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At least 19 recordsLinked to original sources
PubMed1994

An autosomal locus causing autoimmune disease: autoimmune polyglandular disease type I assigned to chromosome 21.

Autoimmune polyglandular disease type I (APECED) is an autosomal recessive autoimmune disease characterized by a variable combination of the failure of the endocrine glands. The pathogenesis of this unique autoimmune disease is unknown; unlike many other autoimmune diseases, APECED does not show association to specific HLA haplotypes. Unravelling the APECED locus will identify a novel gene outside the HLA loci influencing the outcome of autoimmune diseases. We have assigned the disease locus to chromosome 21q22.3 by linkage analyses in 14 Finnish families. Linkage disequilibrium studies have significantly increased the informativeness of the analyses and helped to locate the critical DNA region for the APECED locus to just 500 kilobases, a much more precise definition than linkage analyses alone could achieve.

Chromosome Mapping↗
PubMed1995

[Collagen disease. Autoimmune disease].

Collagen disease is systemic autoimmune disease and consists of a lot of diseases with each clinical entity. for exact diagnosis, it is important to choose essential laboratory tests for the patient suspected of collagen disease in daily primary medical care. A guideline for the use of clinical laboratory tests for patients with collagen disease was proposed by the Japan Society of Clinical Pathology. This guideline was discussed repeatedly by subcommittee members of "the uses of clinical laboratory tests in daily primary medical care" and published on September of 1990. When the clinicians are suspected of the collagen disease from detailed history taking and physical examination, they must precisely interpret results of the essential laboratory tests. Urinalysis, hematology, ESR and CRP and Biochemistry show characteristic findings in the collagen disease, respectively. If further suspicion of the collagen disease is intensive, the clinicians proceed with the primary screening tests for collagen disease; rheumatoid factor, ANF, anti DNA antibody, LE test, STS and CH50. Finally, specific tests for each collagen disease are carried out to define the diagnosis; e.g. LE cell, anti-Sm antibody, IC, Coombs test and biopsy of kidney for SLE. This paper is presented on the intention of the guideline of clinical laboratory tests for the collagen disease and its issues. As it passed 4 years after published, this guideline should be more discussed and revised.

Autoimmune Diseases↗
PubMed1982

Genetic factors predisposing to autoimmune diseases. Autoimmune hemolytic anemia, chronic thrombocytopenic purpura, and systemic lupus erythematosus.

Genetic factors predisposing to autoimmune diseases were investigated in 10 families having more than one affected member. Seventy relatives and 23 spouses from two large kindreds (one in whom the proband had autoimmune hemolytic anemia and the other immune thrombocytopenic purpura) were examined for immunologically mediated disorders, autoantibodies, immunoglobulin abnormalities, and HLA genotypes. Significant differences between relatives and spouses were found for immune diseases (21 percent versus 0 percent; p = 0.02), antinuclear antibody titer of 1:80 or more (18 percent versus 0 percent; p = 0.04), single-strand DNA antibodies (18 percent versus 0 percent; p = 0.04), high-titer antinuclear antibody or antibodies to single-strand DNA or both (33 percent versus 0 percent; p = 0.001), and the combined frequencies of immune diseases and serologic abnormalities (44 percent versus 4 percent; p = 0.0004). Similar frequencies were found in 41 relatives from eight families in whom the proband had SLE. Segregation analyses using these abnormalities as genetic traits were most compatible with a Mendelian dominant model. Impressive odds (100:1) against linkage to HLA were calculated.

Adolescent↗
PubMed1984

Atypical lymphoplasmacytic and immunoblastic proliferation in lymph nodes of patients with autoimmune disease (autoimmune-disease-associated lymphadenopathy).

