Resumen de Epigenetic dysregulation of monocytes as a sensor of activity and progression in arthritis
Arthritis is a spectrum of chronic, systemic inflammatory diseases that mainly affect joints. It includes entities like rheumatoid arthritis (RA) or psoriatic arthritis (PsA), characterized by aberrantly high inflammatory activities. The main clinical feature of these diseases is the inflammation of the synovium, where a variety of cell types undergo pathogenic activation and secrete high amounts of inflammatory cytokines that eventually reach the blood stream. Evidence linking systemic inflammation and local inflammation at the synovium is reinforced by the observation of alterations occurring simultaneously in both joints and peripheral blood of patients with RA. Monocytes and macrophages are essential players in the pathology of arthritis. For instance, in RA, these cells are major contributors to the damage observed in the joints. Additionally, they can sense and react to inflammatory cues inherent to arthritis patients, both at the synovium and at the peripheral level. Among others, one of the mechanisms through which these stimuli are integrated into their phenotype is DNA methylation (DNAm). DNAm is an epigenetic modification that acts as a dynamic mediator of the environment–genome interface, through which it has the potential to shape cell function and phenotype. This sensing capability makes DNAm especially useful for providing insights into the molecular alterations of both general conditions and individual patient features. For this reason, its application as a biomarker for personalized diagnosis is gaining importance. In this thesis, the DNAm-mediated ability of peripheral blood mononuclear cells, and especially of monocytes, as sensors of arthritisassociated features has been investigated and exploited in different ways with different specific objectives. First, it has been used to identify molecular signatures associated to disease activity and inflammatory cytokine signaling in RA patients. And second, it has served as a biomarker of prognosis in early arthritis patients, revealing a potential utility in predicting patient future outcomes.
