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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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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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