title: B Cell Depletion Therapy Normalizes Circulating Follicular Th Cells in Primary Sjögren Syndrome.
abstract: To assess the effect of B cell depletion therapy on effector CD4+ T cell homeostasis and its relation to objective measures of disease activity in patients with primary Sjögren syndrome (pSS).
  
  
  
  Twenty-four patients with pSS treated with rituximab (RTX) and 24 healthy controls (HC) were included. Frequencies of circulating effector CD4+ T cell subsets were examined by flow cytometry at baseline and 16, 24, 36, and 48 weeks after the first RTX infusion. Th1, Th2, follicular Th (TFH), and Th17 cells were discerned based on surface marker expression patterns. Additionally, intracellular cytokine staining was performed for interferon-γ, interleukin (IL)-4, IL-21, and IL-17 and serum levels of these cytokines were analyzed.
  
  
  
  In patients with pSS, frequencies of circulating TFH cells and Th17 cells were increased at baseline compared with HC, whereas frequencies of Th1 and Th2 cells were unchanged. B cell depletion therapy resulted in a pronounced decrease in circulating TFH cells, whereas Th17 cells were only slightly lowered. Frequencies of IL-21-producing and IL-17-producing CD4+ T cells and serum levels of IL-21 and IL-17 were also reduced. Importantly, the decrease in circulating TFH cells was associated with lower systemic disease activity over time, as measured by the European League Against Rheumatism Sjögren's Syndrome Disease Activity Index scores and serum IgG levels.
  
  
  
