Role of B-Cell in the Pathogenesis of Systemic Sclerosis

Abstract

Systemic sclerosis (SSc) is a rare multisystem autoimmune disease, characterized by fibrosis, vasculopathy, and autoimmunity. Recent advances have highlighted the significant implications of B-cells in SSc. B-cells are present in affected organs, their subpopulations are disrupted, and they display an activated phenotype, and the regulatory capacities of B-cells are impaired, as illustrated by the decrease in the IL-10+ producing B-cell subpopulation or the inhibitory membrane co-receptor density. Recent multi-omics evidence highlights the role of B-cells mainly in the early stage of SSc and preferentially during severe organ involvement. This dysregulated homeostasis partly explains the synthesis of anti-endothelial cell autoantibodies (AECAs) or anti-fibroblast autoantibodies (AFAs), proinflammatory or profibrotic cytokines (interleukin-6 and transforming growth factor-β) produced by B and plasma cells. That is associated with cell-to-cell interactions with endothelial cells, fibroblasts, vascular smooth muscle cells, and other immune cells, altogether leading to cell activation and proliferation, cell resistance to apoptosis, the impairment of regulatory mechanisms, and causing fibrosis of several organs encountered in the SSc. Finally, alongside these exploratory data, treatments targeting B-cells, through their depletion by cytotoxicity (anti-CD20 monoclonal antibody), or the cytokines produced by the B-cell, or their costimulation molecules, seem interesting, probably in certain profiles of early patients with severe organic damage.

Keywords: B-cell; B-cell receptor (BCR); autoantibodies; interleukine 6 (IL-6); pathogenesis; rituximab; systemic sclerosis; transcriptomic.

Figure 1

Illustration of the B-cell presence in the SSc patients skin (adapted from Fetter et al. Cells, 2020 [13)]. CD20⁺ B-cells and plasma cells infiltrate the skin of SSc patients, from the early stages of the disease, especially around blood vessels, accompanied by other peripheral blood mononuclear cells, such as CD3⁺ T cells or follicular dendritic cells. B-cells participate in the functions of antigen-presenting cells, production of autoantibodies and proinflammatory and profibrotic cytokines, as well as direct contact with other cells such as the fibroblast.

Figure 2

B-cell signaling via BCR and costimulation molecules (adapted from Dal Porto et al. Mol Immunol, 2004 [32)]. After ligation of antigen on the B-cell antigen receptor (BCR) at the membrane, signals are transduced and propagated by several protein phosphorylations, modifications and interactions. The end point is the regulation of transcription factors that regulate the expression of genes. Recent results highlight the participation of intracellular signaling perturbations in B-cell including defective phosphorylation of MAPK, STAT3 or mTOR molecules. Solid line: translocation. Dotted line: direct action. AKT, protein kinase B; BCR, B-cell receptor; BLNK, B-cell linker protein; BTK, Bruton’s tyrosine kinase; CD, cluster of differentiation; DAG, diacylglycerol; ERK, extracellular signal-regulated kinases; IL, interleukin; IL6-R, IL6 receptor; IP3, inositol triphosphate; JAK, Janus kinases; JNK, c-Jun N-terminal kinase; Lyn, Lck/Yes novel tyrosine kinase; MAPK, mitogen associated protein kinase; mTOR, mammalian target of rapamycin; NFAT, Nuclear factor of activated T cells; PI3K, phosphoinositide 3-kinase; PLCγ, phospholipase Cγ2; PKC, protein kinase C; STAT3, signal transducer and activator of transcription 3; SYK, spleen tyrosine kinase.

Figure 3

B-cell implications in the pathogenic processes involved in systemic sclerosis. (A) Organ infiltration: B-cell infiltrates are present in various organs involved in SSc. These infiltrates combine B and T cells, plasma cells, dendritic cells and macrophages, underlying their interactions. (B) B-cell subpopulations: B-cells express at their surfaces multiple molecules involved in activation or surviving pathway, as well as decreased levels of inhibitors coreceptors. B-cells also express co-receptors required for interaction with T cell. (C) B-cell intracellular signaling, genomic, transcriptomic and proteomic data argue a B-cell signature in SSc. (D) Autoantibodies. Several autoantibodies have demonstrated their involvement in cell activation, apoptosis induction, proinflammatory and profibrotic processes. (E, F) Cell to cell interactions and cytokines synthesis: B-cells interact with various immune cells, fibroblast and endothelial cell through direct (solid line) and indirect contact (i.e., cytokines and antibodies; dotted line). All participate in profibrotic, proinflammatory processes, vascular remodeling and immune dysregulations. Abs, antibodies; AECA, anti-endothelial cell Abs; AFA, anti-fibroblast Abs; anti-VSMC Abs, anti-vascular smooth muscle cell Abs; BAFF-R, calcium-modulator and cyclophilin ligand-interactor and BAFF receptor; BCMA, B-cell survival membrane receptors: B-cell maturation protein; BCR, B-cell receptor; CD, cluster of differentiation; DCs, dendritic cells; HLA-II, human leukocyte antigen class II; ICOS, inducible T-cell costimulatory; IL, interleukin; IL6-R, IL6 receptorPD-1/PD-L2: programmed death/programmed death ligand immune checkpoint; pDCs, plasmacytoid dendritic cells; TACI, trans-membrane activator.