RITUXIMAB AND CORTICOSTEROID EFFECT ON DESMOGLEIN-SPECIFIC B-CELLS AND DESMOGLEIN-SPECIFIC T-FOLLICULAR-HELPER-CELLS IN PEMPHIGUS.

Abstract Pemphigus is an autoimmune blistering disease mediated by autoantibodies directed against desmogleins. We recently showed that first-line treatment with rituximab enables more patients to achieve long-lasting remission off therapy than corticosteroids alone. To understand the immunological mechanisms that mediate the long-lasting clinical remission after rituximab treatment, we analyzed the phenotype of desmoglein-specific memory B cells and desmoglein-specific T-follicular-helper cells by flow cytometry, and measured antibody-secreting-cells by ELISPOT in patients treated with corticosteroids alone or rituximab. This post hoc analysis of the RITUX3 trial showed that rituximab induced a significant decrease of IgG-switched desmoglein-specific memory B cells. Accordingly, anti-desmoglein antibody-secreting-cells were no longer detected in patients in complete remission after rituximab. In contrast, corticosteroids did not modify the frequency or the phenotype of desmoglein-specific memory B cells, and anti-desmoglein antibody-secreting-cells were still detected after treatment, even in patients in remission. Using peptide-HLADRB1*0402 tetramer staining, we identified desmoglein-3-specific T-follicular-helper cells, which dramatically decreased after rituximab, while remaining stable after corticosteroid treatment. Our findings suggest that the long-lasting response to rituximab in pemphigus relies on the decrease of desmoglein-specific circulating T-follicular-helper cells, which correlates with a sustained depletion of IgG-switched memory autoreactive B cells, leading to the disappearance of anti-desmoglein antibody-secreting-cells.