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Abstract
This article reviews current understanding of the clinical manifestations, diagnosis and treatment of Sjögren's syndrome. Sjögren's syndrome is a chronic inflammatory disorder of the exocrine glands with multiple nonexocrine features. It is found predominantly in middle-aged women but exists throughout the population. The diagnosis of Sjögren's syndrome can be challenging because the cardinal sicca symptoms may be subclinical or attributed to other causes, such as medications or aging. Differential diagnosis of Sjögren's syndrome can be confounded by the multiple exocrine manifestations in the mouth, eyes, ears, nose, skin, vagina, and respiratory and gastrointestinal tracts, as well as seemingly unrelated nonexocrine involvement in the thyroid, liver, kidneys and the musculoskeletal, vascular and nervous systems. This article concludes that early diagnosis of Sjögren's syndrome is crucial to prevent and/or minimize potentially life-threatening complications. Periodic follow-up of patients' status and collaboration between the primary-care physician and the rheumatologist, dentist, ophthalmologist and other specialists are indispensable.
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Affiliation(s)
- Ibtisam Al-Hashimi
- Baylor College of Dentistry, Salivary Dysfunction Clinic, Department of Periodontics, 3302 Gaston Avenue, Dallas, TX 75246, USA and University of Texas Southwestern Medical Centre, Faculty of Surgery, Division of Oral Surgery, Dallas, TX, USA.
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2
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Jacob N, Stohl W. Autoantibody-dependent and autoantibody-independent roles for B cells in systemic lupus erythematosus: past, present, and future. Autoimmunity 2010; 43:84-97. [PMID: 20014977 PMCID: PMC2809122 DOI: 10.3109/08916930903374600] [Citation(s) in RCA: 56] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
It has long been known that B cells produce autoantibodies and, thereby, contribute to the pathogenesis of many autoimmune diseases. Systemic lupus erythematosus (SLE), a prototypic systemic autoimmune disorder, is characterized by high-circulating autoantibody titers and immune-complex deposition that can trigger inflammatory damage in multiple organs/organ systems. Although the interest in B cells in SLE has historically focused on their autoantibody production, we now appreciate that B cells have multiple autoantibody-independent roles in SLE as well. B cells can efficiently present antigen and activate T cells, they can augment T cell activation through co-stimulatory interactions, and they can produce numerous cytokines which affect inflammation, lymphogenesis, and immune regulation. Not surprisingly, B cells have become attractive therapeutic targets in SLE. With these points in mind, this review will focus on the autoantibody-dependent and autoantibody-independent roles for B cells in SLE and on therapeutic approaches that target B cells.
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Affiliation(s)
- Noam Jacob
- Division of Rheumatology, Department of Medicine University of Southern California Keck School of Medicine, Los Angeles, CA 90033
| | - William Stohl
- Division of Rheumatology, Department of Medicine University of Southern California Keck School of Medicine, Los Angeles, CA 90033
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3
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Pandey MK, Rani R, Agrawal S. An update in recurrent spontaneous abortion. Arch Gynecol Obstet 2005; 272:95-108. [PMID: 15906053 DOI: 10.1007/s00404-004-0706-y] [Citation(s) in RCA: 148] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2003] [Accepted: 10/12/2004] [Indexed: 11/29/2022]
Abstract
Recurrent spontaneous abortion (RSA) is defined as three or more consecutive pregnancy losses prior to the 20th week of gestation. The etiology of recurrent spontaneous abortion is often unclear and may be multifactorial, with much controversy regarding diagnosis and treatment. Reasonably accepted etiologic causes include, genetics, anatomical, endocrine, placental anomalies, hormonal problems, infection, smoking and alcohol consumption, exposure to environmental factors, psychological trauma and stressful life event, certain coagulation and immunoregulatory protein defects. Detection of an abnormality in any of these areas may result into specific therapeutic measures, with varying degrees of success. However, the majority of cases of RSA remains unexplained and is found to be associated with certain autoimmune (APA, ANA, ACA, ATA, AECA) and alloimmune (APCA, Ab2, MLR-Bf) antibodies that may play major role in the immunologic failure of pregnancy and may lead to abortion. Alteration in the expression of HLA-G molecules, T-helper-1 (Th-1) pattern of cytokines and natural killer (NK) cells activity may also induce abortion. Various forms of treatment like antithrombotic therapies such as aspirin and heparin, intravenous immunoglobulin (IVIg) therapy, immunotherapy with paternal lymphocytes and vitamin D3 therapy are effective mode of treatment for unexplained cause of fetal loss in women with RSA.
