T cells from induced and spontaneous models of SLE recognize a common T cell epitope on β2-glycoprotein I

Abstract

Systemic lupus erythematosus is a prototypic model for B-cell epitope spread in autoimmunity. Autoantibodies to numerous molecularly distinct self-antigens emerge in a sequential manner over several years, leading to disease manifestations. Among the earliest autoantibodies to appear are those targeting phospholipid-binding proteins, particularly β2-glycoprotein I. Notably, mice immunized with β2-glycoprotein I and lipopolysaccharide develop a strong T cell response to β2-glycoprotein I that is associated with autoantibody production and renal disease, similar to that seen in human SLE. Here we hypothesized that mice with murine systemic lupus erythematosus, whether induced or spontaneous, should have T cells that recognize β2-glycoprotein I. We evaluated the response of splenic T cells from mice with induced (C57BL/6 and C3H/HeN) and spontaneous (MRL/lpr) systemic lupus erythematosus to peptides spanning the entire sequence of human β2GPI. We found that mice with induced and spontaneous systemic lupus erythematosus recognize a common T cell epitope (peptide 31; LYRDTAVFECLPQHAMFG) in domain III of β2-glycoprotein I. β2GPI-reactive CD4 T cells from the two models differed primarily in cytokine production: T cells from mice with induced SLE expressed IFN-γ, while T cells from MRL/lpr mice expressed both IL-17 and IFN-γ, indicating that IL-17-expressing T cells are not necessary for generating a β2GPI-reactive T cell response. These data suggest that the generation of a β2-glycoprotein I-reactive T cell response is shared by both induced and spontaneous models of systemic lupus erythematosus and that this T cell response may mediate epitope spread to autoantibodies in both models.

BCL-6 suppresses miR-142-3p/5p expression in SLE CD4+ T cells by modulating histone methylation and acetylation of the miR-142 promoter

“…This loss of tolerance subsequently leads to uncontrolled T cell overactivation and the overproduction of autoantibodies against multiple self-antigens that trigger inflammation and damage to tissues including the skin, joints, vessels, kidneys, and central nervous system. [1][2][3][4] Recent studies have shown that multiple epigenetic regulatory mechanisms contribute to the pathogenesis of SLE. [5][6][7][8] MicroRNAs (miRNAs) regulate target gene expression by binding to the 3′-untranslated region (3′-UTR) of target messenger RNAs (mRNAs), leading to either translational repression or degradation.…”

Necroptotic cell binding of β2‐glycoprotein I provides a potential autoantigenic stimulus in systemic lupus erythematosus

“…T‐cell responses are shown for LPS‐stimulated BMDCs, as responses with unstimulated BMDCs were very low (data not shown). Only CD4 T cell responses were evaluated, as we have previously shown that mainly CD4, and not CD8, T cells are expanded in β 2 GPI/LPS‐immunized mice . While apoptotic cells suppressed the T‐cell response to β 2 GPI, as measured by interferon‐γ (IFN‐γ) production, necroptotic cells increased the response in a dose‐dependent manner (for dead cell: BMDC ratios of 0.0625, 0.25 and 1) (Figure , bottom).…”

“…Only CD4 T cell responses were evaluated, as we have previously shown that mainly CD4, and not CD8, T cells are expanded in b 2 GPI/LPSimmunized mice. 33 While apoptotic cells suppressed the Tcell response to b 2 GPI, as measured by interferon-c (IFN-c) production, necroptotic cells increased the response in a dose-dependent manner (for dead cell: BMDC ratios of 0.0625, 0.25 and 1) (Figure 3, bottom). Similar findings were observed for IL-2 production by T cells treated with apoptotic cells or necroptotic cells (Figure 3, bottom).…”

Increased MLKL mRNA level in the PBMCs is correlated with autoantibody production, renal involvement and SLE disease activity

“…Considering the role of necroptosis in the pathogenesis and development of SLE [13][14][15][16], we aimed to analyze MLKL mRNA of PBMCs and figure out whether it could serve as a biomarker for disease diagnosis and monitoring.…”