CD55 promotes hematopoietic stem and progenitor cell survival in a mouse model of immune-mediated aplastic anaemia.

Idiopathic aplastic anaemia (AA) is a life-threatening autoimmune bone marrow (BM) failure syndrome characterized by a hypocellular BM and peripheral pancytopenia. While dysregulation of the complement system has been implicated in the pathogenesis of several autoimmune diseases, including rheumatoid arthritis and systemic lupus erythematosus, its role in AA remains poorly understood. Notably, autoantibodies are frequently detected in AA patients and have the potential to activate the complement cascade. Using an immune-mediated murine model of AA, we found that allogeneic transplantation of splenocytes induced BM failure accompanied by activation of the complement system, as evidenced by elevated plasma levels of complement components C3 and C5. To functionally dissect the contributions of direct cytotoxic T-cell effects versus indirect mechanisms such as complement activation, we co-transplanted hematopoietic stem and progenitor cells (HSPCs) congenic to the donor splenocytes into allogeneic recipient mice. In this context, HSPCs deficient in the complement inhibitor Cd55 were negatively selected, indicating increased susceptibility to complement-mediated attack in vivo. Importantly, pharmacological inhibition of the complement cascade rescued the selective disadvantage of Cd55-deficient HSPCs in AA mice, demonstrating that complement activation imposes a negative selective pressure on HSPCs in this model. Together, these findings support a functional role for the complement pathway in the pathogenesis of immune-mediated AA. Further studies are warranted to evaluate the therapeutic potential of combining complement inhibition with standard immunosuppressive therapy in patients with AA.