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Affiliation(s)
- Manoj Kumar Pandey
- Division of Molecular Immunology, Cincinnati Children's Hospital Medical Center, MLC 7021 TCH RF 5503 3333 Burnet Avenue, Cincinnati, OH, 45229-3039, USA.
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4
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Abstract
Xerostomia is a common symptom in the elderly population. Studies have suggested that the underlying cause of approximately 40% of xerostomia in the elderly is Sjögren's syndrome. Although it is highly prevalent among middle-aged individuals, elderly patients account for up to 20% of Sjögren's syndrome cases. Sjögren's syndrome is a multisystem exocrinopathy characterised by dry mouth and dry eyes with wide-ranging extraglandular involvement. The exocrine manifestations of Sjögren's syndrome affect the mouth, eyes, nose, ears, skin, vagina and the entire respiratory and gastrointestinal systems. The nonexocrine involvement may include the joints, thyroid gland, liver, kidneys and the musculoskeletal, vascular and central nervous systems. Currently, the mechanism(s) of development and progression of Sjögren's syndrome is/are not clear. Inflammation and lymphocytic infiltration of the exocrine glands is a classical feature of Sjögren's syndrome. During the progression of the disease, the acinar cells of the exocrine glands are replaced by fibrosis, rendering the glands nonfunctional. Sjögren's syndrome remains one of the most underdiagnosed conditions, particularly in the elderly population, because the cardinal sicca symptoms, which are the hallmark of the disease, are frequently attributed to aging and/or medications, which consequently delays the diagnosis. This delay in diagnosis imposes significant physical, psychological and economic burdens on elderly patients. The diagnosis of Sjögren's syndrome requires evaluation of both the exocrine and nonexocrine components of the disease. Management of Sjögren's syndrome requires collaboration by the primary-care physician, rheumatologist, ophthalmologist and dentist. This article reviews current understanding of the clinical manifestations, diagnosis and treatment of Sjögren's syndrome with special emphasis on the oral component of the disease.
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Affiliation(s)
- Ibtisam Al-Hashimi
- Department of Periodontics, Salivary Dysfunction Clinic, Baylor College of Dentistry, Dallas, TX 75246, USA.
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5
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Expression of matrix metalloproteinase-7 and fas ligand: Their apoptosis-inducing effect on gastric cancer cells. Chin J Cancer Res 2003. [DOI: 10.1007/s11670-003-0025-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/21/2022] Open
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Zheng HC, Sun JM, Wei ZL, Yang XF, Zhang YC, Xin Y. Expression of Fas ligand and Caspase-3 contributes to formation of immune escape in gastric cancer. World J Gastroenterol 2003; 9:1415-20. [PMID: 12854132 PMCID: PMC4615474 DOI: 10.3748/wjg.v9.i7.1415] [Citation(s) in RCA: 50] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
AIM: To study the role of Fas ligand (FasL) and Caspase-3 expression in carcinogenesis and progression of gastric cancer and molecular mechanisms of relevant immune escape.
METHODS: FasL and Caspase-3 expression was studied in adjacent epithelial cells, cancer cells and lymphocytes of primary foci, and cancer cells of metastatic foci from 113 cases of gastric cancer by streptavidin-biotin-peroxidase (S-P) immunohistochemistry. Expression of both proteins in cancer cells of primary foci was compared with clinicopathological features of gastric cancer. The relationship between FasL expression in cancer cells and Caspase-3 expression in cancer cells or infiltrating lymphocytes of primary foci was investigated.
