Grant: Operating Grant

Rheumatoid arthritis (RA) is the most frequent form of chronic inflammatory polyarthritis with a prevalence of 1-2% and an incidence of 50 in 100.000 cases. Patients with RA not only have a reduced quality of life but they have an increased premature mortality risk. Defects in the function of immune cells, which ultimately make the immune system less efficient and more likely to react against self-tissues, characterize RA. The abnormalities of the immune system involve not only mature cells, but also their precursors known as hematopoietic stem and progenitor cells (HSPC). HSPC are the cells that give rise to all the immune and blood cells of our body. In order to do so, HSPC must actively divide (proliferate). In RA patients, the proliferative capacity of HSPC is impaired and thus, their ability to generate the entire immune system is hampered. The mechanism(s) accounting for the proliferative defects of stem cells in RA are largely unknown. RA-HSPC accumulate genomic damage, which is depicted by their early telomere shortening and high number of DNA breaks. We postulate that DNA damage in RA-HSPC triggers the production of inflammatory cytokines, which in turn provide a "stop proliferating signal" to other HSPC and their environment. This proposal will test this hypothesis, define the molecular mechanisms underlying this process and evaluate how modulating the production of HSPC cytokines impacts the efficiency of mature immune cell generation in RA. Understanding the role of HSPC in RA pathogenesis by defining the factors that account for their central functional defect (proliferative arrest), will provide new information concerning the etiology and potentially novel therapeutic targets for this debilitating disease.