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Departments of
*
Medicine and Immunology,
Laboratory Medicine and Pathology,
Health Services Research, and
Orthopedic Surgery, Mayo Clinic, Rochester, MN 55905
In rheumatoid arthritis (RA), tissue-infiltrating lymphocytes can
be arranged in sophisticated organizations that resemble
microstructures 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. Multivariate logistic
regression analysis of tissue cytokines and chemokines identified two
parameters, in situ transcription of lymphotoxin (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 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.
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H.-J. Kim, T. Kammertoens, M. Janke, O. Schmetzer, Z. Qin, C. Berek, and T. Blankenstein Establishment of Early Lymphoid Organ Infrastructure in Transplanted Tumors Mediated by Local Production of Lymphotoxin {alpha} and in the Combined Absence of Functional B and T Cells J. Immunol., April 1, 2004; 172(7): 4037 - 4047. [Abstract] [Full Text] [PDF]
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E. Kanters, M. J.J. Gijbels, I. van der Made, M. N. Vergouwe, P. Heeringa, G. Kraal, M. H. Hofker, and M. P. J. de Winther Hematopoietic NF-{kappa}B1 deficiency results in small atherosclerotic lesions with an inflammatory phenotype Blood, February 1, 2004; 103(3): 934 - 940. [Abstract] [Full Text] [PDF]
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T. Katakai, T. Hara, M. Sugai, H. Gonda, and A. Shimizu Th1-Biased Tertiary Lymphoid Tissue Supported by CXC Chemokine Ligand 13-Producing Stromal Network in Chronic Lesions of Autoimmune Gastritis J. Immunol., October 15, 2003; 171(8): 4359 - 4368. [Abstract] [Full Text] [PDF]
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A. Meissner, O. Zilles, R. Varona, K. Jozefowski, U. Ritter, G. Marquez, R. Hallmann, and H. Korner CC chemokine ligand 20 partially controls adhesion of naive B cells to activated endothelial cells under shear stress Blood, October 15, 2003; 102(8): 2724 - 2727. [Abstract] [Full Text] [PDF]
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A. Sapino, P. Cassoni, E. Ferrero, M. Bongiovanni, L. Righi, N. Fortunati, P. Crafa, R. Chiarle, and G. Bussolati Estrogen Receptor {alpha} Is a Novel Marker Expressed by Follicular Dendritic Cells in Lymph Nodes and Tumor-Associated Lymphoid Infiltrates Am. J. Pathol., October 1, 2003; 163(4): 1313 - 1320. [Abstract] [Full Text] [PDF]
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L. Schiffer, J. Sinha, X. Wang, W. Huang, G. von Gonsdorff, M. Schiffer, M. P. Madaio, and A. Davidson Short Term Administration of Costimulatory Blockade and Cyclophosphamide Induces Remission of Systemic Lupus Erythematosus Nephritis in NZB/W F1 Mice by a Mechanism Downstream of Renal Immune Complex Deposition J. Immunol., July 1, 2003; 171(1): 489 - 497. [Abstract] [Full Text] [PDF]
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 D. L. Drayton, X. Ying, J. Lee, W. Lesslauer, and N. H. Ruddle Ectopic LT{alpha}{beta} Directs Lymphoid Organ Neogenesis with Concomitant Expression of Peripheral Node Addressin and a HEV-restricted Sulfotransferase J. Exp. Med., May 5, 2003; 197(9): 1153 - 1163. [Abstract] [Full Text] [PDF]
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 J. Kuai, E. Nickbarg, J. Wooters, Y. Qiu, J. Wang, and L.-L. Lin Endogenous Association of TRAF2, TRAF3, cIAP1, and Smac with Lymphotoxin beta Receptor Reveals a Novel Mechanism of Apoptosis J. Biol. Chem., April 11, 2003; 278(16): 14363 - 14369. [Abstract] [Full Text] [PDF]
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J. R. Smith, R. M. Braziel, S. Paoletti, M. Lipp, M. Uguccioni, and J. T. Rosenbaum Expression of B-cell-attracting chemokine 1 (CXCL13) by malignant lymphocytes and vascular endothelium in primary central nervous system lymphoma Blood, February 1, 2003; 101(3): 815 - 821. [Abstract] [Full Text] [PDF]
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 H S Carlsen, E S Baekkevold, F-E Johansen, G Haraldsen, and P Brandtzaeg B cell attracting chemokine 1 (CXCL13) and its receptor CXCR5 are expressed in normal and aberrant gut associated lymphoid tissue Gut, September 1, 2002; 51(3): 364 - 371. [Abstract] [Full Text]
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A. J. Marshall, Q. Du, K. E. Draves, Y. Shikishima, K. T. HayGlass, and E. A. Clark FDC-SP, a Novel Secreted Protein Expressed by Follicular Dendritic Cells J. Immunol., September 1, 2002; 169(5): 2381 - 2389. [Abstract] [Full Text] [PDF]
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S. A. Luther, A. Bidgol, D. C. Hargreaves, A. Schmidt, Y. Xu, J. Paniyadi, M. Matloubian, and J. G. Cyster Differing Activities of Homeostatic Chemokines CCL19, CCL21, and CXCL12 in Lymphocyte and Dendritic Cell Recruitment and Lymphoid Neogenesis J. Immunol., July 1, 2002; 169(1): 424 - 433. [Abstract] [Full Text] [PDF]
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Y. M. Kang, X. Zhang, U. G. Wagner, H. Yang, R. D. Beckenbaugh, P. J. Kurtin, J. J. Goronzy, and C. M. Weyand CD8 T Cells Are Required for the Formation of Ectopic Germinal Centers in Rheumatoid Synovitis J. Exp. Med., May 20, 2002; 195(10): 1325 - 1336. [Abstract] [Full Text] [PDF]
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S. Takemura, P. A. Klimiuk, A. Braun, J. J. Goronzy, and C. M. Weyand T Cell Activation in Rheumatoid Synovium Is B Cell Dependent J. Immunol., October 15, 2001; 167(8): 4710 - 4718. [Abstract] [Full Text] [PDF]
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C. M. Weyand, P. J. Kurtin, and J. J. Goronzy Ectopic Lymphoid Organogenesis : A Fast Track for Autoimmunity Am. J. Pathol., September 1, 2001; 159(3): 787 - 793. [Full Text] [PDF]
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