RESULTS: Cancer cells of primary foci expressed FasL in 53.98% (61/113) of gastric cancers, more than their adjacent epithelial cells (34.51%, 39/113) (P = 0.003, χ2 = 8.681), while the expression of Caspase-3 in cancer cells of primary foci was detected in 32.74% (37/113) of gastric cancers, less than in the adjacent epithelial cells (50.44%, 57/113) (P = 0.007, χ2 = 7.286). Infiltrating lymphocytes of the primary foci showed positive immunoreactivity to Caspase-3 in 70.80% (80/113) of gastric cancers, more than their corresponding adjacent epithelial cells (P = 0.001, χ2 = 10.635) or cancer cells of primary foci (P = 0.000, χ2 = 32.767). FasL was less expressed in cancer cells of metastases (51.16%, 22/43) than in those of the corresponding primary foci (81.58%, 31/38) (P = 0.003, χ2 = 9.907). Conversely, Caspase-3 was more expressed in cancer cells of metastases (58.14%, 25/43) than in those of the corresponding primary foci (34.21%, 13/38) (P = 0.031, χ2 = 4.638). FasL expression was significantly correlated with tumor size (P = 0.035, rs = 0.276), invasive depth (P = 0.039, rs = 0.195), metastasis (P = 0.039, rs = 0.195), differentiation (P = 0.015, rs = 0.228) and Lauren’s classification (P = 0.038, rs = 0.196), but not with age or gender of patients, growth pattern or TNM staging of gastric cancer (P > 0.05). In contrast, Caspase-3 expression showed no correlation with any clinicopathological parameters described above in cancer cells of the primary foci (P > 0.05). Interestingly, FasL expression in primary gastric cancer cells paralleled to Caspase-3 expression in infiltrating lymphocytes of the primary foci (P = 0.016, χ2 = 5.825).
CONCLUSION: Up-regulated expression of FasL and down-regulated expression of Caspase-3 in cancer cells of primary foci play an important role in gastric carcinogenesis. As an effective marker to reveal the biological behaviors, FasL is implicated in differentiation, growth, invasion and metastasis of gastric cancer by inducing apoptosis of infiltrating lymphocytes. Chemical substances derived from the primary foci and metastatic microenvironment can inhibit the growth of metastatic cells by enhancing Caspase-3 expression and diminishing FasL expression.
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Affiliation(s)
- Hua-Chuan Zheng
- The Fourth Lab. Cancer Institute, The First Affiliated Hospital of China Medical University, Shenyang 110001, Liaoning Province, China.
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Durant S, Geutskens S, Van Blokland SCA, Coulaud J, Alves V, Pleau JM, Versnel M, Drexhage HA, Homo-Delarche F. Proapoptosis and antiapoptosis-related molecules during postnatal pancreas development in control and nonobese diabetic mice: relationship with innervation. J Transl Med 2003; 83:227-39. [PMID: 12594237 DOI: 10.1097/01.lab.0000053914.93282.a5] [Citation(s) in RCA: 16] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/26/2022] Open
Abstract
The mouse pancreas, an immature organ at birth, reaches its adult size and morphology after weaning (3 weeks of age). Around this time, apoptotic phenomena and various types of macrophages are normally present. During development, Fas-Fas ligand (FasL) interactions are known to play a role in apoptotic events involved in tissue remodeling and elimination of damaged cells, and macrophages are routinely observed near apoptotic cells. Apoptosis and Fas-FasL interactions are also thought to be involved in the pathogenesis of autoimmune diseases, particularly type 1 diabetes (T1D). Therefore, we used early postnatal mouse pancreata from three control strains (C57BL/6, DBA/2, BALB/c) and from two strains with the nonobese diabetic (NOD)-related genetic background (the spontaneous T1D NOD model and the lymphocyte-deficient NODscid strain) to study apoptotic phenomena together with the molecular and immunohistochemical expression of proapoptosis (Fas, FasL) and antiapoptosis (Bcl-2) proteins. First, although no major difference in the numbers of total pancreatic apoptotic cells was noted among strains, significantly more FasL(+) expression was detected immunohistochemically in mice with the NOD genetic background than in control pancreata from birth to 1 month of age. Second, FasL(+), Fas(+), and Bcl-2(+) structures seemed to be associated with innervation, regardless of the strain and age. Third, in control and NOD strains, nerves (identified by immunohistochemical labeling of peripherin or neurofilament 200), were often observed in periductular and peri-insular areas. Finally, some peripherin-positive nerves expressed the interferon-inducible protein-10 chemokine, and various types of macrophages were found to be in close proximity. These data highlight an overlooked, innervation-related aspect of normal mouse postnatal pancreas development with possible implications in T1D pathogenesis.
