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Infections often precede the onset of autoimmune disease and molecular (or epitope) mimicry is a plausible link. Cross-reacting epitopes are common between an infecting microorganism and the host because negative selection of self-reactive T-cells and B-cells is frequently incomplete. Complete eradication could lead to major voids in the immunologic repertoire. The association of an autoimmune disease with a microbial epitope may signify a causal relationship with the organism, an indirect connection through bystander effects, persistent infection or coincidence. There are well-established examples of a microbial mimic inducing a defined model of autoimmune disease in experimental animals but such instances are still relatively rare in humans. Establishing epitope mimicry as a direct cause opens opportunities for preventing the disease. Current approaches to cancer immunotherapy provides new examples of epitope mimicry between cancer antigens and normal tissue antigens. [ABSTRACT FROM AUTHOR]

On September 20, 2016 the American Autoimmune Related Disease Association convened a selected group of 16 experts in Washington DC to discuss current issues and future directions of research in autoimmune diseases from the cell signaling perspective. The major topics considered included new findings on the follicular T cell cells in mice, their metabolic patterns and their control by the newly discovered T follicular regulatory cells. Current work on the metabolic pathways deemed important for the function of T cells was presented. The broader implications of these studies on our understanding of human and murine T regulatory cell and current aspects of B cell biology, innate immunity and organ damage were discussed. This document should provide the reader with a quick update on these topics and help instigate novel studies. [ABSTRACT FROM AUTHOR]

Despite of a multitude of excellent studies, the regulatory role of natural killer (NK) cells in the pathogenesis of inflammatory cardiac disease is greatly underappreciated. Clinical abnormalities in the numbers and functions of NK cells are observed in myocarditis and inflammatory dilated cardiomyopathy (DCMi) as well as in cardiac transplant rejection [1–6] . Because treatment of these disorders remains largely symptomatic in nature, patients have little options for targeted therapies [7,8] . However, blockade of NK cells and their receptors can protect against inflammation and damage in animal models of cardiac injury and inflammation. In these models, NK cells suppress the maturation and trafficking of inflammatory cells, alter the local cytokine and chemokine environments, and induce apoptosis in nearby resident and hematopoietic cells [1,9,10] . This review will dissect each protective mechanism employed by NK cells and explore how their properties might be exploited for their therapeutic potential. [ABSTRACT FROM AUTHOR]

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]

IL6 is a pleiotropic cytokine that is made in response to perturbations in homeostasis. IL6 becomes elevated in the acute response to host injury and can activate immune cells, direct immune cell trafficking, signal protective responses in local tissue, initial the acute phase response or initiate wound healing. In the short term this proinflammatory response is protective and limits host damage. It is when this acute response remains chronically activated that IL6 becomes pathogenic to the host. Chronically elevated IL6 levels lead to chronic inflammation and fibrotic disorders. The heart is a tissue where this temporal regulation of IL6 is very apparent. Studies from myocardial infarction show how short-term IL6 signaling can protect and preserve the heart tissue in response to acute damage, where long term IL6 signaling or an over-production of IL6R protein plays a causal role in cardiovascular disease. Thus, IL6 can be both protective and pathogenic, depending on the kinetics of the host response. [ABSTRACT FROM AUTHOR]

In this article, I trace the historic background of clonal deletion and molecular mimicry, two major pillars underlying our present understanding of autoimmunity and autoimmune disease. Clonal deletion originated as a critical element of the clonal selection theory of antibody formation in order to explain tolerance of self. If we did have complete clonal deletion, there would be major voids, the infamous “black holes”, in our immune repertoire. For comprehensive, protective adaptive immunity, full deletion is necessarily a rare event. Molecular mimicry, the sharing of epitopes among self and non-self antigens, is extraordinary common and provides the evidence that complete deletion of self-reactive clones is rare. If molecular mimicry were not common, protective adaptive immunity could not be all-encompassing. By taking a fresh look at these two processes together we can envision their evolutionary basis and understand the need for regulatory devices to prevent molecular mimicry from progressing to autoimmune disease. [ABSTRACT FROM AUTHOR]

