav
- Department of Immunology, the Weizmann Institute of Science, Rehovot, Israel
| | - Michael Sixt
- Institute of Science and Technology (IST), Klosterneuburg, Austria
| | - Ronen Alon
- Department of Immunology, the Weizmann Institute of Science, Rehovot, Israel
- * E-mail:
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Sereti I, Estes JD, Thompson WL, Morcock DR, Fischl MA, Croughs T, Beq S, Lafaye de Micheaux S, Yao MD, Ober A, Wilson EMP, Natarajan V, Imamichi H, Boulassel MR, Lederman MM, Routy JP. Decreases in colonic and systemic inflammation in chronic HIV infection after IL-7 administration. PLoS Pathog 2014; 10:e1003890. [PMID: 24497828 PMCID: PMC3907377 DOI: 10.1371/journal.ppat.1003890] [Citation(s) in RCA: 78] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2013] [Accepted: 12/04/2013] [Indexed: 12/12/2022] Open
Abstract
Despite antiretroviral therapy (ART), some HIV-infected persons maintain lower than normal CD4(+) T-cell counts in peripheral blood and in the gut mucosa. This incomplete immune restoration is associated with higher levels of immune activation manifested by high systemic levels of biomarkers, including sCD14 and D-dimer, that are independent predictors of morbidity and mortality in HIV infection. In this 12-week, single-arm, open-label study, we tested the efficacy of IL-7 adjunctive therapy on T-cell reconstitution in peripheral blood and gut mucosa in 23 ART suppressed HIV-infected patients with incomplete CD4(+) T-cell recovery, using one cycle (consisting of three subcutaneous injections) of recombinant human IL-7 (r-hIL-7) at 20 µg/kg. IL-7 administration led to increases of both CD4(+) and CD8(+) T-cells in peripheral blood, and importantly an expansion of T-cells expressing the gut homing integrin α4β7. Participants who underwent rectosigmoid biopsies at study baseline and after treatment had T-cell increases in the gut mucosa measured by both flow cytometry and immunohistochemistry. IL-7 therapy also resulted in apparent improvement in gut barrier integrity as measured by decreased neutrophil infiltration in the rectosigmoid lamina propria 12 weeks after IL-7 administration. This was also accompanied by decreased TNF and increased FOXP3 expression in the lamina propria. Plasma levels of sCD14 and D-dimer, indicative of systemic inflammation, decreased after r-hIL-7. Increases of colonic mucosal T-cells correlated strongly with the decreased systemic levels of sCD14, the LPS coreceptor - a marker of monocyte activation. Furthermore, the proportion of inflammatory monocytes expressing CCR2 was decreased, as was the basal IL-1β production of peripheral blood monocytes. These data suggest that administration of r-hIL-7 improves the gut mucosal abnormalities of chronic HIV infection and attenuates the systemic inflammatory and coagulation abnormalities that have been linked to it.
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Affiliation(s)
- Irini Sereti
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America
| | - Jacob D. Estes
- Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc, Frederick, Maryland, United States of America
| | - William L. Thompson
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America
| | - David R. Morcock
- Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc, Frederick, Maryland, United States of America
| | - Margaret A. Fischl
- University of Miami School of Medicine, Miami, Florida, United States of America
| | | | | | | | - Michael D. Yao
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America
| | - Alexander Ober
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America
| | - Eleanor M. P. Wilson
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America
| | - Ven Natarajan
- Frederick National Laboratory for Cancer Research, Leidos Biomedical Research, Inc, Frederick, Maryland, United States of America
| | - Hiromi Imamichi
- National Institute of Allergy and Infectious Diseases, National Institutes of Health, Bethesda, Maryland, United States of America
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Bachelerie F, Ben-Baruch A, Burkhardt AM, Combadiere C, Farber JM, Graham GJ, Horuk R, Sparre-Ulrich AH, Locati M, Luster AD, Mantovani A, Matsushima K, Murphy PM, Nibbs R, Nomiyama H, Power CA, Proudfoot AEI, Rosenkilde MM, Rot A, Sozzani S, Thelen M, Yoshie O, Zlotnik A. International Union of Basic and Clinical Pharmacology. [corrected]. LXXXIX. Update on the extended family of chemokine receptors and introducing a new nomenclature for atypical chemokine receptors. Pharmacol Rev 2013; 66:1-79. [PMID: 24218476 PMCID: PMC3880466 DOI: 10.1124/pr.113.007724] [Citation(s) in RCA: 691] [Impact Index Per Article: 57.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
