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At least 1,009 records · Page 56Linked to original sources

PubMed2000

Type 1 diabetes in offspring of parents with type 1 diabetes: the tip of an autoimmune iceberg?

The objective of the present study was to examine the prevalence of self-reported autoimmune diseases among offspring of type 1 fathers, type 1 diabetic mothers, and non-diabetic parents. Type 1 diabetic probands (n=265; mean age=42 yr), who were ascertained from the Children's Hospital of Pittsburgh Registry for 1950-1964, recently participated in the Familial Autoimmune and Diabetes Study. Non-diabetic probands (n=96), identified from voter registration lists and matched by age, race, median income, and duration of residence in the Pittsburgh area, were also enrolled. Offspring of type 1 diabetic probands were more likely to have a reported autoimmune disease (5.8% vs. 2.4%; p=0.067) than offspring of non-diabetic probands. Half the cases in the diabetic families were disorders other than type 1 diabetes, (e.g., rheumatoid arthritis, Crohn's disease, etc.). Stratification by parental gender revealed a marginally higher risk for type 1 diabetes among offspring of type 1 diabetic fathers compared to mothers (4.9% vs. 3.4%; p=0.38, respectively, through age 20 yr). However, the risk for other autoimmune disorders was statistically significantly increased among offspring of type 1 diabetic mothers (0% vs. 6.2%; p=0.02, respectively, through age 20 yr). These data suggest that offspring of type 1 diabetic parents may be at high risk of developing other autoimmune disorders during childhood, with pediatric diabetes representing the 'tip of an autoimmune iceberg'. The observed risk differences by parental gender, which have also been reported for other autoimmune disorders, warrant further investigation.

Journal Article↗

PubMed2004

Aromatase-deficient mice spontaneously develop a lymphoproliferative autoimmune disease resembling Sjogren's syndrome.

Sjögren's syndrome (SS) is an incurable, autoimmune exocrinopathy that predominantly affects females and whose pathogenesis remains unknown. Like rheumatoid arthritis, its severity increases after menopause, and estrogen deficiency has been implicated. We have reported that estrogen receptor-alpha and -beta-knockout mice develop autoimmune nephritis and myeloid leukemia, respectively, but neither develops SS. One model of estrogen deficiency in rodents is the aromatase-knockout (ArKO) mouse. In these animals, there is elevated B lymphopoiesis in bone marrow. We now report that ArKO mice develop severe autoimmune exocrinopathy resembling SS. By 1 year of age, there is B cell hyperplasia in the bone marrow, spleen, and blood of ArKO mice and spontaneous autoimmune manifestations such as proteinuria and severe leukocyte infiltration in the salivary glands and kidney. Also, as is typically found in human SS, there were proteolytic fragments of alpha-fodrin in the salivary glands and anti-alpha-fodrin antibodies in the serum of both female and male ArKO mice. When mice were raised on a phytoestrogen-free diet, there was a mild but significant incidence of infiltration of B lymphocytes in WT mice and severe destructive autoimmune lesions in ArKO mice. In age-matched WT mice fed a diet containing normal levels of phytoestrogen, there were no autoimmune lesions. These results reveal that estrogen deficiency results in a lymphoproliferative autoimmune disease resembling SS and suggest that estrogen might have clinical value in the prevention or treatment of this disease.

Animals↗

PubMed1988

Functional heterogeneity of L3T4+ T cells in MRL-lpr/lpr mice. L3T4+ T cells suppress major histocompatibility complex-self-restricted L3T4+ T helper cell function in association with autoimmunity.

