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Noone DP, Isendoorn MME, Hamers SMWR, Keizer ME, Wulffelé J, van der Velden TT, Dijkstra DJ, Trouw LA, Filippov DV, Sharp TH. Structural basis for surface activation of the classical complement cascade by the short pentraxin C-reactive protein. Proc Natl Acad Sci U S A 2024; 121:e2404542121. [PMID: 39240968 PMCID: PMC11406272 DOI: 10.1073/pnas.2404542121] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/15/2024] [Accepted: 08/04/2024] [Indexed: 09/08/2024] Open
Abstract
Human C-reactive protein (CRP) is a pentameric complex involved in immune defense and regulation of autoimmunity. CRP is also a therapeutic target, with both administration and depletion of serum CRP being pursued as a possible treatment for autoimmune and cardiovascular diseases, among others. CRP binds to phosphocholine (PC) moieties on membranes to activate the complement system via the C1 complex, but it is unknown how CRP, or any pentraxin, binds to C1. Here, we present a cryoelectron tomography (cryoET)-derived structure of CRP bound to PC ligands and the C1 complex. To gain control of CRP binding, a synthetic mimotope of PC was synthesized and used to decorate cell-mimetic liposome surfaces. Structure-guided mutagenesis of CRP yielded a fully active complex able to bind PC-coated liposomes that was ideal for cryoET and subtomogram averaging. In contrast to antibodies, which form Fc-mediated hexameric platforms to bind and activate the C1 complex, CRP formed rectangular platforms assembled from four laterally associated CRP pentamers that bind only four of the six available globular C1 head groups. Potential residues mediating lateral association of CRP were identified from interactions between unit cells in existing crystal structures, which rationalized previously unexplained mutagenesis data regarding CRP-mediated complement activation. The structure also enabled interpretation of existing biochemical data regarding interactions mediating C1 binding and identified additional residues for further mutagenesis studies. These structural data therefore provide a possible mechanism for regulation of complement by CRP, which limits complement progression and has consequences for how the innate immune system influences autoimmunity.
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Affiliation(s)
- Dylan P. Noone
- Department of Cell and Chemical Biology, Leiden University Medical Center, 2300 RCLeiden, The Netherlands
| | - Marjolein M. E. Isendoorn
- Leiden Institute of Chemistry, Gorlaeus Laboratory, Leiden University, 2333 CCLeiden, The Netherlands
| | - Sebastiaan M. W. R. Hamers
- Department of Cell and Chemical Biology, Leiden University Medical Center, 2300 RCLeiden, The Netherlands
| | - Mariska E. Keizer
- Department of Cell and Chemical Biology, Leiden University Medical Center, 2300 RCLeiden, The Netherlands
| | - Jip Wulffelé
- Department of Cell and Chemical Biology, Leiden University Medical Center, 2300 RCLeiden, The Netherlands
| | - Tijn T. van der Velden
- Department of Cell and Chemical Biology, Leiden University Medical Center, 2300 RCLeiden, The Netherlands
| | - Douwe J. Dijkstra
- Department of Immunology, Leiden University Medical Center, 2333 ZALeiden, The Netherlands
| | - Leendert A. Trouw
- Department of Immunology, Leiden University Medical Center, 2333 ZALeiden, The Netherlands
| | - Dmitri V. Filippov
- Leiden Institute of Chemistry, Gorlaeus Laboratory, Leiden University, 2333 CCLeiden, The Netherlands
| | - Thomas H. Sharp
- Department of Cell and Chemical Biology, Leiden University Medical Center, 2300 RCLeiden, The Netherlands
- School of Biochemistry, University of Bristol, BristolBS8 1TD, United Kingdom
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Li QY, Lv JM, Liu XL, Li HY, Yu F. Association of C-reactive protein and complement factor H gene polymorphisms with risk of lupus nephritis in Chinese population. World J Clin Cases 2023; 11:2934-2944. [PMID: 37215422 PMCID: PMC10198093 DOI: 10.12998/wjcc.v11.i13.2934] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2022] [Revised: 10/25/2022] [Accepted: 02/21/2023] [Indexed: 04/25/2023] Open
Abstract
BACKGROUND Complement overactivation is a major driver of lupus nephritis (LN). Impaired interactions of C-reactive protein (CRP) with complement factor H (CFH) have been shown as a pathogenic mechanism that contributes to the overactivation of complement in LN. However, genetic variations of neither CRP nor CFH show consistent influences on the risk of LN.
AIM To examine whether genetic variations of CRP and CFH in combination can improve the risk stratification in Chinese population.
METHODS We genotyped six CRP single nucleotide polymorphisms (SNPs) (rs1205, rs3093062, rs2794521, rs1800947, rs3093077, and rs1130864) and three CFH SNPs (rs482934, rs1061170, and rs1061147) in 270 LN patients and 303 healthy subjects.
RESULTS No linkage was found among CRP and CFH SNPs, indicating lack of genetic interactions between the two genes. Moreover, CRP and CFH SNPs, neither individually nor in combination, are associated with the risk or clinical manifestations of LN. Given the unambiguous pathogenic roles of the two genes.
CONCLUSION These findings suggest that the biological effects of most genetic variations of CRP and CFH on their expressions or activities are not sufficient to influence the disease course of LN.
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Affiliation(s)
- Qiu-Yu Li
- Department of Respiratory and Critical Care Medicine, Peking University Third Hospital, Beijing 100191, China
| | - Jian-Min Lv
- School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an 710061, Shaanxi Province, China
| | - Xiao-Ling Liu
- School of Life Sciences, Lanzhou University, Lanzhou 730000, Gansu Province, China
| | - Hai-Yun Li
- School of Basic Medical Sciences, Xi’an Jiaotong University, Xi'an 710061, Shaanxi Province, China
| | - Feng Yu
- Department of Medicine, Peking University First Hospital, Beijing 100034, China
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Svanberg C, Enocsson H, Govender M, Martinsson K, Potempa LA, Rajab IM, Fernandez-Botran R, Wetterö J, Larsson M, Sjöwall C. Conformational state of C-reactive protein is critical for reducing immune complex-triggered type I interferon response: Implications for pathogenic mechanisms in autoimmune diseases imprinted by type I interferon gene dysregulation. J Autoimmun 2023; 135:102998. [PMID: 36706536 DOI: 10.1016/j.jaut.2023.102998] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2022] [Revised: 01/11/2023] [Accepted: 01/13/2023] [Indexed: 01/27/2023]
Abstract
Presence of autoantibodies targeting nuclear constituents, i.e., double-stranded DNA and small nuclear ribonucleoproteins (snRNPs), remain a cornerstone in systemic lupus erythematosus (SLE). Fcγ receptor IIa (FcγRIIa) dependent uptake of nucleic acid containing immune complexes (ICs) by plasmacytoid dendritic cells (PDCs) can activate toll-like receptors (TLRs) such as TLR7 and TLR9 resulting in type I interferon (IFN) production. Previously, the classical liver-derived acute-phase reactant C-reactive protein (CRP) has been suggested to reduce IC-induced type I IFN production, whereas monomeric (mCRP) vs. pentameric (pCRP) mediated effects have not yet been unraveled. Herein, peripheral blood mononuclear cells (PBMCs) or enriched blood DCs from healthy volunteers were stimulated with SLE sera, snRNP-IgG (ICs), or TLR ligands with or without pCRP, mCRP, or anti-FcγRIIa antibody. Type I IFNs and cytokine responses were investigated using quantitative PCR, ELISA, and flow cytometry. pCRP inhibited IFN gene expression in PBMCs and enriched DCs after incubation with ICs, compared to ICs alone, whereas mCRP had significantly less inhibitory effect. The effect was independent on the order in which IC or CRP was added to the cells. In addition, pCRP inhibited IFN induced by other TLR stimulators, implicating broader inhibitory effects induced by pCRP. We demonstrate pronounced immunoregulatory functions of CRP whereas the inhibitory properties were evidently dependent on CRP's intact conformational state. The inhibition of type I IFNs was not due to competition of FcγRs, or binding of CRP to the ICs. Our findings have implications for autoimmune IC-mediated conditions imprinted by type I IFN gene dysregulation.
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Affiliation(s)
- Cecilia Svanberg
- Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology, Linköping University, Linköping, Sweden
| | - Helena Enocsson
- Department of Biomedical and Clinical Sciences, Division of Inflammation & Infection, Linköping University, Linköping, Sweden
| | - Melissa Govender
- Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology, Linköping University, Linköping, Sweden
| | - Klara Martinsson
- Department of Biomedical and Clinical Sciences, Division of Inflammation & Infection, Linköping University, Linköping, Sweden
| | - Lawrence A Potempa
- Roosevelt University, College of Science, Health and Pharmacy, Schaumburg, IL, United States
| | - Ibraheem M Rajab
- Roosevelt University, College of Science, Health and Pharmacy, Schaumburg, IL, United States
| | - Rafael Fernandez-Botran
- Department of Pathology & Laboratory Medicine, University of Louisville, Louisville, KY, United States
| | - Jonas Wetterö
- Department of Biomedical and Clinical Sciences, Division of Inflammation & Infection, Linköping University, Linköping, Sweden
| | - Marie Larsson
- Department of Biomedical and Clinical Sciences, Division of Molecular Medicine and Virology, Linköping University, Linköping, Sweden
| | - Christopher Sjöwall
- Department of Biomedical and Clinical Sciences, Division of Inflammation & Infection, Linköping University, Linköping, Sweden.