This study is based on an analysis of the morphologic, clinical, and laboratory findings in 26 patients whose pretherapy lymph node biopsies showed some, but not all, of the diagnostic features of angioimmunoblastic lymphadenopathy with dysproteinemia (AILD). Partial or complete effacement of nodal architecture by a diffuse lymphoplasmacytic and immunoblastic proliferation was a constant histologic finding. In contrast to the findings in AILD, lymphocytic depletion and pronounced arborizing vascular proliferation were often lacking. Clinically, many of the patients had fever, sweats, weight loss, skin rashes, generalized lymphadenopathy, hepatosplenomegaly, and, in some cases, pulmonary infiltrates. Of the 26 patients, 23 had clinical and/or laboratory evidence of autoimmune disease or immune complex disease. In 12 patients (Group I--idiopathic), various autoantibodies or immune complexes were demonstrable, but these patients did not manifest a well-defined immunologic disease or syndrome. In 11 patients (Group II--secondary), the lymphadenopathy occurred secondary to a well-defined, clinically recognized immunologic disease. Three patients (Group III) had neither a well-defined autoimmune disease nor demonstrable autoantibodies, but two of them had a history of exposure to antibiotics. We suggest that patients whose lymph nodes have the morphologic features described here frequently have an autoimmune disorder, and that the pathogenesis of this clinicopathologic picture is probably related to a deficiency in suppressor T-cell function which results in an unopposed proliferation of B cells with autoantibody formation and polyclonal gammopathy. Our observations should stimulate clinicians to consider the possibility of an autoimmune pathogenesis for a lymphadenopathy in which a florid lymphoplasmacytic and immunoblastic proliferation similar to that observed in AILD is demonstrated, even though the sections may not meet all the histologic criteria reported for the diagnosis of AILD. Clinical and laboratory investigations necessary to confirm the presence of autoimmunity are indicated in these cases. Moreover, since there is evidence of genetic factors predisposing to autoimmune disease (17, 43), it would be important to investigate close relatives of patients whose lymph nodes showed the histologic changes described in this paper in prospective studies which include suppressor T-cell function, autoantibodies, HLA type of blood lymphocytes and chromosomal analysis. The median survival of the 23 patients with stigmata of autoimmune disease or immune complex disease was 36 months.(ABSTRACT TRUNCATED AT 400 WORDS)

Adolescent↗
PubMed1992

Sjögren's syndrome in relation to other autoimmune diseases.

Autoimmune diseases can be divided into primary autoimmune diseases, in which the immune system is over-reactive, leading to an oligoclonal B cell stimulation, and secondary autoimmune diseases, in which the immune system is completely normal but some autoantigens are slightly altered, and are thus considered to be foreign. Sjögren's syndrome probably has characteristics of both types of autoimmune disease. The primary autoimmune diseases can be divided into organ-specific autoimmune diseases like thyroiditis, gastritis and adrenalitis, and generalised autoimmune diseases, such as systemic lupus erythematosus (SLE) and rheumatoid arthritis. Sjögren's syndrome has characteristics of both types of primary autoimmune disease, and therefore occupies a central position among the other autoimmune diseases. The focal position of the disease in the present issue of The Netherlands Journal of Medicine is because of the symposium organized for the occasion of the fifth anniversary of the "Dutch Association of Patients with Sjögren's Syndrome", of which this issue is the report.

Autoimmune Diseases↗
PubMed2004

Analysis of the threshold liability model provides new understanding of causation in autoimmune diseases.

Autoimmune diseases include a heterogeneous group of complex traits, the causes of which are essentially unknown. The threshold liability model is a hypothesis that has a significant influence on thinking about causation in these diseases. Here, I analyze this model and assess its utility in understanding causation in autoimmunity. According to the model, members of a population have a normal distribution of genetic liability for a particular autoimmune disease. Further, a threshold value exists for each autoimmune disease such that an individual develops disease when his/her liability exceeds the threshold value; environmental and stochastic factors and epistatic gene interactions may increase or decrease an individual's disease liability. There are, however, two main problems with the threshold liability model. First, for a particular autoimmune disease, the threshold value divides a population into two distinct groups that consist either of affected or of healthy individuals. I show that this dichotomous division is inaccurate and misleading. Second, the threshold value corresponds to the occurrence of a component-cause of disease, i.e. when an appropriate collection of causative factors for a particular autoimmune disease is present, the disease must inevitably occur. I argue, however, that the disease contribution of essentially unknown random or stochastic factors to causation is at least similar in importance to the contributions of genetic and environmental factors. These stochastic factors add a significant element of unpredictability to the effects of genetic and environmental factors. Consequently causes in autoimmunity do not act deterministically, which is implied by the component-cause concept. Instead, the role of causative factors is to alter disease risk. I therefore reject the threshold liability model and conclude that a probabilistic approach provides the only reasonable way to understand causation in autoimmune diseases. This conclusion has important implications for other deterministic hypotheses in autoimmunity including other component-cause hypotheses.