Sixteen years ago, the Nomenclature Committee of the International Union of Pharmacology approved a system for naming human seven-transmembrane (7TM) G protein-coupled chemokine receptors, the large family of leukocyte chemoattractant receptors that regulates immune system development and function, in large part by mediating leukocyte trafficking. This was announced in Pharmacological Reviews in a major overview of the first decade of research in this field [Murphy PM, Baggiolini M, Charo IF, Hébert CA, Horuk R, Matsushima K, Miller LH, Oppenheim JJ, and Power CA (2000) Pharmacol Rev 52:145-176]. Since then, several new receptors have been discovered, and major advances have been made for the others in many areas, including structural biology, signal transduction mechanisms, biology, and pharmacology. New and diverse roles have been identified in infection, immunity, inflammation, development, cancer, and other areas. The first two drugs acting at chemokine receptors have been approved by the U.S. Food and Drug Administration (FDA), maraviroc targeting CCR5 in human immunodeficiency virus (HIV)/AIDS, and plerixafor targeting CXCR4 for stem cell mobilization for transplantation in cancer, and other candidates are now undergoing pivotal clinical trials for diverse disease indications. In addition, a subfamily of atypical chemokine receptors has emerged that may signal through arrestins instead of G proteins to act as chemokine scavengers, and many microbial and invertebrate G protein-coupled chemokine receptors and soluble chemokine-binding proteins have been described. Here, we review this extended family of chemokine receptors and chemokine-binding proteins at the basic, translational, and clinical levels, including an update on drug development. We also introduce a new nomenclature for atypical chemokine receptors with the stem ACKR (atypical chemokine receptor) approved by the Nomenclature Committee of the International Union of Pharmacology and the Human Genome Nomenclature Committee.
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Affiliation(s)
- Francoise Bachelerie
- Chair, Subcommittee on Chemokine Receptors, Nomenclature Committee-International Union of Pharmacology, Bldg. 10, Room 11N113, NIH, Bethesda, MD 20892.
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Guarding the perimeter: protection of the mucosa by tissue-resident memory T cells. Mucosal Immunol 2013; 6:14-23. [PMID: 23131785 PMCID: PMC4034055 DOI: 10.1038/mi.2012.96] [Citation(s) in RCA: 75] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Mucosal tissues are continually bombarded with infectious agents seeking to gain entry into the body. The absence of a tough physical exterior layer surrounding these tissues creates a unique challenge for the immune system, which manages to provide broad protection against a plethora of different organisms with the aid of special adaptations that augment immunity at these vulnerable sites. For example, specialized populations of memory T lymphocytes reside at initial sites of pathogen entry into the body, where they provide an important protective barrier. Similar anatomically-confined populations of pathogen-specific CD8 T cells can be found near the outer margins of the body following recovery from a variety of local infections, where they share very similar phenotypic characteristics. How these tissue-resident T cells are retained in a single anatomic location where they can promote immunity is beginning to be defined. Here, we will review current knowledge of the mechanisms that help establish and maintain these regional lymphocytes in the mucosal tissues and discuss relevant data that enhance our understanding of the contribution of these lymphocyte populations to protective immunity against infectious diseases.
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Kang SM, Song JM, Kim YC. Microneedle and mucosal delivery of influenza vaccines. Expert Rev Vaccines 2012; 11:547-60. [PMID: 22697052 DOI: 10.1586/erv.12.25] [Citation(s) in RCA: 27] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023]
Abstract
In recent years with the threat of pandemic influenza and other public health needs, alternative vaccination methods other than intramuscular immunization have received great attention. The skin and mucosal surfaces are attractive sites probably because of both noninvasive access to the vaccine delivery and unique immunological responses. Intradermal vaccines using a microinjection system (BD Soluvia(TM)) and intranasal vaccines (FluMist®) are licensed. As a new vaccination method, solid microneedles have been developed using a simple device that may be suitable for self-administration. Because coated microneedle influenza vaccines are administered in the solid state, developing formulations maintaining the stability of influenza vaccines is an important issue to be considered. Marketable microneedle devices and clinical trials remain to be developed. Other alternative mucosal routes such as oral and intranasal delivery systems are also attractive for inducing cross-protective mucosal immunity, but effective non-live mucosal vaccines remain to be developed.
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Affiliation(s)
- Sang-Moo Kang
- Center for Inflammation, Immunity and Infection, and Department of Biology, Georgia State University, Atlanta, GA 30303, USA.
