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PubMed2003

Liver transplantation for autoimmune hepatitis: fulminant versus chronic hepatitis presentation.

AIMS: The aim of this study was to analyse long-term outcomes of patients with liver transplantation for autoimmune hepatitis and to determine if fulminant/subfulminant hepatic failure (FSHF) at presentation was a predictor of outcome after ortothopic liver transplantation. PATIENTS AND METHODS: Between April 1990 and October 2002, 18 patients with autoimmune hepatitis underwent 21 liver transplants. Three patients were excluded because of coexisting causes of hepatitis. Seven patients had FSHF and eight patients had chronic disease. The initial immunosuppressive regimen was cyclosporine based in 80%, and all but one patient received steroids or azathioprine. RESULTS: Mean age at time of transplant was 44.2+/-15.5 years. Patients were followed for 38.9+/-29.6 months. Five patients (33.3%) had seven episodes of acute rejection (two steroid-resistant). Three patients developed chronic rejection. One patient displayed histologically proven recurrent autoimmune hepatitis. Actuarial patient and graft survival rates at 1 and 5 years were 80% and 56% and 78.6% and 51%, respectively. No differences in the clinical characteristics of the patients, rates of acute or chronic rejection episodes, end biliary or arterial complications were observed between FSHF and chronic autoimmune hepatitis. The study suggests a better survival for autoimmune FSHF (P=.003). CONCLUSIONS: Liver transplant is indicated for patients displaying autoimmune chronic liver disease and FSHF with similar clinical courses at however, patients with FSHF at presentation had better survivals.

Acute Disease↗

PubMed1993

Heat shock (stress) proteins and autoimmunity in rheumatic diseases.

The rheumatic diseases (RDs) are characterized by acute and chronic inflammation, and autoimmunity plays a major role in their pathogenesis. RDs are for the most part of unknown etiology, but recent evidence indicates that heat shock or stress proteins (HSPs) may have an important role in the etiology/pathogenesis of RDs. HSPs are produced by prokaryotic and eukaryotic cells and are grouped according to molecular weight. Phylogenetically, HSPs are very old and are remarkably conserved molecules in evolution from bacteria to humans. HSPs are induced by a variety of cellular stresses in addition to heat; cognates are expressed constitutively and are essential in a number of normal functions. Some HSPs serve as molecular chaperones, the latter defined as proteins that mediate folding of other polypeptides and either promote their assembly into oligomeric structures or disassemble the final product. Conservation of structure and function of many HSPs may provide a link between immunity to infection and the autoimmune features of RDs. Evidence is reviewed from clinical and laboratory observations that diverse microbial agents, including viruses, bacteria, and parasites, may have putative roles in the development and pathogenesis of some RDs. HSPs also are discussed in relation to the major histocompatibility complex, HLA antigens, and disease associations and how they may alter the balance between tolerance and autoimmunity. Studies are reviewed that are supportive or nonsupportive of the concept of microbial infection associated with autoimmunity; individuals first react to microbial immunizations or infections with enhanced cellular/humoral responses to the agent's HSPs. With the enhanced immune response, cross-reactivity may occur with an HSP of the stressed host because of structural similarities to the microbial HSP. If all of these events occur, the host's homologous HSP or stressed cells now become true autoantigen(s). This sequence has implications for the etiology of immune-mediated RDs, the concept of epitope sharing, and the accompanying autoimmunity. A recurring theme emphasized in some reports to understand better the role of HSPs in autoimmunity is the need to select patients with early-onset disease. A minor subpopulation of T lymphocytes express a CD3-associated T-cell receptor (TCR) heterodimer composed of gamma and delta polypeptide chains. The gamma delta + T cells have several unique features. When analyzed by the polymerase chain reaction, lymphocytes with TCR-gamma delta appear to reflect the polyclonal expansion of preexisting gamma delta clones. They are found in peripheral lymphoid tissue in very low percentage (< 5%) but may represent the majority of T cells within epithelial tissue.(ABSTRACT TRUNCATED AT 400 WORDS)

Amino Acid Sequence↗

PubMed1998

Malignant thymoma associated with autoimmune diseases: a retrospective study and review of the literature.

