Persistence and selection of an expanded B-cell clone in the setting of rituximab therapy for Sjögren’s syndrome
1 School of Biomedical Engineering, Science and Health Systems, 711 Bossone Building, Drexel University, 3141 Chestnut Street, Philadelphia, PA 19104, USA
2 Department of Microbiology and Immunology, College of Medicine, 2900 Queen Lane, Philadelphia, PA 19129, USA
3 Department of Pathology and Laboratory Medicine, Perelman School of Medicine, University of Pennsylvania, 405B Stellar Chance Labs, 422 Curie Boulevard, Philadelphia, PA 19104, USA
4 Duke University Medical Center, 3874 200 Trent Drive, Durham, NC 27710, USA
5 Section of Rheumatology and Temple Autoimmunity Center, Temple University School of Medicine, 3322 North Broad Street, Philadelphia, PA 19140, USA
6 Division of Rheumatology and Clinical Immunology, University of Pittsburgh School of Medicine, 3500 Terrace Street, BST S709, Pittsburgh, PA 15261, USA
Arthritis Research & Therapy 2014, 16:R51 doi:10.1186/ar4481Published: 11 February 2014
Subjects with primary Sjögren’s syndrome (SjS) have an increased risk of developing B-cell lymphoma and may harbor monoclonal B-cell expansions in the peripheral blood. Expanded B-cell clones could be pathogenic, and their persistence could exacerbate disease or predispose toward the development of lymphoma. Therapy with anti-CD20 (rituximab) has the potential to eliminate expanded B-cell clones and thereby potentially ameliorate disease. This study was undertaken to identify and track expanded B-cell clones in the blood of subjects with primary SjS who were treated with rituximab.
To determine whether circulating B-cell clones in subjects with primary SjS emerge or remain after B cell-depleting therapy with rituximab, we studied the antibody heavy-chain repertoire. We performed single-memory B-cell and plasmablast sorting and antibody heavy-chain sequencing in six rituximab-treated SjS subjects over the course of a 1-year follow-up period.
Expanded B-cell clones were identified in four out of the six rituximab-treated SjS subjects, based upon the independent amplification of sequences with identical or highly similar VH, DH, and JH gene segments. We identified one SjS subject with a large expanded B-cell clone that was present prior to therapy and persisted after therapy. Somatic mutations in the clone were numerous but did not increase in frequency over the course of the 1-year follow-up, suggesting that the clone had been present for a long period of time. Intriguingly, a majority of the somatic mutations in the clone were silent, suggesting that the clone was under chronic negative selection.
For some subjects with primary SjS, these data show that (a) expanded B-cell clones are readily identified in the peripheral blood, (b) some clones are not eliminated by rituximab, and (c) persistent clones may be under chronic negative selection or may not be antigen-driven. The analysis of sequence variation among members of an expanded clone may provide a novel means of measuring the chronicity and selection of expanded B-cell populations in humans.