Identification of genes associated with the presence of ectopic lymphoid structures in rheumatoid arthritis synovial tissues
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KeywordsRheumatoid Arthritis Synovial Tissue Follicular Dendritic Cell Cellular Infiltrate Lymph Node Development
Rheumatoid arthritis (RA) is a heterogeneous disease, which is also reflected in the type of cellular infiltrates in the RA synovial tissues. In approximately 25% of the patients, the synovial tissue contains cellular infiltrates that have formed organized structures resembling structures normally observed in lymph nodes, comprising follicular dendritic cells (FDCs), with distinct T-cell and B-cell areas, therefore referred to as ectopic lymphoid structures. In the remainder of the patients the tissues do not contain FDCs and show either a diffuse lymphocytic infiltrate or an aggregated T-cell and B-cell infiltrate .
The aim of our study is to identify the genes that are expressed in tissues with these ectopic lymphoid structures by cDNA microarray analysis to gain more insight into this specific disease process. We previously showed that the gene expression signatures of synovial tissues from RA patients showed considerable variability, resulting in the identification of distinct molecular forms of RA [2, 3]. To evaluate whether the genes involved in the formation of ectopic lymphoid structures could be detected by microarray analysis of whole synovial tissues, we performed an analysis focused on a selection of genes that are known to be involved in normal lymph node development from murine knockout studies.
Indeed, four out of 13 tissues showed an elevated expression of lymph-node-associated genes, indicating that microarray analysis of whole synovial tissue allows the detection of these genes. The expression of the FDC-specific marker CD21L and immune histochemical staining of synovial tissue sections confirmed the presence of ectopic lymphoid structures in these tissues. Detailed histochemical analysis further allowed us to subclassify the tissues without lymphoid structures into tissues containing T-cell and B-cell aggregates and tissues with a diffuse type of infiltrate.
Comparison of large-scale gene expression profiles between tissues with the three different types of cellular infiltrates revealed differential expression of genes involved in several processes such as apoptosis, antigen presentation, angiogenesis, chemotaxis and extracellular matrix formation. The results indicate that tissues with ectopic lymphoid structures comprise a distinct type of gene expression that includes a spectrum of genes encoding for adhesion molecules, chemokines, cytokines and their receptors that is required to maintain their highly organized structure.