Autoimmune Diseases↗
PubMed1997

Immunogenetics and the cause of autoimmune disease.

Autoimmune disease results from the action of environmental factors on a predisposed genotype. In this review, the role of genetic susceptibility in the aetiology of autoimmune disease is examined. As the genetics of autoimmune diabetes has been studied more intensively than that of other autoimmune diseases, supporting evidence is drawn principally from that example. Autoimmune diseases are not inherited as entities but as constitutions which confer an increased probability of developing disease. It is proposed that there are two components to autoimmune disease susceptibility. One confers susceptibility to autoimmunity per se, while the other determines tissue specificity. In this review, the concept of liability is introduced as a tool used in quantitative genetics and is applied to the analysis of autoimmune diabetes by considering a threshold model. In this example, empirically derived incidence figures are used to calculate heritability which is a relative measure of the influence of genetics and environmental factors. The validity of applying the concept of liability to diabetes is confirmed by examining the values of heritability calculated from empirical data obtained from different kindred relationships, and by confirming that the assumptions on which liability is based are supported by recent gene mapping data. Finally, the physiological significance of liability is considered and its significance to the cause of autoimmunity discussed.

Animals↗
PubMed1994

Autoimmune diseases against cell surface receptors: myasthenia gravis, a prototype anti-receptor disease.

Autoimmune diseases against cell surface receptors are the result of a mainly antibody-mediated attack on membrane receptors. This results in a hypofunction of the target organ; occasionally antibodies can exert an agonist effect, e.g. in Graves' disease. Myasthenia gravis (MG) is an autoimmune disease of the neuromuscular junction associated with a plethora of other diseases, mainly autoimmune diseases. Antibodies against the acetylcholine receptor (AChR) reduce the number of receptors necessary for efficient neuromuscular transmission. The effector mechanisms of MG can be studied elegantly in an experimental animal model in rodents immunized with AChR or injected with antibodies against AChR. The thymus is thought to play a central role in the induction of MG. Microscopic analysis of these thymuses revealed a follicular hyperplasia of the medulla or a lympho-epithelial thymoma. Thymectomy results in clinical improvement along with a decline in anti-AChR antibody titres. Additional therapeutic measures include anticholinesterase drugs, immunosuppression and plasmapheresis.

Animals↗
PubMed1998

The role of infection in the pathogenesis of autoimmune disease.

Autoimmune disease has long been considered a shadow following infectious diseases. Epidemiological evidence shows that rheumatic fever follows streptococcal infection and Trypanosoma cruzi infection is the instigator of Chagas' disease. There is, however, very little information of the mechanism by which such a train of events is initiated. Autoimmunity, in a form of autoantibodies, is common after many infections and may well result from the mimicking of host proteins by antigens of the infectious agent. There are, however, few if any examples in humans where molecular mimicry gives rise to autoimmune disease. The progression from benign autoimmunity to pathogenic autoimmune disease depends upon the balance of cytokines produced during the inflammatory process accompanying infection. In many autoimmune diseases, the cytokine profile favors the proinflammatory cytokines, IFN-gamma and IL-1, which support the production of disease. A searching study of cytokine profiles during infection may offer a promising approach to avoiding the harmful consequences of post-infection autoimmune responses.

Animals↗
PubMed2000

Epitope spreading: a mechanism for progression of autoimmune disease.

