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  • Review Article
  • Published:

Genetics and pathogenesis of systemic lupus erythematosus and lupus nephritis

Nature Reviews Nephrology volume 11, pages 329–341 (2015)Cite this article

Subjects

Key Points

  • Some genes implicated in systemic lupus erythematosus (SLE) and lupus nephritis might contribute to the pathology of disease by breaching immune tolerance and promoting autoantibody production

  • A subset of SLE and/or lupus nephritis genes might augment innate immune signalling and IFN-I production; other SLE genes might modulate the molecular pathways that lead to renal tissue damage

  • Genes that affect the accessibility and handling of apoptotic material and chromatin might also contribute to SLE and/or lupus nephritis

  • The presence of cognate antigens on the glomerular matrix, together with intrinsic molecular abnormalities in resident renal cells, could further accentuate disease progression in lupus nephritis

  • Differential involvement of the above-listed mechanisms in patients could potentially explain the wide spectrum of clinical phenotypes observed among individuals with SLE and lupus nephritis

Abstract

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disorder that has a broad spectrum of effects on the majority of organs, including the kidneys. Approximately 40–70% of patients with SLE will develop lupus nephritis. Renal assault during SLE is initiated by genes that breach immune tolerance and promote autoantibody production. These genes might act in concert with other genetic factors that augment innate immune signalling and IFN-I production, which in turn can generate an influx of effector leucocytes, inflammatory mediators and autoantibodies into end organs, such as the kidneys. The presence of cognate antigens in the glomerular matrix, together with intrinsic molecular abnormalities in resident renal cells, might further accentuate disease progression. This Review discusses the genetic insights and molecular mechanisms for key pathogenic contributors in SLE and lupus nephritis. We have categorized the genes identified in human studies of SLE into one of four pathogenic events that lead to lupus nephritis. We selected these categories on the basis of the cell types in which these genes are expressed, and the emerging paradigms of SLE pathogenesis arising from murine models. Deciphering the molecular basis of SLE and/or lupus nephritis in each patient will help physicians to tailor specific therapies.

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Figure 1: Stepwise evolution of systemic lupus erythematosus (SLE) as a function of genetic load.
Figure 2: Gene products associated with systemic lupus erythematosus (SLE) that might affect the adaptive immune system.
Figure 3: Gene products associated with systemic lupus erythematosus (SLE) that might affect innate immune signalling.
Figure 4: Gene products associated with systemic lupus erythematosus (SLE) that might affect intra-renal events leading to lupus nephritis.

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Acknowledgements

The authors would like to acknowledge the editorial assistance of Simanta Pathak, University of Houston, USA. Relevant studies in Dr. Putterman's laboratory were supported by grants from the NIH, DK090319 and AR048692. Dr. Putterman is currently a Weston Visiting Professor at the Weizmann Institute.

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  1. Department of Bioengineering, University of Houston, 3605 Cullen Boulevard, Houston, 77204, TX, USA

    Chandra Mohan

  2. Division of Rheumatology, Albert Einstein College of Medicine, 1300 Morris Park Avenue, Bronx, 10461, NY, USA

    Chaim Putterman

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Mohan, C., Putterman, C. Genetics and pathogenesis of systemic lupus erythematosus and lupus nephritis. Nat Rev Nephrol 11, 329–341 (2015). https://doi.org/10.1038/nrneph.2015.33

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