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Affiliation(s)
- Sylvie Durant
- CNRS UMR 8603 INSERM U25, FRE 2444, Université Paris V, Hôpital Necker, Paris, France
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Koller LD, Stang BV, Hall JA, Posada de la Paz M, Ruiz Mendez MV. Immunoglobulin and autoantibody responses in MRL/lpr mice treated with 'toxic oils'. Toxicology 2002; 178:119-33. [PMID: 12160619 DOI: 10.1016/s0300-483x(02)00232-9] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/27/2022]
Abstract
The toxic oil syndrome (TOS) occurred in Spain in 1981 as a result of ingestion of oil mixtures containing aniline-denatured rapeseed oil. The disease afflicted almost 20000 people, resulted in more than 400 deaths, and mimicked an autoimmune disease in all patients. Phenilamine-propanediol (PAP) has been implicated as a possible etiologic agent of TOS but absence of an acceptable animal model to evaluate the autoimmune potential of the 'case oil' has hindered identification of the actual etiologic agent(s). The purpose of this study was twofold; (1) to develop an animal model of human disease to investigate the immunological etiology and pathogenesis of TOS and (2) to determine if the 'case oil' responsible for TOS and/or two synthesized oils either induced or exacerbated the systemic autoimmune disease that occurs spontaneously in the MRL/lpr mouse. The oils tested were a denatured rapeseed oil collected from a family (case oil) who were affected by the TOS (CO756), a rapeseed oil denatured with 2% aniline and enriched with a mixture of diesters of PAP (RSD), and a rapeseed oil denatured with 2% aniline but contained no diesters of PAP (RSA). Female MRL/lpr mice, 7 weeks of age, received orally either an undiluted (neat) or a 1:10 diluted dose of each test oil, canola oil (oil control), water (nai;ve control), or 50-ppm mercury (positive control). Half of each group was sacrificed after 5 weeks of exposure and the remaining mice after 10 weeks of exposure. Serum IgG1, IgG2a, IgE isotypes and antinuclear (ANA), collagen type II, histone, single-stranded DNA (ssDNA), double-stranded DNA (dsDNA) and Sm autoantibody concentrations were determined after 5 and 10 weeks of exposure. The oils did not significantly affect the concentrations of the serum immunoglobulins, although a shift in the IgG1:IgG2a ratio towards IgG1 was noted from 12 to 17 weeks of age (5-10 weeks of treatment). The oils did however stimulate the systemic autoimmune response. The RSD neat treatment resulted in a nonsignificant but noted increase in autoantibodies to collagen (10 weeks), histone (10 weeks) and dsDNA (5 and 10 weeks). CO756 neat increased the serum levels of ANA (5 weeks), collagen (5 weeks) and dsDNA (5 and 10 weeks). The RSA 1:10 dilution increased ssDNA and dsDNA autoantibodies at 5 weeks. The results suggest that PAP is an active principle of these noted responses. These data, coupled with the toxicology and pathology data from this study (Toxicol. Path. 29 (2001) 630), revealed that the three oils incited induction of the lymphoproliferative syndrome and that the two oils containing PAP induced and enhanced the systemic autoimmune response that develops spontaneously at an early age in the MRL/lpr mouse. There was also a positive correlation noted between serum autoantibody concentrations and progression of the idiopathic autoimmune syndrome in the MRL/lpr mouse.
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Affiliation(s)
- Loren D Koller
- Department of Biomedical Sciences, College of Veterinary Medicine, Oregon State University, 97331, Corvallis, OR, USA
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Christensson M, Pettersson E, Eneslätt K, Christensson B, Bratt J, Rantapää-Dahlqvist S, Sundqvist KG. Serum sFAS levels are elevated in ANCA-positive vasculitis compared with other autoimmune diseases. J Clin Immunol 2002; 22:220-7. [PMID: 12148596 DOI: 10.1023/a:1016040925295] [Citation(s) in RCA: 11] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/21/2023]
Abstract
The role of the Fas/FasL system in ANCA-associated vasculitis is unclear. We therefore assessed levels of soluble Fas (sFas) in sera and Fas expression on mononuclear cells from patients with ANCA-positive vasculitis and compared the results with those found in other rheumatic diseases. Serum levels of sFas were determined by ELISA. The ANCA-positive vasculitis patients studied included 29 at onset, 17 in first remission while on therapy, and 12 in quiescence. For comparison, 10 patients with Sjogren's syndrome (SS), 14 patients with systemic lupus erythematosus (SLE), 29 patients with rheumatoid arthritis (RA), 7 patients on dialysis (DP), and 26 healthy controls (HC) were studied. In addition, Fas expression in mononuclear cells was examined at the mRNA level using reverse transcriptase (RT)-PCR in 6 vasculitis patients at onset and in first remission. The expression of CD95 on the surface of leukocytes was determined by flow cytometry in 6 vasculitis patients at onset of the disease, in 6 patients in clinical remission, and in 6 HC. Expression of Fas and FasL in renal biopsy specimens was studied using immunohistochemistry. Patients with vasculitis had high sFas levels irrespective of disease phase. Both vasculitis patients and patients with RA and SLE had significantly increased sFas levels compared with healthy controls. All patient groups had sFas levels, which correlated with raised serum creatinine values. However, the sFas levels in vasculitis patients in first remission and in quiescence were increased despite a lower serum creatinine compared with onset. Some of the vasculitis patients showed an increased mRNA expression of Fas in mononuclear cells after treatment, suggesting that Fas production fluctuates with the intensity of the disease. The expression of CD95 on leukocytes was slightly decreased in vasculitis patients compared to healthy controls. No alterations of Fas and FasL expression were seen in renal biopsy specimens. These results show that ANCA-positive vasculitis patients have high sFas levels and that the levels remain elevated even in clinical remission. The findings indicate that perturbations in the Fas/Fas ligand system may play a role in the disease process in ANCA vasculitis.
