Aberrant T Cell Signaling and Subsets in Systemic Lupus Erythematosus

Abstract

Systemic lupus erythematosus (SLE) is a chronic multi-organ debilitating autoimmune disease, which mainly afflicts women in the reproductive years. A complex interaction of genetics, environmental factors and hormones result in the breakdown of immune tolerance to “self” leading to damage and destruction of multiple organs, such as the skin, joints, kidneys, heart and brain. Both innate and adaptive immune systems are critically involved in the misguided immune response against self-antigens. Dendritic cells, neutrophils, and innate lymphoid cells are important in initiating antigen presentation and propagating inflammation at lymphoid and peripheral tissue sites. Autoantibodies produced by B lymphocytes and immune complex deposition in vital organs contribute to tissue damage. T lymphocytes are increasingly being recognized as key contributors to disease pathogenesis. CD4 T follicular helper cells enable autoantibody production, inflammatory Th17 subsets promote inflammation, while defects in regulatory T cells lead to unchecked immune responses. A better understanding of the molecular defects including signaling events and gene regulation underlying the dysfunctional T cells in SLE is necessary to pave the path for better management, therapy, and perhaps prevention of this complex disease. In this review, we focus on the aberrations in T cell signaling in SLE and highlight therapeutic advances in this field.

Sex Hormones in Acquired Immunity and Autoimmune Disease

“…While the exact molecular mechanisms of how female hormones regulate the immune system are yet incompletely elucidated, studies show that they control development, homeostasis, gene expression, and signaling processes in T and B lymphocytes to influence their function in health and disease. This review focuses on the role of sex hormones on the adaptive immune system and in autoimmune diseases with a focus on the prototype systemic autoimmune disease SLE ( 10 – 12 ).…”

Amiselimod (MT-1303), a Novel Sphingosine 1-Phosphate Receptor-1 Modulator, Potently Inhibits the Progression of Lupus Nephritis in Two Murine SLE Models

“…Belimumab, which inhibits the B cell activating factor (BAFF), a key survival cytokine for B cells, is currently the only approved biological agent for SLE [12]. However, the efficacy of drugs targeting B cells is limited, and other approaches, including those targeting T cells, are required to improve treatment options for SLE patients [13,14]. S1P 1 receptor modulators suppress infiltration of autoreactive T cells into sites of inflammation by inhibiting lymphocyte egress from secondary lymphoid organs [15] and have proven their therapeutic potential in RRMS and ulcerative colitis [3,16,17].…”

An integrative Bayesian network approach to highlight key drivers in systemic lupus erythematosus

“…We reported significant increased biological functions in CD80®CD28 and CD86®CD28 ( Figure 4C) for the first time, which activate TCR singling pathway following MHCII antigen presentation and finally result in growing up the differentiation and proliferation rate of T cells in response to the apoptotic autoantigens. Recently, Katsuyama et al indicated a T cells hyperresponsiveness following abnormal TCR signaling pathway in SLE patients [12]. At the end of the SLE signaling pathway, end-organ damage reported via several key genes (FCGR1A, C3, C7, C8G and C9).…”

“…Nowadays, genome-wide association studies (GWAS) coupled with gene expression profiling data shed light on the critical role regarding the dysregulation of genes involved in B-cell receptor (BCR) and T-cell receptor (TCR) mediated signaling in B cells and T cells of SLE patients, respectively [7]. As a validation, an aberrant TCR signaling followed by hyperresponsiveness of T cells has been shown in patients with SLE [12]. Despite numerous strongminded studies that have been done, the pathogenesis is still far from clear.…”