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Chung H, Pamp SJ, Hill JA, Surana NK, Edelman SM, Troy EB, Reading NC, Villablanca EJ, Wang S, Mora JR, Umesaki Y, Mathis D, Benoist C, Relman DA, Kasper DL. Gut immune maturation depends on colonization with a host-specific microbiota. Cell 2012; 149:1578-93. [PMID: 22726443 DOI: 10.1016/j.cell.2012.04.037] [Citation(s) in RCA: 889] [Impact Index Per Article: 68.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2011] [Revised: 01/03/2012] [Accepted: 04/07/2012] [Indexed: 02/06/2023]
Abstract
Gut microbial induction of host immune maturation exemplifies host-microbe mutualism. We colonized germ-free (GF) mice with mouse microbiota (MMb) or human microbiota (HMb) to determine whether small intestinal immune maturation depends on a coevolved host-specific microbiota. Gut bacterial numbers and phylum abundance were similar in MMb and HMb mice, but bacterial species differed, especially the Firmicutes. HMb mouse intestines had low levels of CD4(+) and CD8(+) T cells, few proliferating T cells, few dendritic cells, and low antimicrobial peptide expression--all characteristics of GF mice. Rat microbiota also failed to fully expand intestinal T cell numbers in mice. Colonizing GF or HMb mice with mouse-segmented filamentous bacteria (SFB) partially restored T cell numbers, suggesting that SFB and other MMb organisms are required for full immune maturation in mice. Importantly, MMb conferred better protection against Salmonella infection than HMb. A host-specific microbiota appears to be critical for a healthy immune system.
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Affiliation(s)
- Hachung Chung
- Channing Laboratory, Brigham and Women's Hospital, Harvard Medical School, Boston, MA 02115, USA
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The colocalization potential of HIV-specific CD8+ and CD4+ T-cells is mediated by integrin β7 but not CCR6 and regulated by retinoic acid. PLoS One 2012; 7:e32964. [PMID: 22470433 PMCID: PMC3314661 DOI: 10.1371/journal.pone.0032964] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2011] [Accepted: 02/08/2012] [Indexed: 12/22/2022] Open
Abstract
CD4+ T-cells from gut-associated lymphoid tissues (GALT) are major targets for HIV-1 infection. Recruitment of excess effector CD8+ T-cells in the proximity of target cells is critical for the control of viral replication. Here, we investigated the colocalization potential of HIV-specific CD8+ and CD4+ T-cells into the GALT and explored the role of retinoic acid (RA) in regulating this process in a cohort of HIV-infected subjects with slow disease progression. The expression of the gut-homing molecules integrin β7, CCR6, and CXCR3 was identified as a “signature” for HIV-specific but not CMV-specific CD4+ T-cells thus providing a new explanation for their enhanced permissiveness to infection in vivo. HIV-specific CD8+ T-cells also expressed high levels of integrin β7 and CXCR3; however CCR6 was detected at superior levels on HIV-specific CD4+versus CD8+ T-cells. All trans RA (ATRA) upregulated the expression of integrin β7 but not CCR6 on HIV-specific T-cells. Together, these results suggest that HIV-specific CD8+ T-cells may colocalize in excess with CD4+ T-cells into the GALT via integrin β7 and CXCR3, but not via CCR6. Considering our previous findings that CCR6+CD4+ T-cells are major cellular targets for HIV-DNA integration in vivo, a limited ability of CD8+ T-cells to migrate in the vicinity of CCR6+CD4+ T-cells may facilitate HIV replication and dissemination at mucosal sites.