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Affiliation(s)
- Marta Christensson
- Department of Clinical Immunology, Karolinska Institutet, Huddinge University Hospital, Stockholm, Sweden.
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10
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Abstract
BACKGROUND Sjögren's syndrome, or SS, is a multisystem inflammatory disorder of the exocrine glands with a wide range of extraglandular involvement. Symptoms of dry eyes and xerostomia, although not invariably present, are characteristic features of SS. An increased risk of oral and dental diseases is a prominent consequence of SS. TYPES OF STUDIES REVIEWED The author reviewed recent medical and dental studies that have advanced our understanding of the causes and treatment of SS. She particularly focused on studies addressing the diagnosis and treatment of the oral component of the disease. RESULTS Sjögren's syndrome is a widely underdiagnosed disease. A delay in the diagnosis of SS may have a significant physical, psychological and economic impact on the affected person. The pathogenesis of SS appears to involve a number of factors: immunological, genetic, hormonal and possibly infectious. Successful management of SS requires a multidisciplinary approach, and the dentist plays an essential role in the diagnosis and treatment of the disease. ORAL IMPLICATIONS: Impairment of salivary function in SS increases the risk of developing oral diseases. Effective management of oral health comprises enhancement of salivary output (cholinergic agonist drugs such as pilocarpine or cevimeline) and prevention and treatment of dental caries, oral candidiasis and allergic mucositis. Finally, periodic evaluation of various clinical and laboratory parameters is needed to monitor disease status.
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Affiliation(s)
- I al-Hashimi
- Salivary Dysfunction Clinic, Baylor College of Dentistry, Department of Periodontology, 3302 Gastom Ave., Dallas, Texas 75246, USA.
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Homo-Delarche F. Is pancreas development abnormal in the non-obese diabetic mouse, a spontaneous model of type I diabetes? Braz J Med Biol Res 2001; 34:437-47. [PMID: 11285454 DOI: 10.1590/s0100-879x2001000400002] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Despite extensive genetic and immunological research, the complex etiology and pathogenesis of type I diabetes remains unresolved. During the last few years, our attention has been focused on factors such as abnormalities of islet function and/or microenvironment, that could interact with immune partners in the spontaneous model of the disease, the non-obese diabetic (NOD) mouse. Intriguingly, the first anomalies that we noted in NOD mice, compared to control strains, are already present at birth and consist of 1) higher numbers of paradoxically hyperactive beta cells, assessed by in situ preproinsulin II expression; 2) high percentages of immature islets, representing islet neogenesis related to neonatal beta-cell hyperactivity and suggestive of in utero beta-cell stimulation; 3) elevated levels of some types of antigen-presenting cells and FasL+ cells, and 4) abnormalities of extracellular matrix (ECM) protein expression. However, the colocalization in all control mouse strains studied of fibroblast-like cells (anti-TR-7 labeling), some ECM proteins (particularly, fibronectin and collagen I), antigen-presenting cells and a few FasL+ cells at the periphery of islets undergoing neogenesis suggests that remodeling phenomena that normally take place during postnatal pancreas development could be disturbed in NOD mice. These data show that from birth onwards there is an intricate relationship between endocrine and immune events in the NOD mouse. They also suggest that tissue-specific autoimmune reactions could arise from developmental phenomena taking place during fetal life in which ECM-immune cell interaction(s) may play a key role.