OBJECTIVES: To determine whether malignant thymoma is associated with high rates of concomitantly occurring autoimmune diseases. METHODS: Sheba Medical Center computer records from 1966 to 1995 were reviewed to identify patients with malignant thymoma, either type I (invasive thymoma) or type II (thymic carcinoma). All patients who had malignant thymoma and autoimmune phenomena were analyzed. The diagnosis of thymic neoplasm was confirmed by two independent pathologists. The diagnosis of autoimmune diseases was based on both clinical and serological findings. RESULTS: Six of 22 (27%) cases of malignant thymoma had an autoimmune disease. Five patients had type I malignant thymoma and either myasthenia gravis (four patients) or Graves' disease (one patient). Only one patient had type II malignant thymoma with Sjögren's syndrome. The diagnosis of autoimmune disease preceded the diagnosis of thymic neoplasm in four cases, and was diagnosed simultaneously in two. CONCLUSIONS: Malignant thymomas are highly associated with autoimmune diseases, as are benign thymomas. To our knowledge, we report the first documented cases of a patient with thymic carcinoma and Sjögren's syndrome, and another with invasive thymoma and Graves' disease.

Adult↗

PubMed2006

Immunodeficiencies with autoimmune consequences.

Far from being mutually exclusive, immunodeficiency and autoimmunity may occur simultaneously. During the last years, analysis of Autoimmune Polyendocrinopathy--Candidiasis--Ectodermal Dystrophy (APECED) and Immunodysregulation--Polyendocrinopathy--Enteropathy--X-linked (IPEX), two rare monogenic forms of immunodeficiency associated with autoimmunity, has led to the identification of Auto Immune Regulator (AIRE) and Forkhead Box P3 (FOXP3), essential transcriptional regulators, involved in central tolerance and peripheral immune homeostasis, respectively. Characterization of the molecular and cellular mechanisms involved in APECED, and recognition that AIRE expression is sustained by effective thymopoiesis, has recently allowed to define that the autoimmunity of Omenn syndrome, a combined immunodeficiency due to defects of V(D)J recombination, also results from defective expression of AIRE. The implications of identification of the basis of autoimmunity in these rare forms of immunodeficiency have important implications for a better understanding of more common autoimmune disorders, and for development of novel therapeutic approaches.

Animals↗

PubMed1991

Cytokines and autoimmune disease.

A wide array of cytokines are locally present in autoimmune lesions where they are produced by inflammatory cells or by the target cell of the autoimmune attack. The presence of cytokines at the site of autoaggression reflects ongoing inflammatory and activation processes. These mediators exert proinflammatory effects, contribute to the activation and stimulation of the effector function of T or B lymphocytes, directly participate in target cell destruction, and mediate accompanying local reactions, including fibrotic processes. The release of cytokines into the circulation may explain certain systemic reactions, including fever or changes in the profile of plasma proteins. Many, especially systemic, autoimmune diseases are accompanied by a dysregulation of lymphokine secretion at the level of circulating leukocytes or cells situated outside of the local inflammatory event, thus reflecting regulatory disorders that may either have a genetic or an acquired basis. Decreased production of lymphokines in vitro in response to nonspecific stimuli may be accompanied by an elevated spontaneous release in vivo resulting in an increase of circulating cytokine levels (interleukin 2, tumor necrosis factor-alpha). Secretion of interleukin 1, interleukin 2, and tumor necrosis factors-alpha or -beta, in part, is determined by genetic factors and it is possible that a particular secretor phenotype may predispose to the development of autoimmune lesions. Probably due to their pleiotropic nature, systemic administration of cytokines such as interleukin 1, interleukin 2, tumor necrosis factor, and interferon-gamma may exert either accelerating or suppressive effects on autoimmune diseases. Conversely, agents that block the function of the lymphokine interleukin 2 exert an unequivocal autoimmune disease-inhibiting effect.

Autoimmune Diseases↗

PubMed1998

Mechanism of ovarian autoimmunity: induction of T cell and antibody responses by T cell epitope mimicry and epitope spreading.

Autoimmune diseases are often manifested as organ inflammation with loss of function, and detectable autoreactive T cell and autoantibody responses. In the proper genetic context, we have shown that these parameters of autoimmunity can result from a single pivotal event: the induction of a strong and persistent T cell response for a foreign or unrelated self peptide that mimics the target self peptide. This may apply to organ-specific and systemic autoimmunity, independent of whether the tissue inflammation results from T cell immune mechanism or antibodies. T cell peptide mimicry, through sharing of critical residues or by a less defined mechanism, can result in autoimmune disease. Once triggered, the helper T cell response leads rapidly to a concomitant autoantibody response spreading to distant B cell determinants of the self protein antigen. Evidently, with T cell help, endogenous antigens can stimulate B cells to provoke a functional autoantibody response against conformational antigenic determinants. These findings are based on recent studies on a novel autoimmune ovarian disease model induced by a self peptide with well-defined T and B cell epitopes. However, studies reported on systemic lupus erythematosus models have shown that similar events may result in autoantibody response in systemic autoimmunity.

