Can autoimmune disease be cured by deep CD19+ cell depletion?

Abstract

Therapeutic B cell depletion with monoclonal antibodies targeting CD20 forced a rethink about the pathogenic role of B cells and plasma cells in autoimmune diseases; however, it was tempered by frequent clinical relapses or nonresponse to CD20-directed therapy. Here, we re-evaluate B cell depletion strategies in autoimmunity prompted by 4 recent advances. The first is analysis of clonal accumulations of CD20- CD19+ plasma cells making autoantibodies in patients with anti-CD20 refractory autoimmune disease. The second is the remarkable clinical remissions induced by anti-CD19 chimeric antigen receptor T cells in cases of anti-CD20 refractory autoimmunity. The third is evidence that CD19+ plasma cells comprise the majority of plasma cells in humans, are not terminally differentiated, are long-lived, and if self-reactive have potent capacity to capture autoantigens via their surface immunoglobulin and present major histocompatibility complex class II-bound peptides. The fourth is the role of autoantigen-binding B cells and CD19+ plasma cells as key antigen-presenting cells in "T cell-mediated" autoimmune disorders, type 1 diabetes and celiac disease. Viewing human memory B cells and plasma cells from this alternative perspective offers an explanation for why deep CD19 compartmental depletion may be effective at achieving complete and durable remissions in the autoantibody-positive autoimmune diseases as a group, irrespective of whether the autoantibody is pathogenic.

Keywords: B cells; CAR T cells; autoantibodies; autoimmunity; plasma cells.