The present study demonstrates in MRl-lpr/lpr autoimmune mice an age-dependent loss of MHC-self-restricted function by L3T4+ Th. This defect is not present in age-matched, congenic MRL-+/+ spleen cells and appears to be due to the presence of suppressor cells that are selective for L3T4+ Th and not for Lyt-2+ Th. Surprisingly, the suppressor cells are also L3T4+ T cells and can suppress the IL-2 production of congenic MRL/+ L3T4+ Th to MHC-self-restricted antigens. These data support the idea of functional specialization within the L3T4+ population of T cells. Because L3T4+ suppressor cells are detected late in the course of autoimmunity, we interpret their presence not as a primary initiating event in the development of autoimmunity, but rather as a compensatory mechanism. Additionally, similar suppression of L3T4+ Th function has also been reported in a murine graft-vs.-host model of autoimmunity, suggesting that the suppressor cells represent an immunoregulatory mechanism that is a common feature of autoimmunity. Since excessive class II-restricted Th activity for B cells has been reported for both models of autoimmunity, L3T4+ suppressor cells may represent an attempt to down regulate such excessive Th activity. These findings may be relevant to human autoimmune diseases, such as systemic lupus erythematosus, in which B cell hyperactivity is also associated with reduced IL-2 production by Th.

Aging↗

PubMed2000

Autoimmune liver disease.

Regional differences in the manifestations of autoimmune hepatitis underscore the importance of genetic and/or environmental factors in its expression. The -308 polymorphism of TNF-A increases susceptibility to type 1 autoimmune hepatitis; HLA DRB1*13 is an important risk factor in South America; and DRB1*07 characterizes type 2 autoimmune hepatitis. Minocycline and mesalazine can trigger the disease, and interferon therapy can accentuate autoimmune manifestations. Autoimmune cholangitis in Japan is similar to primary biliary cirrhosis, and assays for carbonic anhydrase II lack diagnostic specificity. Perinuclear antineutrophil cytoplasmic antibodies are reactive to diverse nuclear antigens, but high mobility nonhistone chromosomal proteins may be important targets in autoimmune hepatitis. T cells can cross-react with viral and host peptides, and the candidacy of glutathione S-transferases as target autoantigens has been weakened. A murine model of PBC will be useful in studying mechanisms of autoreactivity, and cyclosporine has shown promise in the treatment of children with autoimmune hepatitis. Recurrence after liver transplantation is common, and it may require retransplantation. The human transplantation model will be valuable in understanding the host-and organ-specific contributions to disease expression.

Journal Article↗

PubMed2004

Autoimmune thrombocytopenic purpura and common variable immunodeficiency: analysis of 21 cases and review of the literature.

To describe the main characteristics and outcome of autoimmune thrombocytopenic purpura (AITP) in patients with common variable immunodeficiency (CVID), we analyzed data from 21 patients and reviewed additional cases from the literature. To be included in this study, patients had to have CVID and a previous history of AITP with a platelet count < or = 50 x 10(9)/L at onset. A complete response to treatment was defined by a platelet count > or = 150 x 10(9)/L, and a partial response by a platelet count >>50 x 10(9)/L with an increase of at least twofold the initial level. The median platelet count at AITP diagnosis was 20 x 10(9)/L (range, 2-50 x 10(9)/L). The median age at AITP diagnosis was 23 years (range, 1-51 yr), whereas the median age at CVID diagnosis was 27 years (range, 10-74 yr). CVID was diagnosed before the onset of AITP in only 4 patients (19%), 3 of whom were being treated with intravenous immunoglobulin (i.v.Ig) replacement therapy. CVID was diagnosed more than 6 months after AITP in 13 cases (62%), and the 2 conditions were diagnosed concomitantly in 4 cases. Eleven patients (52%) had at least 1 autoimmune manifestation other than AITP, among which autoimmune hemolytic anemia (7 cases) and autoimmune neutropenia (5 cases) were preeminent. Seventeen of the 21 patients (80%) received at least 1 treatment for AITP; 13 patients received corticosteroids alone and 7 (54%) achieved at least a partial response; 8 patients received i.v.Ig at 1-2 g/kg alone or in combination with steroids, leading to a short-term response rate of 50%. Four patients underwent a splenectomy (2 complete responses, 2 failures); 2 additional splenectomies were performed for associated autoimmune hemolytic anemia. With a mean follow-up of 5.6 years after the surgical procedure, none of the 6 splenectomized patients had a life-threatening infection. With a median follow-up after AITP onset of 12 years, 13/21 patients (62%) were in treatment-free remission (7 complete responses, 6 partial responses), 7 patients (23%) were in remission while on prednisone < or = 20 mg/day with or without azathioprine, and only 1 patient still had a platelet count <50 x 10(9)/L. Five patients had died at the time of the analysis; none of the deaths was related to a hemorrhage. Severe infections including 3 fatal bacterial infections and 2 opportunistic infections occurred in 6 patients during or after treatment of AITP. In conclusion, AITP, alone or in combination with autoimmune hemolytic anemia (Evans syndrome) and/or autoimmune neutropenia, is frequent in patients with CVID, and is not prevented by i.v.Ig substitutive therapy. Since AITP frequently precedes the diagnosis of CVID, testing for immunoglobulin levels should be performed in every patient diagnosed with AITP. Steroids and splenectomy seem to have the same efficacy as in idiopathic AITP, but the increased risk of severe infections must be taken into consideration.

