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Autoimmune diseases represent a family of at least 80 illnesses that share a common pathogenesis: an immune-mediated attack on the body's own organs. Collectively, autoimmune diseases affect some 20 million Americans, predominantly women. Many of these diseases are increasing in frequency in industrialized countries. Treatment of autoimmune diseases improved greatly during the second half of the 20th century but has been hampered because the diseases often progress before a clinical diagnosis is possible. Research in the 21st century is focusing on prospective prediction using the tools of systems biology. [ABSTRACT FROM AUTHOR]

Abstract: Most of our current understanding of the genetic predisposition to autoimmune disease can be traced to experiments performed in the decade from 1971 to 1981. Chella David was a key contributor to this research. Many of these early steps came from studies of experimental autoimmune thyroiditis. This model has been especially valuable because essentially the same disease can occur spontaneously in selected strains of animals or can be induced by deliberate immunization. From a genetic point of view, the disease has been investigated in three different species: mice, rats and chickens. The same antigen, thyroglobulin, initiates the disease in all three species. Among the main discoveries were the relationship of autoimmune disease to the major histocompatibility complex (MHC), the interplay of different subregions within the MHC in promoting or retarding development of disease, the differing roles of MHC class II and MHC I class genes in induction and effector phases, respectively, and the cumulative effect of non-MHC genes, each of which represents a small addition to overall susceptibility. Other experiments revealed that genetic differences in thyroglobulin allotypes influence susceptibility to thyroiditis. Thyroid glands differed in different strains in vulnerability to passive transfer of antibody. The first evidence of modulatory genes on the sex-related X chromosome emerged. All of these genetic findings were concurrently translated to the human disease, Hashimoto’s thyroiditis, where thyroglobulin is also the initiating antigen. [Copyright &y& Elsevier]

Increased emphasis has been placed in recent years on predictive biomarkers to foretell the onset or future course of disease. In autoimmune diseases, autoantibodies have proven to be valuable biomarkers because of their technical sensitivity, specificity, and stability during storage. Their predictive value is limited, however, by their prevalence. At present, predictive studies have utilized long-time evaluation of stable populations, families with one index case or retrospective investigations where large serum repositories are available. Our increasing knowledge of the steps leading from benign autoimmunity to frank autoimmune disease has suggested ways by which subtle genetic differences combined with assessment of the pattern of critical mediators can trace the progression of disease. The new tools of multiplex testing and information handling open opportunities to identify early signposts of disease. [ABSTRACT FROM AUTHOR]

Abstract: Autoimmune thyroiditis, also known as chronic lymphocytic or Hashimoto''s thyroiditis, is characterized by infiltration of the thyroid gland by inflammatory cells and production of autoantibodies to thyroid-specific antigens thyroglobulin and thyroperoxidase. It is accompanied by hypothyroidism due to destruction and eventual fibrous replacement of the follicle cells. Autoimmune thyroiditis is clearly multifactorial in etiology with genetic and environmental factors contributions. Excess dietary Iodine can exacerbate thyroiditis in genetically susceptible hosts such as the NOD.H2h4 mouse. In this mouse excess dietary iodine leads to an increased immunogenicity of the thyroglobulin molecule and enhanced expression of ICAM-1 on thyroidal follicle cells. We present evidence here that ICAM-1 expression is enhanced by the elevated generation of reactive oxygen species (ROS). The anti-oxidant diphenyleneiodium (DPI), an inhibitor of NADPH oxidase, reduced both the generation of ROS and of ICAM-1 expression in cultures of NOD.H2h4 mouse thyrocytes. These results suggest that antioxidants may have therapeutic value in preventing autoimmune thyroiditis. [Copyright &y& Elsevier]

Deals with the diagnostic and prognostic value of heart-reactive antibodies circulating in patients with myocarditis or dilated cardiomyopathy. Characteristics of myocarditis or dilated cardiomyopathy; Myosin antibodies; Antibodies to the cardiac beta1-adrenoceptor; Anti-mitochondrial antibodies; Treatment of myocarditis.

The genetic control of the levels of autoantibodies has rarely been examined. We examined the heritability of autoantibodies to glutamic acid decarboxylase (GAD65) in type 1 diabetes, and to thyroglobulin (Tg) in chronic lymphocytic thyroiditis and thyrotoxicosis, using regression of offspring on midparent (ROMP) methods. Levels of autoantibodies in patients and their parents were significantly correlated in thyrotoxicosis (R² = 0.569, p = 0.001), consistent with the reported Gm association, but not in chronic lymphocytic thyroiditis or type 1 diabetes. Extension of the procedure to other autoantibody disorders could be informative. [ABSTRACT FROM AUTHOR]

