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Review
. 2016 Jan;269(1):100-17.
doi: 10.1111/imr.12348.

SLE-associated risk factors affect DC function

Myoungsun Son  1 , Sun Jung Kim  1 , Betty Diamond  1
Affiliations
Review

SLE-associated risk factors affect DC function

Myoungsun Son et al. Immunol Rev. 2016 Jan.

Abstract

Numerous risk alleles for systemic lupus erythematosus (SLE) have now been identified. Analysis of the expression of genes with risk alleles in cells of hematopoietic origin demonstrates them to be most abundantly expressed in B cells and dendritic cells (DCs), suggesting that these cell types may be the drivers of the inflammatory changes seen in SLE. DCs are of particular interest as they act to connect the innate and the adaptive immune response. Thus, DCs can transform inflammation into autoimmunity, and autoantibodies are the hallmark of SLE. In this review, we focus on mechanisms of tolerance that maintain DCs in a non-activated, non-immunogenic state. We demonstrate, using examples from our own studies, how alterations in DC function stemming from either DC-intrinsic abnormalities or DC-extrinsic regulators of function can predispose to autoimmunity.

Keywords: dendritic cells; immune tolerance; risk alleles; systemic lupus.

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Figures

Figure 1
Figure 1
Tissue‐specific function of Blimp‐1 expression in dendritic cells. In peripheral lymphoid organs, Blimp‐1 expression in cDCs regulates follicular helper T (Tfh) cell expansion and antigenic specificity. Together with Irf4, Blimp‐1 regulates peptides which are presented on major histocompatibility class II (MHC II) through the expression of Cathepsin S. Blimp‐1 expression also negatively regulates IL‐6 which is required for Tfh cell differentiation. Therefore, low levels of Blimp‐1 in DCs lead to an increase in Tfh cell differentiation, and autoreactive B cell activation in germinal centers. Blimp‐1 expression is also necessary in tissue‐resident DCs. Absence of Blimp‐1 in intestinal DCs leads to a hyperactivation of the NOD2 signal pathway. This abnormal response generates increased IL‐1β and IL‐6 production, and subsequently induces increased matrix metalloproteinases (MMPs) from neighboring tissue macrophages. DC, dendritic cell; IL‐6, interleukin‐6.
Figure 2
Figure 2
C1q has a fundamental suppressive role in immune homeostasis. Interaction between C1q and its receptor LAIR‐1 inhibits DC differentiation and activation either during steady state or during inflammation. C1q prevents the production of interferon and inflammatory cytokines by both human and mouse DCs and monocytes. In inflammation or lupus progression, C1q enhances the clearance of apoptotic debris through regulating LAIR‐1 and perhaps other C1q receptors. PDC, plasmacytoid DC; Mono, monocyte; MO‐DC, monocyte‐derived dendritic cell; Mac, macrophage; DAMPs, damage‐associated molecular patterns; PAMPs, pathogen‐associated molecular patterns; Mer, Mer tyrosine kinase.
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