Animals↗

PubMed1999

Reduced corticotropin-releasing factor and enhanced vasopressin gene expression in brains of mice with autoimmunity-induced behavioral dysfunction.

The spontaneous development of autoimmune disease in MRL-lpr mice induces behavioral and endocrine changes that resemble effects of chronic stressors. To further examine the correspondence between autoimmune disease and chronic stress, we asked whether the brains of autoimmune mice show a shift in the corticotropin-releasing factor (CRF) to vasopressin (AVP) ratio. Using in situ hybridization histochemistry with 35S-labelled mouse riboprobes, the levels of mRNA transcripts encoding CRF and AVP were compared between autoimmune MRL-lpr and control MRL +/+ brains. CRF transcript levels were lower in the hypothalamic paraventricular nucleus and in the central nucleus of the amygdala in MRL-lpr mice. AVP transcript levels were higher in the paraventricular and the supraoptic nuclei in MRL-lpr mice compared to controls. CRF mRNA levels were inversely related to performance in stress-sensitive tasks and to measures of autoimmunity. As found previously for behavioral performance, immunosuppressive treatment with cyclophosphamide abolished the group difference in neuropeptide gene expression. These results indicate that an autoimmune disease process is necessary for the shift in the brain CRF:AVP ratio. Furthermore, they support the parallel between chronic stress and chronic autoimmunity/inflammation, and suggest common central mechanisms relevant to endocrine function and behavior.

Animals↗

PubMed2002

Severe autoimmune hepatitis in patients with previous spontaneous recovery of a flare.

BACKGROUND/AIMS: Autoimmune hepatitis can present acutely and pursues a variable, usually progressive course. Spontaneous remissions have been described, but their influence on the course of subsequent attacks has not yet been studied. METHODS: Charts from 1980 to 2000 were reviewed. Cases of autoimmune hepatitis were further examined to identify those with prior episodes of transient elevation of the serum aminotransferase activities of unknown etiology. RESULTS: Fifty-one patients with autoimmune hepatitis were identified, nine of whom (18%) had experienced a transient episode of elevated aminotransferase activities which had resolved spontaneously. The median period of time separating the two flares was 10 months (range: 4 months-23 years). The median age at diagnosis was 41 years in both groups. More than 75% of the patients in either group suffered from a type 1 autoimmune hepatitis. Importantly, patients with spontaneous recovery of a previous episode had a higher serum alanine transaminase activity (P<0.02), were less likely to respond to immunosuppressive therapy (78 versus 98%, P=0.077) and required transplantation more frequently (22 versus 0%, P=0.028). Histologically, these patients did not have more fibrosis than patients without previous flare. CONCLUSIONS: More than 10% of autoimmune hepatitis may begin with a spontaneously resolving episode. However, the spontaneous recovery of a previous attack should not falsely reassure: a subsequent flare of autoimmune hepatitis can still be severe.

Adolescent↗

PubMed1993

Evidence against hepatitis viruses as important causes of severe autoimmune hepatitis in the United States.

To determine if the hepatitis viruses are important etiologic factors in autoimmune hepatitis, the clinical, immunoserologic, virologic and HLA phenotypes of 105 of the latter patients were assessed prospectively and compared to 45 patients with chronic viral hepatitis. Patients with autoimmune hepatitis were more often women with higher serum aspartate aminotransferase and immunoglobulin levels than patients with viral disease. Only eight patients (8%) were seropositive for anti-HBc and anti-HBs (four patients) or anti-HCV (four patients) and none with anti-HCV were reactive by second generation immunoassay or recombinant immunoblot assay. Smooth muscle (90 vs. 22%, P < 0.001) and antinuclear (70 vs. 22%, P < 0.001) antibodies were more common in patients with autoimmune hepatitis and the titers more frequently exceeded 1:80 (84 vs. 11%, P < 0.0001). Patients with autoimmune hepatitis were more often positive for HLA B8 (48 vs. 20%, P < 0.01) and DR3 (49 vs. 20%, P < 0.003) and they more frequently had the HLA A1-B8-DR3 phenotype (38 vs. 10%, P < 0.003). Only one of the 120 patients tested for anti-LKM1 was seropositive. We conclude that in an American referral population autoimmune hepatitis usually lacks virologic markers and has a distinctive clinical, immunoserologic and HLA phenotype. Hepatitis viruses are not important immunogenic stimuli for non-organ specific antibodies and they are unlikely to be important causes of this form of autoimmune hepatitis.