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Thomas S, Baumgart DC. Targeting leukocyte migration and adhesion in Crohn's disease and ulcerative colitis. Inflammopharmacology 2011; 20:1-18. [PMID: 22205271 DOI: 10.1007/s10787-011-0104-6] [Citation(s) in RCA: 130] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2011] [Accepted: 11/23/2011] [Indexed: 12/11/2022]
Abstract
Crohn's disease and ulcerative colitis are two chronic inflammatory bowel diseases. Current biologic therapies are limited to blocking tumor necrosis factor alpha. However, some patients are primary non-responders, experience a loss of response, intolerance or side effects defining the urgent unmet need for novel treatments. The rapid recruitment and inappropriate retention of leukocytes is a hallmark of chronic inflammation and a potentially promising therapeutic target. We discuss the immunological mechanisms of leukocyte homing and adhesion in the gut mucosa. The interaction of lymphocytes (CD4+ T-cells, CD8+ T-cells, T(REG), T(H)1, T(H)17, B-cells), monocytes, macrophages, dendritic cells and granulocytes with endothelial and epithelial cells through integrins [α4β7 (LPAM-1), α(E)β₇ (HML1 Human Mucosal Lymphocyte Antigen 1), α₄β₁ (VLA-4), α(L)β₇, (LFA-1)] and their ligands immunoglobulin superfamily cellular adhesion molecules (CAM) (MAdCAM-1 Mucosal Addressin Cellular Adhesion Molecule 1, ICAM-1 Intercellular Cell Adhesion Molecule, VCAM-1 Vascular Cell Adhesion Molecule), fibronectin as well as chemokine receptors (CCR2, CCR4, CCR5, CCR7, CCR9, CCR10, CXCR3, CX3CR1) and chemokines [CCL5, CCL25 (TECK Thymus Expressed Chemokine), CCL28, CX3CL1, CXCL10, CXCL12] in the process of gut homing is critically reviewed and summarized in scientific cartoons. Moreover, we discuss the clinical trial results of approved and investigational antibodies and small molecules including natalizumab (anti-α₄ Tysabri®, Antegren®), AJM300 (anti-α4), etrolizumab (anti-β7, rhuMAb-Beta7), vedolizumab (anti-α4β7, LDP-02, MLN-02, MLN0002), PF-00547659 (anti-MAdCAM), Alicaforsen (anti-ICAM-1), and CCX282-B (anti-CCR9, GSK-1605786, Traficet-EN™) and their risks such as PML reported for natalizumab. Hopefully, the newer gut specific drug designs discussed in this article will have an impact on both efficacy and safety.
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Affiliation(s)
- Saskia Thomas
- Division of Gastroenterology and Hepatology, Department of Medicine, Charité Medical Center, Virchow Hospital, Medical School of the Humboldt University of Berlin, Berlin, Germany
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Mavigner M, Cazabat M, Dubois M, L'Faqihi FE, Requena M, Pasquier C, Klopp P, Amar J, Alric L, Barange K, Vinel JP, Marchou B, Massip P, Izopet J, Delobel P. Altered CD4+ T cell homing to the gut impairs mucosal immune reconstitution in treated HIV-infected individuals. J Clin Invest 2011; 122:62-9. [PMID: 22156200 DOI: 10.1172/jci59011] [Citation(s) in RCA: 126] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2011] [Accepted: 11/02/2011] [Indexed: 02/04/2023] Open
Abstract
Depletion of CD4+ T cells from the gut occurs rapidly during acute HIV-1 infection. This has been linked to systemic inflammation and disease progression as a result of translocation of microbial products from the gut lumen into the bloodstream. Combined antiretroviral therapy (cART) substantially restores CD4+ T cell numbers in peripheral blood, but the gut compartment remains largely depleted of such cells for poorly understood reasons. Here, we show that a lack of recruitment of CD4+ T cells to the gut could be involved in the incomplete mucosal immune reconstitution of cART-treated HIV-infected individuals. We investigated the trafficking of CD4+ T cells expressing the gut-homing receptors CCR9 and integrin α4β7 and found that many of these T cells remained in the circulation rather than repopulating the mucosa of the small intestine. This is likely because expression of the CCR9 ligand CCL25 was lower in the small intestine of HIV-infected individuals. The defective gut homing of CCR9+β7+ CD4+ T cells - a population that we found included most gut-homing Th17 cells, which have a critical role in mucosal immune defense - correlated with high plasma concentrations of markers of mucosal damage, microbial translocation, and systemic T cell activation. Our results thus describe alterations in CD4+ T cell homing to the gut that could prevent efficient mucosal immune reconstitution in HIV-infected individuals despite effective cART.
