Dendritic cells manipulating immune responses: Understanding the role of Flt3L and Flt3-dependent DCs in rheumatic diseases

Dendritic cells (DCs) are essential in inducing immunity but also in mediating immune tolerance. Although the role of DCs has been investigated in the pathogenesis of rheumatic diseases, it remains unclear whether DC are necessary for disease induction and which DC subsets are involved in the induction and maintenance of the inflammatory process. DCs are a heterogeneous population of cells and several subsets have been identified. With this thesis we showed that DCs are crucial for the induction and maintenance of inflammation in rheumatic diseases and identified which DC subset(s) are involved. We demonstrated that DCs that depend on the growth factor Flt3L for their development (Flt3L-dependent) are essential for the initiation of collagen-induced arthritis in mice. Specifically the CD103+ DC subset is necessary for disease development in mice models of RA. We have also shown that CD141+ DCs (human homologues of CD103+ DCs in mice) contribute for the maintenance of the inflammatory process. Flt3L levels are increased in rheumatoid arthritis (RA) patients and might be involved not only in DC development but also in osteoclast formation and therefore contribute to bone loss. We showed that effective treatment of RA patients with corticosteroids lead to a decrease of Flt3L serum levels suggesting that this molecule might be involved in RA pathogenesis. Overall we have demonstrated that Flt3L and Flt3L dependent DCs play an important role in RA development and perpetuation. Targeting Flt3L dependent-DCs or its products might constitute new possible therapeutic targets for the prevention and treatment of rheumatic diseases.