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Friend SF, Nachnani R, Powell SB, Risbrough VB. C-Reactive Protein: Marker of risk for post-traumatic stress disorder and its potential for a mechanistic role in trauma response and recovery. Eur J Neurosci 2022; 55:2297-2310. [PMID: 33131159 PMCID: PMC8087722 DOI: 10.1111/ejn.15031] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/19/2020] [Revised: 09/17/2020] [Accepted: 10/06/2020] [Indexed: 01/08/2023]
Abstract
Increasing evidence indicates that inflammation plays a role in PTSD and stress disorder pathophysiology. PTSD is consistently associated with higher circulating inflammatory protein levels. Rodent models demonstrate that inflammation promotes enduring avoidance and arousal behaviors after severe stressors (e.g., predator exposure and social defeat), suggesting that inflammation may play a mechanistic role in trauma disorders. C-reactive protein (CRP) is an innate acute phase reactant produced by the liver after acute infection and chronic disease. A growing number of investigations report associations with PTSD diagnosis and elevated peripheral CRP, CRP gene mutations, and CRP gene expression changes in immune signaling pathways. CRP is reasonably established as a potential marker of PTSD and trauma exposure, but if and how it may play a mechanistic role is unclear. In this review, we discuss the current understanding of immune mechanisms in PTSD with a particular focus on the innate immune signaling factor, CRP. We found that although there is consistent evidence of an association of CRP with PTSD symptoms and risk, there is a paucity of data on how CRP might contribute to CNS inflammation in PTSD, and consequently, PTSD symptoms. We discuss potential mechanisms through which CRP could modulate enduring peripheral and CNS stress responses, along with future areas of investigation probing the role of CRP and other innate immune signaling factors in modulating trauma responses. Overall, we found that CRP likely contributes to central inflammation, but how it does so is an area for further study.
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Affiliation(s)
- Samantha F. Friend
- Veterans Affairs Center of Excellence for Stress and Mental HealthSan DiegoCAUSA
- Department of PsychiatryUniversity of California San DiegoSan DiegoCAUSA
| | - Rahul Nachnani
- Department of PharmacologyPenn State College of MedicineHersheyPAUSA
| | - Susan B. Powell
- Department of PsychiatryUniversity of California San DiegoSan DiegoCAUSA
- Research ServiceVA San Diego Healthcare SystemSan DiegoCAUSA
| | - Victoria B. Risbrough
- Veterans Affairs Center of Excellence for Stress and Mental HealthSan DiegoCAUSA
- Department of PsychiatryUniversity of California San DiegoSan DiegoCAUSA
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5
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Liu XR, Qi YY, Zhao YF, Cui Y, Wang XY, Zhao ZZ. Albumin-to-globulin ratio (AGR) as a potential marker of predicting lupus nephritis in Chinese patients with systemic lupus erythematosus. Lupus 2021; 30:412-420. [PMID: 33407045 DOI: 10.1177/0961203320981139] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/14/2023]
Abstract
OBJECTIVES To evaluate a potential role of albumin-to-globulin ratio (AGR) in the development of lupus nephritis (LN) and determine the potential to use AGR as a marker for future LN in systemic lupus erythematosus (SLE) patients. METHODS 194 newly diagnosed SLE patients without renal impairment were followed. The clinical data were collected and analyzed at the time of initial diagnosis of SLE and the end of follow-up. We compared baseline characteristics between those who did or did not develop LN on follow-up. Univariate and multivariate Cox hazard analysis were used to identify predictors of lupus nephritis. RESULTS Among the 194 newly diagnosed SLE patients without renal impairment, 26 (13.40%) patients were diagnosed with LN during a median follow-up of 53.87 months. On univariate Cox analysis, patients with the history of alopecia, higher SBP, lower AGR, lower CRP, lower C3, lower C4, higher anti-dsDNA Ab, presence of ANA homogeneous patterns or higher SLEDAI had an increased probability of developing LN. In a multivariate model, the history of alopecia (adjust hazard ratio, aHR = 3.614, 95%CI 1.365-9.571 P = 0.010), lower AGR (aHR = 6.968, 95%CI 1.873-25.919, P = 0.004), lower CRP (aHR = 4.230, 95%CI 1.591-11.247, P = 0.004) and higher level of anti-dsDNA (aHR = 2.675, 95%CI 1.008-7.093, P = 0.048) were independently associated with an increased risk of developing LN after adjusting for covariates. CONCLUSION Our findings indicated that SLE patients with low AGR, low CRP, high anti-dsDNA and the history of alopecia were more likely to develop LN in the course of SLE. AGR shown the greatest hazard for developing LN among them, it may be a strong predictor.
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Affiliation(s)
- Xin-Ran Liu
- Nephrology Hospital, The First Affiliated Hospital of Zhengzhou University, Henan, China.,Institute of Nephrology, Zhengzhou University, Henan, China
| | - Yuan-Yuan Qi
- Nephrology Hospital, The First Affiliated Hospital of Zhengzhou University, Henan, China.,Institute of Nephrology, Zhengzhou University, Henan, China
| | - Ya-Fei Zhao
- Nephrology Hospital, The First Affiliated Hospital of Zhengzhou University, Henan, China.,Institute of Nephrology, Zhengzhou University, Henan, China
| | - Yan Cui
- Nephrology Hospital, The First Affiliated Hospital of Zhengzhou University, Henan, China.,Institute of Nephrology, Zhengzhou University, Henan, China
| | - Xiao-Yang Wang
- Nephrology Hospital, The First Affiliated Hospital of Zhengzhou University, Henan, China.,Institute of Nephrology, Zhengzhou University, Henan, China
| | - Zhan-Zheng Zhao
- Nephrology Hospital, The First Affiliated Hospital of Zhengzhou University, Henan, China.,Institute of Nephrology, Zhengzhou University, Henan, China
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Perper SJ, Westmoreland SV, Karman J, Twomey R, Seagal J, Wang R, McRae BL, Clarke SH. Treatment with a CD40 Antagonist Antibody Reverses Severe Proteinuria and Loss of Saliva Production and Restores Glomerular Morphology in Murine Systemic Lupus Erythematosus. THE JOURNAL OF IMMUNOLOGY 2019; 203:58-75. [PMID: 31109957 DOI: 10.4049/jimmunol.1900043] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/11/2019] [Accepted: 04/29/2019] [Indexed: 12/28/2022]
Abstract
CD40 is a costimulatory receptor on APCs that is critical for the induction and maintenance of humoral and cell-mediated immunity. Accordingly, CD40 and its ligand, CD40L, have long been considered targets for the treatment of autoimmune diseases. We developed a rat/mouse chimeric anti-mouse CD40 antagonist mAb, 201A3, and evaluated its ability to alleviate murine lupus. Treatment of NZB/W-F1 mice with 201A3 after the onset of severe proteinuria rapidly reversed established severe proteinuria and nephritis and largely restored normal glomerular and tubular morphology. This coincided with a normalization of the expression of genes associated with proteinuria and injury by kidney parenchymal cells. Anti-CD40 treatment also prevented and reversed loss of saliva production and sialadenitis. These effects on kidney and salivary gland function were confirmed using mice of a second strain, MRL/Mp-lpr/lpr, and extended to alleviating joint inflammation. Immunologically, anti-CD40 treatment disrupted multiple processes that contribute to the pathogenesis of systemic lupus erythematosus (SLE), including autoreactive B cell activation, T effector cell function in target tissues, and type I IFN production. This ability to disrupt disease-critical immunological mechanisms, to reverse glomerular and tubular injury at the cellular and gene expression levels, and to confer exceptional therapeutic efficacy suggests that CD40 is a central disease pathway in murine SLE. Thus, a CD40 antagonist Ab could be an effective therapeutic in the treatment of SLE.
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Affiliation(s)
| | | | | | | | - Jane Seagal
- AbbVie Bioresearch Center, Worcester, MA 01605
| | - Rui Wang
- AbbVie Bioresearch Center, Worcester, MA 01605
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Toubi E, Vadasz Z. Innate immune-responses and their role in driving autoimmunity. Autoimmun Rev 2019; 18:306-311. [PMID: 30639645 DOI: 10.1016/j.autrev.2018.10.005] [Citation(s) in RCA: 60] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2018] [Accepted: 10/31/2018] [Indexed: 01/11/2023]
Abstract
Autoimmunity and autoimmune diseases were always considered to be driven mainly by adaptive immune responses, namely by auto-reactive B and T cell over-activity. The continuous stimulation of dendritic cells by autoantigens increases B cell activity, driving auto-reactive B cells to increase the production of autoantibodies and of pro-inflammatory cytokines. On the other hand, a subset of dendritic cells is established being of tolerogenic properties thus becoming important in maintaining self-tolerance. However, early innate immune responses are continuously appreciated to be highly important in the development of immune-mediated inflammation in general and autoimmunity in particular. The innate immune system is a complex network of structured cells/proteins such as antigen presenting cells (macrophages and dendritic cells), the complement cascade, and many receptors/cytokines/proteins. Of these, one may mention the high expression of toll-like receptors 7 and 9 in antigen presenting cells, and B cells of systemic lupus erythematosus patients contributing to the expansion of auto-reactive B cells. C-reactive protein (CRP) and C1q are crucially important for efficient uptake of apoptotic cells. However, CRP is appreciated to have a role in maintaining anti-inflammatory responses and in altering autoimmunity. Natural killer cells (NK) are responsible for cytotoxicity responses but some of them (mainly CD56high), are important in maintaining peripheral self-tolerance, thus considered to be immune-regulatory cells. In this review we will cover most of the new data on innate immune system and discuss its importance in the development of autoimmunity. New treatments were developed following our better understanding of these pathways, the targeting of which, opened new therapeutic avenues in treating autoimmune diseases.
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Affiliation(s)
- Elias Toubi
- Division of Allergy and Clinical Immunology, Bnai-Zion Medical Center, Faculty of Medicine, Technion, Haifa, Israel
| | - Zahava Vadasz
- Division of Allergy and Clinical Immunology, Bnai-Zion Medical Center, Faculty of Medicine, Technion, Haifa, Israel.
