Cytopenia and autoimmune diseases: A vicious cycle fueled by mTOR dysregulation in hematopoietic stem cells

A long-standing but poorly understood defect in autoimmune diseases is dysfunction of the hematopoietic cells. Leukopenia is often associated with systemic lupus erythematous (SLE) and other autoimmune diseases. In addition, homeostatic proliferation of T cells, which is a host response to T-cell lymphopenia, has been implicated as potential cause of rheumatoid arthritis (RA) in human and experimental models of autoimmune diabetes in the NOD mice and the BB rats. Conversely, successful treatments of aplastic anemia by immune suppression suggest that the hematologic abnormality may have a root in autoimmune diseases. Traditionally, the link between autoimmune diseases and defects in hematopoietic cells has been viewed from the prism of antibody-mediated hemolytic cytopenia. While autoimmune destruction may well be part of pathogenesis of defects in hematopoietic system, it is worth considering the hypothesis that either leukopenia or pancytopenia may also result directly from defective hematopoietic stem cells (HSC). We have recently tested this hypothesis in the autoimmune Scurfy mice which has mutation Foxp3, the master regulator of regulatory T cells. Our data demonstrated that due to hyperactivation of mTOR, the HSC in the Scurfy mice are extremely poor in hematopoiesis. Moreover, rapamycin, an mTOR inhibitor rescued HSC defects and prolonged survival of the Scurfy mice. Our data raised the intriguing possibility that targeting mTOR dysregulation in the HSC may help to break the vicious cycle between cytopenia and autoimmune diseases.

► Cytopenia and autoimmunity paradoxically co-exist in patients with autoimmune diseases.
► Cytopenia promotes autoimmune diseases through increased risk of infection and lymphopenia-driven homeostatic proliferation.
► Autoimmune diseases cause mTOR dysregulation and loss of stemness of HSC.
► mTOR inhibitors may break the vicious cycle between cytopenia and autoimmune diseases.