Hematopoietic stem and progenitor cell function in Rheumatoid Arthritis

Rheumatoid arthritis (RA) is a systemic disorder that can be taken as the prototype to study the molecular and pathological modus operandi of chronic autoimmune inflammation. While the exact cause of RA is unknown, the disruption of immune tolerance is a central driver in the pathogenesis of this disease. It has been proposed that the immune system is prematurely aged in RA patients and that features of immunosenescence, such as the decline in T cell generation and diversity, contribute to the initiation and perpetuation of RA. Several features of premature aging have been recently identified in hematopoietic stem and progenitor cells (HSPC) from patients with RA (RA-HSPC). Specifically, RA-HSPC are decreased in frequency, have prematurely shortened telomeres, reduced proliferative potential, and display an increased propensity toward myeloid differentiation. The mechanisms underlying the defects in RA-HSPC and their contribution to disease onset however are incompletely understood. The work presented in the first section of this thesis, described in Chapter 2, contributes further evidence to the characterization of RA-HSPC. We demonstrate that RA-HSPC have increased DNA damage compared to healthy controls. The accumulation of DNA damage in RA-HSPC was also associated with other functional defects that have been previously reported in HSPC from healthy elderly individuals, such as increased susceptibility to cell death, decreased clonogenic potential, and increased proportion of circulating immature CD34+CD38- subsets. We further demonstrate that the CD34+CD38- subpopulation in RA is hyporesponsive to cytokines that stimulate self-renewal. In the second study, presented in Chapter 3, we assessed extrinsic mechanisms that could be relevant to RA-HSPC immunosenescence. Specifically, we examined the crosstalk between HSPC and mesenchymal stromal cells (MSC), which are a critical component of the HSPC bone marrow microenvironment. Using an in vitro co-culture system, we evaluated how age related defects in MSC impact HSPC viability, proliferation and the frequency of CD34+ subpopulations. We further demonstrate that similar to radiation-induced senescent MSC in contrast to MSC from pediatric donors (age 40 years) have an impaired capacity to maintain HSPC quiescence. This difference is in part mediated by the increased production of IL-6 by adult- and senescent-MSC and by neutralizing IL-6, we were able to restore normal MSC-HSPC crosstalk. The work presented herein demonstrates that RA-HSPC from treatment naive patients have intrinsic defects that could impact their key function in immune system regeneration. Moreover, it provides evidence that the aging of the microenvironment could further contribute to the RA-HSPC defects.%%%%La polyarthrite rhumatoide (PR) est une maladie systemique qui peut etre considere comme le prototype de l'etude moleculaire et pathologiques modus operandi de l'inflammation chronique auto-immune. Bien que la cause exacte de la PR soit inconnue, la…