Etudes des mécanismes synoviaux impliqués dans la résistance aux agents bloquant le TNF-alpha dans la polyarthrite rhumatoïde
(2011)
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- (en) The identification of new markers of response to therapy is a major medical need in the care of patients with rheumatoid arthritis (RA). The introduction of TNF blocking agents in the therapy of RA patients resulted in a dramatic improvement in terms of disease course and functional outcomes. However, 30% of the patients do not respond to the drugs, and require alternative therapies. This results in disease progression in these very patients and unnecessary exposure to a costly, and potentially toxic, drug. There is therefore a need of markers predicting response to TNF blockade in RA. In order to understand the mechanisms of action of TNF blockade in the RA synovium, and identify potential markers of response to therapy, we performed high-density transcriptomic studies using synovial biopsies of 25 methotrexate-resistant RA patients, obtained before and 3 months after initiation of adalimumab therapy (an anti-TNFα blocking antibody). We found that genes involved in “cell proliferation” and “regulation of immune responses” pathways are significantly over-expressed at baseline in synovial biopsies of patients displaying a poor-response to TNF blockade compared to patients displaying a good- or a moderate-response to the drug. These results were confirmed by RT-PCR and immunostaining experiments. We next studied the regulation of the expression of a panel of those genes associated with poor-response to TNF blockade : genes involved in cell proliferation (Ki67, CDC2, GTSE1) and genes involved in the regulation of immune responses (IL-7Rα, IL-6, IDO). We found that they are induced in vitro in fibroblast-like synovial cells by the addition of TNF-α, IL-1β and additive or synergistic combinations of TNFα and IL-1β or TNFα and IL-17, thereby suggesting that these cytokines, or combinations of cytokines, play a role in the resistance to TNF blockade in RA. Next, we focused on one particular gene, encoding the IL-7Rα molecule. In our previous work, we described that over-expression of this gene is characteristic of the RA synovium. Here, we found that over-expression of the gene predicts poor-response to TNF blockade in RA. We found that RAFLS produce two isoforms of the IL-7Rα transcript : one full-length, and one soluble form (sIL-7R), which results from an alternative splicing of the gene. TNFα and IL-1β, alone or in combination, (or the combination of TNFα and IL-17) induce the expression of sIL-7R in RAFLS. We also demonstrated that sIL-7R plays an inhibitory role on the activation of synovial CD4 T cells. Finally, we detected sIL-7R in sera of controls and RA patients. Higher sIL-7R serum concentrations are found in RA patients, in particular in patients who will not respond to TNF blockade, thereby suggesting that serum levels of the protein could be a novel marker of response to TNF blockade in RA.
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Badot, V. (2011). Etudes des mécanismes synoviaux impliqués dans la résistance aux agents bloquant le TNF-alpha dans la polyarthrite rhumatoïde. https://hdl.handle.net/2078.5/156703