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

Abstract

Numerous chronic human disorders are associated with immune activation by obscure antigen(s). We identified a novel sarcoidosis-epitope (ChainA) by immunoscreening of a novel T7 phage library and confirmed an abundance of ChainA IgG-antibody in sarcoidosis. We tested whether ChainA epitope elicits immune responses through B-cell activation, plasma cell differentiation and antibody production. PBMCs from healthy controls and sarcoidosis patients were challenged by chemically synthesized ChainA epitope, and assessed cellular activation markers of B-cells, T-cells, MHC classes, plasma cell differentiation and Unfolded Protein Response (UPR) transcription factors. Chain A increased expression of MHCII class and CD80/CD86 costimulatory molecules. ChainA significantly augmented the transition of naïve B-cells to memory B-cells and plasma cells in sarcoidosis PBMCs compared to healthy PBMCs. B-Cells differentiation to antibody-secreting plasma cells requires activation of UPR, B lymphocyte-induced maturation protein 1 (Blimp-1) and X-box binding protein 1 (XBP-1). ChainA treatment upregulated the expression of Blimp-1 and spliced form of XBP-1, a transcriptional activator of endoplasmic reticulum (ER) 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, a robust UPR responses, and an increased production of IgG specific antibody against ChainA. These results indicate ChainA epitope may be involved in the pathogenesis of sarcoidosis, as it activates MHCII, memory B-cells, plasma cell differentiation and production of ChainA specific IgG.