Pemphigus vulgaris (PV) is an autoimmune disease clinically characterized by blisters on the skin and/or mucosa. Pathophysiologically, PV is mediated by close interaction of B cells and autoreactive T cells, inducing proliferation, differentiation, and production of autoantibodies targeting desmosomal adhesion proteins, namely desmoglein 3 and/or 1. To elucidate B cell changes at different stages of PV, canonical B cell populations, like naïve, memory, transitional, non-switched, switched B cells, and plasmablasts were monitored in peripheral blood. Our results revealed that transitional B cells, which represent a crucial link between immature B cells in the bone marrow and mature peripheral B cells, were significantly decreased in active PV patients, i.e. newly diagnosed and chronic, compared to remittent PV patients and healthy controls. Moreover, after B cell depletion therapy, their frequencies in active patients recovered to levels of healthy controls, suggesting a deficit in this population may contribute to the PV pathophysiology. As a regulatory role of transitional B cells under inflammatory conditions was suggested in other autoimmune diseases, we determined their regulatory capacity via TGF-β, IL-10, and IL-35 secretion but also pro-inflammatory IL-6. Interestingly, transitional B cells from active patients were refractory to further stimulation by CpG and CD40L, resulting in diminished production of regulatory cytokines. Thus, our findings indicate that both diminished frequency and decreased regulatory capacity of transitional B cells in active stages render them unable to effectively inhibit autoimmune processes in PV.
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