  B cell depletion therapy in patients with pSS results in normalization of the elevated levels of circulating TFH cells. This reduction is associated with improved objective clinical disease activity measures. Our observations illustrate the pivotal role of the crosstalk between B cells and TFH cells in the pathogenesis of pSS.
authors.affiliation: From the departments of Rheumatology and Clinical Immunology, Oral and Maxillofacial Surgery, and Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen; the Department of Pulmonary Medicine, Erasmus MC, Rotterdam, the Netherlands. g.m.p.j.verstappen@umcg.nl.|G.M. Verstappen, MSc, departments of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen; F.G. Kroese, PhD, departments of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen; P.M. Meiners, MD, PhD, DMD, Oral and Maxillofacial Surgery, University of Groningen, University Medical Center Groningen; O.B. Corneth, PhD, Department of Pulmonary Medicine, Erasmus MC; M.G. Huitema, BSc, departments of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen; E.A. Haacke, MD, departments of Rheumatology and Clinical Immunology, and departments of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen; B. van der Vegt, MD, PhD, Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen; S. Arends, PhD, departments of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen; A. Vissink, DMD, MD, PhD, Oral and Maxillofacial Surgery, University of Groningen, University Medical Center Groningen; H. Bootsma, MD, PhD, departments of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen; W.H. Abdulahad, PhD, departments of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen. g.m.p.j.verstappen@umcg.nl.
authors.forename: Gwenny M
authors.initials: GM
authors.lastname: Verstappen
authors.affiliation: From the departments of Rheumatology and Clinical Immunology, Oral and Maxillofacial Surgery, and Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen; the Department of Pulmonary Medicine, Erasmus MC, Rotterdam, the Netherlands.|G.M. Verstappen, MSc, departments of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen; F.G. Kroese, PhD, departments of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen; P.M. Meiners, MD, PhD, DMD, Oral and Maxillofacial Surgery, University of Groningen, University Medical Center Groningen; O.B. Corneth, PhD, Department of Pulmonary Medicine, Erasmus MC; M.G. Huitema, BSc, departments of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen; E.A. Haacke, MD, departments of Rheumatology and Clinical Immunology, and departments of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen; B. van der Vegt, MD, PhD, Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen; S. Arends, PhD, departments of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen; A. Vissink, DMD, MD, PhD, Oral and Maxillofacial Surgery, University of Groningen, University Medical Center Groningen; H. Bootsma, MD, PhD, departments of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen; W.H. Abdulahad, PhD, departments of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen.
authors.forename: Frans G M
authors.initials: FG
authors.lastname: Kroese
authors.affiliation: From the departments of Rheumatology and Clinical Immunology, Oral and Maxillofacial Surgery, and Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen; the Department of Pulmonary Medicine, Erasmus MC, Rotterdam, the Netherlands.|G.M. Verstappen, MSc, departments of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen; F.G. Kroese, PhD, departments of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen; P.M. Meiners, MD, PhD, DMD, Oral and Maxillofacial Surgery, University of Groningen, University Medical Center Groningen; O.B. Corneth, PhD, Department of Pulmonary Medicine, Erasmus MC; M.G. Huitema, BSc, departments of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen; E.A. Haacke, MD, departments of Rheumatology and Clinical Immunology, and departments of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen; B. van der Vegt, MD, PhD, Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen; S. Arends, PhD, departments of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen; A. Vissink, DMD, MD, PhD, Oral and Maxillofacial Surgery, University of Groningen, University Medical Center Groningen; H. Bootsma, MD, PhD, departments of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen; W.H. Abdulahad, PhD, departments of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen.
authors.forename: Petra M
authors.initials: PM
authors.lastname: Meiners
authors.affiliation: From the departments of Rheumatology and Clinical Immunology, Oral and Maxillofacial Surgery, and Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen; the Department of Pulmonary Medicine, Erasmus MC, Rotterdam, the Netherlands.|G.M. Verstappen, MSc, departments of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen; F.G. Kroese, PhD, departments of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen; P.M. Meiners, MD, PhD, DMD, Oral and Maxillofacial Surgery, University of Groningen, University Medical Center Groningen; O.B. Corneth, PhD, Department of Pulmonary Medicine, Erasmus MC; M.G. Huitema, BSc, departments of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen; E.A. Haacke, MD, departments of Rheumatology and Clinical Immunology, and departments of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen; B. van der Vegt, MD, PhD, Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen; S. Arends, PhD, departments of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen; A. Vissink, DMD, MD, PhD, Oral and Maxillofacial Surgery, University of Groningen, University Medical Center Groningen; H. Bootsma, MD, PhD, departments of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen; W.H. Abdulahad, PhD, departments of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen.
authors.forename: Odilia B
authors.initials: OB
authors.lastname: Corneth
authors.affiliation: From the departments of Rheumatology and Clinical Immunology, Oral and Maxillofacial Surgery, and Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen; the Department of Pulmonary Medicine, Erasmus MC, Rotterdam, the Netherlands.|G.M. Verstappen, MSc, departments of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen; F.G. Kroese, PhD, departments of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen; P.M. Meiners, MD, PhD, DMD, Oral and Maxillofacial Surgery, University of Groningen, University Medical Center Groningen; O.B. Corneth, PhD, Department of Pulmonary Medicine, Erasmus MC; M.G. Huitema, BSc, departments of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen; E.A. Haacke, MD, departments of Rheumatology and Clinical Immunology, and departments of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen; B. van der Vegt, MD, PhD, Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen; S. Arends, PhD, departments of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen; A. Vissink, DMD, MD, PhD, Oral and Maxillofacial Surgery, University of Groningen, University Medical Center Groningen; H. Bootsma, MD, PhD, departments of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen; W.H. Abdulahad, PhD, departments of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen.
authors.forename: Minke G
authors.initials: MG
authors.lastname: Huitema
authors.affiliation: From the departments of Rheumatology and Clinical Immunology, Oral and Maxillofacial Surgery, and Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen; the Department of Pulmonary Medicine, Erasmus MC, Rotterdam, the Netherlands.|G.M. Verstappen, MSc, departments of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen; F.G. Kroese, PhD, departments of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen; P.M. Meiners, MD, PhD, DMD, Oral and Maxillofacial Surgery, University of Groningen, University Medical Center Groningen; O.B. Corneth, PhD, Department of Pulmonary Medicine, Erasmus MC; M.G. Huitema, BSc, departments of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen; E.A. Haacke, MD, departments of Rheumatology and Clinical Immunology, and departments of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen; B. van der Vegt, MD, PhD, Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen; S. Arends, PhD, departments of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen; A. Vissink, DMD, MD, PhD, Oral and Maxillofacial Surgery, University of Groningen, University Medical Center Groningen; H. Bootsma, MD, PhD, departments of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen; W.H. Abdulahad, PhD, departments of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen.
