Tolerance to RBC antigens; pathogenesis of autoimmune haemolytic anaemia

Autoimmune haemolytic anaemia (AIHA) ensues when humoral tolerance is lost to antigens on red blood cells (RBCs), resulting in RBC autoantibodies and haemolysis. Haemolysis can be profound, and lead to substantial morbidity, and in some cases, mortality. The pathogenesis of primary AIHA remains poorly understood. Using murine models of RBC tolerance, we have recently described that baseline tolerance to RBC antigens is complete in the CD4+ compartment. However, the T cell tolerance is not due to thymic deletion; rather, autoreactive CD4+ T cells exist in the periphery, but in an anergic and non-functional state. In contrast, B cell tolerance to RBC antigens is incomplete. Moreover, autoreactive B cells rapidly differentiate into plasma cells secreting anti-RBC autoantibodies if provided CD4+ T cell help. Together, these data indicate that the stop-gap immunological safety measure for humoral autoimmunity to RBC antigens is anergy of autoreactive CD4+ T cells, in a murine model. This model predicts that factors that reverse CD4+ T cell anergy may be instrumental in the pathogenesis of AIHA. If translatable to human biology, these findings represent a fundamental shift in understanding of AIHA pathogenesis, which has heretofore assumed that tolerance in the B cell compartment was the determining factor.