Abstract: Cardiac inflammatory disease represents a significant public health burden, and interesting questions of immunopathologic science and clinical inquiry. Novel insights into the diverse programming and functions within the macrophage lineages in recent years have yielded a view of these cells as dynamic effectors and regulators of immunity, host defense, and inflammatory disease. In this review, we examine and discuss recent investigations into the complex participation of mononuclear phagocytic cells in the pathology of animal models of myocarditis. [Copyright &y& Elsevier]

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]

Biomarkers, represented by genetically determined traits or biologic changes predictive of disease onset or outcome, are increasingly employed by academic and industrial investigators. They can identify unusually susceptible populations or individuals, facilitate prognosis, forecast the outcome of therapy in clinical trials, or aid in developing improved treatments or preventative measures. All of these applications have been applied to the autoimmune diseases. As a case in point, we have through the years used biomarkers to predict susceptibility and the longer-range outcome of thyroid autoimmunity employing, a number of different approaches. They have taught us valuable lessons for future broader applications of biomarkers. The clues for susceptibility include major histocompatibility complex (MHC) and non-MHC genes combined with the fine specificity of thyroid autoantibodies in siblings of patients with juvenile thyroid disease. Together these biomarkers are highly predictive of later thyroid autoimmunity and subclinical thyroid dysfunction. For example, the progression from benign autoimmunity to clinical thyroid disease is marked by the appearance of autoantibodies to species-restricted epitopes on thyroglobulin. Thus, predictive biomarkers aid in identifying individuals with inordinate risk of disease and provide opportunities for earlier interventions to arrest the disease process. [ABSTRACT FROM AUTHOR]

Abstract: An epidemiologic study of the autoimmune diseases taken together has not been done heretofore. The National Patient Register of Denmark is used to estimate the population prevalence of 31 possible or probable autoimmune diseases. Record linkage is used to estimate 465 pairwise co-morbidities in individuals among the 31 diseases, and familial aggregation among sibs, parents and offspring. The prevalence of any of the 31 diseases in the population is more than 5%. Within individuals, there is extensive comorbidity across the 31 diseases. Within families, aggregation is strongest for individual diseases and weak across diseases. These data confirm the importance of the autoimmune diseases as a group and suggest that common etiopathologies exist among them. [Copyright &y& Elsevier]

Abstract: Excellent animal models are available for virus-induced and autoimmune heart disease that are remarkably similar to human disease. Developing good animal models for heart disease is crucial because cardiovascular disease is now the leading cause of death in the United States and is estimated to be the leading cause of death in the world by the year 2020. A significant proportion of heart disease in Western populations is associated with inflammation. Myocarditis, or inflammation of the heart muscle, is the major cause of sudden death in young adults. Although most individuals recover from acute myocarditis, genetically susceptible individuals may go on to develop chronic myocarditis and dilated cardiomyopathy (DCM) resulting in congestive heart failure. In this article, we describe a model of autoimmune myocarditis and DCM induced by inoculation with heart-passaged coxsackievirus B3 (CVB3). Intraperitoneal inoculation of susceptible mice with CVB3 induces acute cardiac inflammation from days 7 to 14 postinfection (pi) that progresses to chronic myocarditis and DCM from day 28 to at least 56 pi. The model of CVB3-induced myocarditis presented here allows dissection of the contribution of viral infection and xenobiotics on immune dysregulation and inflammation in the heart. An improved understanding of the interaction between environmental exposures and the development of heart disease represents a clear challenge for immunotoxicologists. [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.

Autoimmune disease includes a large spectrum of clinically distinct entities that share a common etiology, a misguided, self-directed immune response. Collectively, they are major contributors to morbidity and mortality. Normally, the body utilizes a number of strategies to avoid the pathologic consequences of autoimmune reactions, but these defenses may fail for a combination of hereditary and environmental factors. Infection has long been regarded as a common environmental trigger of autoimmune disease. Our laboratory has developed a mouse model of myocarditis induced by Coxsackievirus B3 infection and demonstrated some of the steps involved in the transition from an infection to an autoimmune disease. Such basic studies may suggest improved treatment or preventive measures for this group of diseases. [ABSTRACT FROM AUTHOR]