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Hahn BH, Kono DH. Animal Models in Lupus. DUBOIS' LUPUS ERYTHEMATOSUS AND RELATED SYNDROMES 2019:164-215. [DOI: 10.1016/b978-0-323-47927-1.00014-1] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Lu J, Mold C, Du Clos TW, Sun PD. Pentraxins and Fc Receptor-Mediated Immune Responses. Front Immunol 2018; 9:2607. [PMID: 30483265 PMCID: PMC6243083 DOI: 10.3389/fimmu.2018.02607] [Citation(s) in RCA: 59] [Impact Index Per Article: 8.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/11/2018] [Accepted: 10/23/2018] [Indexed: 12/27/2022] Open
Abstract
C-reactive protein (CRP) is a member of the pentraxin family of proteins. These proteins are highly conserved over the course of evolution being present as far back as 250 million years ago. Mammalian pentraxins are characterized by the presence of five identical non-covalently linked subunits. Each subunit has a structurally conserved site for calcium-dependent ligand binding. The biological activities of the pentraxins established over many years include the ability to mediate opsonization for phagocytosis and complement activation. Pentraxins have an important role in protection from infection from pathogenic bacteria, and regulation of the inflammatory response. It was recognized early on that some of these functions are mediated by activation of the classical complement pathway through C1q. However, experimental evidence suggested that cellular receptors for pentraxins also play a role in phagocytosis. More recent experimental evidence indicates a direct link between pentraxins and Fc receptors. The Fc receptors were first identified as the major receptors for immunoglobulins. The avidity of the interaction between IgG complexes and Fc receptors is greatly enhanced when multivalent ligands interact with the IgG binding sites and activation of signaling pathways requires Fc receptor crosslinking. Human pentraxins bind and activate human and mouse IgG receptors, FcγRI and FcγRII, and the human IgA receptor, FcαRI. The affinities of the interactions between Fc receptors and pentraxins in solution and on cell surfaces are similar to antibody binding to low affinity Fc receptors. Crystallographic and mutagenesis studies have defined the structural features of these interactions and determined the stoichiometry of binding as one-to-one. Pentraxin aggregation or binding to multivalent ligands increases the avidity of binding and results in activation of these receptors for phagocytosis and cytokine synthesis. This review will discuss the structural and functional characteristics of pentraxin Fc receptor interactions and their implications for host defense and inflammation.
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Affiliation(s)
- Jinghua Lu
- Structural Immunology Section, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, United States
| | - Carolyn Mold
- Department of Molecular Genetics and Microbiology, Albuquerque, NM, United States.,Department of Internal Medicine, University of New Mexico, Albuquerque, NM, United States
| | | | - Peter D Sun
- Structural Immunology Section, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, United States
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Chen HM, Lee LC, Hu KY, Tsai WJ, Huang C, Tsay HJ, Liu HK. The application of post-translational modification oriented serum proteomics to assess experimental diabetes with complications. PLoS One 2018; 13:e0206509. [PMID: 30395577 PMCID: PMC6218044 DOI: 10.1371/journal.pone.0206509] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/13/2018] [Accepted: 10/14/2018] [Indexed: 01/01/2023] Open
Abstract
Proteome analysis of serum from type 2 diabetics with complications may lead to the discovery of diagnostic or prognostic biomarkers. To circumvent the principal barrier of serum proteomics, our investigation aimed to evaluate whether a study of post-translational modification enriched serum proteins could be valuable for the discovery of biomarkers or metabolic pathways related to type 2 diabetes pathogenesis. Type 2 diabetes was induced from high-fat diet fed Sprague Dawley rats with streptozotocin injection. Once diabetic status was confirmed, serum samples from either fasted healthy or diabetic rats were pooled and profiled by two-dimensional difference gel electrophoresis or comparative 2D electrophoresis after protein enrichments using immobilized metal ion, concanavalin A, and lentil affinity chromatography, respectively. Differential expressed proteins were identified and the associated networks were established by an Ingenuity Pathway Analysis. As a result, induced rats became severe diabetic and accompanied by hyperlipidemia, fatty liver, and glomerular hypertrophy. There were 3 total, 14 phosphorylated and 23 glycosylated protein targets differentially expressed. Proteins could be linked to HNF4A, HNF1A, and NFκB transcriptional factors and antigen presentation, humoral immune response, and inflammatory response pathways. Predicted organ toxicity in kidney, heart, and liver matched with our histopathological results. In conclusion, post-translational modification based serum protein enrichment could be a valuable approach to enhance the resolution of serum proteomics without depleting potentially valuable abundant proteins. Our results also indicated the potential association of the hepatic secretome and hepatocyte nuclear factors in the pathogenesis of type 2 diabetes and its complications.
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Affiliation(s)
- Han-Min Chen
- Department of Life Science, Fu Jen Catholic University, New Taipei city, Taiwan, ROC
| | - Lin-Chien Lee
- Department of Physical Medicine and Rehabilitation, Cheng Hsin General Hospital, Taipei, Taiwan, ROC
| | - Kuang-Yu Hu
- Department of Biochemistry, National Defense Medical Center, Taipei, Taiwan, ROC
| | - Wei-Jern Tsai
- Division of Chinese Medicine Literature and Informatics, National Research Institute of Chinese Medicine, Ministry of Health and Welfare, Taipei, Taiwan, ROC
| | - Cheng Huang
- Department of Biotechnology and Laboratory Science in Medicine, National Yang-Ming University, Taipei, Taiwan, ROC
- Department of Earth and Life Sciences, University of Taipei, Taipei, Taiwan, ROC
| | - Hui-Jen Tsay
- Institute of Neuroscience, Brain Research Center, school of life science, National Yang-Ming University, Taipei, Taiwan, ROC
| | - Hui-Kang Liu
- Division of Basic Chinese Medicine, National Research Institute of Chinese Medicine, Ministry of Health and Welfare, Taipei, Taiwan, ROC
- Ph.D. Program in Clinical Drug Development of Chinese Herbal Medicine, Taipei Medical University, Taipei, Taiwan, ROC
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Kraus VB, Jordan JM. Article Commentary: Serum C-Reactive Protein (CRP), Target for Therapy or Trouble? Biomark Insights 2017. [DOI: 10.1177/117727190600100020] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
High sensitivity serum C-reactive protein (hs-CRP) has come into clinical use as a marker of risk for cardiovascular disease (CVD). In addition to a role as a marker of disease, CRP has also been implicated in the pathogenesis of CVD. Specific small-molecule inhibitors of CRP have recently been developed with the intent of mitigating cardiac damage during acute myocardial infarction. However, the use of CRP, both as a risk marker and a disease target are controversial for several reasons. Serum hs-CRP concentrations can be elevated on the basis of genetics, female gender, and non-Caucasian ethnicity. It is not clear, in these contexts, that elevations of hs-CRP have any pathological significance. As a non-specific indicator of inflammation, CRP is also not a specific indicator of a single disease state such as cardiovascular disease but elevated concentrations can be seen in association with other comorbidities including obesity and pulmonary disease. In sharp contrast to the proposed inhibition of CRP for cardiovascular disease treatment, the infusion of CRP has been shown to have profound therapeutic benefits for autoimmune disease and septic shock. The balance between the risks and benefits of these competing views of the role of CRP in disease and disease therapy is reminiscent of the ongoing controversy regarding the use of non-steroidal anti-inflammatory drugs (NSAIDs) for musculoskeletal disease and their cardiovascular side effects. Soon, NSAIDs may not be the only agents about which Rheumatologists and Cardiologists may spar.
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Affiliation(s)
| | - Joanne M. Jordan
- Thurston Arthritis Research Center, University of North Carolina, Chapel Hill, NC 27599
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12
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Monocyte differentiation and macrophage priming are regulated differentially by pentraxins and their ligands. BMC Immunol 2017; 18:30. [PMID: 28619036 PMCID: PMC5472910 DOI: 10.1186/s12865-017-0214-z] [Citation(s) in RCA: 25] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2017] [Accepted: 06/08/2017] [Indexed: 01/01/2023] Open
Abstract
Background Circulating bone marrow-derived monocytes can leave the blood, enter a tissue, and differentiate into M1 inflammatory, M2a remodeling/fibrotic, or M2c/Mreg resolving/immune-regulatory macrophages. Macrophages can also convert from one of the above types to another. Pentraxins are secreted proteins that bind to, and promote efficient clearance of, microbial pathogens and cellular debris during infection, inflammation, and tissue damage. The pentraxins C-reactive protein (CRP), serum amyloid P (SAP), and pentraxin-3 (PTX3) can also bind a variety of endogenous ligands. As monocytes and macrophages are exposed to differing concentrations of pentraxins and their ligands during infection, inflammation, and tissue damage, we assessed what effect pentraxins and their ligands have on these cells. Results We found that many polarization markers do not discriminate between the effects of pentraxins and their ligands on macrophages. However, pentraxins, their ligands, and cytokines differentially regulate the expression of the hemoglobin-haptoglobin complex receptor CD163, the sialic acid-binding lectin CD169, and the macrophage mannose receptor CD206. CRP, a pentraxin generally thought of as being pro-inflammatory, increases the extracellular accumulation of the anti-inflammatory cytokine IL-10, and this effect is attenuated by GM-CSF, mannose-binding lectin, and factor H. Conclusions These results suggest that the presence of pentraxins and their ligands regulate macrophage differentiation in the blood and tissues, and that CRP may be a potent inducer of the anti-inflammatory cytokine IL-10. Electronic supplementary material The online version of this article (doi:10.1186/s12865-017-0214-z) contains supplementary material, which is available to authorized users.
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13
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Delongui F, Lozovoy MAB, Iriyoda TMV, Costa NT, Stadtlober NP, Alfieri DF, Flauzino T, Dichi I, Simão ANC, Reiche EMV. C-reactive protein +1444CT (rs1130864) genetic polymorphism is associated with the susceptibility to systemic lupus erythematosus and C-reactive protein levels. Clin Rheumatol 2017; 36:1779-1788. [DOI: 10.1007/s10067-017-3695-5] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2016] [Revised: 04/24/2017] [Accepted: 05/18/2017] [Indexed: 02/02/2023]
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14
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Li QY, Li HY, Fu G, Yu F, Wu Y, Zhao MH. Autoantibodies against C-Reactive Protein Influence Complement Activation and Clinical Course in Lupus Nephritis. J Am Soc Nephrol 2017; 28:3044-3054. [PMID: 28566480 DOI: 10.1681/asn.2016070735] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2016] [Accepted: 04/12/2017] [Indexed: 12/14/2022] Open
Abstract
Autoantibodies against the major acute-phase reactant C-reactive protein (CRP) are frequently found in patients with lupus nephritis. Further defining the autoimmune epitopes on CRP may not only improve patient stratification but also, hint at mechanisms of CRP action. Herein, we show that amino acids 35-47 constitute the major epitope recognized by anti-CRP autoantibodies in patients with lupus nephritis. Notably, the presence of autoantibodies against amino acids 35-47 associated with more severe renal damage and predicted worse outcome. This epitope is exposed on CRP only after irreversible structure changes, yielding a conformationally altered form termed modified or monomeric CRP (mCRP). ELISA and surface plasmon resonance assays showed that amino acids 35-47 mediate the interaction of mCRP with complement factor H, an inhibitor of alternative pathway activation, and this interaction greatly enhanced the in vitro cofactor activity of complement factor H. In contrast, autoantibodies against amino acids 35-47 inhibited these actions of mCRP. Our results thus provide evidence for the in vivo generation of mCRP in a human disease and suggest that mCRP actively controls the pathogenesis of lupus nephritis by regulating complement activation. Therefore, amino acids 35-47 constitute a functional autoimmune epitope on CRP that can be targeted therapeutically and diagnostically.
