TAM receptors in rheumatoid arthritis: focus on synovial expression, relationship with synovial histopathology and association with clinical evolution and response to treatment
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Emerging evidence highlighted the role of Tyro3, Axl and Mer receptors (TAMs) and their ligands Gas6/ProteinS in the pathogenesis of autoimmunity, however little is known about their expression and function in Rheumatoid Arthritis (RA). RA is a heterogeneous disease: clinical variability and diverse rates of response to treatment are likely due to distinct patterns of synovitis and to the activation of different inflammatory pathways. Three histopathotypes have been recognised: Lymphoid, Myeloid and Fibroid, defined according to the type and distribution of the inflammatory infiltrate. In the first part of my PhD, I characterised TAMs expression in rheumatoid synovial tissue, synovial fluid (SF) and plasma. I showed that a dysregulation of this system might contribute to the uncontrolled inflammation characterising rheumatoid synovitis; accordingly, treatment with Gas6 induced an anti-inflammatory phenotype in RA SF macrophages confirmed by increased IL10-secretion. I observed that Axl/ProteinS were differentially expressed in RA-joints according to synovial histopathology and degree of inflammation. I demonstrated that SF levels of the Axl cleaved form, acting as a decoy and inhibiting the anti-inflammatory activities of Gas6, associated with a higher degree of synovitis and the formation of synovial lymphoid structures. Given this observation Given this observation and the known role of TAMs in regulating TNFα- dependent pathways, I investigated whether synovial pathotypes and TAMs expression could help predicting clinical response to treatment with an anti- TNFα-agent. To test this hypothesis, I examined a cohort of RA-patients nonresponders to conventional DMARDs demonstrating that the presence of a fibroid pathotype and the up-regulation of Axl/ProteinS mRNA at baseline significantly associated with reduced chance of achieving clinical response following treatment with certolizumab-pegol. Overall, I showed that differential expression and activation of TAMs in RA synovium likely contribute to the regulation of synovial inflammation, can influence disease progression and maybe be used in predicting the response to TNFα blocking agents.
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