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Studies of the immune response of mammals to infectious agents have revealed that members of the hsp60 and hsp70 family are highly immunodominant. Given their high conservation during evolution this was surprising, because of the apparent risk of triggering of autoimmunity and autoimmune disease during the defense of a mammal against infection. However, detailed studies of the immune responses to HSP in models of autoimmune diseases in animals resulted in a change of the view that autoimmunity necessarily leads to autoimmune disease. It has been found that modulation of autoimmunity to HSP is one way to prevent autoimmune disease. At least in some cases even treatment of autoimmune diseases by immunization with heat shock protein appears feasible. This was shown in adjuvant arthritis in Lewis rats and insulin dependent diabetes in NOD mice. Hsp60 and hsp70 are ubiquitous proteins. Their involvement in regulatory loops of autoimmunity may serve as basis for the development of strategies to prevent and/or treat autoimmune diseases even without knowledge of the causative (auto-)antigen.
HSP60
NOD mice
Molecular mimicry
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Hepatitis C virus (HCV)-host interaction, namely the host immune reaction against various viral proteins, determines viral persistency and the severity of liver damage. The strong lymphotropism of HCV has been proven to be responsible in part for its ability to evade the peripheral immune response and possibly the frequency of HCV-related autoimmunity. Various mechanisms were reported to be responsible for HCV persistency and its association with autoimmunity. Of these, enhanced T cell apoptosis was reported to contribute to viral persistency and disease severity. The issue of HCV-related autoimmunity has partly been shown to be related to the resistance of CD5+ B cell subpopulation to apoptosis. Autoimmunity has been reported by many to include a wide range of autoantibodies such as rheumatoid factor, ani-cardiolipin and smooth muscle antibodies. In this review our aim is to summarize the data on the mechanisms responsible for HCV persistence and HCV-related autoimmunity. We will try to determine the importance of autoimmunity in the evaluation of chronic HCV infected patients. Keywords: Chronic hepatitis C virus, Autoimmunity, Virus persistence, Anti-nuclear antibodies
Persistence (discontinuity)
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Hygiene hypothesis
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During the last years, studies investigating the intriguing association between immunodeficiency and autoimmunity led to the discovery of new monogenic disorders, the improvement in the knowledge of the pathogenesis of autoimmunity, and the introduction of targeted treatments. Autoimmunity is observed with particular frequency in patients with primary antibody deficiencies, such as common variable immunodeficiency (CVID) and selective IgA deficiency, but combined immunodeficiency disorders (CIDs) and disorders of innate immunity have also been associated with autoimmunity. Among CIDs, the highest incidence of autoimmunity is described in patients with autoimmune polyendocrine syndrome 1, LRBA, and CTLA-4 deficiency, and in patients with STAT-related disorders. The pathogenesis of autoimmunity in patients with immunodeficiency is far to be fully elucidated. However, altered germ center reactions, impaired central and peripheral lymphocyte negative selection, uncontrolled lymphocyte proliferation, ineffective cytoskeletal function, innate immune defects, and defective clearance of the infectious agents play an important role. In this paper, we review the main immunodeficiencies associated with autoimmunity, focusing on the pathogenic mechanisms responsible for autoimmunity in each condition and on the therapeutic strategies. Moreover, we provide a diagnostic algorithm for the diagnosis of PIDs in patients with autoimmunity.
Primary Immunodeficiency
Common Variable Immunodeficiency
Pathogenesis
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Pathogenesis
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Monogenic autoimmune syndromes provide a rare yet powerful glimpse into the fundamental mechanisms of immunologic tolerance. Such syndromes reveal not only the contribution of an individual breakpoint in tolerance but also patterns in the pathogenesis of autoimmunity. Disturbances in innate immunity, a system built for ubiquitous sensing of danger signals, tend to generate systemic autoimmunity. For example, defects in the clearance of self-antigens and chronic stimulation of type 1 interferons lead to the systemic autoimmunity seen in C1q deficiency, SPENCDI, and AGS. In contrast, disturbances of adaptive immunity, which is built for antigen specificity, tend to produce organ-specific autoimmunity. Thus, the loss of lymphocyte homeostasis, whether through defects in apoptosis, suppression, or negative selection, leads to organ-specific autoimmunity in ALPS, IPEX, and APS1. We discuss the unique mechanisms of disease in these prominent syndromes as well as how they contribute to the spectrum of organ-specific or systemic autoimmunity. The continued study of rare variants in autoimmune disease will inform future investigations and treatments directed at rare and common autoimmune diseases alike.
Self Tolerance
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Increased risk of developing autoimmune manifestations has been identified in different primary immunodeficiencies (PID). In such conditions, autoimmunity and immune deficiency represent intertwined phenomena that reflect inadequate immune function. Autoimmunity in PIDs may be caused by different mechanisms including defects of tolerance to self-antigens, and persistent stimulation as a result of the inability to eradicate antigens. This general immune dysregulation leads to compensatory and exaggerated chronic inflammatory responses that lead to tissue damage and autoimmunity. Each PID may be characterized by distinct, peculiar autoimmune manifestations. Moreover, different pathogenetic mechanisms may underlie autoimmunity in PID. In this review, the main autoimmune manifestations observed in different PID, including humoral immunodeficiencies, combined immunodeficiencies, and syndromes with immunodeficiencies, are summarized. When possible, the pathogenetic mechanism underlying autoimmunity in a specific PID has been explained.
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It is well established that the autoantibodies that characterize both rheumatoid arthritis (RA) and systemic lupus erythematosus (SLE) are present systemically years before patients develop disease. In both these autoimmune rheumatic diseases, evidence is growing that local autoimmune processes occur at epithelial surfaces potentially initiating localized autoimmunity. For RA, these are mucosal surfaces including the oral mucosa, lung, and gut. At the oral mucosa and lung, risk factors such as periodontal disease and smoking may contribute to autoimmunity by driving the local generation of citrullinated autoantigens. For SLE, the skin may be integral in pathogenesis. It is proposed that defective clearance of apoptotic debris leads to initial innate immune responses preceding autoimmunity. Many tissues may be implicated but the frequency of skin disease, even without autoantibodies, and the role of UV light as a trigger suggest that keratinocytes may be a key site of initiation. In both diseases, a local break in immune tolerance could lead to systemic autoimmunity, and, in the gut, bacterial organisms that colonize the intestine may influence the localized gut immune response through T-cells and promote the development of systemic autoimmunity. In this review, we discuss the evidence for localized epithelial autoimmunity in those at risk of RA and SLE and early disease. Localized autoimmunity at the oral mucosa, lung, gut, and skin will be considered as potential initiating sites of ARD-related autoimmunity.
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