Adolescent↗

PubMed2007

Lupus erythematosus and other autoimmune diseases related to statin therapy: a systematic review.

BACKGROUND: Statins have been increasingly associated with drug-induced autoimmune reactions, including lupus erythematosus. OBJECTIVE: To identify and determine the clinical and biological characteristics of statin-induced autoimmune reactions. MATERIAL AND METHODS: The MEDLINE database (1966 to September 2005) was used to identify all reported cases of statin-induced autoimmune diseases. The keywords used were statins, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors, adverse effects, autoimmune disease, lupus erythematosus, dermatomyositis and polymyositis. RESULTS: Twenty-eight cases of statin-induced autoimmune diseases have been published so far. Systemic lupus erythematosus was reported in 10 cases, subacute cutaneous lupus erythematosus in three cases, dermatomyositis and polymyositis in 14 cases and lichen planus pemphigoides in one case. Autoimmune hepatitis was observed in two patients with systemic lupus erythematosus. The mean time of exposure before disease onset was 12.8+/-18 months; range 1 month-6 years. Systemic immunosuppressive therapy was required in the majority of cases. In many patients, antinuclear antibodies were still positive many months after clinical recovery. A lethal outcome has been recorded in two patients despite aggressive immunosuppressive therapy. CONCLUSION: Long-term exposure to statins may be associated with drug-induced lupus erythematosus and other autoimmune disorders. Fatal cases have been reported despite early drug discontinuation and aggressive systemic immunosuppressive therapy.

Humans↗

PubMedDate not supplied

Incidence of autoimmune antibodies in failed embryo transfer cycles.

PROBLEM: The presence of antiphospholipid antibodies lupus anticoagulant (LAC), anticardiolipin antibody (ACA) as well as antinuclear antibody (ANA) has been associated with early spontaneous pregnancy loss and adverse pregnancy outcome. The purpose of this study was to investigate the possible role of autoimmune antibodies (LAC, ACA, and ANA) as a cause of implantation failure following embryo transfer (ET) after in vitro fertilization (IVF). METHOD: Three groups were studied: Group I, 56 patients who failed to conceive following ET; group II, 14 patients who have conceived following IVF-ET and delivered or are carrying an uncomplicated ongoing pregnancy; and group III, 69 patients who were new candidates for IVF-ET. RESULTS: Eighteen out of 56 (32.1%) of patients who failed to conceive following previous IVF-ET cycle (group I) tested positive for one or more of the autoimmune antibodies. None of the 14 patients of group II tested positive for autoimmune antibodies (P < .02). Seven out of the 69 patients (10%) of group III were found positive to one or more of the autoimmune factor. This rate is significantly lower than the rate of positive autoimmune antibodies detected in group I (P < .003). Fifteen patients of the 18 who tested positive for autoimmune antibodies and who had previously failed to conceive following ET underwent a subsequent IVF-ET cycle while being treated with prednisone and aspirin. Seven out of the 15 (46.6%) conceived and were able to sustain a clinical ongoing pregnancy. CONCLUSIONS: Patients receiving ET are carrying viable embryos within the intrauterine environment. Therefore, in this unique group of patients, failure to demonstrate a positive pregnancy test represents an implantation failure or a very early postimplantation loss. The results of this study suggest that periimplantation events may be affected by autoimmune antibodies. Very early miscarriage or implantation failure may be related to the same pathophysiological mechanism that causes recurrent miscarriages and is diagnosed incorrectly as infertility.

