Research ArticleAutoimmunity

Rituximab-resistant splenic memory B cells and newly engaged naive B cells fuel relapses in patients with immune thrombocytopenia

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Science Translational Medicine  14 Apr 2021:
Vol. 13, Issue 589, eabc3961
DOI: 10.1126/scitranslmed.abc3961

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B cells behaving badly

Patients diagnosed with B cell–mediated autoimmune diseases, such as immune thrombocytopenia (ITP), can benefit from treatment with the B cell–depleting antibody, rituximab. Unfortunately, a large proportion of patients relapse after treatment. To understand why, Crickx et al. evaluated B cell phenotypes and specificity, finding two populations of B cells that may contribute to such relapses. The first consisted of a population of rituximab-resistant memory B cells, whereas the second consisted of a new population of autoreactive B cells never exposed to rituximab. Rituximab-resistant B cell populations maintained expression of the B cell marker CD19, suggesting that CD19-targeting therapies could provide another line of treatment for patients who do not respond to rituximab.

Abstract

Rituximab (RTX), an antibody targeting CD20, is widely used as a first-line therapeutic strategy in B cell–mediated autoimmune diseases. However, a large proportion of patients either do not respond to the treatment or relapse during B cell reconstitution. Here, we characterize the cellular basis responsible for disease relapse in secondary lymphoid organs in humans, taking advantage of the opportunity offered by therapeutic splenectomy in patients with relapsing immune thrombocytopenia. By analyzing the B and plasma cell immunoglobulin gene repertoire at bulk and antigen-specific single-cell level, we demonstrate that relapses are associated with two responses coexisting in germinal centers and involving preexisting mutated memory B cells that survived RTX treatment and naive B cells generated upon reconstitution of the B cell compartment. To identify distinctive characteristics of the memory B cells that escaped RTX-mediated depletion, we analyzed RTX refractory patients who did not respond to treatment at the time of B cell depletion. We identified, by single-cell RNA sequencing (scRNA-seq) analysis, a population of quiescent splenic memory B cells that present a unique, yet reversible, RTX-shaped phenotype characterized by down-modulation of B cell–specific factors and expression of prosurvival genes. Our results clearly demonstrate that these RTX-resistant autoreactive memory B cells reactivate as RTX is cleared and give rise to plasma cells and further germinal center reactions. Their continued surface expression of CD19 makes them efficient targets for current anti-CD19 therapies. This study thus identifies a pathogenic contributor to autoimmune diseases that can be targeted by available therapeutic agents.

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