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Affiliation(s)
- Qiu-Yu Li
- Renal Division, Department of Medicine, Peking University First Hospital, Beijing, People's Republic of China.,Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, People's Republic of China.,Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China, Beijing, People's Republic of China.,Department of Pneumology, Peking University Third Hospital, Beijing, People's Republic of China
| | - Hai-Yun Li
- Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shanxi, People's Republic of China
| | - Ge Fu
- State Key Laboratory of Natural and Biomimetic Drugs, Department of Chemical Biology, School of Pharmaceutical Science, Peking University, Beijing, People's Republic of China
| | - Feng Yu
- Renal Division, Department of Medicine, Peking University First Hospital, Beijing, People's Republic of China; .,Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, People's Republic of China.,Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China, Beijing, People's Republic of China.,Department of Nephrology, Peking University International Hospital, Beijing, People's Republic of China; and
| | - Yi Wu
- Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, School of Basic Medical Sciences, Xi'an Jiaotong University, Xi'an, Shanxi, People's Republic of China;
| | - Ming-Hui Zhao
- Renal Division, Department of Medicine, Peking University First Hospital, Beijing, People's Republic of China.,Key Laboratory of Renal Disease, Ministry of Health of China, Beijing, People's Republic of China.,Key Laboratory of CKD Prevention and Treatment, Ministry of Education of China, Beijing, People's Republic of China.,Peking-Tsinghua Center for Life Sciences, Beijing, People's Republic of China
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15
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Swisher JFA, Feldman GM. The many faces of FcγRI: implications for therapeutic antibody function. Immunol Rev 2016; 268:160-74. [PMID: 26497519 DOI: 10.1111/imr.12334] [Citation(s) in RCA: 34] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Fcγ receptor I (FcγRI or CD64) is the sole human Fc receptor with high affinity for monovalent IgG. While it contains an immunoreceptor tyrosine-based activation motif in its cytoplasmic domain, binding of FcγRI can result in a complex array of activating and inhibitory outcomes. For instance, binding of monomeric IgG provides a low-intensity tonic signal through FcγRI that is necessary for full interferon γ receptor signaling in the same cell. Interaction of FcγRI with larger high-avidity complexes can result in phagocytosis, the generation of reactive oxygen species, as well as the synthesis and release of inflammatory cytokines. However, numerous reports also document potent anti-inflammatory effects brought about by FcγRI engagement with immune complexes such as the inhibition of IFNγ and TLR4 signaling, and secretion of interleukin-10. This has led to conflicting hypotheses regarding the function of FcγRI, especially with regard to its role in the efficacy of several therapeutic monoclonal antibodies. While many of these issues are still unclear, continued characterization of the regulation and context dependence of FcγRI function, as well as the molecular mechanisms responsible for these various outcomes, will improve our understanding of FcγRI biology as well as the therapeutic strategies designed to harness or constrain its actions.
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Affiliation(s)
- Jennifer F A Swisher
- Laboratory of Immunobiology, Division of Biotechnology Research and Review IV, Office of Biotechnology Products, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA
| | - Gerald M Feldman
- Laboratory of Immunobiology, Division of Biotechnology Research and Review IV, Office of Biotechnology Products, Center for Drug Evaluation and Research, Food and Drug Administration, Silver Spring, MD, USA
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16
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Zhang L, Liu SH, Wright TT, Shen ZY, Li HY, Zhu W, Potempa LA, Ji SR, Szalai AJ, Wu Y. C-reactive protein directly suppresses Th1 cell differentiation and alleviates experimental autoimmune encephalomyelitis. THE JOURNAL OF IMMUNOLOGY 2015; 194:5243-52. [PMID: 25917100 DOI: 10.4049/jimmunol.1402909] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 11/19/2014] [Accepted: 03/30/2015] [Indexed: 01/14/2023]
Abstract
Human C-reactive protein (CRP) is a serum-soluble pattern recognition receptor that serves as a marker of inflammation and directly contributes to innate immunity. In this study, we show that human CRP also directly contributes to adaptive immunity, that is, native CRP binds specifically to human Jurkat T cells and to mouse naive CD4(+) T cells and modulates their Th1 and Th2 responses. In vitro both exogenously added (purified) and endogenously expressed (via transfection) human CRP inhibited Th1 differentiation and augmented Th2 differentiation of naive CD4(+) T cells. In vivo for human CRP transgenic compared with wild-type mice, a lesser proportion of the T cells recovered from the spleens of healthy animals were Th1 cells. Moreover, in both CRP transgenic mice and in wild-type mice treated with human CRP, during myelin oligodendrocyte glycoprotein peptide-induced experimental autoimmune encephalomyelitis both the Th1 cell response and disease severity were inhibited. These pattern recognition-independent actions of CRP directly on T cells highlights the potential for this soluble pattern recognition receptor to act as a tonic regulator of immunity, shaping global adaptive immune responses during both homeostasis and disease.
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Affiliation(s)
- Lin Zhang
- Ministry of Education Key Laboratory of Cell Activities and Stress Adaptations, School of Life Sciences, Lanzhou University, Lanzhou 730000, People's Republic of China
| | - Shan-Hui Liu
- Ministry of Education Key Laboratory of Cell Activities and Stress Adaptations, School of Life Sciences, Lanzhou University, Lanzhou 730000, People's Republic of China
| | - Tyler T Wright
- Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, AL 35294
| | - Zhi-Yuan Shen
- Ministry of Education Key Laboratory of Cell Activities and Stress Adaptations, School of Life Sciences, Lanzhou University, Lanzhou 730000, People's Republic of China
| | - Hai-Yun Li
- Ministry of Education Key Laboratory of Cell Activities and Stress Adaptations, School of Life Sciences, Lanzhou University, Lanzhou 730000, People's Republic of China
| | - Wei Zhu
- Second Hospital of Lanzhou University, Lanzhou 730030, People's Republic of China
| | - Lawrence A Potempa
- Department of Biopharmaceutical Sciences, Roosevelt University College of Pharmacy, Schaumburg, IL 60173; and
| | - Shang-Rong Ji
- Ministry of Education Key Laboratory of Cell Activities and Stress Adaptations, School of Life Sciences, Lanzhou University, Lanzhou 730000, People's Republic of China;
| | - Alexander J Szalai
- Division of Clinical Immunology and Rheumatology, University of Alabama at Birmingham, Birmingham, AL 35294;
| | - Yi Wu
- Ministry of Education Key Laboratory of Cell Activities and Stress Adaptations, School of Life Sciences, Lanzhou University, Lanzhou 730000, People's Republic of China; Key Laboratory of Preclinical Study for New Drugs of Gansu Province, Lanzhou University, Lanzhou 730000, People's Republic of China
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17
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Jung JY, Suh CH. Incomplete clearance of apoptotic cells in systemic lupus erythematosus: pathogenic role and potential biomarker. Int J Rheum Dis 2015; 18:294-303. [PMID: 25884792 DOI: 10.1111/1756-185x.12568] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/29/2022]
Abstract
Systemic lupus erythematosus (SLE) is a chronic autoimmune disease with repeated inflammation against multiple organs. Although its pathophysiology is not yet unveiled, uncleared apoptotic cells and their accumulation in tissue contribute to the autoimmune disturbance in SLE. Apoptosis is a programmed cell death process, which maintains tissue homeostasis and inhibits the development of any further immune response against apoptotic remnants. Earlier studies revealed that various 'eat-me' signals on apoptotic cells, bridging molecules and their receptors on phagocytes play a role in such a complicated process. Tyro3-Axl-Mer receptors, their bridging molecules, milk fat globulin epidermal growth factor-8, T-cell immunoglobulin mucin domain protein family, scavenger receptors, C1q, and pentraxins were found to be abnormal in SLE. In this review, apoptosis and clearance of its remnants are summarized, and the molecules involved in the incomplete clearance of apoptotic cells in SLE are discussed.
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Affiliation(s)
- Ju-Yang Jung
- Department of Rheumatology, Ajou University School of Medicine, Suwon, Korea
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18
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Dorta-Estremera SM, Cao W. Human Pentraxins Bind to Misfolded Proteins and Inhibit Production of Type I Interferon Induced by Nucleic Acid-Containing Amyloid. JOURNAL OF CLINICAL & CELLULAR IMMUNOLOGY 2015; 6. [PMID: 31080694 DOI: 10.4172/2155-9899.1000332] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
Abstract
Objective Amyloid deposition is linked to multiple human ailments, including neurodegenerative diseases, type 2 diabetes, and systemic amyloidosis. The assembly of misfolded proteins into amyloid fibrils involves an intermediate form, i.e., soluble amyloid precursor (AP), which exerts cytotoxic function. Insoluble amyloid also stimulates innate immune cells to elicit cytokine response and inflammation. How any of these misfolded proteins are controlled by the host remains obscure. Serum amyloid-P component (SAP) is a universal constituent of amyloid deposits. Short-chain pentraxins, which include both SAP and C-reactive protein (CRP), are pattern recognition molecules that bind to diverse ligands and promote the clearance of microbes and cell debris. Whether these pentraxins interact with AP and cofactor-containing amyloid and subsequently impact their function is not known. Methods and Results To detect the interaction between SAP and different types of amyloids, we performed dot blot analysis. The results showed that SAP invariably bound to protein-only, nucleic acid-containing and glycosaminoglycan-containing amyloid fibrils. This interaction required the presence of calcium. By ELISA, both SAP and CRP bound to soluble AP in the absence of divalent cations. Further characterization, by gel filtration, implied that SAP decamer may recognize AP whereas aggregated SAP preferentially associates with amyloid fibril. Although SAP binding did not affect cytotoxic function of AP, SAP potently inhibited the production of interferon-α from human plasmacytoid dendritic cells triggered by DNA-containing amyloid. Conclusions Our data suggest that short pentraxins differentially interact with various forms of misfolded proteins and, in particular, modulate the ability of nucleic acid-containing amyloid to stimulate aberrant type I interferon response. Hence, pentraxins may function as key players in modulating the pathogenesis of protein misfolding diseases as well as interferon-mediated autoimmune manifestation.