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Affiliation(s)
- F Homo-Delarche
- CNRS UMR 8603, Université Paris V, Hôpital Necker, 161, rue de Sévres, 55015 Paris, France.
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Wahlsten JL, Gitchell HL, Chan CC, Wiggert B, Caspi RR. Fas and Fas ligand expressed on cells of the immune system, not on the target tissue, control induction of experimental autoimmune uveitis. JOURNAL OF IMMUNOLOGY (BALTIMORE, MD. : 1950) 2000; 165:5480-6. [PMID: 11067900 DOI: 10.4049/jimmunol.165.10.5480] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/19/2022]
Abstract
The Fas-Fas ligand (FasL) interaction is important for maintaining lymphocyte homeostasis by signaling for activation-induced cell death. Mice homozygous for the lpr or gld mutations do not express functional Fas or FasL, respectively, and spontaneously develop progressive autoimmune symptoms. Recent studies implicated expression of FasL on immunologically privileged tissues in protection from immune-mediated damage. Conversely, tissue expression of Fas may facilitate damage. We evaluated the susceptibility of lpr and gld mice to induction of experimental autoimmune uveitis (EAU), a T cell-mediated autoimmune disease induced with retinal Ags, which targets the neural retina. gld as well as lpr mice immunized with a retinal Ag developed disease of lower incidence and severity than wild-type controls. Delayed hypersensitivity responses were not significantly different among immunized gld, lpr, or wild-type mice, although in vitro Ag-specific lymphocyte responses of the mutant mice were lower. To evaluate whether the diminished ability of gld and lpr mice to develop EAU was due to a defect at the level of the tissue or the immune system, radiation bone marrow chimeras constructed between wild-type and mutant mice were immunized to induce EAU. Mutant recipients of wild-type bone marrow, but not wild-type recipients of mutant bone marrow, developed normal disease scores. These results indicate that normal expression of Fas and of FasL on cells of the immune system is important for EAU expression. Unexpectedly, neither lack of Fas nor lack of FasL on the ocular tissues affected expression of EAU.
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Affiliation(s)
- J L Wahlsten
- Laboratory of Immunology, National Eye Institute, National Institutes of Health, Bethesda, MD 20892, USA
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13
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Fortunato F, Gates LK. Alcohol feeding and lipopolysaccharide injection modulate apoptotic effectors in the rat pancreas in vivo. Pancreas 2000; 21:174-80. [PMID: 10975712 DOI: 10.1097/00006676-200008000-00011] [Citation(s) in RCA: 15] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
Abstract
The purpose of this study was to determine if alcohol consumption and endotoxin injection change the rate of apoptosis in the pancreas. Rats were fed a Lieber-DeCarli diet for 14 weeks. At 14 weeks, the animals were injected with lipopolysaccharide (LPS) or saline and killed. The pancreata were resected and snap frozen. Apoptosis was detected by TUNEL assay. Caspase-3 activity, Bcl-2 (protein), and Fas ligand (mRNA) were assayed in pancreas extracts and alpha-amylase in plasma. Alcohol feeding significantly decreased alpha-amylase and caspase-3 activity, and significantly increased Bcl-2. LPS injection increased caspase-3 activity and decreased Bcl-2. Fas ligand mRNA was increased only in alcohol-fed, LPS-injected rats. TUNEL labeling was significantly increased only in alcohol-fed, LPS-injected rats. These data show that (a) long-term alcohol feeding suppresses apoptosis in the pancreas; (b) LPS increases the rate of apoptosis in the pancreas; (c) caspase-3 activity and Bcl-2 expression change in opposite directions; (d) TUNEL positivity and Fas ligand expression are increased, and Bcl-2 is decreased in ethanol-fed + LPS-injected rats. These results suggest that prolonged alcohol consumption may sensitize acinar cells to endotoxin-induced injury and raise the possibility that a similar mechanism may cause pancreatitis in human alcoholics.
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Affiliation(s)
- F Fortunato
- Division of Digestive Diseases and Nutrition, Department of Internal Medicine, University of Kentucky, Lexington 40536-0084, USA.
