Autoimmunity andor Infection

The thymus negatively selects T cells with autoantigen-specific surface receptors. This negative selection process requires the presence of peripheral autoantigen in the thymus. Although this review will not focus on the thymic selection process, it is noteworthy that the transcription factor AIRE has been proposed to assure thymic expression of peripheral antigens [3]. AIRE was identified as the mutated gene in humans with Autoimmune Polyendocrinopathy-Candidiasis-Ectodermal Dystrophy (APECED), a familiar polyendocrine autoimmune disease [4]. To study central tolerance and peripheral autoimmunity, several T cell receptor transgenic mice specific for relevant extralymphatic peripheral autoantigens have been developed during the past decade [5]. Interestingly, central tolerance appeared to be more the exception than the rule. These findings implicate that naive autoantigen-specific T cells are probably common, much more than widely believed. However, most T cell receptor transgenic autoimmune mouse models fail to induce disease spontaneously, at least during the relatively short lifespan of a laboratory mouse [5]. Thus, while accepting the importance of the presence of the final adaptive effector cells in mediating clinical disease, it seems even more essential to understand the pathways that initially led to their induction, i.e., why, where, and how are these autoreactive B and T cells primed? Several explanations have been offered:

1. Molecular mimicry, meaning that an infectious agent shares a protein-epitope with a self-protein within the peripheral target tissue [6]. Cross-

reactivity has been proposed to be involved in the association of infection with beta hemolytic streptococci and rheumatic fever, B3 Coxsackievirus and myocarditis, various viruses and multiple sclerosis, Borrelia burgdor-feri and Lyme arthritis and B4 Coxsackie virus, rubella virus or CMV and diabetes type I. Since epitope binding occurs in a MHC-restricted manner, molecular mimicry may also explain the associations with MHC alleles [7]. However, confirmation of molecular mimicry involvement in autoimmunity requires more than simple associations. The endogenous as well as the foreign epitopes must be identified and the induction of cross-reactive T cells during disease should be confirmed. In a best case scenario, deletion of either epitope should result in absence or reduction of autoimmunity in an animal model [8]. Based on these criteria, molecular mimicry has not been demonstrated convincingly. Nevertheless, molecular mimicry may sometime still contribute to autoimmunity in some cases [9-11].

2. A more common first step in the autoimmune disease pathway involves organ damage and release of so far immunologically ignored autoantigen and its presentation by antigen-presenting cells (APCs) in draining lymph nodes and the spleen. For example, ischemic myocardial infarction leads to the increase of myocardial proteins measurable in blood and may induce autoimmune myo/epi/pericarditis some weeks later (Dressler syndrome). Similarly, mechanical eye injury may lead to autoimmune destruction of the other undamaged eye [12,13]. In infection-associated autoimmunity, cytopathic virus (e.g., B3 Coxsackie virus) replication may cause myocardial apoptosis and release of heart muscle proteins. T cells against both the virus and against autoantigen are primed in local lymph nodes and the spleen and are recruited to the heart [14]. Depending on the virus, molecular mimicry may in addition enhance autoimmune attack. Once started, autoimmunity destroys additional heart muscle tissue and autoantigen is again released, which maintains the process and may involve additional epitopes (epitope spreading).

Despite these complexities, autoantigen-specific T cells usually seem to ignore the peripheral antigen in the absence of an organ pathology or inflammation. This view was supported from experiments in a mouse diabetes model where a viral antigen (lymphocytic choriomeningitis virus (LCMV) -glycoprotein GP or LCMV-nucleoprotein NP) is expressed solely in the pancreatic islets due to expression control by the rat insulin promoter (RIP-GP and RIP-NP mice) [15, 16]. If these mice are crossed with mice in which all (transgenic) T cells recognize the same viral antigen, no activation of T cells is induced (Ignorance) (Fig. 1). In contrast, if the RIP-GP or RIP-NP mice are systemically

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