Adult↗

PubMed1996

Evidence for an overlap syndrome of autoimmune hepatitis and primary sclerosing cholangitis.

BACKGROUND/AIMS: Autoimmune hepatitis, primary biliary cirrhosis and primary sclerosing cholangitis are chronic liver diseases with probable autoimmune background. Overlapping features have been described for primary biliary cirrhosis and autoimmune hepatitis. In contrast, there have been only a few case reports on an overlap of autoimmune hepatitis and primary sclerosing cholangitis. METHODS: We describe three male patients with clinical and histological overlapping features of primary sclerosing cholangitis and autoimmune hepatitis. RESULTS: All initially asymptomatic patients had elevated levels of aminotransferases, alkaline phosphatase, gamma-glutamyltranspeptidase and IgG. Anti-nuclear antibodies and/or smooth muscle antibodies were positive and anti-neutrophil cytoplasmic antibodies were detected in all patients. Retrograde endoscopic cholangiography showed bile-duct strictures characteristic for primary sclerosing cholangitis. Histopathology showed necro-inflammatory activity of portal tracts with bridging necrosis in all patients at the time of first diagnosis. Aminotransferase levels and the necro-inflammatory activity responded well to immunosuppressive treatment. Predominant periductular fibrosis as a typical histopathological feature of primary sclerosing cirrhosis was seen to develop in all patients. Cholestatic serum parameters remained elevated and periductular fibrosis as endoscopic bile duct changes progressed despite immunosuppression. CONCLUSIONS: We suggest that these patients present an overlap syndrome of autoimmune hepatitis and primary sclerosing cholangitis as they fulfill the diagnostic criteria for both conditions.

Adolescent↗

PubMed1996

GBV-C/HGV is not the major cause of autoimmune hepatitis.

Recently, GBV-C and HGV-two isolates of the same new flavivirus-were identified in serum samples of patients with indeterminate hepatitis and posttransfusion hepatitis, respectively. The pathogenic relevance of these viruses is still uncertain. As viral infections are presumed to trigger autoimmune processes, we investigated GBV-C in autoimmune hepatitis as well as in cryptogenic hepatitis, and compared the prevalences to patients with chronic viral hepatitis and those of blood donors. We found only a slightly higher prevalence of the virus in cryptogenic (12%) and autoimmune hepatitis type I-III (6.7%, 10%, and 12.5%) compared to blood donors (4.7%). In contrast, patients with viral hepatitis B, C, and D were more frequently infected with GBV-C (16%, 20%, 36%). These results suggest that GBV-C is not a major cause for inducing autoimmunity and leading to autoimmune hepatitis. We analyzed the nucleic acid sequences of a representative number of GBV-C positive patients (24/42) and found a broad range of nucleotide similarity in the NS3 helicase region (74-100%) among the isolates and the prototype sequences. However, we could not identify a specific sequence, which would point to a certain strain or subtype of the virus associated with autoimmune or cryptogenic liver disease.

Autoimmune Diseases↗

PubMed1999

Long-term follow-up after liver transplantation for autoimmune hepatitis: evidence of recurrence of primary disease.

BACKGROUND/AIMS: After liver transplantation for autoimmune hepatitis, the long-term results and the incidence of recurrence of primary disease are unknown. METHODS: In this retrospective study we reviewed the clinical course of 25 patients transplanted for autoimmune hepatitis and followed for a mean of 5.3 years (2-8.5 years). RESULTS: The actuarial 5-year patient and graft survival rates were 91% (+/-6%) and 83% (+/-8%). The actuarial 1-year rate of acute rejection was 50% (+/-10.2%), which was comparable to that of patients transplanted for primary biliary cirrhosis and primary sclerosing cholangitis. Autoantibodies persisted in 77% of patients, at a lower titer than before liver transplantation. Ten patients were excluded from the study of autoimmune hepatitis recurrence, one because of an early postoperative death and nine because of hepatitis C virus infection acquired before or after liver transplantation. In the remaining 15 patients, who were free of hepatitis C virus infection, 5-year patient and graft survivals were 100% and 87%, respectively. Despite triple immunosuppressive therapy, three patients (20%) developed chronic hepatitis with histological and serological features of autoimmune hepatitis in the absence of any other identifiable cause. The disease was severe in two patients, leading to graft failure and asymptomatic in another, despite marked histological abnormalities. In one of these three patients, autoimmune hepatitis recurred on the second liver graft as well. CONCLUSIONS: Patients undergoing liver transplantation for autoimmune hepatitis have an excellent survival rate although severe primary disease may recur, suggesting the need for stronger post-operative immunosuppressive therapy.

