Mechanisms of B cell autoimmunity in SLE

Thomas Dörner,Claudia Giesecke,Peter E Lipsky

doi:10.1186/ar3433

Abstract

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease that is known to be associated with polyclonal B-cell hyperreactivity. The underlying causes of the diffuse B-cell over-reactivity are unclear, but potential candidates include (a) intrinsic hyper-reactivity leading to polyclonal B-cell activation with disturbed activation thresholds and ineffective negative selection; (b) lack of immunoregulatory functions; (c) secondary effects of an overactive inflammatory environment, such as overactive germinal center and ectopic follicular activity; and/or (d) disturbed cytokine production by non-B immune cells. These mechanisms are not mutually exclusive and may operate to varying extents and at varying times in SLE. Phenotypic and molecular studies as well as the results of recent clinical trials have begun to provide new insights to address these possibilities. Of importance, new information has made it possible to distinguish between the contribution played by abnormalities in central checkpoints that could lead to a pre-immune repertoire enriched in autoreactive B cells, on the one hand, and the possibility that autoimmunity arises in the periphery from somatic hypermutation and abnormal selection during T cell-dependent B-cell responses on the other. There is an intriguing possibility that apoptotic material bound to the surface of follicular dendritic cells positively selects autoreactive B cells that arise from non-autoreactive B-cell precursors as a result of somatic hypermutation and thereby promotes the peripheral emergence of autoimmunity.

Highlights

Systemic lupus erythematosus (SLE) is considered a prototypic autoimmune disease, it cannot beBoth mice and human subjects with SLE produce a number of autoantibodies against nuclear complexes, the profile of these antibodies can vary widely between individual subjects and murine models
An understanding of the potential role of these checkpoints for selftolerance is based on the analysis of Ig genes cloned from single purified B cells at different stages during their development [12,13,42,43,44]. The results of these analyses indicate that autoantigen-binding B cells occur fairly frequently early in B-cell ontogeny but that these autoreactive B cells are culled at various stages of subsequent B-cell ontogeny
Generation of germinal centers Given the enhanced GC activity and increased formation of ectopic GCs known to result in the generation of antigen-experienced memory B and plasma cells, there is a possibility that factors involved in establishing GC structures, including T follicular helper (TFH) cells, IL-21, IL-6, CXCL13, TNFβ, and inducible T-cell co-stimulator (ICOS), play a critical role in SLE

Summary

Introduction

Systemic lupus erythematosus (SLE) is considered a prototypic autoimmune disease, it cannot be. Systemic lupus erythematosus may develop as a result of enhanced germinal center activity and preferential selection by autoantigen An alternative hypothesis postulates that pathogenic autoimmunity in SLE arises as a result of increased T cell-dependent GC-like activity that generates autoantibodies from B cells whose BCRs had no intrinsic reactivity with autoantigens in germline configuration Intrinsic to this hypothesis are the concepts of B-cell hyper-responsiveness or exaggerated T-cell responses or both, coupled with enhanced somatic hypermutation and the accumulation of apoptotic material within GCs with the capacity to positively select autoreactive B cells. Generation of germinal centers Given the enhanced GC activity and increased formation of ectopic GCs known to result in the generation of antigen-experienced memory B and plasma cells, there is a possibility that factors involved in establishing GC structures, including T follicular helper (TFH) cells, IL-21, IL-6, CXCL13, TNFβ, and inducible T-cell co-stimulator (ICOS), play a critical role in SLE In this regard, the sanroque mouse that harbors a mutation that regulates ICOS expression on T cells develops a very aggressive form of lupus. Mutations targeted especially to the Gs and Cs of RGYW/WRCY motifs have become of special interest since they are thought to be the direct consequence of AIDCA deamination [69] occurring typically within GCs, as this pattern is reduced in CD154-deficient individuals, virtually lacking [Frequency] %

CDR SLE

Conclusions

Findings

Autoimmune Basis of Rheumatic Diseases