Lymphoid Neogenesis in Rheumatoid Synovitis Seisuke Takemura, Andrea Braun, Cynthia Crowson, Paul J. Kurtin, Robert H. Cofield, William M. O'Fallon, Jörg J. This information is current as Goronzy and Cornelia M. Weyand of September 25, 2021. J Immunol 2001; 167:1072-1080; ; doi: 10.4049/jimmunol.167.2.1072 http://www.jimmunol.org/content/167/2/1072 Downloaded from References This article cites 41 articles, 16 of which you can access for free at: http://www.jimmunol.org/content/167/2/1072.full#ref-list-1 http://www.jimmunol.org/ Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication by guest on September 25, 2021 *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2001 by The American Association of Immunologists All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. Lymphoid Neogenesis in Rheumatoid Synovitis1 Seisuke Takemura,2* Andrea Braun,2* Cynthia Crowson,‡ Paul J. Kurtin,† Robert H. Cofield,§ William M. O’Fallon,‡ Jo¨rg J. Goronzy,* and Cornelia M. Weyand3* In rheumatoid arthritis (RA), tissue-infiltrating lymphocytes can be arranged in sophisticated organizations that resemble mi- crostructures usually formed in secondary lymphoid organs. Molecular pathways and host risk factors involved in this process of lymphoid neogenesis remain to be defined. In a series of 64 synovial tissue biopsies, lymphoid follicles with germinal centers (GCs) were found in 23.4% of the patients. Follicular dendritic cells (FDCs) were exclusively present in tissues with GCs, suggesting that the recruitment or in situ maturation of FDCs is a critical factor for GC formation in the synovial membrane. Primary follicles were absent, emphasizing the role of Ag recognition in the generation of inflammation-associated lymphoid organogenesis. Mul- tivariate logistic regression analysis of tissue cytokines and chemokines identified two parameters, in situ transcription of lym- photoxin (LT)-␤ and of B lymphocyte chemoattractant (BLC; BLC/CXCL13), that were predictors for FDC recruitment and synovial GC formation. LT-␤ and BLC/CXCL13 were found to be independent variables that could, in part, compensate for each Downloaded from other to facilitate GC formation. Prediction models incorporating in situ transcription of LT-␤ and BLC/CXCL13 had high negative yet moderate positive predictive values, suggesting that LT-␤ and BLC/CXCL13 are necessary but not sufficient. LT-␤ protein was detected on a subset of mantle zone and GC B cells, but also on T cells in follicular structures. BLC/CXCL13 was produced by FDCs in follicular centers, but was predominantly found in endothelial cells and synovial fibroblasts, suggesting heterotypic signaling between cells of the synovial membrane and infiltrating lymphocytes in regulating extranodal lymphoid neogenesis. The Journal of Immunology, 2001, 167: 1072–1080. http://www.jimmunol.org/ he preferred targets of inflammatory attack in rheumatoid A close relationship between inflammation and lymphoid orga- arthritis (RA)4 are the synovial membrane, cartilage, and nogenesis has been suggested by the finding that proinflammatory T bone of diarthrodial joints. T cells, B cells, macrophages, cytokines, such as members of the TNF superfamily, have a crit- and dendritic cells (DCs) accumulate in the synovial layer, induc- ical role in both processes (4, 5). Initially, it was found that mice ing hyperplasia and tissue invasiveness of the synoviocytes. A dis- deficient in lymphotoxin (LT) had no lymph nodes or Peyer’s tinguishing feature of the rheumatoid lesion is the high degree of patches and failed to form GCs in the spleen (6, 7). Despite the cellular organization acquired by the tissue-infiltrating lympho- Ϫ/Ϫ absence of GCs, LT-␣ mice still produced high-affinity IgG1 by guest on September 25, 2021 cytes. Rheumatoid synovitis is associated with the formation of responses, provided the mice were immunized with high doses of complex lymphoid microstructures, to the extent that the rheuma- Ag (8). Gene targeting has been successfully used to implicate toid process induces the formation of T cell-B cell follicles with other molecules in the process of lymphoid organogenesis, includ- germinal center (GC) reactions in the synovium (1–3). These mi- ing LT-␤, type I TNFR, and the LT-␤R (9–11). Mice with defects crostructures share many features with secondary lymphoid tissue, in these genes display different structural abnormalities and func- and the formation of