Adolescent↗

PubMed1999

HLA antigens in patients with interferon-alpha-induced autoimmune thyroid disorders in chronic hepatitis C.

BACKGROUND/AIMS: To determine the immunological predisposition to autoimmune thyroid disorders induced by interferon-alpha therapy, human leukocyte antigen (HLA) was analyzed in patients with chronic hepatitis C who developed autoimmune thyroid disorders during or after treatment with interferon-alpha. METHODS: Four hundred and thirty-nine patients with chronic hepatitis C (278 males and 161 females, aged 20-73 years) were treated with interferon-alpha (natural-alpha, 169; alpha-2a, 82; alpha-2b, 188) for 24 weeks. RESULTS: Seventeen of 439 (3.9%) patients developed symptomatic autoimmune thyroid disorders; these included nine cases of hyperthyroidism and eight cases of hypothyroidism. The incidence of HLA-A2, B46 and Cw7 increased in patients with interferon-alpha-induced autoimmune thyroid disorders. Especially, the incidence of HLA-A2 (15/17; 88.2%) was significantly higher than that observed in the general population in Japan (corrected p-value (p(c)): p(c)<0.003). The odds ratios for the relative risk of the autoimmune thyroid disorders were A2, 10.6 [95% confidence interval, 2.4-46.5]; B46, 4.8 [1.6-14.0]; and Cw7, 3.0 [1.1-7.9]. CONCLUSIONS: Our study revealed that HLA-A2 is highly linked to the autoimmune thyroid disorders induced by interferon-alpha-therapy in patients with chronic hepatitis C.

Adult↗

PubMed2001

Differential expression of metallothioneins in the CNS of mice with experimental autoimmune encephalomyelitis.

Multiple sclerosis is an inflammatory, demyelinating disease of the CNS. Metallothioneins-I+II are antioxidant proteins induced in the CNS by immobilisation stress, trauma or degenerative diseases which have been postulated to play a neuroprotective role, while the CNS isoform metallothionein-III has been related to Alzheimer's disease. We have analysed metallothioneins-I-III expression in the CNS of mice with experimental autoimmune encephalomyelitis. Moreover, we have examined the putative role of interferon-gamma, a pro-inflammatory cytokine, in the control of metallothioneins expression during experimental autoimmune encephalomyelitis in interferon-gamma receptor knockout mice with two different genetic backgrounds: 129/Sv and C57BL/6x129/Sv. Mice with experimental autoimmune encephalomyelitis showed a significant induction of metallothioneins-I+II in the spinal cord white matter, and to a lower extent in the brain. Interferon-gamma receptor knockout mice suffered from a more severe experimental autoimmune encephalomyelitis, and interestingly showed a higher metallothioneins-I+II induction in both white and grey matter of the spinal cord and in the brain. In contrast to the metallothioneins-I+II isoforms, metallothionein-III expression remained essentially unaltered during experimental autoimmune encephalomyelitis; interferon-gamma receptor knockout mice showed an altered metallothionein-III expression (a slight increase in the spinal cord white matter) only in the C57BL/6x129/Sv background. Metallothioneins-I+II proteins were prominent in areas of induced cellular infiltrates. Reactive astrocytes and activated monocytes/macrophages were the sources of metallothioneins-I+II proteins. From these results we suggest that metallothioneins-I+II but not metallothionein-III may play an important role during experimental autoimmune encephalomyelitis, and indicate that the pro-inflammatory cytokine interferon-gamma is unlikely an important factor in this response.

Animals↗

PubMed2000

Autoimmunity and toxicity testing.

Major difficulties when addressing autoimmunity today within the context of regulatory toxicology are the following: (i) the incidence of auto-immunity related to chemical exposure is not known; (ii) the mechanisms involved are not understood in most instances; and (iii) no fully validated models are available. Although no relationship has been firmly established between the serum levels of autoantibodies and the development and/or the severity of autoimmune diseases, these are considered the hallmarks of autoimmunity. It has proved impossible so far to detect reproducibly autoantibodies indicative of organ-specific autoimmune reactions induced by chemicals in conventional toxicity testing. The detection of autoantibodies suggestive of a systemic autoimmune reaction has been successful with very few compounds only, and most often using non-conventional strains of animals. Genetically-deficient animal strains were sometimes helpful, but these models should be standardised and validated. This also applies to experimental autoimmune disease models. The popliteal lymph node (PLN) assay is potentially helpful, but more research and validation efforts are warranted. From a regulatory toxicology perspective, the search for serum autoantibodies, as it is performed today, does not seem to be a reliable tool, and progress is more likely to be expected from the design, standardisation and validation of dedicated models.

