Expansion of Activated Peripheral Blood Memory B Cells in Rheumatoid Arthritis, Impact of B Cell Depletion Therapy, and Biomarkers of Response

• Authors: Diana G. Adlowitz, University of Rochester; Jennifer Barnard, University of Rochester; Jamie N. Biear, University of Rochester; Christopher Cistrone, University of Rochester; Teresa Owen, University of Rochester; Wensheng Wang, University of Rochester; Arumugam Palanichamy, University of Rochester; Ezinma Ezealah, University of Rochester; Debbie Campbell, University of Rochester; Chungwen Wei, Emory University; R. John Looney, University of Rochester; Ignacio Sanz, Emory University; Jennifer H. Anolik, University of Rochester
• Journal Title: PLoS ONE
• Volume: Volume 10, Number 6
• Publisher: Public Library of Science | 2015-06-05, Pages e0128269-e0128269
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.1371/journal.pone.0128269
• Subjects: Health Sciences, Immunology
• Keywords: Science & Technology; Multidisciplinary Sciences; Science & Technology - Other Topics; SYSTEMIC-LUPUS-ERYTHEMATOSUS; TUMOR-NECROSIS-FACTOR; RITUXIMAB THERAPY; BONE-MARROW; LYMPHOCYTES; SUBSETS; DISEASE; IDENTIFICATION; EXPRESSION; PREDICT; B cells; Memory B cells; Cytokines; Biomarkers; Flow cytometry; Rheumatoid arthritis; Cell staining; Homeostasis

Abstract

Although B cell depletion therapy (BCDT) is effective in a subset of rheumatoid arthritis (RA) patients, both mechanisms and biomarkers of response are poorly defined. Here we characterized abnormalities in B cell populations in RA and the impact of BCDT in order to elucidate B cell roles in the disease and response biomarkers. In active RA patients both CD27 +IgD- switched memory (SM) and CD27-IgD- double negative memory (DN) peripheral blood B cells contained significantly higher fractions of CD95+ and CD21- activated cells compared to healthy controls. After BCD the predominant B cell populations were memory, and residual memory B cells displayed a high fraction of CD21- and CD95+ compared to pre-depletion indicating some resistance of these activated populations to anti-CD20. The residual memory populations also expressed more Ki-67 compared to pre-treatment, suggesting homeostatic proliferation in the B cell depleted state. Biomarkers of clinical response included lower CD95+ activated memory B cells at depletion time points and a higher ratio of transitional B cells to memory at reconstitution. B cell function in terms of cytokine secretion was dependent on B cell subset and changed with BCD. Thus, SM B cells produced pro-inflammatory (TNF) over regulatory (IL10) cytokines as compared to naïve/transitional. Notably, B cell TNF production decreased after BCDT and reconstitution compared to untreated RA. Our results support the hypothesis that the clinical and immunological outcome of BCDT depends on the relative balance of protective and pathogenic B cell subsets established after B cell depletion and repopulation.