Pilot Project-Characterization of antigen presentation by ABCs

Pilot Project Summary/Abstract SLE is a systemic autoimmune disease in which B cells have a major role in pathogenesis. Recent studies identified a non-classical subset of B cells, named age-associated B cells (ABCs), which is expanded in inflammatory diseases such as SLE. In SLE patients, expansion of ABCs is more evident in those with lupus nephritis (LN) and with high titers of autoantibodies. Functionally, ABCs produce autoantibodies following ex vivo stimulation with a toll-like receptor (TLR) 7/8 agonist and cytokines. ABCs also display features of professional antigen presenting cells (APCs) with higher expression of MHC II and co-stimulatory molecules than what is observed in other B cell subsets. In mice, inhibition of ABC generation alleviated lupus manifestation mediated, in part, by prevention of effector T cell differentiation, especially follicular helper T (Tfh) cells. While these observations support the contribution of ABCs to SLE pathogenesis, significant gaps in knowledge exist regarding their pathogenic function. Our laboratory and others found that ABCs are a metabolically and transcriptionally distinct B cell population compared to naïve or memory B cells. ABCs produce higher levels of proinflammatory cytokines, including IL-6, IL-10 and IL-1β, and exhibit inflammasome formation. ABCs can uptake soluble antigens through B cell receptor-independent manner. We also observed expression of HIF1A in ABCs. An inflammatory function of HIF1A has been identified in myeloid cells, but not in B cells. The pilot project will characterize the function of ABCs as antigen presenting cells (APCs). There is the potential to relate this phenotypic characterization of ABCs to the ANA response studied in the Principal Project. Single cell analyses will also be available from patients with active SLE and pre-flare samples; this data will be generated by the Collaborative Project. The pilot project will benefit from the infrastructure of the ACE project and will use B cells derived from patients being studied in the cohorts available through the Collaborative Project.