Mononuclear cell infiltration of the thyroid gland is a common histologic feature of chronic lymphocytic thyroiditis. Although the infiltrating mononuclear cells have been implicated in the destruction of the thyroid, information concerning the progression of infiltration into the thyroid is limited. In this report, we examine the composition and kinetics of mononuclear cell infiltration in the thyroid and the expression of major histocompatibility complex class II (I-Ak), IL-12, and IFN-γ in the thyroid of the NOD-H2h4 mouse, a model of spontaneous autoimmune thyroiditis accelerated by the administration of excess dietary iodine. Mice were given a low dose of 0.015% NaI in their drinking water for 2, 4, 6, 8, and 16 weeks, and thyroids were removed, serially sectioned, and stained in an avidin-biotin peroxidase assay. The thyroid infiltrate included CD4+ and CD8+ T cells, F4/80+ macrophages, and B220+ B cells. After 2 weeks of iodine treatment, CD4+ T cells were the first seen in the thyroid, followed by CD8+ T cells and F4/80+ macrophages. B220+ B cells entered the thyroid after 4 weeks of iodine treatment. IL-12 and IFN-γ positive cells were located in the thyroid early in disease and were up-regulated in the focal accumulations of infiltrating cells. Thyrocytes clearly expressed I-Ak after 4 weeks of iodine treatment near the location of mononuclear cell infiltration. [Copyright &y& Elsevier]

Mononuclear cell infiltration of the thyroid is a prominent feature of chronic lymphocytic thyroiditis. Adhesion molecules play a major role in determining the localization of inflammatory mononuclear cells in the thyroid. Previous reports from animal models and human studies have described the thyroidal expression of adhesion molecules only late in clinical disease. In this study, we examined the distribution and kinetics of expression of E-selectin, VCAM-1, LFA-1, and ICAM-1 in the NOD-H2h4 mouse, a model of spontaneous autoimmune thyroiditis accelerated by dietary iodine. Mice were fed 0.015% NaI in their drinking water for 2, 4, 6, 8, and 16 weeks, and thyroids were removed, serially sectioned, and stained in an avidin–biotin–peroxidase assay. We found a dramatic increase in E-selectin and VCAM-1 expression on intrathyroidal endothelial cells after 16 weeks of iodine treatment. In addition, we describe for the first time that thyrocytes from the NOD-H2h4 mouse, and the parental NOD, constitutively express ICAM-1 independent of iodine treatment and prior to mononuclear cell infiltration of the thyroid gland. ICAM-1 was not detected on the thyrocytes of other untreated strains of mice, implicating expression of this adhesion molecule as a critical event in the recruitment of inflammatory mononuclear cells to the thyroid. [Copyright &y& Elsevier]

Like most autoimmune diseases of humans, chronic lymphocytic (Hashimoto''s) thyroiditis results from the combination of a genetic predisposition and an environmental trigger. A body of clinical and epidemiologic evidence points to excessive ingestion of iodine as an environmental agent. In genetically determined thyroiditis in animals, iodine enrichment has been shown to increase the incidence and severity of disease. Its mechanism of action is still uncertain. Using a new animal model of autoimmune thyroiditis, the NOD.H2h4 mouse, we have been able to show that iodine enhances disease in a dose-dependent manner. Immunochemical studies suggest that iodine incorporation in the thyroglobulin may augment the antigenicity of this molecule by increasing the affinity of its determinants for the T-cell receptor or the MHC-presenting molecule either altering antigen processing or by affecting antigen presentation. [Copyright &y& Elsevier]

Presents a study on in vitro assay of staphylococcus aureus enterotoxin A (SEA) activity in food, focusing on the use of the assay alternative, the T-cell proliferation to measure SEA activity in food. Reference to staphylococcus aureus enterotoxin A (SEA) being the lead cause of food poisoning; Animals used in testing of functional activity of SEA; Disadvantages of animal assays; Content of reports on study of SEA; Indepth look at study.

The role of humoral and cellular immunity in experimental autoimmune thyroiditis was examined in inbred rat strains. A significant relationship between thyroiditis and both in vitro proliferative responses to rat thyroglobulin and in vivo delayed hypersensitivity (ear test) was observed in responsive rats. Comparison of the autoantibody response and thyroiditis among rat strains revealed no direct correlation of RT1 genotype with either parameter. [ABSTRACT FROM AUTHOR]

