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.
Subject(s)
Arthritis, Rheumatoid/immunology , Arthritis, Rheumatoid/therapy , B-Lymphocytes/immunology , B-Lymphocytes/pathology , Lymphocyte Depletion/methods , Aged , Antirheumatic Agents/therapeutic use , Arthritis, Rheumatoid/pathology , B-Lymphocytes/drug effects , Biomarkers/analysis , Female , Humans , Immunoglobulin D/analysis , Immunoglobulin D/immunology , Interleukin-10/analysis , Interleukin-10/immunology , Ki-67 Antigen/analysis , Ki-67 Antigen/immunology , Male , Middle Aged , Receptors, Complement 3d/analysis , Receptors, Complement 3d/immunology , Rituximab/therapeutic use , Tumor Necrosis Factor-alpha/analysis , Tumor Necrosis Factor-alpha/immunology , fas Receptor/analysis , fas Receptor/immunologyABSTRACT
To characterize the humoral response to the unglycosylated central region of the respiratory syncytial virus (RSV) attachment (G) protein, we generated glutathione S-transferase (GST)-RSV G subdomains (central core (CC), residues 151-190; proximal central core (PCC), 151-172; and distal central core (DCC), 173-190) to screen paired sera from RSV subtype A- or B-infected adults in hospitalized or outpatient settings. Following RSV infection, a >or=4-fold increase in homo- and heterosubtypic IgG response was noted in most subjects against the RSV G CC and PCC regions; in contrast, such titer increases against the RSV G DCC was only noted in a homosubtypic manner. Our results have implications for RSV G-based serological diagnostics and vaccine development.