The many faces of type I interferon in systemic lupus erythematosus
Claudia Mauri, Madhvi Menon
Claudia Mauri, Madhvi Menon
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Commentary

The many faces of type I interferon in systemic lupus erythematosus

Abstract

Systemic lupus erythematosus (SLE) is a multisystem autoimmune disease with a broad spectrum of clinical presentations involving multiple organ systems. An abnormal response to self-antigens is thought to drive the development of SLE; however, the factors that underlie this dysfunction are not clear. In this issue of the JCI, Li and colleagues present compelling evidence to show that type I interferons (IFNs) produced by plasmacytoid dendritic cells inhibit the clearance of apoptotic cells (ACs) by marginal zone macrophages. Specifically, type I IFNs increase the translocation of marginal zone (MZ) B cells to the follicular region of the spleen, thereby disrupting interactions between these B cells and MZ macrophages (MZMs), which in turn disrupts megakaryoblastic leukemia 1–mediated (MKL1-mediated) mechanosensing and inhibits AC phagocytosis by MZMs. The results of this study provide important insight into factors that inhibit AC clearance and promote the development of SLE.

Authors

Claudia Mauri, Madhvi Menon

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Figure 1

AC clearance in healthy individuals and patients with SLE.

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AC clearance in healthy individuals and patients with SLE. (A) mLT-expre...
(A) mLT-expressing MZ B cells interact with LTβR-expressing MZMs in the perifollicular region of the spleen, which promotes MKL1 expression by MZMs and maintains their numbers and phagocytic function. (B) In lupus spleens, pDCs accumulate at the perifollicular region and produce IFNα, which induces the migration of mLT+ MZ B cells to the follicle. This results in the loss of MZM numbers and function, leading to defective AC clearance and loss of tolerance to self-antigens. Furthermore, MZ B cells in the follicle interact with FDCs and T follicular helper (Tfh) cells and stimulate germinal center reactions that result in autoantibody production. The antinuclear autoantibodies form immune complexes to further stimulate pDCs to produce type I IFNs. Amplification of these defective interactions contributes to and perhaps initiates the pathogenesis of SLE.