Pathogenesis of systemic lupus erythematosus revisited 2011: end organ resistance to damage, autoantibody initiation and diversification, and HLA-DR

Abstract

Systemic lupus erythematosus (SLE) is a multi-system disorder resulting from interaction of susceptibility genes and environmental factors. SLE has protean clinical presentations at the initial diagnosis and relapses. SLE-related autoantibodies have unique patterns of diversification to linked proteins such as the snRNP particle and the diversification takes years before clinical diagnosis. There are both clinical and experimental evidence to indicate that separate genes contribute to autoimmunity and end organ damage and these genes are independent and interactive. Among the numerous susceptibility genes, HLA-D complex is dominant. Results from the authors' laboratories led us to postulate a unified hypothesis for SLE pathogenesis. This hypothesis states that SLE-autoantibodies are initiated by environmental T cell epitope mimics of the SLE-related autoantigens in hosts with susceptible HLA-D alleles. These autoantibodies diversify over a period of years due the accumulation of cross-reactive T cells. This process ultimately leads to the generation of organ specific autoantibodies and autoreactive effector T cells due to the polyreactive nature of T and B cell receptors from hosts with susceptibility genes to end organ damage, resulting in protean clinical presentations. This hypothesis accounts for most of the features unique to SLE and has clinical implications as to how patients should be treated.

Figure 1

NZM.C57/Lc1 (Lc1) and NZM.C57Lc4 (Lc4) congenic lines were derived by replacing the genetic intervals in NZM2328 with those from C57L/J (hatched bar). The genetic intervals with SLE susceptibility genes in NZM2328 delineated by informative microsatellite markers are shown (open bars). Chromosome intervals are drawn to scale. The genes involved in Lc1 and Lc4 congenic lines are Cgnz1 and Agnz1, and Adaz1 respectively. The characteristics of these two congenic lines are included (modified from 26).

Figure 2

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 (26).

Figure 3

Possible mechanisms for intermolecular epitope spreading within the snRNP complex. For simplicity, only three components of snRNP are included in this illustration. Four possible mechanisms are illustrated: I. Intrastructural T cell help hypothesis. II. Role of immune complexes in epitope spreading. III. Role of cross-reactivity in epitope spreading and IV. Epitope spreading controlled by cross-reactive T cells. Mechanisms I-III cannot account for the specific patterns of epitope spreading. There is no evidence for the generation of specific Abs from cross-reactive Abs. There is evidence to support mechanism IV and further experimental approaches can be designed to test its validity.

Figure 4

Generation of autoreactive Abs and effector T cells in SLE by environmental T cell epitope mimics. A. Accumulation of cross-reactive T cells as a consequence of response to environmental mimics in hosts (HLA-DR3+) with lupus susceptibility genes but not in hosts (HLA-DR3+) without these genes. B. The accumulation of diverse autoantibodies as a response to these mimics generates pathogenic autoreactive Abs and effector T cells. 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 effect 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.