Defining altered regulome structured in response to antigen co-receptors, toll-like receptors, and cytokine receptors stimuli to predispose early developing B cells for pathogenic fate in Systemic lupus erythematosus

Abstract

Abstract A TLR7-IFNg driven IL-21 mediated unique extra-follicular pathway of ASC differentiation of activated naïve B cells through an intermediary DN2 B cell subset has been characterized in pathogenesis of SLE. It has been correlated to distinct priming of naïve B cells characterized by the presence of SLE disease signatures which indicates towards the convergence of TLR, and cytokine signaling along with BCR signaling in the expansion and differentiation of peripheral B cells in SLE. Thus, we hypothesize that distinct combinations of innate, cytokines and antigen driven stimuli cause pathogenesis of SLE by maneuvering disease-related epigenetic programs and molecular networks during B cell development resulting in perturbed activation and differentiation. Indeed, initial data from bulk RNA-seq show enrichment of Type I interferon production and signature genes in HSCs to transitional B cells in SLE BM. Confounded by scRNA-seq, these populations also show profound type II interferon signature genes in SLE BM. Interestingly, BCR devoid Pro-B cells show reduced expression of BCR signaling intermediates with enhanced proliferation. However, expression of Pre-BCR or BCR on the surface of Pre-B cells or Immature B cells respectively are accompanied by increased expression of BCR co-receptors in SLE BM. On the other hand, metabolically SLE early BM B cells are less dependent on oxidative phosphorylation with reduced protein synthesis and processing. Together, these initial findings provide evidence that the proinflammatory microenvironment in SLE BM exerts its effect by differentially regulating BCR signaling factors and co-receptors in early B cell populations and thereby could define the pathogenic fate of B cell in periphery in SLE.