Adult↗

PubMed1992

Serum autoantibodies and the diagnosis of type-1 autoimmune hepatitis in Italy: a reappraisal at the light of hepatitis C virus infection.

Antinuclear antibodies with the homogeneous pattern (ANA-H) and smooth muscle antibodies with antiactin specificity (SMA-AA) are regarded as the serum markers of type-1 autoimmune chronic hepatitis. Their diagnostic relevance, however, has been questioned recently after the detection of signs of hepatitis C virus infection in autoimmune chronic hepatitis patients. To further evaluate this point, antihepatitis C virus antibodies were sought by two second generation assays (ELISA 2 and RIBA 2) in 100 Italian patients with chronic liver disease of unknown aetiology, including 46 with (autoimmune chronic hepatitis) and 54 without the above antibodies (cryptogenic). By ELISA 2, antihepatitis C virus, although significantly prevalent in cryptogenic (83%), were found also in a substantial proportion of autoimmune chronic hepatitis patients (46%) (p < 0.0001), their occurrence was confirmed by RIBA 2 in almost all cases (96% and 86%, respectively). Autoimmune patients with either ANA-H or SMA-AA exhibited similar antihepatitis C virus prevalences (59% and 52%, respectively); by contrast, the eight cases positive for both the autoantibodies were consistently antihepatitis C virus negative. These findings confirm that in countries with high hepatitis C virus circulation (like Italy) an overlap between autoimmune chronic hepatitis and hepatitis C virus infection, reflected by 'true' antihepatitis C virus antibodies, does occur. The detection of ANA-H or SMA-AA, in fact, identifies chronic liver disease patients with a relatively low prevalence of antihepatitis C virus, but does not exclude hepatitis C virus infection. Positive findings for both ANA-H and SMA-AA, however, is an appropriate marker for hepatitis C virus free 'primary' autoimmune chronic hepatitis.

Actins↗

PubMed2005

Abnormal regulation of the cytoskeletal regulator Rho typifies macrophages of the major murine models of spontaneous autoimmunity.

Macrophages (mphi) from prediseased mice of all the major murine models of spontaneous autoimmunity have an identical defect in cytokine expression that is triggered by serum and/or apoptotic cells. We show here that mphi from prediseased mice of the same models of spontaneous autoimmunity share a serum-dependent defect in the activity of Rho, a cytoplasmic G protein and cytoskeletal regulator. Affected strains include those developing lupus (BXSB, LG, MRL/l+, MRL/lpr, NZBWF1) and autoimmune diabetes (nonobese diabetic). No similar defect in Rho activity occurred in seven control strains. In the presence of serum, Rho activity in mphi from all autoimmune-prone strains was reduced to less than 10% of that in control mice. In contrast, under serum-free conditions, Rho activity was completely normal in autoimmune-prone mphi. The activities of Ras, another cytoplasmic G protein, and Rac and Cdc42, two additional G protein regulators of the cytoskeleton, were regulated normally in autoimmune-prone strains. Serum-dependent dysregulation of Rho was associated with multiple abnormalities, including increased adhesion to various surfaces, a more spread dendritic morphology, and an altered actin cytoskeletal organization. Our results suggest that mphi from multiple, genetically diverse, autoimmune-prone strains share a mutation or allelic difference affecting signal transduction within a specific Rho-regulatory pathway.

Alleles↗

PubMed2000

Cellular and molecular mechanism for Kilham rat virus-induced autoimmune diabetes in DR-BB rats.