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Putaala H, Barrangou R, Leyer GJ, Ouwehand AC, Hansen EB, Romero DA, Rautonen N. Analysis of the human intestinal epithelial cell transcriptional response to Lactobacillus acidophilus, Lactobacillus salivarius, Bifidobacterium lactis and Escherichia coli. Benef Microbes 2011; 1:283-95. [PMID: 21831765 DOI: 10.3920/bm2010.0003] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/13/2023]
Abstract
The complex microbial population residing in the human gastrointestinal tract consists of commensal, potential pathogenic and beneficial species, which are probably perceived differently by the host and consequently could be expected to trigger specific transcriptional responses. Here, we provide a comparative analysis of the global in vitro transcriptional response of human intestinal epithelial cells to Lactobacillus acidophilus NCFM™, Lactobacillus salivarius Ls-33, Bifidobacterium animalis subsp. lactis 420, and enterohaemorrhagic Escherichia coli O157:H7 (EHEC). Interestingly, L. salivarius Ls-33 DCE-induced changes were overall more similar to those of B. lactis 420 than to L. acidophilus NCFM™, which is consistent with previously observed in vivo immunomodulation properties. In the gene ontology and pathway analyses both specific and unspecific changes were observed. Common to all was the regulation of apoptosis and adipogenesis, and lipid-metabolism related regulation by the probiotics. Specific changes such as regulation of cell-cell adhesion by B. lactis 420, superoxide metabolism by L. salivarius Ls-33, and regulation of MAPK pathway by L. acidophilus NCFM™ were noted. Furthermore, fundamental differences were observed between the pathogenic and probiotic treatments in the Toll-like receptor pathway, especially for adapter molecules with a lowered level of transcriptional activation of MyD88, TRIF, IRAK1 and TRAF6 by probiotics compared to EHEC. The results in this study provide insights into the relationship between probiotics and human intestinal epithelial cells, notably with regard to strain-specific responses, and highlight the differences between transcriptional responses to pathogenic and probiotic bacteria.
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Affiliation(s)
- H Putaala
- Health & Nutrition, Danisco Sweeteners, Kantvik, Finland
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Tubo NJ, McLachlan JB, Campbell JJ. Chemokine receptor requirements for epidermal T-cell trafficking. THE AMERICAN JOURNAL OF PATHOLOGY 2011; 178:2496-503. [PMID: 21641376 DOI: 10.1016/j.ajpath.2011.02.031] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/22/2010] [Revised: 01/17/2011] [Accepted: 02/01/2011] [Indexed: 11/16/2022]
Abstract
Inflamed skin contains CD4 T-cell subsets that express chemokine receptors CCR4, CCR6, and/or CCR10. Prior attempts to reveal the distinct role(s) of each receptor in T-cell trafficking to skin have not produced a coherent story. Different conclusions drawn by separate research groups are difficult to reconcile because of the disparate inflammation models used. Here we directly compare CD4 T cells from wild-type, CCR4(-/-), CCR6(-/-), and CCR10(-/-) mice in parallel assays of trafficking to skin. Our models require direct competition between wild-type and receptor-deficient populations for access to inflamed cutaneous sites. Major histocompatibility complex-peptide tetramers allowed us to identify antigen-specific endogenous long-term memory CD4 T cells within skin after multiple topical immunizations. We separately analyzed cells from the dermal and epidermal layers, allowing us to assess the involvement of each receptor in trafficking between dermis and epidermis. We found that CCR4 deficiency reduces accumulation of memory CD4 T cells in skin by approximately 20-fold, but neither CCR6 nor CCR10 deficiency yielded any detectable effects. Strikingly, no differences in dermal versus epidermal localization were observed for cells lacking any of these three receptors. Our findings raise the possibility that CCR6 and CCR10 play (as yet) unknown roles in cutaneous T-cell immunology, unrelated to skin-specific trafficking.
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Affiliation(s)
- Noah J Tubo
- Department of Dermatology, Brigham and Women's Hospital, Boston, Massachusetts, USA
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Oakley OR, Frazer ML, Ko C. Pituitary-ovary-spleen axis in ovulation. Trends Endocrinol Metab 2011; 22:345-52. [PMID: 21600783 PMCID: PMC3161174 DOI: 10.1016/j.tem.2011.04.005] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/20/2010] [Revised: 04/05/2011] [Accepted: 04/07/2011] [Indexed: 01/08/2023]
Abstract
Leukocytes are rapidly recruited to the preovulatory ovary and play a crucial role as facilitators of ovulation and luteal formation. In this article, recent findings on leukocyte trafficking to the ovary, as well as the physiological role of leukocytes in the ovary, will be summarized and discussed. We then explore the novel hypothesis that the hypothalamus-pituitary-ovary (HPO) axis might include the spleen as a reservoir of leukocytes by summarizing recent reports on this topic, both in the fields of immunology and reproductive biology.
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Affiliation(s)
- Oliver R Oakley
- Division of Clinical and Reproductive Sciences, Department of Clinical Sciences, College of Health Sciences, University of Kentucky, Lexington, Kentucky 40536, USA
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