Infectious agents have been implicated as triggers of autoimmunity. Prospective epidemiologic studies of infection with specific pathogens and the subsequent elevation of specific autoantibodies are difficult and costly to conduct. As a result, a solid body of evidence regarding this theoretically intriguing connection remains to be accrued. We studied term sera from 1807 pregnancies in 1591 women for whom IgG status for cytomegalovirus, Epstein—Barr virus, herpes simplex virus type 1, herpes simplex virus type 2, and/or Toxoplasma gondii was available from prior analyses. We tested the sera (masked regarding infectious status) for autoantibodies to thyroid peroxidase (TPOaAb) and then unmasked and linked them. Adjusted for other cofactors, prior infection with T. gondii was associated significantly with the elevation of TPOaAb, whereas seropositivity for other infections was not. Negative and positive findings for suspected triggers of autoimmunity should be reported to build the evidentiary basis needed to advance our understanding of the disease process. The positive association observed between prior infection with T. gondii and the elevation of TPOaAb is supported by an almost simultaneous study. These findings require further investigation. We believe that if T. gondii is in fact confirmed to trigger or enhance a TPOaAb response, the most likely mechanism involved is the bystander effect. [ABSTRACT FROM AUTHOR]

Abstract: In April 2007, an international Colloquium bridging scientific and clinical disciplines was held to discuss the role of cellular and tissue damage in the initiation, development and persistence of autoimmune disease. Five potential etiologic and pathophysiologic processes fundamental to autoimmune disease (i.e. inflammation, infection, apoptosis, environmental exposure and genetics) were the focus of the presentations and integrative discussions at the Colloquium. The information presented on these topics is condensed in this review. Inflammation has close clinico-pathologic associations with autoimmunity, but future analyses will require better definition and metrics of inflammation, particularly for the earliest cellular and molecular components dependent on recruitment of elements of innate immunity. Although infection may be associated with increased levels of autoantibodies, most infections and virtually all vaccinations in humans lack well-established links to autoimmune diseases. Further application of well-designed, long-term epidemiologic and population-based studies is urgently needed to relate antecedent exposures with later occurring stigmata of autoimmunity with a goal of discerning potentially susceptible individuals or subpopulations. Suspect infections requiring closer interrogation include EB virus (SLE and other diseases), HCV (autoimmune hepatitis), beta hemolytic streptococci (rheumatic carditis) and Helicobacter pylori (autoimmune gastritis) among others. And even if a micro-organism was to be incriminated, mechanisms of initiation/perpetuation of autoimmunity continue to challenge investigators. Plausible mechanisms include potentiation and diversion of innate immunity; exposure or spillage of intracellular autoantigens; or provision of autoantigenic mimics. Integrity of apoptosis as a critical safeguard against autoimmunity was discussed in the contexts of over-reactivity causing autoantigens to gain enhanced exposure to the immune system, or under-reactivity producing insufficient elimination of autoreactive clones of lymphocytes. Although environmental agents are widely believed to serve as necessary “triggers” of autoimmune disease in genetically predisposed individuals, only a few such agents (mainly drugs and some nutrients) have been clearly identified and their mechanism of action defined. Finally an essential genetic foundation underlies all these hazards for autoimmunity in the form of risk-associated polymorphisms in immunoregulatory genes. They may be predictive of future or impending disease. [Copyright &y& Elsevier]

Only a few methods can be applied in a simple manner to estimate the genetic control of autoimmunity in humans. Here we examined the heritability of autoantibodies to two thyroid antigens; thyroglobulin (Tg) and thyroperoxidase (TPO, formerly known as thyroid microsomal antigen), using methods of regression of offspring on mid-parental values (ROMP). With the data sets available, affected and unaffected siblings were compared by this rapid screening method using results determined by hemagglutination (HA). The presence of both types of autoantibodies showed positive heritability in patients with Graves' thyrotoxicosis (TT), but it was not observed in chronic lymphocytic or Hashimoto's thyroiditis (CLT) patients. Since these assays have been extensively used over the years by most diagnostic and research laboratories, they should provide some insight as to which quantifiable parameters may be usefully accumulated to help select groups of patients and their families for further genetic study. ROMP may also be useful to determine the sequential appearance of different types of antibody in predicting disease onset in other family members, and in distinguishing maternal and paternal effects on imprinting. The method may be extended to study epitope spreading and other measures of disease progression. [ABSTRACT FROM AUTHOR]

Abstract: The mechanisms leading to autoimmune diseases remain largely unknown despite numerous lines of experimental inquiry and epidemiological evidence. The growing number of genome-wide association studies and the largely incomplete concordance for autoimmune diseases in monozygotic twins support the role of the environment (including infectious agents and chemicals) in the breakdown of tolerance leading to autoimmunity via numerous mechanisms. The present article reviews the major theories on the mechanisms of the environmental influence on autoimmunity by addressing the different degrees of confidence that characterize our knowledge. The theories discussed herein include (i) the role of innate immunity mediated by toll-like receptors in triggering the autoimmune adaptive response characterizing the observed pathology; (ii) changes in spleen marginal zone B cells in autoantibody production with particular focus on the B10 subpopulation; (iii) Th17 cell differentiation and T regulatory cells in the aryl hydrocarbon receptor model; (iv) self antigen changes induced by chemical and infectious agents which could break tolerance by post-translational modifications and molecular mimicry; and finally (v) epigenetic changes, particularly DNA methylation, that are induced by environmental stimuli and may contribute to autoimmunity initiation. We are convinced that these working hypotheses, in most cases supported by solid evidence, should be viewed in parallel with animal models and epidemiological observations to provide a comprehensive picture of the environmental causes of autoimmune diseases. [Copyright &y& Elsevier]