Elsevier

Seminars in Immunology

Volume 19, Issue 1, February 2007, Pages 11-23
Seminars in Immunology

Review
Regulation of lupus-related autoantibody production and clinical disease by Toll-like receptors

https://doi.org/10.1016/j.smim.2006.12.005Get rights and content

Abstract

Autoantigens that contain DNA, RNA, or self-IgG are preferred targets for autoantibodies in systemic lupus erythematosus (SLE). B cells promote SLE pathogenesis by producing autoantibodies, activating autoreactive T cells, and secreting cytokines. We discuss how certain autoreactive B cells are selectively activated, with emphasis on the roles of key Toll-like receptors (TLRs). Although TLR7, which recognizes ssRNA, promotes autoimmune disease, TLR9, which recognizes DNA, unexpectedly regulates disease, despite being required for the secretion of anti-chromatin autoantibodies. We describe positive feedback loops involving B cells, T cells, DCs, and soluble mediators, and how these networks are regulated by TLR signals.

Introduction

Systemic autoimmune diseases, such as systemic lupus erythematosus (SLE), are chronic—typically waxing and waning—syndromes that result in damage to diverse organ systems by a variety of immune mechanisms. They are undoubtedly the product of multiple and stepwise failures of immune regulation, leading to a complex scenario of established disease. Nonetheless, this does not mean that in lupus there is simply global immune activation. Rather, there is clearly specificity both in terms of lymphocyte activation, and also in the pivotal role of certain cell types and cytokines. The clues to better understanding and therapy of these diseases must come from a better understanding of the specific nature of aberrant immune activation and the temporal relationship of these events. What stimulates and what sustains autoimmunity? What specific immune circuits are dysregulated? What are the targets of self-reactivity and why?

Section snippets

Positive feedback in autoimmunity

Normally, the immune system is autoregulatory in the sense that the immune response is damped by a variety of counter-regulatory mechanisms that are induced at the time of immune activation. It is reasonable to assume that among the many genetic factors that contribute to disease are alterations in regulatory molecules or circuits, essentially reducing the brakes on (auto)immune responses [1], [2], [3], [4], [5], [6], [7], [8]. In the context of a positive feedback loop, small changes in tuning

B Cells are central to SLE pathogenesis

The discovery in the mid to late 1990s that B cells played central roles in the pathogenesis of lupus [9], [10], [11], [12], [13] and other autoimmune diseases [14], [15], [16], gave some specific detail to the concept of positive feedback. In particular, T cell activation and target tissue infiltration were both decreased in lupus-prone MRL/Mp mice, either in the presence or absence of the Faslpr/lpr mutation, when B cells were eliminated by genetic means [9], [10], [13]. This elucidated one

Specificity of B cell autoimmune responses

These questions are in turn linked to the issue of specificity in systemic autoimmune disease. Although systemic autoimmunity is characterized by multiple syndromes with protean clinical manifestations and different genetic predispositions, the loss of self-tolerance at the level of B cells and autoantibodies is remarkably focused on a small group of self-antigens [39], [40]. The anti-nuclear antibody response is a common feature among a number of systemic autoimmune diseases. Although in many

BCR transgenic models of autoreactivity

Regardless of the reasons, the preferential targeting of certain autoantigens implied that B cells specific for these antigens would likely have unique behaviors among the universe of self-reactive B cells. In order to better study this, BCR transgenic (Tg) mice specific for these antigens, including DNA, Sm and IgG, were created by several groups [55], [81], [82], [83], [84]. These Tg mice represented a second generation, coming after initial models that targeted “self” antigens that were not

Use of the RF Tg system to discover a role for Toll-like receptors in autoreactive B cell activation

Although, as of 5 years ago, in vivo studies of B cells with transgene-encoded specificity for lupus-associated autoantigens had not yet revealed the mechanisms underlying the preference for their activation in vivo, it seemed likely that these cells would be important tools in the process of elucidating this question. Indeed, studies with AM14 Tg B cells carried out in the laboratory of Dr. Ann Marshak-Rothstein in collaboration with our group turned out to be pivotal in this respect. While

Requirement for Toll-like receptors in autoantibody production in vivo

Conclusive in vivo evidence of a role for TLRs in autoimmune disease came from mice with genetic deficiency of TLR9 crossed to established models of murine lupus. We initially crossed TLR9−/− mice to Fas-deficient MRL/Mplpr/lpr mice to generate an F2 cohort of lupus-prone littermates that were either TLR9 wild-type (TLR9+/+) or TLR9−/−. In this model, we found that TLR9 was required for the generation of anti-chromatin and anti-dsDNA antibodies in vivo [107]. This effect on autoantibody

Functional consequences of TLR activation in SLE

In addition to their parallel effects on autoantibody production, TLR7 and TLR9 also affect the development of clinical autoimmune disease. Surprisingly, however, these two receptors appear to have divergent effects. In MRL/Mplpr/lpr mice, the absence of TLR7 led to decreased lymphadenopathy and decreased markers of T and B cell activation. TLR9-deficiency, in contrast, led to increased lymphadenopathy, the accumulation of activated lymphocytes, and increased levels of circulating IgG [107],

Concluding remarks

Studies on the role of TLRs in systemic autoimmunity are likely to reveal novel therapeutic avenues for the treatment of autoimmune diseases. The clear requirement for TLRs in the generation of anti-nuclear antibodies, as well as the amelioration of immune activation and clinical disease in TLR7-deficient lupus-prone mice, highlights these receptors as potential candidates for pharmacologic inhibition in SLE. However, the exacerbation of disease in TLR9-deficient mice provides a note of

Acknowledgements

We thank Jon Shupe for expert technical work, Kevin Nickerson for unpublished data and discussions, Ann Marshak-Rothstein for many useful discussions and collaboration, and the Yale Animal Resources Center for excellent animal husbandry that made our studies possible. Supported by NIH grants P01-AI36529 and P01-AR050256.

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