GCs at an extranodal site can, therefore, be tional impairment of secondary lymphoid organs. In essence, sig- considered as an example of lymphoid neogenesis. The structural ␣ ␤ requirements permitting the generation of tertiary lymphoid tissue nals transmitted by LT- 1 2 appear to be pivotal in the ontogeny have not been examined. Also, it is not known which molecular of secondary lymphoid organs (12, 13). pathways are used or which factors determine the type of lymphoid More recently, studies of lymphoid organogenesis have focused organization in individual patients. on the contribution of chemokines that provide the cues to guide cell movement inside lymphoid organs (14, 15). Much progress has been made in understanding how the two major populations of Departments of *Medicine and Immunology, †Laboratory Medicine and Pathology, lymphocytes are directed either to B cell or T cell zones and how ‡Health Services Research, and §Orthopedic Surgery, Mayo Clinic, Rochester, MN chemokines control the movements of such cells during the devel- 55905 opment of Ag-specific immune responses. Mice homozygous for Received for publication January 24, 2001. Accepted for publication May 9, 2001. the spontaneous mutation, paucity of lymph node T cells ( plt), are The costs of publication of this article were defrayed in part by the payment of page characterized by major abnormalities in T cell trafficking into charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. lymph nodes and disturbances in the organization of T cell zones 1 This work was supported by grants from the National Institutes of Health (R01 (16, 17). These mice lack expression of secondary lymphoid che- AI44142, R01 AR42527, and R01 AR41974) and the Mayo Foundation. moattractant (SLC/CCL21) (18), which binds to CCR7. Defects in 2 S.T. and A.B. contributed equally to this study. the movement of lymphocytes and DCs through the T cell areas of 3 Address correspondence and reprint requests to Dr. Cornelia M. Weyand, Mayo spleen, lymph nodes, and Peyer’s patches are shared by plt and Clinic, Guggenheim 401, 200 First Street SW, Rochester, MN 55905. E-mail address: [email protected] CCR7-deficient mice, establishing a critical role of this receptor- 4 Abbreviations used in this paper: RA, rheumatoid arthritis; GC, germinal center; ligand pair in compartmental homing of T cells (19). Homeostatic BLC, B lymphocyte chemoattractant; CD21L, CD21 long isoform; DC-CK1, den- trafficking of B cells into lymphoid tissue and B cell follicles ap- dritic cell-derived C-C chemokine 1; FDC, follicular DC; LT, lymphotoxin; MCP, pears to be critically controlled by B lymphocyte chemoattractant macrophage chemoattractant protein; plt, paucity of lymph node T cells; SLC, sec- ondary lymphoid chemoattractant. (BLC/CXCL13) (20, 21). The receptor for BLC/CXCL13, Copyright © 2001 by The American Association of Immunologists 0022-1767/01/$02.00 The Journal of Immunology 1073 CXCR5, is expressed on recirculating B cells; in in vitro chemo- was unaware of any clinical or laboratory findings. Tissue specimens were taxis assays, BLC/CXCL13 attracts B cells. In mice with a targeted grouped according to the following criteria: 1) T cell-B cell aggregates inactivation of CXCR5, the normal development of Peyer’s with GCs, 2) T cell-B cell aggregates without GCs, or 3) diffuse infiltration of T cells and B cells and the absence of lymphoid organization. GCs patches, inguinal lymph nodes, splenic follicles, and peripheral within lymphoid aggregates were identified by standard histological crite- lymphocytes is disrupted, making the BLC/CXCL13-CXCR5 re- ria (22). These included well-circumscribed clusters of centrocytes and ceptor-ligand pair critical in lymphoid tissue organization (15). centroblasts with variable numbers of tingible body macrophages and mi- We studied a large cohort of patients with RA who presented totic figures within aggregates of small lymphocytes. In most cases, cells with the morphological features of FDCs were also associated with the with different phenotypes of lymphoid microarchitectures in the centrocytes and centroblasts. synovial lesions and examined whether cytokines and chemokines implicated in the genesis of secondary lymphoid organs are in- RT-PCR and cytokine semiquantification volved in the process of lymphoid neogenesis in RA. Analysis of Total RNA was extracted from synovial tissue specimens using a commer- the cellular