Pathophysiology of immune thrombocytopenic purpura: a bird's-eye view

Immune thrombocytopenic purpura (ITP) is a common autoimmune disorder resulting in isolated thrombocytopenia. It is a bleeding disorder characterized by low platelet counts due to decreased platelet production as well as increased platelet destruction by autoimmune mechanisms. ITP can present either alone (primary) or in the setting of other conditions (secondary) such as infections or altered immune states. ITP is associated with a loss of tolerance to platelet antigens and a phenotype of accelerated platelet destruction and impaired platelet production. Although the etiology of ITP remains unknown, complex dysregulation of the immune system is observed in ITP patients. Antiplatelet antibodies mediate accelerated clearance from the circulation in large part via the reticuloendothelial (monocytic phagocytic) system. In addition, cellular immunity is perturbed and T-cell and cytokine profiles are significantly shifted toward a type 1 and Th17 proinflammatory immune response with impaired regulatory compartment, including Tregs and Bregs, have been reported, suggesting a generalized immune dysregulation in ITP. Understanding how Th1/Th17/Treg differentiation and expansion are controlled is central to uncovering how autoimmunity may be sustained in ITP. INTRODUCTION Immune thrombocytopenia (ITP) is recognized as an immune mediated disorder in which platelets are opsonized by autoantibodies and prematurely destroyed by reticuloendothelial system. It is a hematologic disorder affecting children with an incidence of four to five cases per 100,000 children per year.It is characterized by immune-mediated accelerated platelet destruction and suppressed platelet production. Although the etiology of ITP is not yet known, and the diagnosis continues to be one of exclusion. A number of studies have provided evidence of disturbed innate and adaptive immune responses in patients with ITP. The pathophysiology of ITP increasingly is understood better. Not surprisingly, it is complex with involvement of many players in the human immune orchestra, including antibodies, cytokines, antigenpresenting cells, costimulatory molecules, and T and B lymphocytes (including T-helper, Tcytotoxic, and T-regulatory lymphocytes) . The triggering event for ITP is unknown, but continued research is providing new insights into the underlying immunopathogenic processes as well as the cellular and molecular mechanisms involved in megakaryocytopoiesis and platelet turnover. Although historically ITP-associated thrombocytopenia was attributed solely to increased rates of destruction of antibodycoated platelets, it has become evident that suboptimal platelet production also plays a role . Bleeding is due to decreased platelet production as well as accelerated platelet destruction mediated in part by autoantibody-based destruction mechanisms. Most autoantibodies in ITP are isotype switched and harbor somatic mutations, and as such a role for CD4+ helper T cells in disease pathogenesis has been invoked. Consistent with this, ITP patients have activated plateletautoreactive T cells with increasing cytokine imbalance toward IL-2 and IFN-γ, indicating a shift toward Th1 cells. More recently, increased Th17 cells or IL-17 cytokine were reported in ITP patients, implicating a possible role for Th17 cells in ITP immunopathology. Moreover, a role for cytotoxic T cells in direct lysis of platelets and megakaryocytes in the bone marrow has been proposed . In addition to an increase in the effector T cell arm of the immune response (Th1, Th17 and CD8 cells); a decrease in the regulatory immune compartment of patients with ITP has been described. Specifically, a deficiency in generation and/or defective functions of ITP regulatory T cell (Treg) and regulatory B cells (Bregs). This brief review will highlights the mechanisms, and their elements, underlying the pathogenesis and cellular kinetics of ITP and discusses the aspects of current understanding of immune dysregulation. Also it addresses the recent findings on the state of the Breg and Treg compartments by which this information may guide therapy in ITP patients in the future. Review article