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Affiliation(s)
- Stephanie M Dorta-Estremera
- Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.,The University of Texas Graduate School of Biomedical Sciences, Houston, TX 77030, USA
| | - Wei Cao
- Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA.,The University of Texas Graduate School of Biomedical Sciences, Houston, TX 77030, USA
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19
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Mutations of C-reactive protein (CRP) -286 SNP, APC and p53 in colorectal cancer: implication for a CRP-Wnt crosstalk. PLoS One 2014; 9:e102418. [PMID: 25025473 PMCID: PMC4099363 DOI: 10.1371/journal.pone.0102418] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2014] [Accepted: 06/18/2014] [Indexed: 11/19/2022] Open
Abstract
C-reactive protein (CRP) is an established marker of inflammation with pattern-recognition receptor-like activities. Despite the close association of the serum level of CRP with the risk and prognosis of several types of cancer, it remains elusive whether CRP contributes directly to tumorigenesis or just represents a bystander marker. We have recently identified recurrent mutations at the SNP position -286 (rs3091244) in the promoter of CRP gene in several tumor types, instead suggesting that locally produced CRP is a potential driver of tumorigenesis. However, it is unknown whether the -286 site is the sole SNP position of CRP gene targeted for mutation and whether there is any association between CRP SNP mutations and other frequently mutated genes in tumors. Herein, we have examined the genotypes of three common CRP non-coding SNPs (rs7553007, rs1205, rs3093077) in tumor/normal sample pairs of 5 cancer types (n = 141). No recurrent somatic mutations are found at these SNP positions, indicating that the -286 SNP mutations are preferentially selected during the development of cancer. Further analysis reveals that the -286 SNP mutations of CRP tend to co-occur with mutated APC particularly in rectal cancer (p = 0.04; n = 67). By contrast, mutations of CRP and p53 or K-ras appear to be unrelated. There results thus underscore the functional importance of the -286 mutation of CRP in tumorigenesis and imply an interaction between CRP and Wnt signaling pathway.
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20
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Ramirez GA, Maugeri N, Sabbadini MG, Rovere-Querini P, Manfredi AA. Intravascular immunity as a key to systemic vasculitis: a work in progress, gaining momentum. Clin Exp Immunol 2014; 175:150-66. [PMID: 24128276 DOI: 10.1111/cei.12223] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/07/2013] [Indexed: 01/06/2023] Open
Abstract
Vascular inflammation contributes to the defence against invading microbes and to the repair of injured tissues. In most cases it resolves before becoming apparent. Vasculitis comprises heterogeneous clinical entities that are characterized by the persistence of vascular inflammation after it has served its homeostatic function. Most underlying mechanisms have so far remained elusive. Intravascular immunity refers to the surveillance of the vasculature by leucocytes that sense microbial or sterile threats to vessel integrity and initiate protective responses that entail most events that determine the clinical manifestations of vasculitis, such as end-organ ischaemia, neutrophil extracellular traps generation and thrombosis, leucocyte extravasation and degranulation. Understanding how the resolution of vascular inflammation goes awry in patients with systemic vasculitis will facilitate the identification of novel pharmacological targets and bring us a step closer in each patient to the selection of more effective and less toxic treatments.
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Affiliation(s)
- G A Ramirez
- Istituto Scientifico San Raffaele and Università Vita Salute San Raffaele, Milano, Italy
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21
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Agassandian M, Shurin GV, Ma Y, Shurin MR. C-reactive protein and lung diseases. Int J Biochem Cell Biol 2014; 53:77-88. [PMID: 24853773 DOI: 10.1016/j.biocel.2014.05.016] [Citation(s) in RCA: 60] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2014] [Revised: 05/06/2014] [Accepted: 05/07/2014] [Indexed: 12/13/2022]
Abstract
C-reactive protein (CRP), a member of the pentraxin family of plasma proteins, is one of the most distinctive acute phase reactants. In response to inflammation, cell damage or tissue injury, plasma level of CRP rapidly and dramatically increases up to 1000-fold, a phenomenon that has been used for years to monitor infections and many destructive/inflammatory conditions. The magnitude of CRP increase usually correlates with the severity of injury or inflammation and reflects an important physiological role of this interesting but still under-investigated protein. It is now generally accepted that CRP is involved in host defense and inflammation. However, the exact function of this protein in health and disease remains unclear. Many studies have demonstrated that in different pathophysiological conditions CRP might be involved in the regulation of lung function and may participate in the pathogenesis of various pulmonary disorders. The fluctuation of CRP concentrations in both alveolar fluid and serum associated with different pulmonary diseases suggests its important role in lung biology. Discussion of the still controversial functions of CRP in lung physiology and diseases is the main focus of this review.
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Affiliation(s)
- Marianna Agassandian
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
| | - Galina V Shurin
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Yang Ma
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
| | - Michael R Shurin
- Department of Pathology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA; Department of Immunology, University of Pittsburgh Medical Center, Pittsburgh, PA, USA
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22
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Du Clos TW. Pentraxins: structure, function, and role in inflammation. ISRN INFLAMMATION 2013; 2013:379040. [PMID: 24167754 PMCID: PMC3791837 DOI: 10.1155/2013/379040] [Citation(s) in RCA: 163] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/30/2013] [Accepted: 08/19/2013] [Indexed: 12/03/2022]
Abstract
The pentraxins are an ancient family of proteins with a unique architecture found as far back in evolution as the Horseshoe crab. In humans the two members of this family are C-reactive protein and serum amyloid P. Pentraxins are defined by their sequence homology, their pentameric structure and their calcium-dependent binding to their ligands. Pentraxins function as soluble pattern recognition molecules and one of the earliest and most important roles for these proteins is host defense primarily against pathogenic bacteria. They function as opsonins for pathogens through activation of the complement pathway and through binding to Fc gamma receptors. Pentraxins also recognize membrane phospholipids and nuclear components exposed on or released by damaged cells. CRP has a specific interaction with small nuclear ribonucleoproteins whereas SAP is a major recognition molecule for DNA, two nuclear autoantigens. Studies in autoimmune and inflammatory disease models suggest that pentraxins interact with macrophage Fc receptors to regulate the inflammatory response. Because CRP is a strong acute phase reactant it is widely used as a marker of inflammation and infection.
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Affiliation(s)
- Terry W. Du Clos
- The Department of Veterans Affairs Medical Center, Research Service 151, 1501 San Pedro SE, Albuquerque, NM 87108, USA
- Department of Internal Medicine, The University of New Mexico School of Medicine, Albuquerque, NM 87108, USA
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23
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Mold C, Clos TWD. C-reactive protein inhibits plasmacytoid dendritic cell interferon responses to autoantibody immune complexes. ACTA ACUST UNITED AC 2013; 65:1891-901. [PMID: 23576062 DOI: 10.1002/art.37968] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/02/2012] [Accepted: 04/04/2013] [Indexed: 02/02/2023]
Abstract
OBJECTIVE C-reactive protein (CRP) is a serum pattern recognition molecule that binds to apoptotic cells and nucleoprotein autoantigens and Fcγ receptors (FcγR). In systemic lupus erythematosus (SLE), immune complexes (ICs) containing nucleoprotein autoantigens activate plasmacytoid dendritic cells (PDCs) to produce type I interferon (IFN), which contributes to disease pathogenesis. Autoantibody ICs are taken up by PDCs through FcγR type IIa into endosomes, where the nucleic acid components activate Toll-like receptor 7 (TLR-7) or TLR-9. The objective of this study was to investigate the effect of CRP on PDC and monocyte responses to nucleoprotein autoantigens and ICs. METHODS Peripheral blood mononuclear cells (PBMCs), purified monocytes, and PDCs were isolated from healthy volunteers and stimulated with autoantibody ICs containing apoptotic cells, small nuclear RNPs (snRNPs), or DNA, or directly with TLR-7 and TLR-9 agonists. Supernatants were analyzed for IFNα and cytokine levels by enzyme-linked immunosorbent assay and multiplex assay. Small nuclear RNPs were fluorescence-labeled, and the effect of CRP on binding, uptake, and intracellular localization of autoantibody snRNP complexes was measured by flow cytometry and confocal microscopy. RESULTS CRP bound to autoantigen did not induce IFNα in PBMCs or PDCs, whereas complexes formed with autoantibody did. Significantly, CRP inhibited the IFNα response to both anti-U1 RNP-snRNP complexes and anti-DNA-DNA complexes, but not to other TLR-7 and TLR-9 agonists. CRP directly inhibited PDC IFNα release, promoted PDC differentiation, and increased late endosome localization of autoantigen in PDCs and monocytes. CONCLUSION CRP is a regulator of the type I IFN response to SLE ICs. CRP increased the intracellular processing of ICs in late endosomes, which is associated with decreased synthesis of type I IFN after intracellular TLR activation.
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Affiliation(s)
- Carolyn Mold
- University of New Mexico Health Sciences Center, Albuquerque, NM, USA.
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Abrams ST, Zhang N, Dart C, Wang SS, Thachil J, Guan Y, Wang G, Toh CH. Human CRP defends against the toxicity of circulating histones. THE JOURNAL OF IMMUNOLOGY 2013; 191:2495-502. [PMID: 23894199 DOI: 10.4049/jimmunol.1203181] [Citation(s) in RCA: 103] [Impact Index Per Article: 8.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/19/2023]
Abstract
C-reactive protein (CRP) is an acute-phase protein that plays an important defensive role in innate immunity against bacterial infection, but it is also upregulated in many noninfectious diseases. The generic function of this highly conserved molecule in diseases that range from infection, inflammation, trauma, and malignancy is not well understood. In this article, we demonstrate that CRP defends the human body against the toxicity of histones released into the circulation after extensive cell death. In vitro, CRP significantly alleviates histone-induced endothelial cell damage, permeability increase, and platelet aggregation. In vivo, CRP rescues mice challenged with lethal doses of histones by inhibiting endothelial damage, vascular permeability, and coagulation activation, as reflected by significant reductions in lung edema, hemorrhage, and thrombosis. In patients, elevation of CRP significantly increases the capacity to neutralize extracellular histones in the circulation. We have also confirmed that CRP interacts with individual histones in vitro and forms CRP-histone complexes in serum from patients with both elevated CRP and histones. CRP is able to compete with phospholipid-containing liposomes for the binding to histones. This explains how CRP prevents histones from integrating into cell membranes, which would otherwise induce calcium influx as the major mechanism of cytotoxicity caused by extracellular histones. Because histone elevation occurs in the acute phase of numerous critical illnesses associated with extensive cell death, CRP detoxification of circulating histones would be a generic host defense mechanism in humans.