Kilham rat virus (KRV) causes autoimmune diabetes in diabetes-resistant BioBreeding (DR-BB) rats; however, the mechanism by which KRV induces autoimmune diabetes without the direct infection of beta cells is not well understood. We first asked whether molecular mimicry, such as a common epitope between a KRV-specific peptide and a beta cell autoantigen, is involved in the initiation of KRV-induced autoimmune diabetes in DR-BB rats. We found that KRV peptide-specific T cells generated in DR-BB rats infected with recombinant vaccinia virus expressing KRV-specific structural and nonstructural proteins could not induce diabetes, indicating that molecular mimicry is not the mechanism by which KRV induces autoimmune diabetes. Alternatively, we asked whether KRV infection of DR-BB rats could disrupt the finely tuned immune balance and activate autoreactive T cells that are cytotoxic to beta cells, resulting in T cell-mediated autoimmune diabetes. We found that both Th1-like CD45RC+CD4+ and cytotoxic CD8+ T cells were up-regulated, whereas Th2-like CD45RC-CD4+ T cells were down-regulated, and that isolated and activated CD45RC+CD4+ and CD8+ T cells from KRV-infected DR-BB rats induced autoimmune diabetes in young diabetes-prone BioBreeding (DP-BB) rats. We conclude that KRV-induced autoimmune diabetes in DR-BB rats is not due to molecular mimicry, but is due to a breakdown of the finely tuned immune balance of Th1-like CD45RC+CD4+ and Th2-like CD45RC-CD4+ T cells, resulting in the selective activation of beta cell-cytotoxic effector T cells.

Acute Disease↗

PubMed2004

Up-regulation of CD1d expression restores the immunoregulatory function of NKT cells and prevents autoimmune diabetes in nonobese diabetic mice.

The immunoregulatory function of NKT cells is crucial for prevention of autoimmunity. The prototypical NKT cell Ag alpha-galactosylceramide is not present in mammalian cells, and little is known about the mechanism responsible for NKT cell recruitment and activation. Up-regulation of CD1d, the NKT cell restriction molecule, expressed on mononuclear cells infiltrating the target organ, could represent the physiological trigger for NKT cells to self-contain T cell immunity and to prevent autoimmune disease. Recognition of CD1d, either by itself or bound to self-ligands (selfCD1d), could drive NKT cells toward an immunoregulatory phenotype. Hence, ineffective NKT cell-mediated immunoregulation in autoimmune-prone individuals including nonobese diabetic (NOD) mice could be related to defective signals that regulate CD1d expression at time and site of autoimmunity. To test this hypothesis, we transgenically overexpressed CD1d molecules under the control of the insulin promoter within the pancreatic islets of NOD mice (insCD1d). Recognition of overexpressed CD1d molecules rescued NKT cell immunoregulatory function and prevented autoimmune diabetes in insCD1d transgenic NOD mice. Protection from diabetes was associated with a biased IL-4-secreting cytokine phenotype of NKT cells and alteration of the cytokine microenvironment in the pancreatic lymph nodes of transgenic mice. The net effect was a reduced development of the autoimmune T cell repertoire. Our findings suggest that up-regulation of CD1d expression during inflammation is critical to maintain T cell homeostasis and to prevent autoimmunity.

Animals↗

PubMed2001

Spontaneous formation of germinal centers in autoimmune mice.

The mechanisms of autoantibody production are not well understood. Germinal centers (GC) may be important sites of immune disregulation in autoimmune diseases. In this study, we document the presence of spontaneous GC formation in the spleens of several autoimmune mouse strains that spontaneously develop autoimmune Type I diabetes and a lupus-like disease. In contrast, mouse strains that do not develop lupus did not exhibit spontaneous formation of GC. In all of the autoimmune strains studied, GC were present at 1-2 months of age, a time that closely parallels the appearance of autoantibodies. Like the GC that develop after purposeful immunization, GC in autoimmune mice contained B220(+), PNA(+), and GL-7(+) B cells, and FDC-M1(+) follicular dendritic cells. In addition, spontaneously formed GC in autoimmunity and those caused by immunization were abrogated in a similar way by a short-term treatment with anti-CD40 ligand antibody. These data indicate that spontaneously forming GC in autoimmunity are similar to those appearing after purposeful immunization.

Animals↗

PubMed2003

C-peptide and autoimmune markers in diabetes.

