Autoimmune effector mechanisms associated with a defective immunosuppressive axis in immune thrombocytopenia (ITP)
Qian Li, Geneviève Marcoux, Yuefen Hu, Johan Rebetz, Li Guo, Elisabeth Semple, Drew Provan, Shuqian Xu, Ming Hou, Jun Peng, John W. Semple
Abstract
Immune thrombocytopenia (ITP) is an autoimmune disease characterized by an isolated thrombocytopenia and variable phenotype as some patients suffer no bleeding whilst others have bleeding from mild to severe, which may be fatal. This variability probably reflects the disease's complex pathophysiology; a dysregulated hyperreactive immune effector cell response involving the entire adaptive immune system (e.g. B and T cell subsets) that leads to platelet and megakaryocyte (MK) destruction. It appears that these effector responses are due to a breakdown in immune tolerance, and this is characterized by defects in several immunosuppressive cell types. These include defective T regulatory cells (Tregs), B regulatory cells (Bregs) and Myeloid-derived suppressor cells (MDSC), all of which are all intimately associated with antigen presenting cells (APC) such as dendritic cells (DC). The loss of this immunosuppressive axis allows for the activation of unchecked autoreactive T cells and B cells, leading to the development of autoantibodies and cytotoxic T cells (CTL), which can directly destroy platelets in the periphery and inhibit MK platelet production in the bone marrow (BM). This review will focus on the effector cell mechanisms in ITP and highlight the defective immunosuppressive axis that appears responsible for this platelet-specific immune hyperreactivity. • Immune thrombocytopenia (ITP) is initiated by abnormal antigen presentation events by macrophages and dendritic cells to autoreactive Th0 cells. • Activated Th0 cells are able to differentiate into several autoreactive T cell subsets such as Th1, Th17, Th9 and Th22 cells which propagate autoimmunity. • These differentiated T cells lead to production of IgG autoantibodies, cytotoxic T cells and NK cells which cause destruction of platelets and megakaryocytes. • The platelet autoimmunity is due to a faulty immunosuppressive axis involving T regulatory cells, B regulatory cells and myeloid derived suppressor cells.