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Affiliation(s)
- Simon T Abrams
- Department of Blood Sciences, Royal Liverpool and Broadgreen University Hospitals National Health Service Trust, Liverpool L7 8XP, United Kingdom
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25
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Aggarwal A, Agarwal V. C-reactive protein and systemic lupus erythematosus: What is their association? INDIAN JOURNAL OF RHEUMATOLOGY 2013; 8:59-60. [DOI: 10.1016/j.injr.2013.04.006] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/26/2022] Open
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26
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Lech M, Rommele C, Anders HJ. Pentraxins in nephrology: C-reactive protein, serum amyloid P and pentraxin-3. Nephrol Dial Transplant 2012; 28:803-11. [PMID: 23243042 DOI: 10.1093/ndt/gfs448] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022] Open
Abstract
Every clinician uses C-reactive protein (CRP) levels as a biomarker for systemic inflammation in acute disorders. Nephrologists also consider CRP levels as a predictor for overall mortality in patients with chronic kidney disease or end-stage renal disease. But what is the biological function of CRP? CRP is a member of the family of pentraxins, which are small pentameric innate immunity effector proteins. Pentraxins are absent or weakly expressed during homeostasis. However, the pro-inflammatory cytokines interleukin (IL)-1, IL-6 and tumour necrosis factor induce CRP and serum amyloid P (SAP) in hepatocytes, whereas the long pentraxins, such as pentraxin (PTX)-3, are produced in peripheral tissues and monocytic phagocytes. Pentraxins opsonize pathogens or other particles such as dead cells, for their phagocytic clearance or induce pathogen killing in extracellular compartments. In this review, we discuss the immunoregulatory properties of the different members of the pentraxin family. We discuss the evolving evidence demonstrating their roles in acute and chronic forms of kidney disease and the significance of SAP and PTX3 as additional biomarkers of innate immune activation and systemic inflammation.
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Affiliation(s)
- Maciej Lech
- Medizinische Klinik und Poliklinik IV, Campus Innenstadt, University of Munich-LMU, Ziemssenstr 1 D-80336, Munich, Germany
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27
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Abstract
Pentraxins are innate pattern recognition molecules whose major function is to bind microbial pathogens or cellular debris during infection and inflammation and, by doing so, contribute to the clearance of necrotic cells as well as pathogens through complement activations. Fc receptors are the cellular mediators of antibody functions. Although conceptually separated, both pentraxins and antibodies are important factors in controlling acute and chronic inflammation and infections. In recent years, increasing experimental evidence suggests a direct link between the innate pentraxins and humoral Fc receptors. Specifically, both human and mouse pentraxins recognize major forms of Fc receptors in solution and on cell surfaces with affinities similar to antibodies binding to their low affinity Fc receptors. Like immune complex, pentraxin aggregation and opsonization of pathogen result in Fc receptor and macrophage activation. The recently published crystal structure of human serum amyloid P (SAP) in complex with FcγRIIA further illustrated similarities to antibody recognition. These recent findings implicate a much broader role than complement activation for pentraxins in immunity. This review summarizes the structural and functional work that bridge the innate pentraxins and the adaptive Fc receptor functions. In many ways, pentraxins can be regarded as innate antibodies.
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Affiliation(s)
- Jinghua Lu
- Structural Immunology Section, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, USA
| | - Kristopher D. Marjon
- Department of Internal Medicine and Department of Molecular Genetics and Microbiology, University of New Mexico, Albuquerque, NM, USA
| | - Carolyn Mold
- Department of Internal Medicine and Department of Molecular Genetics and Microbiology, University of New Mexico, Albuquerque, NM, USA
| | - Terry W. Du Clos
- Department of Internal Medicine and Department of Molecular Genetics and Microbiology, University of New Mexico, Albuquerque, NM, USA
- VA Medical Center, Albuquerque, NM, USA
| | - Peter D. Sun
- Structural Immunology Section, Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, USA
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28
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Herraiz S, Pellicer B, Serra V, Cauli O, Cortijo J, Felipo V, Pellicer A. Sildenafil citrate improves perinatal outcome in fetuses from pre-eclamptic rats. BJOG 2012; 119:1394-402. [DOI: 10.1111/j.1471-0528.2012.03430.x] [Citation(s) in RCA: 60] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/30/2022]
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29
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Zhang W, Cai Y, Xu W, Xiong S. C-reactive protein functions as a negative regulator of macrophage activation induced by apoptotic DNA. Protein Cell 2011; 2:672-9. [PMID: 21904982 DOI: 10.1007/s13238-011-1084-4] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2011] [Accepted: 08/08/2011] [Indexed: 01/25/2023] Open
Abstract
C-reactive protein (CRP), an acute-phase protein with an ability to bind to nuclear antigen, has been reported to regulate cytokine secretion and modulate immune responses. We previously reported that activated syngeneic lymphocyte-derived apoptotic DNA (apopDNA) could induce macrophage activation and contribute to the initiation and progression of lupus nephritis. It is reasonable to hypothesize that CRP might regulate apopDNA-induced macrophage activation. Herein, CRP was shown to promote macrophage-mediated apopDNA uptake by binding to apopDNA (CRP/apopDNA complex). Notably, CRP/apopDNA treatment inhibited the production of inflammatory cytokines and chemokines by macrophages which could be induced by apopDNA alone. Further coculture and transwell studies revealed that CRP/apopDNA-induced macrophages prohibited apopDNA-induced macrophage activation in an IL-10 dependent manner. These results provide insight into the potential mechanism of CRP regulatory activity in macrophage activation induced by apopDNA in the context of lupus nephritis and other autoimmune diseases.
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Affiliation(s)
- Weijuan Zhang
- Institute for Immunobiology and Department of Immunology, Shanghai Medical College, Fudan University, Shanghai 200032, China
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Rhodes B, Fürnrohr BG, Vyse TJ. C-reactive protein in rheumatology: biology and genetics. Nat Rev Rheumatol 2011; 7:282-9. [DOI: 10.1038/nrrheum.2011.37] [Citation(s) in RCA: 146] [Impact Index Per Article: 10.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/09/2022]
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Sule S, Rosen A, Petri M, Akhter E, Andrade F. Abnormal production of pro- and anti-inflammatory cytokines by lupus monocytes in response to apoptotic cells. PLoS One 2011; 6:e17495. [PMID: 21423726 PMCID: PMC3056659 DOI: 10.1371/journal.pone.0017495] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/08/2010] [Accepted: 02/07/2011] [Indexed: 11/27/2022] Open
Abstract
Monocytes are a key component of the innate immune system involved in the regulation of the adaptive immune response. Previous studies have focused on apoptotic cell clearance abnormalities in systemic lupus erythematosus (SLE) monocytes. However, whether SLE monocytes might express unique patterns of cytokine secretion in response to apoptotic cells is still unknown. Here, we used monocytes from healthy controls and SLE patients to evaluate the production of TNF-α and TGF-β in response to apoptotic cells. Upon recognition of apoptotic material, monocytes from healthy controls showed prominent TGF-β secretion (mean ± SD: 824.6±144.3 pg/ml) and minimal TNF-α production (mean ± SD: 32.6±2.1 pg/ml). In contrast, monocytes from SLE patients had prominent TNF-α production (mean ± SD: 302.2±337.5 pg/ml) and diminished TGF-β secretion (mean ± SD: 685.9±615.9 pg/ml), a difference that was statistically significant compared to normal monocytes (p≤10(-6) for TNF-α secretion, and p = 0.0031 for TGF-β, respectively). Interestingly, the unique cytokine response by SLE monocytes was independent of their phagocytic clearance efficiency, opsonizing autoantibodies and disease activity. We further showed that nucleic acids from apoptotic cells play important role in the induction of TNF-α by lupus monocytes. Together, these observations suggest that, in addition to potential clearance defects, monocytes from SLE patients have an abnormal balance in the secretion of anti- and pro-inflammatory cytokines in response to apoptotic cells. Since the abnormal cytokine response to apoptotic material in SLE is not related to disease activity and opsonizing autoantibodies, it is possible that this response might be an intrinsic property of lupus monocytes. The studies focus attention on toll-like receptors (TLRs) and their downstream pathways as mediators of this response.
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Affiliation(s)
- Sangeeta Sule
- Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
| | - Antony Rosen
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
- Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
| | - Michelle Petri
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
| | - Ehtisham Akhter
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
| | - Felipe Andrade
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, United States of America
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Du Clos TW, Mold C. Pentraxins (CRP, SAP) in the process of complement activation and clearance of apoptotic bodies through Fcγ receptors. Curr Opin Organ Transplant 2011; 16:15-20. [PMID: 21150611 PMCID: PMC3153594 DOI: 10.1097/mot.0b013e32834253c7] [Citation(s) in RCA: 48] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/15/2022]
Abstract
PURPOSE OF REVIEW Ischemia/reperfusion injury and organ allograft rejection both entail excessive cell and tissue destruction. A number of innate immune proteins, including the pentraxins, participate in the removal of this potentially inflammatory and autoimmunogenic material. The classical pentraxins, C-reactive protein (CRP) and serum amyloid P component (SAP) are serum opsonins, which bind to damaged membranes and nuclear autoantigens. Understanding the role of pentraxins in inflammation has been advanced by the recent identification and structural analysis of their receptor interactions. RECENT FINDINGS The ligand-binding, complement-activating and opsonic properties of pentraxins have been known for some time. However, the establishment of Fcγ receptors as the primary receptors for pentraxins is a recent finding with important implications for CRP and SAP functions. The crystal structure of SAP in complex with FcγRIIa was recently solved, leading to new insights into function and new opportunities for pentraxin-based therapeutics. In addition, new approaches to inhibit CRP synthesis or binding are being developed based on clinical associations between CRP levels and cardiovascular disease. SUMMARY This review will summarize data on the function of pentraxins in clearance of injured tissue and cells and discuss the implications of this clearance pathway for autoimmunity and ischemia/reperfusion injury.
