Pathophysiology of Immune Thrombocytopenic Purpura: a Bird's-Eye View

Egypt J Pediatr Allergy Immunol 2014;12(2):49-61. Review article Pathophysiology of immune thrombocytopenic purpura: a bird's-eye view. Amira Abdel Moneam Adly Pediatrics Department, Faculty of Medicine, Ain Shams University, Cairo, Egypt ABSTRACT and B lymphocytes (including T-helper, T- Immune thrombocytopenic purpura (ITP) is a cytotoxic, and T-regulatory lymphocytes) 6. common autoimmune disorder resulting in isolated The triggering event for ITP is unknown7, but thrombocytopenia. It is a bleeding disorder continued research is providing new insights into characterized by low platelet counts due to decreased the underlying immunopathogenic processes as well platelet production as well as increased platelet as the cellular and molecular mechanisms involved destruction by autoimmune mechanisms. ITP can in megakaryocytopoiesis and platelet turnover. present either alone (primary) or in the setting of other Although historically ITP-associated thrombo- conditions (secondary) such as infections or altered cytopenia was attributed solely to increased rates of immune states. ITP is associated with a loss of destruction of antibody- coated platelets, it has tolerance to platelet antigens and a phenotype of become evident that suboptimal platelet production accelerated platelet destruction and impaired platelet also plays a role 8. production. Although the etiology of ITP remains Bleeding is due to decreased platelet production unknown, complex dysregulation of the immune as well as accelerated platelet destruction mediated system is observed in ITP patients. Antiplatelet in part by autoantibody-based destruction antibodies mediate accelerated clearance from the mechanisms9. Most autoantibodies in ITP are circulation in large part via the reticuloendothelial isotype switched and harbor somatic mutations10, (monocytic phagocytic) system. In addition, cellular and as such a role for CD4+ helper T cells in immunity is perturbed and T-cell and cytokine profiles disease pathogenesis has been invoked. Consistent are significantly shifted toward a type 1 and Th17 with this, ITP patients have activated platelet- proinflammatory immune response with impaired autoreactive T cells with increasing cytokine regulatory compartment, including Tregs and Bregs, imbalance toward IL-2 and IFN-γ, indicating a shift have been reported, suggesting a generalized immune toward Th1 cells11. More recently, increased Th17 dysregulation in ITP. Understanding how cells or IL-17 cytokine were reported in ITP Th1/Th17/Treg differentiation and expansion are patients12, implicating a possible role for Th17 cells controlled is central to uncovering how autoimmunity in ITP immunopathology. may be sustained in ITP. Moreover, a role for cytotoxic T cells in direct lysis of platelets and megakaryocytes in the bone 13 INTRODUCTION marrow has been proposed . In addition to an Immune thrombocytopenia (ITP) is recognized as increase in the effector T cell arm of the immune an immune mediated disorder in which platelets are response (Th1, Th17 and CD8 cells); a decrease in opsonized by autoantibodies and prematurely the regulatory immune compartment of patients destroyed by reticuloendothelial system1. It is a with ITP has been described. Specifically, a hematologic disorder affecting children with an deficiency in generation and/or defective functions 14 incidence of four to five cases per 100,000 children of ITP regulatory T cell (Treg) and regulatory B 15 per year2.It is characterized by immune-mediated cells (Bregs) . accelerated platelet destruction and suppressed This brief review will highlights the platelet production. Although the etiology of ITP is mechanisms, and their elements, underlying the not yet known, and the diagnosis continues to be pathogenesis and cellular kinetics of ITP and one of exclusion.3 A number of studies have discusses the aspects of current understanding of provided evidence of disturbed innate and adaptive immune dysregulation. Also it addresses the recent immune responses in patients with ITP.4 The findings on the state of the Breg and Treg pathophysiology of ITP increasingly is understood compartments by which this information may guide better5. Not surprisingly, it is complex with therapy in ITP patients in the future. involvement of many players in the human immune orchestra, including antibodies, cytokines, antigen- presenting cells, costimulatory molecules, and T 49 Adly Implicating agents in ITP of ITP often occurs seemingly rapidly and between ITP is a heterogeneous group of disorders with monitoring time points19. potentially differing etiologies, natural histories and Despite these limitations, data from numerous response to therapy3. Some ITP patients appear to studies in recent years