Heterogeneity in rheumatoid tissue revealed by gene expression profiling

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Large-scale gene expression profiling of synovial tissues from patients with erosive RA (n=23) using DNA microarrays with a complexity of ~11.5K genes (the so-called Lymphochip as described in [23, 27]) and ~18K genes [28] revealed considerable heterogeneity among different patients. A systematic characterisation of the differentially expressed genes highlighted the existence of at least two molecular distinct forms of RA tissues (Tab. 1, Fig. 1). One group revealed abundant expression of clusters of genes indicative of an ongoing inflammation and involvement of the adaptive immune response and is therefore referred to as high inflammation group. The expression of immunoglobulin genes showed the largest variation among RA patients with a high expression in the high inflammation RA tissues. Detailed analysis of the genes involved provide evidence for a prominent role of an activated STAT-1 pathway, including STAT-1 signalling receptors and STAT-1 target genes, among these STAT-1 itself [29]. Obviously, the various cytokines present in the RA synovi-um create a complex situation with simultaneous activation of multiple signalling pathways that may influence STAT-1 signalling. The importance of STAT activation in arthritis has been demonstrated in an animal model that periarticular administration of adenoviral suppressor of cytokine signalling 3 dramatically reduced the severity of collagen-induced arthritis and synovial IgG production [29]. These findings justify further research on the cell-specific expression of STAT signalling components, including the activating receptors and their ligands, which is crucial for our understanding of the molecular and cellular events that take place in the effector phase.

The expression profiles of the other group of RA tissues revealed a low inflammatory gene expression signature and an increased expression of genes involved in tissue remodelling activity, which is associated with fibroblast dedifferentiation. The gene expression signature of the latter tissues was reminiscent of that of tissues from patients with osteoarthritis. Careful analysis of the differentially expressed genes suggests the contribution of independent processes to disease and tissue destruction in RA.

The presence of the high inflammation tissues correlated with increased levels of systemic inflammation as is indicated by a significant increased erythrocyte sedimentation rate. However, the design of this study does not allow any firm conclusions to be drawn concerning the clinical parameters associated with the molecular phenotype. Therefore, further studies are necessary, which may provide a means to dissect and analyse the rheumatoid synovium of these patients and perform a thorough clinical association study based on molecular variation among patients.

Among the rheumatoid tissues that were grouped as high-inflammation tissues were tissues that contain organised lymph-node like follicular structures. Accordingly, the gene expression signature of these tissues revealed increased expression of 374 genes involved in, e.g., antigen presentation, chemotaxis and specific cytokine-induced activity. In contrast, tissues with a diffuse type of infiltrate showed a profile that indicated repression of angiogenesis and increased extracellular matrix remodelling. Based on the unique expression profile of tissues with a follicular infiltrate, we were able to predict the presence of lymphoid structures in rheumatoid synovia with a 100% correct classification in a ten-fold cross validation using PAM [30]. These results indicate that in tissues with ectopic lymphoid structures genes are overexpressed that reflect activation of distinct processes that allow attraction, retention and survival of FDC, T-, and B-cells with a high level of organisation. It is anticipated that patients with this type of tissue may require specific treatments to resolve the complex inflammatory processes that differs from that of the other types of synovial infiltrates.

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Arthritis Relief and Prevention

Arthritis Relief and Prevention

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