title: Expansion of Activated Peripheral Blood Memory B Cells in Rheumatoid Arthritis, Impact of B Cell Depletion Therapy, and Biomarkers of Response.
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.
authors.affiliation: Department of Medicine, Division of Allergy, Immunology and Rheumatology, University of Rochester Medical Center, Rochester, New York, 14642, United States of America.
authors.forename: Diana G
authors.initials: DG
authors.lastname: Adlowitz
authors.affiliation: Department of Medicine, Division of Allergy, Immunology and Rheumatology, University of Rochester Medical Center, Rochester, New York, 14642, United States of America.
authors.forename: Jennifer
authors.initials: J
authors.lastname: Barnard
authors.affiliation: Department of Medicine, Division of Allergy, Immunology and Rheumatology, University of Rochester Medical Center, Rochester, New York, 14642, United States of America.
authors.forename: Jamie N
authors.initials: JN
authors.lastname: Biear
authors.affiliation: Department of Medicine, Division of Allergy, Immunology and Rheumatology, University of Rochester Medical Center, Rochester, New York, 14642, United States of America.
authors.forename: Christopher
authors.initials: C
authors.lastname: Cistrone
authors.affiliation: Department of Medicine, Division of Allergy, Immunology and Rheumatology, University of Rochester Medical Center, Rochester, New York, 14642, United States of America.
authors.forename: Teresa
authors.initials: T
authors.lastname: Owen
authors.affiliation: Department of Medicine, Division of Allergy, Immunology and Rheumatology, University of Rochester Medical Center, Rochester, New York, 14642, United States of America.
authors.forename: Wensheng
authors.initials: W
authors.lastname: Wang
authors.affiliation: Department of Medicine, Division of Allergy, Immunology and Rheumatology, University of Rochester Medical Center, Rochester, New York, 14642, United States of America.
authors.forename: Arumugam
authors.initials: A
authors.lastname: Palanichamy
authors.affiliation: Department of Medicine, Division of Allergy, Immunology and Rheumatology, University of Rochester Medical Center, Rochester, New York, 14642, United States of America.
authors.forename: Ezinma
authors.initials: E
authors.lastname: Ezealah
authors.affiliation: Department of Medicine, Division of Allergy, Immunology and Rheumatology, University of Rochester Medical Center, Rochester, New York, 14642, United States of America.
authors.forename: Debbie
authors.initials: D
authors.lastname: Campbell
authors.affiliation: Department of Medicine, Emory University, Atlanta, Georgia, 30332, United States of America.
authors.forename: Chungwen
authors.initials: C
authors.lastname: Wei
authors.affiliation: Department of Medicine, Division of Allergy, Immunology and Rheumatology, University of Rochester Medical Center, Rochester, New York, 14642, United States of America.
authors.forename: R John
authors.initials: RJ
authors.lastname: Looney
authors.affiliation: Department of Medicine, Emory University, Atlanta, Georgia, 30332, United States of America.
authors.forename: Inaki
authors.initials: I
authors.lastname: Sanz
authors.affiliation: Department of Medicine, Division of Allergy, Immunology and Rheumatology, University of Rochester Medical Center, Rochester, New York, 14642, United States of America.
authors.forename: Jennifer H
authors.initials: JH
authors.lastname: Anolik
mesh_terms: D000368:Aged; D018501:Antirheumatic Agents / Q000627:therapeutic use; D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000473:pathology / Q000628:therapy*; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology* / Q000473:pathology*; D015415:Biomarkers / Q000032:analysis; D005260:Female; D006801:Humans; D007072:Immunoglobulin D / Q000032:analysis / Q000276:immunology; D016753:Interleukin-10 / Q000032:analysis / Q000276:immunology; D019394:Ki-67 Antigen / Q000032:analysis / Q000276:immunology; D008212:Lymphocyte Depletion / Q000379:methods*; D008297:Male; D008875:Middle Aged; D017464:Receptors, Complement 3d / Q000032:analysis / Q000276:immunology; D000069283:Rituximab / Q000627:therapeutic use; D014409:Tumor Necrosis Factor-alpha / Q000032:analysis / Q000276:immunology; D019014:fas Receptor / Q000032:analysis / Q000276:immunology
chemical_list: D018501:Antirheumatic Agents; D015415:Biomarkers; D007072:Immunoglobulin D; D019394:Ki-67 Antigen; D017464:Receptors, Complement 3d; D014409:Tumor Necrosis Factor-alpha; D019014:fas Receptor; D016753:Interleukin-10; D000069283:Rituximab