Lymphoid neogenesis in rheumatoid synovitis

In rheumatoid arthritis (RA), tissue-infiltrating lymphocytes can be arrang ed in sophisticated organizations that resemble microstructures usually for med 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 cen ters (GCs) were found in 23.4% of the patients. Follicular dendritic cells (FDCs) were exclusively present in tissues with GCs, suggesting that the re cruitment or in situ maturation of FDCs is a critical factor for GC formati on in the synovial membrane. Primary follicles were absent, emphasizing the role of Ag recognition in the generation of inflammation-associated lympho id organogenesis. Multivariate logistic regression analysis of tissue cytok ines and chemokines identified two parameters, in situ transcription of lym photoxin (LT)-beta and of B lymphocyte chemoattractant (BLC; BLC/CXCL13), t hat were predictors for FDC recruitment and synovial GC formation. LT-beta and BLC/CXCL13 were found to be independent variables that could, in part, compensate for each other to facilitate GC formation. Prediction models inc orporating in situ transcription of LT-beta and BLC/CXCL13 had high negativ e yet moderate positive predictive values, suggesting that LT-beta and BLC/ CXCL13 are necessary but not sufficient. LT-beta protein was detected on a subset of mantle zone and GC B cells, but also on T cells in follicular str uctures. BLC/CXCL13 was produced by FDCs in follicular centers, but was pre dominantly found in endothelial cells and synovial fibroblasts, suggesting heterotypic signaling between cells of the synovial membrane and infiltrati ng lymphocytes in regulating extranodal lymphoid neogenesis.