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Spinardi-Barbisan AL, Kaneno R, Marchesan Rodrigues MA, Fávero Salvadori DM, Trindade Moreira EL, Barbisan LF, Viana de Camargo JL. Lymphoproliferative response and T lymphocyte subsets in a medium-term multi-organ bioassay for carcinogenesis in Wistar rats. Cancer Lett 2000; 154:121-9. [PMID: 10806299 DOI: 10.1016/s0304-3835(00)00344-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 10/18/2022]
Abstract
The lymphoproliferative response and T lymphocyte subsets were evaluated at different stages of carcinogenesis in male Wistar rats sequentially initiated with N-diethylnitrosamine (DEN), N-butyl-N-4(hydroxybutyl)nitrosamine (BBN), N-methyl-N-nitrosourea (MNU), dihydroxy-di-N-propylnitrosamine (DHPN) and N, N'-dimethylhydrazine (DMH) (DMBDD initiation). One group was evaluated at the 4th week and other initiated group at the 30th week. Two initiated groups were also exposed through diet to 2-acetylaminofluorene (2-AAF) or phenobarbital (PB), from the 6th until the 30th week. Two groups received only 2-AAF or PB until the 30th week. Five groups were studied to evaluate the effects of each initiator. The lymphoproliferative response was induced in vitro by concanavalin A and the percentage of T lymphocyte subsets was determined by flow cytometry. All groups submitted to initiation only, initiation plus promotion, or promotion only, developed significantly more preneoplastic lesions than the untreated control group. The main target organs for tumor development were the liver, colon, urinary bladder, kidneys and Zymbal glands, mainly in the group treated with DMBDD+2-AAF. There were no alterations of the lymphoproliferative response and of the T lymphocyte subsets percentage in the DMBDD-treated group at the 4th and 30th weeks. At the 30th week, the T lymphocyte subsets percentage was also not affected in the initiated groups after treatments with 2-AAF or PB. The lymphoproliferative response, however, was decreased in the DMBDD+2-AAF group and in the groups treated only with 2-AAF or PB. The present results indicate that the initiating chemicals used in the DMBDD initiation protocol do not exert any influence on the immune system. The alteration of lymphoproliferative response induced at the advanced stage of carcinogenesis without alteration of T lymphocyte subsets may indicate that the influence of 2-AAF and PB on the immune system is functional and not toxic.
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Affiliation(s)
- A L Spinardi-Barbisan
- Department of Pathology, Faculty of Medicine, UNESP, Botucatu, 18618-000, SP, Brazil
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Mackewicz CE, Ridha S, Levy JA. Fas and Fas ligand are not involved in the suppression of HIV replication by CD8 cells. AIDS 2000; 14:204-5. [PMID: 10708293 DOI: 10.1097/00002030-200001280-00018] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/10/2023]
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Abstract
Systemic lupus erythematosus (SLE) is a systemic autoimmune disease that affects most of the organs and tissues of the body, causing glomerulonephritis, arthritis, and cerebritis. SLE can be fatal with nephritis, in particular, predicting a poor outcome for patients. In this review, we highlight what has been learned about SLE from the study of mouse models, and pay particular attention to anti-DNA autoantibodies, both as pathological agents of lupus nephritis and as DNA-binding proteins. We summarize the current approaches used to treat SLE and discuss the targeting of anti-DNA autoantibodies as a new treatment for lupus nephritis.
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Affiliation(s)
- N B Blatt
- Department of Chemistry, University of Michigan, Ann Arbor 48109-1055, USA
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Abstract
Pregnancy is an immunological balancing act in which the mother's immune system has to remain tolerant of paternal major histocompatibility (MHC) antigens and yet maintain normal immune competence for defense against microorganisms. The placenta separates fetal and maternal blood and lymphatic systems and it is fetal trophoblast that plays the major role in evading recognition by the maternal immune system. Trophoblast cells fail to express MHC class I or class II molecules and the extravillous cytotrophoblast cells strongly express the nonclassic MHC gene encoding HLA-G, which may downregulate natural killer (NK) cell function. In addition, the trophoblast expresses Fas ligand, thereby conferring immune privilege: maternal immune cells expressing Fas will undergo apoptosis at the placenta/decidua interface. A third protective mechanism exploited by the trophoblast is the expression of the complement regulatory proteins CD46, CD55, and CD59. Uterine decidual and placental cells produce a huge array of cytokines which, in part, contribute to the deviation of the immune response from Th1 to Th2. This may leave the mother more open to infection whose control is Th1-dependent, but increased production of Th1 cytokines has been linked to spontaneous abortion and small-for-dates babies. This bias in cytokines and hormonally mediated effects on the thymus and on B cells may also contribute to the suppression of autoimmune responses and changes in circulating and local T-cell subsets in pregnancy.