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Affiliation(s)
- Terry W Du Clos
- Department of Veterans Affairs Medical Center and the University of New Mexico School of Medicine, Albuquerque, New Mexico 87108, USA.
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Inefficient clearance of dying cells in patients with SLE: anti-dsDNA autoantibodies, MFG-E8, HMGB-1 and other players. Apoptosis 2010; 15:1098-113. [PMID: 20198437 DOI: 10.1007/s10495-010-0478-8] [Citation(s) in RCA: 63] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
Abstract
Systemic lupus erythematosus (SLE) is a complex disease resulting from inflammatory responses of the immune system against several autoantigens. Inflammation is conditioned by the continuous presence of autoantibodies and leaked autoantigens, e.g. from not properly cleared dying and dead cells. Various soluble molecules and biophysical properties of the surface of apoptotic cells play significant roles in the appropriate recognition and further processing of dying and dead cells. We exemplarily discuss how Milk fat globule epidermal growth factor 8 (MFG-E8), biophysical membrane alterations, High mobility group box 1 (HMGB1), C-reactive protein (CRP), and anti-nuclear autoantibodies may contribute to the etiopathogenesis of the disease. Up to date knowledge about these key elements may provide new insights that lead to the development of new treatment strategies of the disease.
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Sacquépée M, Rouleau V, Cantin JF, Quirin N, Doussy Y, Valéry JC, Picu C, Tivollier JM. [Active WHO class IV lupus nephritis in a patient treated with etanercept for a psoriasic arthritis]. Nephrol Ther 2010; 6:537-40. [PMID: 20599469 DOI: 10.1016/j.nephro.2010.05.003] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/12/2009] [Revised: 03/23/2010] [Accepted: 05/24/2010] [Indexed: 12/30/2022]
Abstract
INTRODUCTION Drug-induced lupus nephritis in patients treated with TNF α inhibitor is a rare adverse effect. Anti-TNF α therapies are commonly associated with the induction of auto-antibodies, whereas anti-TNF α-induced lupus is rare, most frequently involving arthritis and cutaneous lesions. However, several renal involvement has been reported. OBSERVATION A 26-year old woman with a history of psoriasic arthritis treated with TNF α inhibitor (etanercept) presented with a biopsy-proved class IV lupus nephritis. The diagnosis of drug-induced lupus nephritis was probable and anti-TNF α therapy was discontinued. Standard lupus nephritis therapy was then started with prednisolone pulses and mycophenolate mofetil (MMF). Two weeks later, a septic shock following a leg cellulitis was caused by Pseudomonas aeruginosa and had a fatal evolution despite MMF withdrawal, adapted antibiotherapy and large wound excision. DISCUSSION Our therapy was not different than for other class IV lupus nephritis. Our observation highlights two points: first the attributability to etanercept in lupic manifestations in our patient and second the therapeutic strategy in this particular case of drug-induced lupus. CONCLUSION We reported a possible first case of IV lupus nephritis induced by anti-TNF α with a fatal evolution.
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Affiliation(s)
- Mathieu Sacquépée
- Association pour le traitement de l'insuffisance rénale en Nouvelle-Calédonie, 193, rue Benebig, 98800 Nouméa, Nouvelle-Calédonie.
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Peisajovich A, Marnell L, Mold C, Du Clos TW. C-reactive protein at the interface between innate immunity and inflammation. Expert Rev Clin Immunol 2010; 4:379-90. [PMID: 20476927 DOI: 10.1586/1744666x.4.3.379] [Citation(s) in RCA: 72] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
C-reactive protein (CRP), the prototypic acute-phase protein, increases rapidly in response to infection and inflammation. Although CRP was thought to be a passive, nonspecific marker of inflammation, recent studies indicate that CRP plays a key role in the innate immune system by recognizing pathogens and altered self determinants. Activation of complement and interaction with Fcgamma receptors by CRP provides a link between the innate and adaptive immune systems. Recent evidence suggests that CRP is a marker of atherosclerotic disease and may play a role in its induction. However, CRP has an anti-inflammatory role in autoimmune diseases, such as systemic lupus erythematosus. In this article, we review the biological mechanisms by which CRP exerts its effects on the immune system and discuss its role in infection, cardiovascular disease, malignancy and systemic lupus erythematosus.
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Affiliation(s)
- Andres Peisajovich
- Department of Internal Medicine, Division of Rheumatology, MSC10 5550 1, University of New Mexico, Albuquerque, NM 87131, USA.
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Outinen TK, Mäkelä SM, Ala-Houhala IO, Huhtala HS, Hurme M, Paakkala AS, Pörsti IH, Syrjänen JT, Mustonen JT. The severity of Puumala hantavirus induced nephropathia epidemica can be better evaluated using plasma interleukin-6 than C-reactive protein determinations. BMC Infect Dis 2010; 10:132. [PMID: 20500875 PMCID: PMC2885391 DOI: 10.1186/1471-2334-10-132] [Citation(s) in RCA: 68] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2010] [Accepted: 05/25/2010] [Indexed: 12/16/2022] Open
Abstract
Background Nephropathia epidemica (NE) is a Scandinavian type of hemorrhagic fever with renal syndrome caused by Puumala hantavirus. The clinical course of the disease varies greatly in severity. The aim of the present study was to evaluate whether plasma C-reactive protein (CRP) and interleukin (IL)-6 levels associate with the severity of NE. Methods A prospectively collected cohort of 118 consecutive hospital-treated patients with acute serologically confirmed NE was examined. Plasma IL-6, CRP, and creatinine, as well as blood cell count and daily urinary protein excretion were measured on three consecutive days after admission. Plasma IL-6 and CRP levels higher than the median were considered high. Results We found that high IL-6 associated with most variables reflecting the severity of the disease. When compared to patients with low IL-6, patients with high IL-6 had higher maximum blood leukocyte count (11.9 vs 9.0 × 109/l, P = 0.001) and urinary protein excretion (2.51 vs 1.68 g/day, P = 0.017), as well as a lower minimum blood platelet count (55 vs 80 × 109/l, P < 0.001), hematocrit (0.34 vs 0.38, P = 0.001), and urinary output (1040 vs 2180 ml/day, P < 0.001). They also stayed longer in hospital than patients with low IL-6 (8 vs 6 days, P < 0.001). In contrast, high CRP did not associate with severe disease. Conclusions High plasma IL-6 concentrations associate with a clinically severe acute Puumala hantavirus infection, whereas high plasma CRP as such does not reflect the severity of the disease.
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Affiliation(s)
- Tuula K Outinen
- Department of Internal Medicine, Tampere University Hospital, POBox 2000, Tampere, FI-33521, Finland.
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Frese-Schaper M, Zbaeren J, Gugger M, Monestier M, Frese S. Reversal of Established Lupus Nephritis and Prolonged Survival of New Zealand Black × New Zealand White Mice Treated with the Topoisomerase I Inhibitor Irinotecan. THE JOURNAL OF IMMUNOLOGY 2010; 184:2175-82. [DOI: 10.4049/jimmunol.0903153] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/22/2023]
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Carlucci F, Cook HT, Garg A, Pepys MB, Botto M. Lack of effect of a single injection of human C-reactive protein on murine lupus or nephrotoxic nephritis. ARTHRITIS AND RHEUMATISM 2010; 62:245-9. [PMID: 20039408 PMCID: PMC3625741 DOI: 10.1002/art.27232] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Indexed: 01/26/2023]
Abstract
OBJECTIVE It has been reported that a single dose of human C-reactive protein (CRP) can prevent and reverse the renal damage in murine models of spontaneous lupus, as well as the rapid-onset immune complex disease induced in the accelerated nephrotoxic nephritis (ANTN) model. This study was undertaken to attempt to replicate these observations using a highly purified and fully characterized human CRP preparation. METHODS (NZB x NZW)F(1) (NZB/NZW) mice were treated with a single 200-microg subcutaneous injection of CRP or control reagents either before disease onset at 4 months of age or when high-grade proteinuria was present at 7 months of age. Mice were monitored at least monthly for proteinuria and autoantibody levels. ANTN was induced by preimmunizing C57BL/6 mice with sheep IgG, followed 5 days later by injection of sheep anti-mouse glomerular basement membrane antibody and CRP or control reagents. Renal disease was assessed by regular urinalysis and histologic evaluation. RESULTS CRP treatment of NZB/NZW mice, either early or late in the disease, had no effect on proteinuria, autoantibody titers, or survival. CRP administration did not reduce renal injury or alter disease in the ANTN model. Human serum amyloid P component, a pentraxin protein that is very closely related to CRP, similarly had no effect. CONCLUSION Our completely negative observations do not confirm that human CRP has reproducible antiinflammatory or immunomodulatory effects in these murine models, nor do they support the suggestion that CRP might be useful for therapy of lupus or immune complex-mediated nephritis.
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Marjon KD, Marnell LL, Mold C, Du Clos TW. Macrophages activated by C-reactive protein through Fc gamma RI transfer suppression of immune thrombocytopenia. THE JOURNAL OF IMMUNOLOGY 2009; 182:1397-403. [PMID: 19155486 DOI: 10.4049/jimmunol.182.3.1397] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
C-reactive protein (CRP) is an acute-phase protein with therapeutic activity in mouse models of systemic lupus erythematosus and other inflammatory and autoimmune diseases. To determine the mechanism by which CRP suppresses immune complex disease, an adoptive transfer system was developed in a model of immune thrombocytopenic purpura (ITP). Injection of 200 microg of CRP 24 h before induction of ITP markedly decreased thrombocytopenia induced by anti-CD41. CRP-treated splenocytes also provided protection from ITP in adoptive transfer. Splenocytes from C57BL/6 mice were treated with 200 microg/ml CRP for 30 min, washed, and injected into mice 24 h before induction of ITP. Injection of 10(6) CRP-treated splenocytes protected mice from thrombocytopenia, as did i.v. Ig-treated but not BSA-treated splenocytes. The suppressive cell induced by CRP was found to be a macrophage by depletion, enrichment, and the use of purified bone marrow-derived macrophages. The induction of protection by CRP-treated cells was dependent on FcRgamma-chain and Syk activation, indicating an activating effect of CRP on the donor cell. Suppression of ITP by CRP-treated splenocytes required Fc gamma RI on the donor cell and Fc gamma RIIb in the recipient mice. These findings suggest that CRP generates suppressive macrophages through Fc gamma RI, which then act through an Fc gamma RIIb-dependent pathway in the recipient to decrease platelet clearance. These results provide insight into the mechanism of CRP regulatory activity in autoimmunity and suggest a potential new therapeutic approach to ITP.
