title: Ig gene analysis reveals altered selective pressures on Ig-producing cells in parotid glands of primary Sjögren's syndrome patients.
abstract: In this study, we sought to understand the selective pressures shaping the Ig-producing cell repertoire in the parotid glands of primary Sjögren's syndrome (pSS) patients before and after rituximab treatment (RTX). In particular, we evaluated the role of potential N-glycosylation motifs acquired by somatic hypermutation (ac-Nglycs) within Ig H chain V region (IGHV) genes as alternative selective pressures for B cells in pSS. Five pSS patients received RTX. Sequential parotid salivary gland biopsies were taken before RTX, at 12 wk and at 36-52 wk after treatment. Parotid biopsies from four non-pSS patients served as controls. Sequence analysis was carried out on the IgA and IgG RNA transcripts expressing IGHV3 genes in all parotid biopsies. Both IgG and IgA sequences from pSS patients exhibited no evidence for positive Ag-driven selection pressure in their CDRs in contrast to non-pSS controls. The prevalence of IgG sequences with ac-Nglycs was significantly higher in pSS patients than in non-pSS controls. Selection pressures shaping the IgG and IgA repertoire within pSS patients' parotid glands are distinct from those in non-pSS controls, with very little evidence for positive (auto)antigen selection. The higher prevalence of ac-Nglycs on pSS-IgG compared with non-pSS IgG indicates that ac-Nglycs could be an alternative form of selection pressure. We speculate that B cell hyperproliferation within parotid glands of pSS patients may result from Ag-independent interactions such as that between glycosylated B cell receptors and lectins within the microenvironment rather than (auto)antigen-specific stimulation. Our study brings a new perspective into research on pSS.
authors.affiliation: Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen, 9713 AV Groningen, the Netherlands;
authors.forename: Nishath
authors.initials: N
authors.lastname: Hamza
authors.affiliation: School of Biomedical Engineering, Science and Health Systems, Drexel University, Philadelphia, PA 19104; and.
authors.forename: Uri
authors.initials: U
authors.lastname: Hershberg
authors.affiliation: Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen, 9713 AV Groningen, the Netherlands;
authors.forename: Cees G M
authors.initials: CG
authors.lastname: Kallenberg
authors.affiliation: Department of Oral and Maxillofacial Surgery, University of Groningen, University Medical Center Groningen, 9713 AV Groningen, the Netherlands.
authors.forename: Arjan
authors.initials: A
authors.lastname: Vissink
authors.affiliation: Department of Oral and Maxillofacial Surgery, University of Groningen, University Medical Center Groningen, 9713 AV Groningen, the Netherlands.
authors.forename: Frederik K L
authors.initials: FK
authors.lastname: Spijkervet
authors.affiliation: Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen, 9713 AV Groningen, the Netherlands;
authors.forename: Hendrika
authors.initials: H
authors.lastname: Bootsma
authors.affiliation: Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen, 9713 AV Groningen, the Netherlands;
authors.forename: Frans G M
authors.initials: FG
authors.lastname: Kroese
authors.affiliation: Department of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen, 9713 AV Groningen, the Netherlands; n.a.bos@umcg.nl.
authors.forename: Nicolaas A
authors.initials: NA
authors.lastname: Bos
mesh_terms: D000328:Adult; D000368:Aged; D001483:Base Sequence; D049109:Cell Proliferation / Q000235:genetics; D005260:Female; D006801:Humans; D007070:Immunoglobulin A / Q000235:genetics / Q000276:immunology; D007074:Immunoglobulin G / Q000235:genetics / Q000276:immunology; D007143:Immunoglobulin Heavy Chains / Q000235:genetics / Q000276:immunology; D007135:Immunoglobulin Variable Region / Q000235:genetics / Q000276:immunology; D008875:Middle Aged; D008969:Molecular Sequence Data; D010306:Parotid Gland / Q000276:immunology / Q000473:pathology; D012859:Sjogren's Syndrome / Q000235:genetics / Q000276:immunology / Q000473:pathology
chemical_list: D007070:Immunoglobulin A; D007074:Immunoglobulin G; D007143:Immunoglobulin Heavy Chains; D007135:Immunoglobulin Variable Region