Autoimmune markers such as islet cell antibodies (ICA), glutamic acid decarboxylase antibodies (GADA) and islet antigen-2 antibodies (IA-2A) are found in high frequencies among type 1 patients and especially among younger patients. Presence of these autoantibodies confirms the destructive process of the beta cells associated with immune-mediated type 1 diabetes. Type 2 diabetes is characterised by peripheral insulin resistance and a relative deficiency in insulin production. However, when autoimmune markers are analysed these are found in about 10% of patients clinically classified as type 2 diabetes, indicating that the frequency of type 1 diabetes is underestimated. GADA is the most frequent marker both among patients clinically classified as type 1 and type 2. GADA is also highly predictive for insulin treatment in patients not classified as type 1 diabetes. C-peptide is the best marker of the endogenous insulin production. Sampling of C-peptide is preferably done in the non-fasting condition since these values differentiate better between autoimmune and non-autoimmune diabetes. The presence of autoimmune markers at diagnosis predicts a course of further deteriorating beta cell function, whereas absence of autoimmune markers predicts stable beta cell function for the first two years in adults. Presence of GADA and in particular in high levels are prognostic for a low beta cell function within the next few years after diagnosis. Positivity only for ICA indicates a more preserved beta cell function for the first three years compared to positivity for other autoimmune markers.

Autoantibodies↗

PubMed2004

Different familial association patterns of autoimmune diseases between juvenile-onset systemic lupus erythematosus and juvenile rheumatoid arthritis.

The aim of this study was to determine if the prevalence of autoimmune disorders in the relatives of patients with systemic lupus erythematosus (SLE) is greater than that of relatives of patients with juvenile rheumatoid arthritis (JRA). Interviews were used to obtain histories of the following autoimmune disorders among living or deceased first-, second-, and third-degree relatives of 91 SLE and 110 JRA families: ankylosing spondylitis, SLE, rheumatoid arthritis (RA), JRA, multiple sclerosis, juvenile dermatomyositis, Sjögren's syndrome, myasthenia gravis, psoriasis, and thyroid diseases. There were statistically significant differences between the SLE and JRA probands in mean age and gender ratio (19.1 +/- 4.8 vs 14.0 +/- 5.5 years; M (male)/F (female): 17/74 vs 62/48, p<0.005). The prevalence rate of autoimmune diseases in relatives of SLE families (20.9%) was greater than in JRA families (11.8%), but not statistically significantly so. The mean age (18.0 +/- 5.3 vs 14.0 +/- 4.3 years), mean age at diagnosis (13.4 +/- 4.3 vs 7.9 +/- 3.9 years) and gender ratio (F/M, 16/3 vs 5/8) of the patients with affected relatives between these 2 groups all had statistically significant differences. A higher prevalence of SLE in relatives was found in SLE families than in JRA cases. Furthermore, this study revealed a higher incidence of autoimmune disorders among second- and third-degree relatives of SLE or JRA probands versus first-degree ones, especially sisters (including 1 pair of twins) and the maternal aunt in SLE families. These data demonstrate that the prevalence of autoimmune disorders in the relatives of patients with SLE is greater than those of relatives of patients with JRA. This suggests that clinically different autoimmune phenotypes may share common susceptibility genes, which may act as risk factors for autoimmunity.

Adolescent↗

PubMed1993

Polyendocrine autoimmunity in thyroid diseases.

Anti-adrenal and anti-pituitary autoantibodies have been determined in 45 patients with autoimmune diseases of the thyroid, including 25 patients with Graves' disease and 20 patients with hypothyroidism of autoimmune origin. The determinations were carried out with the use of solid-phase RIA methods previously developed by us, involving polyethylene tubes coated with the solubilized microsomal fractions obtained from human adrenal and pituitary glands. In the majority of patients with autoimmune diseases of the thyroid the presence of both anti-adrenal and anti-pituitary autoantibodies was detected. In 13 among 20 patients with hypothyroidism of autoimmune origin, the presence of anti-adrenal autoantibodies, and in 12 the presence of anti-pituitary autoantibodies was found. Among 25 patients with Graves' disease, 19 had both anti-adrenal and anti-pituitary autoantibodies. In the majority of patients with autoimmune diseases of the thyroid the titers of autoantibodies of both types were high but in no case were the clinical symptoms of adrenal or pituitary hypofunction observed. Our studies indicate that the thyroid diseases of autoimmune origin can be regarded as manifestation of some more generalized autoimmunization process.

