Novel Sarcoidosis Epitope Augments MHCII, CD80, and CD86 Expression and Promotes B-Cell Differentiation and IgG Production

Numerous chronic human disorders are associated with immune activation by an obscure antigen (or antigens). We identified ChainA, a novel sarcoidosis epitope, by immunoscreening of a novel T7 phage library and confirmed an abundance of ChainA IgG antibody in sarcoidosis. We tested whether the ChainA epitope elicits immune responses through B-cell activation, plasma cell differentiation, and antibody production. Peripheral blood mononuclear cells (PBMCs) from healthy control participants and patients with sarcoidosis were challenged by chemically synthesized ChainA epitope, and cellular activation markers of B cells, T cells, major histocompatibility complex (MHC) classes, plasma cell differentiation, and unfolded protein response (UPR) transcription factors were assessed. ChainA increased the expression of MHC Class II (MHCII) and CD80/CD86 costimulatory molecules. ChainA significantly augmented the transition of naive B cells to memory B cells and plasma cells in PBMCs from patients with sarcoidosis compared with those from healthy control participants. B cell differentiation to antibody-secreting plasma cells requires the activation of UPR, B lymphocyte-induced maturation protein 1 (or, Blimp-1), and X-box binding protein 1 (XBP-1). ChainA treatment upregulated the expression of Blimp-1 and the spliced form of XBP-1, a transcriptional activator of endoplasmic reticulum stress response. Furthermore, the transition of B cells to plasma cells in response to ChainA induced the production of anti-ChainA IgG. In parallel to human PBMCs, utilizing murine splenocytes, we validated our observations that ChainA challenge augments MHCII expression, robust UPR responses, and an increased production of IgG-specific antibody against ChainA. These results indicate that the ChainA epitope may be involved in the pathogenesis of sarcoidosis, as it activates MHCII, memory B cells, plasma cell differentiation, and the production of ChainA-specific IgG.