B‐ and T‐Lymphocyte Attenuator in Systemic Lupus Erythematosus Disease Pathogenesis

B‐ and T‐lymphocyte attenuator (BTLA; CD272) is an immunoglobulin superfamily member and part of a family of checkpoint inhibitory receptors that negatively regulate immune cell activation. The natural ligand for BTLA is herpes virus entry mediator (HVEM; TNFRSF14), and binding of HVEM to BTLA leads to attenuation of lymphocyte activation. In this study, we evaluated the role of BTLA and HVEM expression in the pathogenesis of systemic lupus erythematosus (SLE), a multisystem autoimmune disease. Peripheral blood mononuclear cells from healthy volunteers ( N = 7) were evaluated by mass cytometry by time‐of‐flight to establish baseline expression of BTLA and HVEM on human lymphocytes compared with patients with SLE during a self‐reported flare ( N = 5). High levels of BTLA protein were observed on B cells, CD4+, and CD8+ T cells, and plasmacytoid dendritic cells in healthy participants. HVEM protein levels were lower in patients with SLE compared with healthy participants, while BTLA levels were similar between SLE and healthy groups. Correlations of BTLA‐HVEM hub genes' expression with patient and disease characteristics were also analyzed using whole blood gene expression data from patients with SLE ( N = 1,760) and compared with healthy participants ( N = 60). HVEM , being one of the SLE‐associated genes, showed an exceptionally strong negative association with disease activity. Several other genes in the BTLA‐HVEM signaling network were strongly (negative or positive) correlated, while BTLA had a low association with disease activity. Collectively, these data provide a clinical rationale for targeting BTLA with an agonist in SLE patients with low HVEM expression.