Animals↗

PubMed2002

Autoantibodies in autoimmune polyendocrine syndrome type II.

The autoimmune polyendocrine syndrome type II (APS-II) is characterized by the association of autoimmune Addison's disease with thyroid autoimmune diseases or type-1 diabetes mellitus. 21-Hydroxylase autoantibodies enable the accurate diagnosis of autoimmune Addison's disease and, in patients with other endocrine autoimmune diseases, identify subjects at high risk for clinical adrenal insufficiency. 17 alpha-Hydroxylase (17OH) and side-chain-cleavage enzyme (P450scc) are target autoantigens of steroid-cell autoantibodies, and in women with Addison's disease, 17OH autoantibodies and P450scc autoantibodies are markers of increased risk for premature ovarian failure. Thyroperoxidase autoantibodies, thyroglobulin autoantibodies, H+/K(+)-ATPase autoantibodies, and GAD65 autoantibodies are frequently detected in patients with isolated Addison's or APS-II. Screening for other organ-specific autoimmune diseases should be performed in every patient with at least one major disease component of APS-II.

Addison Disease↗

PubMed1999

Autoimmunity against desmosomal cadherins in pemphigus.

Pemphigus is a unique and interesting autoimmune disease, in which autoantibodies play a major pathogenic role and cause blister formation. Several questions raised from clinical observation in pemphigus have been answered with logic at the molecular level owing to recent remarkable progress in research in the field of pemphigus. The clinical phenotype of classic pemphigus, pemphigus vulgaris (PV) and pemphigus foliaceus (PF), is defined by anti-desmoglein autoantibody profile. Sera containing anti-Dsg3 IgG alone cause mucosal dominant PV with limited skin involvement. Sera containing both anti-Dsg3 and anti-Dsg1 cause mucocutaneous PV, which affects both the skin and mucous membrane. Sera containing only anti-Dsg1 cause PF, which shows cutaneous but no mucosal involvement. In herpetiform pemphigus (HP) most sera recognize Dsg1 and the rest of them recognize Dsg3, indicating that HP is a clinical variant of PF or PV. Patients with paraneoplastic pemphigus (PNP) have autoantibodies against multiple molecules. Now we know that they have autoantibodies against all members of the plakin family, which are cytoplasmic proteins and include desmoplakin, BPAG1, envoplakin, periplakin, and plectin. Cell surface target antigens of PNP, which blister-inducing pathogenic autoantibodies attack, were finally discovered to be Dsg3 and Dsg1. Therefore, PNP is characterized as an autoimmune disease against plakin molecules and desmogleins. Autoimmune targets of IgA pemphigus are likely more heterogeneous than originally thought. So far, desmocollin 1, Dsg3, and Dsg1 are known as their target antigens. Thus, pemphigus has become one of well-characterized tissue-specific autoimmune diseases. Pemphigus will be a good model disease in the next century to address the central issue of autoimmune disease and basic immunology; why and how do patients with autoimmune diseases start to recognize self as non-self?

Animals↗

PubMed1999

MHC structure and autoimmune T cell repertoire development.

Recent work has continued to clarify the relationship between MHC structure and thymic selection that leads to peripheral T cell repertoire development in the pathogenesis of autoimmune diseases. Particular attention has been focused on the nonobese diabetic model of autoimmune diabetes, in which a unique MHC class II molecule (I-Ag7) plays a central role. In the past year, reports on the biochemistry of I-Ag7-combined with analysis of the role of I-Ag7 in T cell repertoire selection--support a model of defective thymic selection as the basis of the association between particular MHC molecules and autoimmune diseases. Analogous work has been done on the structure of the human MHC disease-susceptible and -resistant alleles, DQA1*0301 DQB1*0302 and DQA1*0102 DQB1*0602, and their effect on autoimmune repertoire selection. Comparison of these results (in naturally occurring, spontaneous autoimmune human and murine diabetes), with results in a variety of transgenic and knockout models, has produced an integrated view of how avidity considerations in repertoire selection in the thymus could affect predisposition towards autoimmunity.

Animals↗