Inflammation and ectopic lymphoid structures in rheumatoid arthritis synovial tissues dissected by genomics technology: Identification of the interleukin‐7 signaling pathway in tissues with lymphoid neogenesis

Abstract

Objective. In ϳ25% 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 ␣ and ␤ 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, Fc 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 ␣ (IL-7R␣)/IL-2R␥ 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.

Ectopic lymphoid follicles: inducible centres for generating antigen‐specific immune responses within tissues

“…Notably, ELFs are described at all stages of the disease and include patients with early active disease who have not received biological agents, patents with more progressive forms of rheumatoid arthritis, and those that have already received biological intervention 43, 112, 113. Although the mechanisms contributing the development of this form of pathology are largely unclear, ELFs in rheumatoid arthritis are associated with heightened synovial expression of CXCL13, CCL21, CCL19 and CXCL12, and cytokines LT α 1 β 2 and IL‐7 21, 44, 114, 115. Importantly, these structures correlate with disease severity and are associated with local T‐cell priming and autoantibody production 43, 116, 117, 118.…”

Collagen Induces Maturation of Human Monocyte-Derived Dendritic Cells by Signaling through Osteoclast-Associated Receptor

“…38). It is thought that functional DC/T cell interaction can take place locally (39,40), and the perivascular region may act as a site for cell activation (41). Intriguingly, surgical removal of cartilage in RA patients led to reduced inflammation and suppression of functional differentiation of DCs in the synovium (42).…”

B Lymphocyte Autoimmunity in Rheumatoid Synovitis Is Independent of Ectopic Lymphoid Neogenesis

“…Chemokines (CXCL13, CCL19, and CCL21) and cytokines (lyphotoxin ␤, LTb) play a central role in the development, organization, and maintenance of lymphoid architecture (34) and are produced locally during RA synovitis (15,23,35). To understand why synovial lymphoid neogenesis only occasionally progresses toward differentiated GC-reactions, we assessed the synovial expression of these factors by quantitative RT-PCR.…”