are beginning to come have fundamental disturbances in their innate and together to form a picture of an unbalanced immune adaptive immunity, while in others a specific often response. Not surprisingly, the immune changes times self-liming inciting agent may be involved. observed during ITP are complex. The long-held Several potential inciting agents have been dogma of platelet-bound Abs leading to identified or proposed. Fc_receptor (Fc_R)–mediated clearance of platelets In the case of childhood ITP, many patients give by phagocytes residing in the spleen (and liver) a history of a recent infection. In adults, infection continues to be a central theme in our current with human immune deficiency virus, Helicobacter understanding of ITP. In addition to this, the pylori and hepatitis C have been implicated in a evidence supports a wide array of immune shifts high percentage of cases of ITP in endemic areas; involving all components of the immune system, the causal relationship is strongest in settings where resulting in both shortened platelet survival and microbial elimination leads to resolution of the inhibition of the production of platelets20. associated ITP16. Acute ITP can also occur after vaccination. The evidence for vaccine associated The role of the spleen ITP is most compelling in those immunized with In 1916, Kaznelson, while a medical student in measles-mumps-rubella vaccine (~1:40,000). There Vienna, prevailed upon the attending surgeon to have also been case reports of ITP in children perform a splenectomy in a patient with ITP. The following other vaccinations against hepatitis B, splenectomy was successful in normalizing the diphtheria-tetanus-pertussis, and hepatitis A, but the platelet count and, with other cases, first established relationship is less compelling17. the critical role of the spleen in ITP21. However, the It has been hypothesized that ITP results from cause of thrombocytopenia remained unclear. Was molecular mimicry engrafted on a normal immune the spleen destroying the platelets or did it secrete a repertoire, such that the immune thrombocytopenia suppressive substance that inhibited platelet resolves once the inciting antigen has been production and/ or release into the circulation? eliminated. Although microbial antigens may play a Doan et al.22 examined a number of spleens from role in the induction of vaccine associated ITP, patients with ITP. They demonstrated sea blue many vaccines also contain adjuvants (e.g., alum) (lipid laden) histiocytes in the spleen, suggesting it that might potentiate the immune response. was the platelet ‘destroyer’. What directed the Recent work from Shoenfeld and coworkers spleen to prematurely destroy platelets, however, suggests that some autoimmune syndromes and remained unclear23. The spleen, with its unique inflammatory states might be induced by these microvascular architecture, is well suited for immune adjuvants themselves18. The name they immunologic surveillance of the body platelet mass have given to this activity is as it has the capacity to store a large number of Autoimmune/Inflammatory Syndrome Induced by platelets in an exchangeable pool in close proximity Adjuvants (ASIA). The role that ASIA might play to cells of the immune system23. The intrasplenic in the initiation of ITP requires further study, but platelet transit time has been estimated to be around the observation that ITP has been seen after the 10 min and is independent of spleen size. The administration of several different vaccines demonstration that splenic tissue from patients with provides an interest in this possibility. ITP produces antiplatelet IgG suggests that the Identification of factors that precipitate ITP is spleen has capacity of forming these autoantibodies extremely difficult due to the likely transient nature and that this mechanism is active in the disease24. In of the provoking event, the inherent difficulty in addition, the splenic macrophages have been shown diagnosing ITP early in its course, and the to avidly phagocytose platelets sensitized by serum prolonged time period over which monitoring from ITP patients25. The spleen therefore, both would need to occur to capture the onset of ITP. produces antiplatelet antibodies and sequesters Even in subjects known to be at high risk for ITP opsonized platelets. The central role of the spleen in due to a personal history of ITP, a strong family ITP is further illustrated by the fact that 70% of history of ITP (rare), or comorbidity with a chronic ITP patients enter a durable remission after condition predisposing to secondary ITP, the onset splenectomy26. 50 Pathophysiology of ITP Figure 1. Model of relationship of contributing factors in ITP. (Johnsen J. Pathogenesis in immune thrombocytopenia: new insights. Hematology Am Soc Hematol

Load more