Toxicology of autoimmune diseases

Abstract

Susceptibility to most autoimmune diseases is dependent on polygenic inheritance, environmental factors, and poorly defined stochastic events. One of the significant challenges facing autoimmune disease research is in identifying the specific events that trigger loss of tolerance and autoimmunity. Although many intrinsic factors, including age, sex, and genetics, contribute to autoimmunity, extrinsic factors such as drugs, chemicals, microbes, or other environmental factors can also act as important initiators. This review explores how certain extrinsic factors, namely, drugs and chemicals, can promote the development of autoimmunity, focusing on a few better characterized agents that, in most instances, have been shown to produce autoimmune manifestations in human populations. Mechanisms of autoimmune disease induction are discussed in terms of research obtained using specific animal models. Although a number of different pathways have been delineated for drug/chemical-induced autoimmunity, some similarities do exist, and a working model is proposed.

Figure 1. Putative mechanism of drug/chemical-induced autoimmunity

Exposure to a toxicant results in aberrant cell death making available cellular material which activates Nod-like receptors (NLR) and Toll-like receptors (TLR). In the case of NLR activation this leads to NLRP3-inflammasome activation and proinflammatory events including production of proinflammatory cytokines such as IL-1β, IL-6, and IFN-γ. For TLR-mediated response, activation of TLR by nuclear material is essential for autoantibody responses to nuclear antigens such as chromatin and RNA/protein complexes. Activation of self-reactive T cells proceeds via breaking of self-tolerance which may be mediated by a number of mechanisms (see text). Reduction in the expression of regulators of T cell activation, such as Daf1, enhances T cell responses and promotes the activation of autoantibody producing B cells. The binding of autoantibodies to self-antigen leads to immune-complex formation and tissue injury which in turn can release cellular material to amplify the response. Self-antigen containing immune complexes can also be taken up by B cells and other antigen presenting cells (e.g. dendritic cells) and amplify activation of autoreactive T cells.