| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
* Clinical Immunology and Rheumatology and
Department of Experimental Immunology, Academic Medical Center/University of Amsterdam, The Netherlands;
Department of Neurology, University of California Irvine, Irvine, CA 92697;
Department of Molecular Cell Biology and Immunology and
¶ Department of Pathology, Vrije Universiteit Medical Center, Amsterdam, The Netherlands;
|| Internal Medicine, Ghent University Hospital, Ghent, Belgium;
# Unitat d'Artritis, Servei de Reumatología, Hospital Clínic de Barcelona and Institut d'Investigacions Biomèdiques August Pi i Sunyer, Barcelona, Spain; and
** Department of Rheumatology, Karolinska University Hospital, Solna, Karolinska Institutet, Stockholm, Sweden
B lymphocyte autoimmunity plays a crucial role in the pathogenesis of rheumatoid arthritis. The local production of autoantibodies and the presence of ectopic lymphoid neogenesis in the rheumatoid synovium suggest that these dedicated microenvironments resembling canonical lymphoid follicles may regulate the initiation and maturation of B cell autoimmunity. In this study, we assessed experimentally the relevance of ectopic lymphoid neogenesis for B cell autoimmunity by a detailed structural, molecular, and serological analysis of seropositive and seronegative human synovitis. We demonstrate that synovial lymphoid neogenesis is a reversible process associated with inflammation which is neither restricted to nor preferentially associated with autoantibody positive rheumatic conditions. Despite the abundant expression of key chemokines and cytokines required for full differentiation toward germinal center reactions, synovial lymphoid neogenesis in rheumatoid arthritis only occasionally progresses toward fully differentiated follicles. In agreement with that observation, we could not detect Ag-driven clonal expansion and affinity maturation of B lymphocytes. Furthermore, ectopic lymphoid neogenesis is not directly associated with local production of anti-citrullinated protein Abs and rheumatoid factor in the rheumatoid joint. Therefore, we conclude that synovial lymphoid neogenesis is not a major determinant of these rheumatoid arthritis-specific autoantibody responses.
The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
1 This work was partially supported by a Human Immunology Research Grant of the Dana Foundation and by the European Community’s FP6 funding. B.V. is a research assistant of the fund for scientific research Flanders. J.K. and Y.Z. were supported by a National Institutes of Health Grant (RO1 54911). J.D.C. was supported by FIS PI 041027 and FIS04/1023, as well as a grant from Fundación Española de Reumatología/Laboratorios Abbott. D.B. is supported by an Nederlandse organisatie voor Wetenschappelijk ondorzoek Vidi Grant. This publication reflects only the authors’ views. The European Community is not liable for any use that may be made of the information herein.
2 Address correspondence and reprint requests to Dr. Dominique Baeten, Clinical Immunology and Rheumatology, F4-218, Academic Medical Center/University of Amsterdam, Meibergdreef 9, 1105 AZ Amsterdam, The Netherlands. E-mail address: D.L.Baeten{at}amc.uva.nl
3 Abbreviations used in this paper: RA, rheumatoid arthritis; ACPA, anti-citrullinated protein antibodies; anti-CCP, anti-cyclic citrullinated peptide; APRIL, A proliferation-inducing ligand; BAFF, B cell activation factor of the tumor necrosis factor family; FDC, follicular dendritic cells; GC, germinal center; HEV, high endothelial venules; LTb, lymphotoxin β; OA, osteoarthritis; PNAd, peripheral node addressin; RF, rheumatoid factor; SpA, spondyloarthritis; SLO, secondary lymphoid organs; TACI, transmembrane activator and calcium modulator and cyclophilin ligand-interactor; SF, synovial fluid.
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