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Gaitonde S, Samols D, Kushner I. C-reactive protein and systemic lupus erythematosus. ACTA ACUST UNITED AC 2009; 59:1814-20. [PMID: 19035410 DOI: 10.1002/art.24316] [Citation(s) in RCA: 78] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/11/2023]
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Agrawal A, Singh PP, Bottazzi B, Garlanda C, Mantovani A. Pattern Recognition by Pentraxins. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2009; 653:98-116. [DOI: 10.1007/978-1-4419-0901-5_7] [Citation(s) in RCA: 116] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
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Tan Y, Yu F, Yang H, Chen M, Fang Q, Zhao MH. Autoantibodies against monomeric C-reactive protein in sera from patients with lupus nephritis are associated with disease activity and renal tubulointerstitial lesions. Hum Immunol 2008; 69:840-4. [DOI: 10.1016/j.humimm.2008.09.006] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2008] [Revised: 08/29/2008] [Accepted: 09/15/2008] [Indexed: 11/17/2022]
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Wiesendanger M, Stanevsky A, Kovsky S, Diamond B. Novel therapeutics for systemic lupus erythematosus. Curr Opin Rheumatol 2008; 18:227-35. [PMID: 16582684 DOI: 10.1097/01.bor.0000218941.04613.85] [Citation(s) in RCA: 14] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
PURPOSE OF REVIEW This review provides an update on recently explored therapies in systemic lupus erythematosus and introduces novel therapeutic approaches under consideration. Recent advances in our understanding of systemic lupus are highlighted as well, as these must now inform consideration of therapeutics. RECENT FINDINGS Many therapeutic strategies have been shown to be beneficial in murine models of lupus. Compounds that inhibit cellular signaling in response to autoantigens or other triggers and protocols that reconstitute the immune repertoire to diminish autoreactivity are now entering clinical trials. SUMMARY Requirements for novel approaches in lupus include improved efficacy and lower toxicity than current therapies, with the goal to reduce tissue damage while preserving immunocompetence.
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Affiliation(s)
- Margrit Wiesendanger
- Department of Medicine, Columbia University Medical Center, New York, New York 10032, USA
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Edberg JC, Wu J, Langefeld CD, Brown EE, Marion MC, McGwin G, Petri M, Ramsey-Goldman R, Reveille JD, Frank SG, Kaufman KM, Harley JB, Alarcón GS, Kimberly RP. Genetic variation in the CRP promoter: association with systemic lupus erythematosus. Hum Mol Genet 2008; 17:1147-55. [DOI: 10.1093/hmg/ddn004] [Citation(s) in RCA: 53] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
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Kessel A, Elias G, Pavlotzky E, Zuckerman E, Rosner I, Toubi E. Anti-C-reactive protein antibodies in chronic hepatitis C infection: Correlation with severity and autoimmunity. Hum Immunol 2007; 68:844-8. [DOI: 10.1016/j.humimm.2007.06.008] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2007] [Revised: 06/10/2007] [Accepted: 06/10/2007] [Indexed: 01/21/2023]
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Huang ZS, Lo SC, Tsay W, Hsu KL, Chiang FT. Revision in Reference Ranges of Peripheral Total Leukocyte Count and Differential Leukocyte Percentages Based on a Normal Serum C-Reactive Protein Level. J Formos Med Assoc 2007; 106:608-16. [PMID: 17711793 DOI: 10.1016/s0929-6646(08)60017-0] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/28/2022] Open
Abstract
BACKGROUND/PURPOSE A higher total leukocyte count is a predictor of all-cause mortality and cardiovascular morbidity. The currently used reference range for peripheral total leukocyte count is wide (4.5-11.0 x 10(9)/L) and is associated with a low sensitivity in identifying non-infectious chronic diseases. We attempt to revise it based on a normal serum C-reactive protein (CRP) level. METHODS Study subjects were participants in a health check program at our hospital between 2000 and 2002. Those whose leukocyte analysis had been checked with the Sysmex Cell Counter NE-9000 were enrolled. RESULTS Significantly positive relationships between CRP level and total leukocyte count, neutrophil percentage, and monocyte percentage were found in all subjects (n = 14,114; p < 0.0001). In contrast, CRP level had a significantly inverse correlation with lymphocyte percentage (p < 0.0001). A proposed new reference range for total leukocyte count was estimated based on the data in the normal CRP level group (CRP < 0.1 mg/dL; n = 4839). To rest on the essence of statistics that the range of [mean +/- 2 standard deviations] contains approximately the middle 95% of observations in a sampled population, a new reference range for total leukocyte count was accordingly estimated to be 3.11-8.83 x 10(9)/L. CONCLUSION In view of the abundant evidence showing that a higher peripheral total leukocyte count is harmful to health, a down-correction of its upper reference range from the currently used 11.0 x 10(9)/L to the proposed 8.83 x 10(9)/L, based on a normal CRP level, should allow more abnormal health conditions to be identified and promote the usefulness of peripheral leukocyte analysis.
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Affiliation(s)
- Zei-Shung Huang
- Department of Internal Medicine, College of Medicine and Hospital, National Taiwan University, Taipei, Taiwan
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Schwedler SB, Kuhlencordt PJ, Ponnuswamy PP, Hatiboglu G, Quaschning T, Widder J, Wanner C, Potempa LA, Galle J. Native C-reactive protein induces endothelial dysfunction in ApoE-/- mice: implications for iNOS and reactive oxygen species. Atherosclerosis 2007; 195:e76-84. [PMID: 17669410 DOI: 10.1016/j.atherosclerosis.2007.06.013] [Citation(s) in RCA: 27] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/29/2007] [Revised: 05/25/2007] [Accepted: 06/19/2007] [Indexed: 12/18/2022]
Abstract
OBJECTIVE In addition to being a risk marker for cardiovascular disease, recent data suggests that C-reactive protein (CRP) induces endothelial dysfunction and promotes oxidative stress. We evaluated the effects of two conformers of CRP (pentameric, or native [nCRP], versus monomeric, or modified [mCRP]) on vessel function and production of reactive oxygen species (ROS) in an in-vivo model of atherosclerosis. METHODS AND RESULTS Female ApoE(-/-) mice, fed a "western-type" diet, were treated with either human nCRP or mCRP (2.5mg/kg s.c., weekly) or saline for 8 weeks. Endothelium-dependent and endothelium-independent vascular functions were assessed in isolated aortic rings under isometric conditions. Production of ROS in aortic rings was measured by electron spin resonance (ESR). Endothelium-dependent relaxation was impaired in nCRP-treated but not in mCRP-treated ApoE(-/-) mice. This impairment was reversed by preincubation with an inhibitor of inducible nitric oxide synthase (iNOS). Endothelium-independent relaxation, and iNOS and endothelial NOS (eNOS) protein expressions were similar among all groups. ESR experiments revealed lesser amounts of superoxide in the nCRP group as compared to the saline group, which is consistent with an increased transformation of NO to peroxynitrite. CONCLUSIONS nCRP can facilitate cardiovascular disease through impairment of endothelium-dependent vasoreactivity, in a manner that involves increased iNOS activity and a potential for increased peroxynitrite formation.
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Affiliation(s)
- Susanne B Schwedler
- Department of Medicine I, University Hospital Würzburg, Josef-Schneider-Str. 2, D-97080 Würzburg, Germany.
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Ng PML, Le Saux A, Lee CM, Tan NS, Lu J, Thiel S, Ho B, Ding JL. C-reactive protein collaborates with plasma lectins to boost immune response against bacteria. EMBO J 2007; 26:3431-40. [PMID: 17581635 PMCID: PMC1933394 DOI: 10.1038/sj.emboj.7601762] [Citation(s) in RCA: 91] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2006] [Accepted: 05/24/2007] [Indexed: 01/15/2023] Open
Abstract
Although human C-reactive protein (CRP) becomes upregulated during septicemia, its role remains unclear, since purified CRP showed no binding to many common pathogens. Contrary to previous findings, we show that purified human CRP (hCRP) binds to Salmonella enterica, and that binding is enhanced in the presence of plasma factors. In the horseshoe crab, Carcinoscorpius rotundicauda, CRP is a major hemolymph protein. Incubation of hemolymph with a range of bacteria resulted in CRP binding to all the bacteria tested. Lipopolysaccharide-affinity chromatography of the hemolymph co-purified CRP, galactose-binding protein (GBP) and carcinolectin-5 (CL5). Yeast two-hybrid and pull-down assays suggested that these pattern recognition receptors (PRRs) form pathogen recognition complexes. We show the conservation of PRR crosstalk in humans, whereby hCRP interacts with ficolin (CL5 homologue). This interaction stabilizes CRP binding to bacteria and activates the lectin-mediated complement pathway. We propose that CRP does not act alone but collaborates with other plasma PRRs to form stable pathogen recognition complexes when targeting a wide range of bacteria for destruction.
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Affiliation(s)
- Patricia M L Ng
- Department of Biological Sciences, Faculty of Science, National University of Singapore, Singapore
| | - Agnès Le Saux
- Department of Biological Sciences, Faculty of Science, National University of Singapore, Singapore
| | - Chia M Lee
- Department of Biological Sciences, Faculty of Science, National University of Singapore, Singapore
| | - Nguan S Tan
- School of Biological Sciences, Nanyang Technological University, Singapore
| | - Jinhua Lu
- Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
| | - Steffen Thiel
- Department of Medical Microbiology and Immunology, Wilhelm Meyers Allé, Bartholin Building, University of Aarhus, Aarhus, Denmark
| | - Bow Ho
- Department of Microbiology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore
- These authors contributed equally to this work
| | - Jeak L Ding
- Department of Biological Sciences, Faculty of Science, National University of Singapore, Singapore
- These authors contributed equally to this work
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