One to four trachea-specific antigens were demonstrated regularly by means of various rabbit antisera to human tracheal mucosa, using immunoelectrophoresis or Ouchterlony tests. in addition, one or more antigens common to trachea and oesophagus were found. Trachea-specific antisera cross-reacted with rhesus monkey but not with bovine, ovine, equine or porcine trachea. The three most prominent trachea-specific antigens were localized in the same fraction by chromatography. The chromatographic fraction was usable in tanned cell haemagglutination, but only trachea-oesophagus antigen, and not trachea-specific antigen, seemed to attach to tanned cells. Of the ten cancers of the respiratory tract tested, three were found to retain some trachea-specific antigen. [ABSTRACT FROM AUTHOR]

Abstract: This essay honors the lifetime achievements of Julius Cruse. It relates some of my personal experiences of the past and my views of the future in two areas in which Professor Cruse has made lasting contributions—the history of science and scientific communication. We can best chart the future by understanding the past. [Copyright &y& Elsevier]

A preface for the October 31, 2008 issue of the journal "Annals of New York Academy of Sciences," is presented.

Until recently, autoimmune disease research has primarily been focused on elucidating the role of the adaptive immune system. In the past decade or so, the role of the innate immune system in the pathogenesis of autoimmunity has increasingly been realized. Recent findings have elucidated paradigm-shifting concepts, for example, the implications of "trained immunity" and a dysbiotic microbiome in the susceptibility of predisposed individuals to clinical autoimmunity. In addition, the application of modern technologies such as the quantum dot (Qdot) system and 'Omics' (e.g., genomics, proteomics, and metabolomics) data-processing tools has proven fruitful in revisiting mechanisms underlying autoimmune pathogenesis and in identifying novel therapeutic targets. This review highlights recent findings discussed at the American Autoimmune Related Disease Association (AARDA) 2019 colloquium. The findings covering autoimmune diseases and autoinflammatory diseases illustrate how new developments in common innate immune pathways can contribute to the better understanding and management of these immune-mediated disorders. • The role of the innate immune system in the pathogenesis of autoimmunity is increasingly being realized. • 'Trained immunity' or 'innate immune memory' is a paradigm-shifting concept with broad applications. • Environmental factors, including host-resident microbiota, have a profound effect on autoimmunity • Common innate immune pathways can be targeted for the management of both autoimmune and autoinflammatory diseases. [ABSTRACT FROM AUTHOR]

The article discusses the author's experience of discovering autoimmune disease. He started to study about autoimmunity when immunologist Ernest Witebsky recruited him to join his immunology team at a university to study on medical studies. The study the team conducted was about antibody response as a chemical reaction. He narrates the process Witebsky used in the study and how they decided to publish their findings.

Examines the role of dichotomous helper T cell subset model in immunology. Mediation of delayed type hypersensitivity; Phenomenon of polarization in cytokine secretion patterns; Generation of ovalbumin specific T cells which secrete interleukins in response to antigenic stimulation.

Discusses the susceptibility of insulin-producing beta cells to acute infection by Coxsackie virus that could result in diabetes. Production of interferon; Virus-mediated cell damage of target organs; Virus-induced autoimmune disease.

Describes the relationship between autoimmunity and lymphoma. Role of defective apoptosis; Sustained antigen drive; Paradigm of autoimmunity and lymphomagenesis.

Oncology has recently undergone a revolutionary change with widespread adoption of immunotherapy for many cancers. Immunotherapy using monoclonal antibodies against checkpoint molecules, including programmed death (PD)-1, PD ligand (PD-L)1, and cytotoxic T lymphocyte-associated antigen (CTLA)-4, is effective in a significant subset of patients. However, immune-related adverse events (irAEs) have emerged as frequent complications of checkpoint blockade, likely due to the physiological role of checkpoint pathways in regulating adaptive immunity and preventing autoimmunity. As immunotherapy becomes more common, a better understanding of the etiology of irAEs and ways to limit these events is needed. At the same time, studying these new therapy-related disorders provides an opportunity to better understand naturally occurring human autoimmune and inflammatory disorders, with the potential to improve therapies for cancer and autoimmune diseases. IrAEs represent a major obstacle for safely administering checkpoint blockade in cancer patients. Developing methods to minimize irAEs while maintaining effective antitumor immunity could make immunotherapy safer for more cancer patients. Diverse mechanisms likely drive irAEs, which may share varying degrees of similarities and differences with spontaneous autoimmunity. IrAEs that develop following checkpoint blockade in cancer provide an opportunity to better understand spontaneous autoimmune and inflammatory disorders. A deeper understanding of why some patients develop irAEs and others do not is needed to determine who is at highest risk for developing life threatening irAEs and to develop biomarkers to identify these individuals. Improvements in managing, investigating, and reporting on these irAEs are needed to reduce clinical challenges and maximize opportunities to learn from irAEs. [ABSTRACT FROM AUTHOR]

