Autoimmunity, end organ damage, and the origin of autoantibodies and autoreactive T cells in systemic lupus erythematosus

Abstract

Systemic lupus erythematosus (SLE) is a prototype of systemic autoimmunity affecting many systems. Both antibodies and autoreactive T cells play significant roles in its pathogenesis. Experimental data and clinical observations indicate that autoimmunity and end organ damage are under separate genetic controls and that there are significant interactions between these two pathways. Experimental evidence has been obtained to support the hypothesis that autoantibodies and autoreactive T effector cells may be initiated by environmental factors through molecular mimicry and the inherent polyreactive nature of antigen receptors. A unified hypothesis has been postulated for the pathogenesis of SLE that has practical implications.

Figure 1

Proposed model for the pathogenesis of SLE describes the independent and yet interactive nature of the genes contributes to autoimmunity and end organ damage. I, Autoantibody production and activation of effector T cells and II, activation of susceptibility for end organ damage, can be initiated independently while they interact at different levels as indicated by pathways III and IV. Interaction of these pathways leads to end organ damage (Waters et al., 2004).

Figure 2

Generation of autoreactive Abs and effector T cells in SLE by environmental T cell epitope mimics. Accumulation of cross-reactive T cells is a consequence of responses to environmental mimics in hosts withsusceptibility genes as depicted in A but not in hosts without these genes as depicted in B. In C, the accumulation of diverse autoreactive Abs and T cells as a response to these mimic results in varied SLE clinical presentation. After therapy, the complexity of these autoantibodies and autoreactive T cells are reduced, leading to remission. Over a period of time after discontinuing therapy, the complexity of autoantibodies and effector T cells returns, leading to a protean clinical presentation in relapses. The mimics reside on a diverse array of environmental antigens and the chances for exposure to these mimics are random, providing a scenario in that SLE is not caused by a single pathogen. This mechanism has the flavor of a stochastic process (Fu et al., 2011).