Mechanisms of Kidney Injury in Lupus Nephritis - the Role of Anti-dsDNA Antibodies.

Susan Yung,Tak Mao Chan

doi:10.3389/fimmu.2015.00475

Susan Yung, Tak Mao Chan

Open Access

https://doi.org/10.3389/fimmu.2015.00475

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Abstract

Systemic lupus erythematosus (SLE) is an autoimmune disease characterized by a breakdown of self-tolerance, production of auto-antibodies and immune-mediated injury, resulting in damage accrual in multiple organs. Kidney involvement, termed lupus nephritis, is a major cause of morbidity and mortality that affects over half of the SLE population during the course of disease. The etiology of lupus nephritis is multifactorial and remains to be fully elucidated. Accumulating evidence suggests that in addition to forming immune complexes and triggering complement activation, anti-dsDNA antibodies contribute to the pathogenesis of lupus nephritis through binding, either directly or indirectly, to cross-reactive antigens or chromatin materials, respectively, to resident renal cells and/or extracellular matrix components, thereby triggering downstream cellular activation and proliferation as well as inflammatory and fibrotic processes. Several cross-reactive antigens that mediate anti-dsDNA antibody binding have been identified, such as annexin II and alpha-actinin. This review discusses the mechanisms through which anti-dsDNA antibodies contribute to immunopathogenesis in lupus nephritis. Corticosteroids combined with either mycophenolic acid (MPA) or cyclophosphamide is the current standard of care immunosuppressive therapy for severe lupus nephritis. This review also discusses recent data showing distinct effects of MPA and cyclophosphamide on inflammatory and fibrotic processes in resident renal cells.

Highlights

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that affects multiple organ systems
Cell Proliferation, Apoptosis, and DNase I Synthesis Interaction of nephritogenic human polyclonal anti-double-stranded DNA (dsDNA) antibodies with cultured human or rat mesangial cells induced cell proliferation, apoptosis, protein kinase C (PKC) activation, secretion of IL-6, IL-1β, tumor necrosis factor-α (TNF-α), transforming growth factor-β1 (TGF-β1), and hyaluronan, and fibronectin synthesis [37, 55, 56, 78, 79], suggesting that anti-dsDNA antibodies may contribute to mesangial expansion, hypercellularity, increased apoptosis, inflammation, and fibrogenesis observed in lupus nephritis
The mechanisms through which IL-6 secretion is induced in resident renal cells has yet to be fully elucidated, we have demonstrated that binding of anti-dsDNA antibodies to annexin II in mesangial cells can induce IL-6 secretion [37]

Summary

Introduction

Systemic lupus erythematosus (SLE) is a chronic autoimmune disease that affects multiple organ systems. Nephritogenic anti-dsDNA antibodies have been shown to regulate gene and protein expression of inflammatory and fibrotic mediators in resident renal cells, thereby exerting a direct effect on kidney inflammation and fibrosis [10].

Results

Conclusion