The author addresses the issue whether recurrent pericarditis can be considered as an autoimmune disease. He first differentiate the formation of pericardium and the heart embryologically. Despite improvements in the diagnosis of pericarditis, he believes that uncertainty remains over its aetiology and pathogenesis. He adds that there is also a lack of understanding on how much of pericarditis can be attributed to infectious process itself and to a host that generated immune response.

A preface to the January 2010 issue of the journal "Annals of the New York Academy of Sciences" is presented.

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]

The mechanism of polyclonal activation suggested that it was the indirect and nonspecific result of cytokine release by either B cells stimulated by antigen or T cells stimulated by viral peptide bound to major histocompatibility complexes (MHCs) on antigen-presenting cells (APCs). The mechanism proposed by researchers however, differs by postulating that virusspecific CD4 cells interact with viral peptide-MHC complexes exposed on the surface of B cells acting as APCs and directly stimulate these B cells to differentiate, regardless of their BCR specificity. Authors suggest that the phenomenon of polyclonal B cell activation is much more general and wish also to comment on some further theoretical implications of their study. T cells may also be engaged in non-specific polyclonal activation. Thus, only a small proportion of passively administered specific T cells is found in the infiltrates that mediate skin graft rejection or delayed-type hypersensitivity. The implication of these findings is that any specific antigenimmunocyte interaction may serve the purpose. Researchers have suggested that this phenomenon is an important contributor to the luxuriant mononuclear infiltrates found in all immunogenic inflammatory reactions involving B and T cells.

Discusses the interaction between viral infection and autoimmune diseases. Principal cause of heart failure; Pathogenesis of myocarditis; Mechanism of virus-induced autoimmunity.

In the broad field of autoimmunity and clinical immunology, experimental evidence over the past few years have demonstrated several connections between the immune system and the nervous system, both central and peripheral, leading to the definition of neuroimmunology and of an immune-brain axis. Indeed, the central nervous system as an immune-privileged site, thanks to the blood-brain barrier, is no longer a dogma as the barrier may be altered during chronic inflammation with disruptive changes of endothelial cells and tight junctions, largely mediated by adenosine receptors and the expression of CD39/CD73. The diseases that encompass the neuroimmunology field vary from primary nervous diseases such as multiple sclerosis to systemic conditions with neuropsychiatric complications, such as systemic lupus erythematosus or vasculitidies. Despite potentially similar clinical manifestations, the pathogenesis of each condition is different, but the interaction between the ultra-specialized structure that is the nervous system and inflammation mediators are crucial. Two examples come from anti-dsDNA cross-reacting with anti- N -Methyl- d -Aspartate receptor (NMDAR) antibodies in neuropsychiatric lupus or the new family of antibody-associated neuronal autoimmune diseases including classic paraneoplastic syndromes with antibodies directed to intracellular antigens (Hu, Yo, Ri) and autoimmune encephalitis. In the case of multiple sclerosis, the T cell paradigm is now complicated by the growing evidence of a B cell involvement, particularly via aquaporin antibodies, and their influence on Th1 and Th17 lineages. Inspired by a productive AARDA-sponsored colloquium among experts we provide a critical review of the literature on the pathogenesis of different immune-mediated diseases with neurologic manifestations and we discuss the basic immunology of the central nervous system and the interaction between immune cells and the peripheral nervous system. [ABSTRACT FROM AUTHOR]

Precision Medicine is an emerging approach for disease treatment and prevention that takes into account individual variability in genes, environment, and lifestyle. Autoimmune diseases are those in which the body's natural defense system loses discriminating power between its own cells and foreign cells, causing the body to mistakenly attack healthy tissues. These conditions are very heterogeneous in their presentation and therefore difficult to diagnose and treat. Achieving precision medicine in autoimmune diseases has been challenging due to the complex etiologies of these conditions, involving an interplay between genetic, epigenetic, and environmental factors. However, recent technological and computational advances in molecular profiling have helped identify patient subtypes and molecular pathways which can be used to improve diagnostics and therapeutics. This review discusses the current understanding of the disease mechanisms, heterogeneity, and pathogenic autoantigens in autoimmune diseases gained from genomic and transcriptomic studies and highlights how these findings can be applied to better understand disease heterogeneity in the context of disease diagnostics and therapeutics. [ABSTRACT FROM AUTHOR]

