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OBJECTIVE: To investigate the relationship between lymphoid neogenesis in the synovium of patients with rheumatoid arthritis (RA) and characteristics of inflammation and disease severity. METHODS: Arthroscopic synovial biopsy was performed in 103 patients with active RA (Disease Activity Score 28-joint assessment >/=3.2) who had not received treatment with biologic agents. Sections were stained and assessed by digital image analysis. Lymphocyte aggregates were counted and graded for size (1-3). Synovial lymphoid neogenesis was defined as the presence of grade 2 or 3 aggregates and subclassified based on the presence of follicular dendritic cells (FDCs). RESULTS: Lymphoid neogenesis was present in 31% of the RA synovial tissues, whereas an additional 25% contained only grade 1 aggregates. FDCs were present in 28% of the samples with lymphoid neogenesis, corresponding to 8% of the total RA cohort. Histologically, synovia with lymphoid neogenesis showed increased infiltration by T and B lymphocytes, plasma cells, and macrophages, and increased expression of tumor necrosis factor alpha and lymphotoxin beta compared with samples without lymphoid neogenesis. Patients with lymphoid neogenesis also had higher C-reactive protein levels, erythrocyte sedimentation rates, and leukocyte and thrombocyte counts, but exhibited no increase in the severity of clinical signs and symptoms. Of importance, there was no relationship between the presence of lymphoid neogenesis and IgM rheumatoid factor or anti-citrullinated protein antibodies. The presence of lymphocyte aggregates with FDCs did not define a specific clinical phenotype compared with lymphocyte aggregates without FDCs. CONCLUSION: These findings indicate that synovial lymphoid neogenesis is associated with more severe synovial and systemic inflammation, but this is not confined to a specific clinical subset of RA. [ABSTRACT FROM AUTHOR]

OBJECTIVE: In approximately 25% of synovial tissues from rheumatoid arthritis (RA) patients, infiltrates of T cells, B cells, and follicular dendritic cells (FDCs) are spatially organized into structures resembling lymph nodes with germinal centers. The remainder of the tissues lack FDCs and show either a diffuse or an aggregated T cell and B cell infiltrate. To gain more insight into this specific disease process, we sought to identify the genes expressed in RA tissues with ectopic lymphoid structures. METHODS: Gene expression profiling of RA synovial tissues was determined by complementary DNA microarray analysis and quantitative real-time polymerase chain reaction. The presence of lymphoid follicles and localization of interleukin-7 (IL-7) in synovial tissue sections was determined by immunofluorescence staining using specific antibodies. RESULTS: Findings of gene expression analysis confirmed previous reports that tissues with lymphoid structures showed elevated expression of CXCL13, CCL21, CCR7, and lymphotoxin alpha and beta messenger RNA. In addition, the tissues also showed enhanced expression of the chemokines CXCL12 and CCL19 and the associated receptors CXCR4 and CXCR5, which are important for the attraction of T cells, B cells, and dendritic cells. Pathway analysis revealed increased expression of genes involved in JAK/STAT signaling, T cell- and B cell-specific pathways, Fcepsilon receptor type I signaling in mast cells, and IL-7 signal transduction in the tissues with ectopic lymphoid follicles, accompanied by increased expression of IL-7 receptor alpha (IL-7Ralpha)/IL-2Rgamma chains and IL-7. Protein expression of IL-7 in RA tissues was localized within fibroblast-like synoviocytes, macrophages, and blood vessels and was colocalized with extracellular matrix structures around the B cell follicles. CONCLUSION: Activation of the IL-7 pathway may play an important role in lymphoid neogenesis, analogous to its role in the development of normal lymphoid tissue. [ABSTRACT FROM AUTHOR]