Ms. Timmer and Dr. Baltus contributed equally to this work.
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†
Article first published online: 30 JUL 2007
Copyright © 2007 by the American College of Rheumatology
Arthritis & Rheumatism
Volume 56, Issue 8, pages 2492–2502, August 2007
How to Cite
Timmer, T. C. G., Baltus, B., Vondenhoff, M., Huizinga, T. W. J., Tak, P. P., Verweij, C. L., Mebius, R. E. and van der Pouw Kraan, T. C. T. M. (2007), 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. Arthritis & Rheumatism, 56: 2492–2502. doi: 10.1002/art.22748
The views expressed herein are those of the authors.
- Issue published online: 30 JUL 2007
- Article first published online: 30 JUL 2007
- Manuscript Accepted: 17 APR 2007
- Manuscript Received: 15 DEC 2006
- Marie Curie Training Network (EURO-RA)
- European Community Sixth Framework Programme (project AutoCure)
- Innovation Oriented Research Program on Genomics, The Netherlands Organization for Scientific Research Genomics Program. Grant Number: 050-10-120
- Centre for Medical Systems Biology (a center of excellence approved by The Netherlands Genomics Initiative/Netherlands Organization for Scientific Research)
In ∼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.
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.
Findings of gene expression analysis confirmed previous reports that tissues with lymphoid structures showed elevated expression of CXCL13, CCL21, CCR7, and lymphotoxin α and β 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, Fcε 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 α (IL-7Rα)/IL-2Rγ 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.
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.