Abstract: Pregnancy modulates autoimmune diseases through diverse and still incompletely defined mechanisms, in part operating at the decidua–placenta interface. To assess the immunological contribution of placenta, we administered mouse placental proteins to a mouse model of autoimmune hypophysitis, a disease known to be strongly associated with pregnancy. Emulsified placental proteins suppressed both the cellular and humoral aspects of hypophysitis. Suppression was specific to self antigens and not seen when two foreign antigens, tetanus toxoid or tuberculin purified protein derivative, were used. Proteomic analysis revealed high levels of soluble TNF receptor 1 in placenta, suggesting that blockade of the TNF-α pathway was a mechanism of disease suppression. Placentas derived from mice deficient in TNF receptor 1 lost the ability to suppress hypophysitis. Notably, hypophysitis suppression was seen only when the TNF-α pathway was blocked locally, at the site of immunization, and not systemically. These findings provide evidence that placenta contributes to the immune tolerance of pregnancy by locally inhibiting the TNF-α pathway. [Copyright &y& Elsevier]

This article focuses on the characteristics of autoimmune diseases. Autoimmunity represents a breakdown of normal self/nonself discrimination, The three mechanisms currently believed to explain this specific recognition of self antigens are clonal deletion, clonal anergy, and clonal suppression. The first step in assigning an autoimmune etiology for a human disease of unknown origin is the demonstration of an autoimmune response to a relevant antigen. The mere presence of autoantibodies does not assure that a disease has an autoimmune etiology.

Abstract: The paradoxical relationship between immunodeficiency (under-responsiveness) and autoimmunity (over-responsiveness) affecting the immune system was debated at the Fourth AARDA Colloquium on cross-disciplinary issues in autoimmunity. Immunodeficiency disease and autoimmune disease, far from being mutually exclusive, share profound dysregulation of the immune system. Among the most keenly discussed issues were: i) the remarkably high number of molecularly identified primary immunodeficiencies with autoimmune expressions; ii) the homeostasis of immune function such that deficiency in any one given compartment can result in over activity in the same or another compartment; iii) whilst some immune deficiency states are essentially monogenic, each of them can exhibit striking variability in autoimmune outcome, indicative of epigenetic or environmental influences on phenotypic expression; iv) innate immunity, particularly complement defects, as well as adaptive immunity, is complicit in the immunodeficiency-autoimmunity axis; v) features of certain of the disorders discussed at the meeting forced a reappraisal of what actually is meant by ‘autoimmune disease’. It was concluded that genes that determine inherited immunodeficiencies, hitherto rather neglected by autoimmunologists, compel attention to consideration of molecular genetic anomalies critical for emergence of autoimmune disease in humans and animals. [ABSTRACT FROM AUTHOR]

Abstract: Despite the widespread use of cardiac troponins as biomarkers for the diagnosis and quantitation of cardiac injury, the effect of troponin release and a possible autoimmune response to the troponins is unknown. Other investigators reported that programmed cell death-1 (PD-1)-receptor deficient mice developed severe cardiomyopathy with autoantibodies to troponin I. We found that immunization of genetically susceptible mice with troponin I but not troponin T induced a robust autoimmune response leading to marked inflammation and fibrosis in the myocardium. At later times, antibodies to cardiac myosin were detected in troponin-immunized mice. The severity of inflammation correlated with expression of chemokines RANTES, MIP-2, IP-10 and MCP-1 in the myocardium. Prior immunization with troponin I increased the severity of experimental infarctions, indicating that an autoimmune response to troponin I aggravates acute cardiac damage. Cardiac inflammation, fibrosis and functional impairment were transferred from immunized to naive recipients by CD4+ T cells, and the cytokine profile suggested both Th2 and Th17 profiles in A/J mice. Finally we identified an 18-mer of troponin I containing an immuno-dominant epitope. [Copyright &y& Elsevier]

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]