Adrenal Glands↗

PubMed2001

A T cell receptor transgenic model of severe, spontaneous organ-specific autoimmunity.

The development of mouse models of human organ-specific autoimmune diseases has been hampered by the need to immunize mice with autoantigens in potent adjuvants. Even autoantigen-specific T cell receptor transgenic models of autoimmunity have proven to be complex as the transgenic mice frequently fail to develop disease spontaneously. We have isolated a CD4(+) T cell clone (TxA23)that recognizes the gastric parietal cell antigen, H/K ATPase alpha-chain(630-641), from a mouse with autoimmune gastritis that developed after thymectomy on day 3 of life. The T cell receptor alpha and beta genes from this clone were used to generate A23 transgenic mice. All A23 transgenic animals spontaneously developed severe autoimmune gastritis, and evidence of disease was detected as early as day 10 of life. Gastritis could be transferred to immunocompromised mice with a limited number of transgenic thymocytes (10(3)), but as many as 10(7) induced only mild disease in wild-type animals. Due to the complete penetrance of spontaneous disease, identity of the auto-antigen, susceptibility to immunoregulation, and close relation to autoimmune gastritis in man, A23 transgenic mice represent a unique CD4(+) T cell-mediated disease model for understanding the multiple factors regulating organ-specific autoimmunity.

Amino Acid Sequence↗

PubMed2006

Autoimmune hepatitis, from mechanisms to therapy.

In 1950, Waldenström was the first to describe a chronic form of hepatitis in young women. Subsequently, the disease was found to be associated with other autoimmune syndromes and was later termed "lupoid hepatitis" because of the presence of antinuclear antibodies. In 1965, it became designated by Mackay et al. as "autoimmune hepatitis" at an international meeting, at which the general concept of autoimmunity was endorsed by the scientific community. In the early 1960s and 1970s, the value of immunosuppressive therapy with glucocorticoids and/or azathioprine was well documented in several studies. The original association of autoimmune hepatitis (AIH) and HLA alleles, which has remarkably stood the test of time, was published in 1972. In the 1970s and 1980s, several autoantibodies were identified in patients with autoimmune hepatitis directed against proteins of the endoplasmatic reticulum expressed in liver and kidney and against soluble liver antigens. Subsequently, the molecular targets of these antibodies were identified and more precisely characterized. In the last two decades many additional pieces of the AIH puzzle have been collected leading to the identification of additional antibodies and genes associated with AIH and to the emergence of new therapeutic agents. Meanwhile, the immunoserological and genetic heterogeneity of AIH is well established and it has become obvious that clinical manifestations, disease behavior, and treatment outcome may vary by racial groups, geographical regions and genetic predisposition. Currently, the International Autoimmune hepatitis group is endorsing multi-center collaborative studies to more precisely define the features at disease presentation and to define prognostic indices and appropriate treatment algorithms. Given the importance of serological testing, the IAHG is also working on guidelines and procedures for more reliable and standardized testing of autoantibodies.

Antibodies, Antineutrophil Cytoplasmic↗

PubMed2001

From infection to autoimmunity.

We have investigated two models of virally-induced autoimmune myocarditis in mice using widely different infectious agents. Infection of susceptible BALB/c mice with either Coxsackievirus or murine cytomegalovirus results in the development of acute myocarditis from day 7-14 after infection, and chronic myocarditis from day 28 onwards. The chronic phase of myocarditis is associated with mononuclear infiltration of the myocardium and the production of autoantibodies to cardiac myosin, although infectious virus cannot be detected past day 14 of infection. T cells and autoantibodies have been shown to be important for the development of autoimmune myocarditis. Many researchers have investigated the role of molecular mimicry in the development of myocarditis after viral infection. This review explores the 'adjuvant' effect of infection on the innate immune response and how this determines the progression to autoimmune disease. We show that NK cells protect against the development of disease, while complement and complement receptors are involved in the development of autoimmune myocarditis induced by inoculation with virus or cardiac myosin, respectively. Our results suggest that the innate immune response to viral and self-antigens may determine whether susceptible strains of mice progress to chronic autoimmune disease. These findings have broad implications for understanding the role of infection in inducing autoimmune disease.

Animals↗