Autoimmune diseases are typically characterized by a persistent inflammatory self-recognition process that ultimately leads to chronic progressive disability. Over the past several years we have addressed the fundamental question of why autoimmune diseases are chronic. Our working hypothesis in these studies has been that autoimmunity involves a continuous acquisition of new self-recognition events, thereby providing an inflammatory steady-state that leads to chronicity. This acquired T cell neoautoreactivity is commonly referred to as epitope spreading. By studying multiple sclerosis (MS) and its related animal model, experimental autoimmune encephalomyelitis (EAE), we have found that chronic progression of autoimmune disease is invariably linked to the development of an epitope-spreading process that manifests as a cascade of inflammatory T cell neoautoreactivities to a sequential series of predictable new target self-antigens. However, our most recent observations indicate that the emergence of epitope spreading is accompanied by a concurrent regression of the established primary autoreactivity associated with disease onset. Thus, our studies indicate that progression of autoimmune disease involves a shifting of T cell autoreactivity from primary initiating self-determinants to defined cascades of secondary determinants that sustain the inflammatory self-recognition process during progression to chronicity. Our data support the view that the natural development of self-recognition during autoimmune disease may best be understood when considered in the temporal context of an "epitope du jour" and "moving target" perspective.

Animals↗
PubMed1992

Inhibition of T cell activation by MHC blockade: a possible strategy for immunointervention in autoimmune diseases.

Autoimmune diseases result from the activation of self-reactive T cells induced by autoantigens or by foreign antigens cross-reactive with an autoantigen. A striking characteristic of autoimmune diseases is the increased frequency of certain HLA alleles in affected individuals. Moreover, as demonstrated for example in rheumatoid arthritis and insulin-dependent diabetes mellitus, class II alleles positively associated with autoimmune diseases share amino acid residues in the hypervariable HLA regions involved in peptide binding. Therefore, it is likely that disease-associated HLA class II molecules have the capacity to bind the autoantigen and present it to T cells, thereby inducing and maintaining, under appropriate conditions, the autoimmune disease. The data reviewed here demonstrate MHC-selective inhibition of antigen-induced T cell responses in vivo by parenterally administered soluble, MHC-binding peptide competitors, under conditions in which the competitor is not immunogenic. This suggests the feasibility of a therapeutic approach based on blockade of MHC class II molecules in the treatment of HLA-linked autoimmune diseases.

Animals↗
PubMed2002

Occupational exposures and autoimmune diseases.

Autoimmune diseases are pathologic conditions defined by abnormal autoimmune responses and characterized by immune system reactivity in the form of autoantibodies and T cell responses to self-structures. Here we review the limited but growing epidemiologic and experimental literature pertaining to the association between autoimmune diseases and occupational exposure to silica, solvents, pesticides, and ultraviolet radiation. The strongest associations (i.e., relative risks of 3.0 and higher) have been documented in investigations of silica dust and rheumatoid arthritis, lupus, scleroderma and glomerulonephritis. Weaker associations are seen, however, for solvent exposures (in scleroderma, undifferentiated connective tissue disease, and multiple sclerosis) and for farming or pesticide exposures (in rheumatoid arthritis). Experimental studies suggest two different effects of these exposures: an enhanced proinflammatory (TH1) response (e.g., TNF-alpha and IL-1 cytokine production with T cell activation), and increased apoptosis of lymphocytes leading to exposure to or modification of endogenous proteins and subsequent autoantibody formation. The former is a general mechanism that may be relevant across a spectrum of autoimmune diseases, whereas the latter may be a mechanism more specific to particular diseases (e.g., ultraviolet radiation, Ro autoantibodies, and lupus). Occupational exposures are important risk factors for some autoimmune diseases, but improved exposure assessment methods and better coordination between experimental/animal models and epidemiologic studies are needed to define these risks more precisely.

Animals↗
PubMed1992

Interleukin-1 and tumor necrosis factor: effector cytokines in autoimmune diseases.

Autoimmune diseases have been studied from the perspective of an abnormal immune response in genetically vulnerable hosts. Although the immune response is responsible for the initiation of autoimmune diseases, the effectors of the disease process likely involves cytokines such as interleukin-1 (IL-1) and tumor necrosis factor (TNF). These polypeptides induce a wide variety of inflammatory events which contribute to the destruction of tissue and tissue remodeling in several autoimmune diseases. Blocking IL-1 with its naturally occurring receptor antagonist, the IL-1 receptor antagonist reduces the severity of disease in animal models of inflammation and autoimmune processes. Clinical studies with the IL-1 receptor antagonist will define the role for this cytokine in the pathogenesis of autoimmune diseases such as arthritis, inflammatory bowel disease, type I diabetes and vasculitis.

Animals↗