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Affiliation(s)
- A P Weetman
- Clinical Sciences Centre, University of Sheffield, Northern General Hospital, United Kingdom.
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18
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Furuke K, Shiraishi M, Mostowski HS, Bloom ET. Fas Ligand Induction in Human NK Cells Is Regulated by Redox Through a Calcineurin-Nuclear Factors of Activated T Cell-Dependent Pathway. THE JOURNAL OF IMMUNOLOGY 1999. [DOI: 10.4049/jimmunol.162.4.1988] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/02/2023]
Abstract
Abstract
Fas ligand (FasL) on cytotoxic lymphocytes is important for mediating apoptosis of activated lymphocytes and other target cells. We have reported that NK cell functions, such as proliferation, cell death, and killing activity, are subject to regulation by cellular redox status. Here, we report that expression of FasL protein and mRNA in activated NK cells is also regulated by redox. Ligation of CD16 on IL-2-preactivated NK cells resulted in reduction of intracellular peroxide level as well as induction of FasL expression. This CD16-induced FasL expression was suppressed by oxidative stress, including thiol deprivation or treatment with hydrogen peroxide (H2O2). Addition of thiol-reducing compounds, such as l-cystine, 2-ME, or N-acetyl cysteine, restored FasL expression. These data suggest that CD16 stimulation requires cellular reducing status for FasL induction in NK cells. Because FasL gene activation following CD16 cross-linking is regulated by the NF of activated T cells (NFAT), we examined the effect of oxidative stresses on NFAT activation. Electrophoretic mobility shift assays revealed that both thiol insufficiency and H2O2 treatment suppressed DNA-binding activity of NFAT and that addition of thiol-reducing compounds reversed or even enhanced it. Furthermore, these oxidative stresses inhibited activity of calcineurin, a serine/threonine phosphatase that regulates NFAT activation. These results suggest that suppression of calcineurin and NFAT activation is a mechanism by which oxidative stress inhibits FasL induction in activated NK cells and further support the hypothesis that thiol-reducing compounds might be required for maintenance of optimal NK functions under physiologic oxidative conditions.
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Affiliation(s)
- Keizo Furuke
- Laboratory of Cellular Immunology, Division of Cellular and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892
| | - Mitsuhiro Shiraishi
- Laboratory of Cellular Immunology, Division of Cellular and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892
| | - Howard S. Mostowski
- Laboratory of Cellular Immunology, Division of Cellular and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892
| | - Eda T. Bloom
- Laboratory of Cellular Immunology, Division of Cellular and Gene Therapies, Center for Biologics Evaluation and Research, Food and Drug Administration, Bethesda, MD 20892
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19
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Kong L, Ogawa N, McGuff HS, Nakabayashi T, Sakata KM, Masago R, Vela-Roch N, Talal N, Dang H. Bcl-2 family expression in salivary glands from patients with primary Sjögren's syndrome: involvement of Bax in salivary gland destruction. CLINICAL IMMUNOLOGY AND IMMUNOPATHOLOGY 1998; 88:133-41. [PMID: 9714690 DOI: 10.1006/clin.1998.4556] [Citation(s) in RCA: 60] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/15/2023]
Abstract
To investigate the molecular mechanism of glandular parenchyma destruction in Sjögren's syndrome (SS), Bcl-2, Bax, Bcl-X, and Bak expression were studied. SS (n = 18) and control salivary glands (n = 6) were examined by immunohistochemistry. Apoptosis was assessed by in situ DNA nick end labeling. Infiltrating mononuclear cells in the SS salivary gland showed elevated Bcl-2. These mononuclear cells expressed increased Bax but did not undergo apoptosis. Both SS and control salivary gland ductal epithelial cells expressed Bcl-2, Bax, and Bcl-X. SS, but not normal, salivary gland acinar cells expressed Bax and underwent apoptosis. These results suggest that elevated Bax expression in SS salivary gland acinar cells may play an important role in the apoptotic pathway. In contrast, Bcl-2 expression in SS infiltrating mononuclear cells and ductal cells may contribute to their survival.
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Affiliation(s)
- L Kong
- Division of Clinical Immunology, The University of Texas Health Science Center at San Antonio, San Antonio, Texas, 78284, USA
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