authors.forename: Erlin A
authors.initials: EA
authors.lastname: Haacke
authors.affiliation: From the departments of Rheumatology and Clinical Immunology, Oral and Maxillofacial Surgery, and Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen; the Department of Pulmonary Medicine, Erasmus MC, Rotterdam, the Netherlands.|G.M. Verstappen, MSc, departments of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen; F.G. Kroese, PhD, departments of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen; P.M. Meiners, MD, PhD, DMD, Oral and Maxillofacial Surgery, University of Groningen, University Medical Center Groningen; O.B. Corneth, PhD, Department of Pulmonary Medicine, Erasmus MC; M.G. Huitema, BSc, departments of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen; E.A. Haacke, MD, departments of Rheumatology and Clinical Immunology, and departments of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen; B. van der Vegt, MD, PhD, Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen; S. Arends, PhD, departments of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen; A. Vissink, DMD, MD, PhD, Oral and Maxillofacial Surgery, University of Groningen, University Medical Center Groningen; H. Bootsma, MD, PhD, departments of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen; W.H. Abdulahad, PhD, departments of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen.
authors.forename: Bert
authors.initials: B
authors.lastname: van der Vegt
authors.affiliation: From the departments of Rheumatology and Clinical Immunology, Oral and Maxillofacial Surgery, and Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen; the Department of Pulmonary Medicine, Erasmus MC, Rotterdam, the Netherlands.|G.M. Verstappen, MSc, departments of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen; F.G. Kroese, PhD, departments of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen; P.M. Meiners, MD, PhD, DMD, Oral and Maxillofacial Surgery, University of Groningen, University Medical Center Groningen; O.B. Corneth, PhD, Department of Pulmonary Medicine, Erasmus MC; M.G. Huitema, BSc, departments of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen; E.A. Haacke, MD, departments of Rheumatology and Clinical Immunology, and departments of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen; B. van der Vegt, MD, PhD, Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen; S. Arends, PhD, departments of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen; A. Vissink, DMD, MD, PhD, Oral and Maxillofacial Surgery, University of Groningen, University Medical Center Groningen; H. Bootsma, MD, PhD, departments of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen; W.H. Abdulahad, PhD, departments of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Arends
authors.affiliation: From the departments of Rheumatology and Clinical Immunology, Oral and Maxillofacial Surgery, and Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen; the Department of Pulmonary Medicine, Erasmus MC, Rotterdam, the Netherlands.|G.M. Verstappen, MSc, departments of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen; F.G. Kroese, PhD, departments of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen; P.M. Meiners, MD, PhD, DMD, Oral and Maxillofacial Surgery, University of Groningen, University Medical Center Groningen; O.B. Corneth, PhD, Department of Pulmonary Medicine, Erasmus MC; M.G. Huitema, BSc, departments of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen; E.A. Haacke, MD, departments of Rheumatology and Clinical Immunology, and departments of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen; B. van der Vegt, MD, PhD, Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen; S. Arends, PhD, departments of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen; A. Vissink, DMD, MD, PhD, Oral and Maxillofacial Surgery, University of Groningen, University Medical Center Groningen; H. Bootsma, MD, PhD, departments of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen; W.H. Abdulahad, PhD, departments of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen.
authors.forename: Arjan
authors.initials: A
authors.lastname: Vissink
authors.affiliation: From the departments of Rheumatology and Clinical Immunology, Oral and Maxillofacial Surgery, and Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen; the Department of Pulmonary Medicine, Erasmus MC, Rotterdam, the Netherlands.|G.M. Verstappen, MSc, departments of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen; F.G. Kroese, PhD, departments of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen; P.M. Meiners, MD, PhD, DMD, Oral and Maxillofacial Surgery, University of Groningen, University Medical Center Groningen; O.B. Corneth, PhD, Department of Pulmonary Medicine, Erasmus MC; M.G. Huitema, BSc, departments of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen; E.A. Haacke, MD, departments of Rheumatology and Clinical Immunology, and departments of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen; B. van der Vegt, MD, PhD, Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen; S. Arends, PhD, departments of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen; A. Vissink, DMD, MD, PhD, Oral and Maxillofacial Surgery, University of Groningen, University Medical Center Groningen; H. Bootsma, MD, PhD, departments of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen; W.H. Abdulahad, PhD, departments of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen.
authors.forename: Hendrika
authors.initials: H
authors.lastname: Bootsma
authors.affiliation: From the departments of Rheumatology and Clinical Immunology, Oral and Maxillofacial Surgery, and Pathology and Medical Biology, University of Groningen, University Medical Center Groningen, Groningen; the Department of Pulmonary Medicine, Erasmus MC, Rotterdam, the Netherlands.|G.M. Verstappen, MSc, departments of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen; F.G. Kroese, PhD, departments of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen; P.M. Meiners, MD, PhD, DMD, Oral and Maxillofacial Surgery, University of Groningen, University Medical Center Groningen; O.B. Corneth, PhD, Department of Pulmonary Medicine, Erasmus MC; M.G. Huitema, BSc, departments of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen; E.A. Haacke, MD, departments of Rheumatology and Clinical Immunology, and departments of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen; B. van der Vegt, MD, PhD, Department of Pathology and Medical Biology, University of Groningen, University Medical Center Groningen; S. Arends, PhD, departments of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen; A. Vissink, DMD, MD, PhD, Oral and Maxillofacial Surgery, University of Groningen, University Medical Center Groningen; H. Bootsma, MD, PhD, departments of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen; W.H. Abdulahad, PhD, departments of Rheumatology and Clinical Immunology, University of Groningen, University Medical Center Groningen.
authors.forename: Wayel H
authors.initials: WH
authors.lastname: Abdulahad
mesh_terms: D000328:Adult; D001402:B-Lymphocytes / Q000378:metabolism / Q000473:pathology*; D015496:CD4-Positive T-Lymphocytes; D016207:Cytokines / Q000378:metabolism; D005260:Female; D005434:Flow Cytometry; D006801:Humans; D007166:Immunosuppressive Agents / Q000627:therapeutic use*; D018655:Lymphocyte Count; D008212:Lymphocyte Depletion / Q000379:methods*; D008297:Male; D008875:Middle Aged; D000069283:Rituximab / Q000627:therapeutic use*; D012859:Sjogren's Syndrome / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D006377:T-Lymphocytes, Helper-Inducer / Q000378:metabolism / Q000473:pathology*; D016896:Treatment Outcome
chemical_list: D016207:Cytokines; D007166:Immunosuppressive Agents; D000069283:Rituximab
keywords: AUTOIMMUNITY; B LYMPHOCYTES; RITUXIMAB; SJÖGREN SYNDROME; T LYMPHOCYTES