Immune Thrombocytopenia: Recent Advances in Pathogenesis and Treatments

Abstract

Immune thrombocytopenia (ITP) is a rare autoimmune disease due to both a peripheral destruction of platelets and an inappropriate bone marrow production. Although the primary triggering factors of ITP remain unknown, a loss of immune tolerance-mostly represented by a regulatory T-cell defect-allows T follicular helper cells to stimulate autoreactive splenic B cells that differentiate into antiplatelet antibody-producing plasma cells. Glycoprotein IIb/IIIa is the main target of antiplatelet antibodies leading to platelet phagocytosis by splenic macrophages, through interactions with Fc gamma receptors (FcγRs) and complement receptors. This allows macrophages to activate autoreactive T cells by their antigen-presenting functions. Moreover, the activation of the classical complement pathway participates to platelet opsonization and also to their destruction by complement-dependent cytotoxicity. Platelet destruction is also mediated by a FcγR-independent pathway, involving platelet desialylation that favors their binding to the Ashwell-Morell receptor and their clearance in the liver. Cytotoxic T cells also contribute to ITP pathogenesis by mediating cytotoxicity against megakaryocytes and peripheral platelets. The deficient megakaryopoiesis resulting from both the humoral and the cytotoxic immune responses is sustained by inappropriate levels of thrombopoietin, the major growth factor of megakaryocytes. The better understanding of ITP pathogenesis has provided important therapeutic advances. B cell-targeting therapies and thrombopoietin-receptor agonists (TPO-RAs) have been used for years. New emerging therapeutic strategies that inhibit FcγR signaling, the neonatal Fc receptor or the classical complement pathway, will deeply modify the management of ITP in the near future.

Figure 1.

ITP pathogenesis. ITP results from a peripheral destruction of platelets that takes place in the blood, the spleen, and the liver, together with an inappropriate bone marrow production due to an autoimmune response against megakaryocytes and insufficient TPO levels. In the blood, platelet destruction is most probably mediated by CDC: the binding of antibodies to platelet GP leads to the activation of the classical complement pathway and the formation of the MAC, leading to platelet lysis. Complement activation also leads to the deposition of C3b on platelet surface, which promotes the phagocytosis of opsonized platelets by macrophages in the spleen, mediated by the ligation of antiplatelet antibodies to FcγR and C3b to CR1. Splenic macrophages are the major antigen-presenting cells that stimulate autoreactive CD4 T cells in ITP. These autoreactive T cells contain TFH cells that interact with autoreactive B cells and induce their proliferation, their differentiation into plasma cells, and the production of antiplatelet antibodies by a mechanism dependent on IL-21 secretion and CD40/CD154 interactions. BAFF is a cytokine produced by monocytes (and polymorphonuclear cells) that participates to the stimulation and survival of B cells and plasma cells. Antiplatelet antibodies, by the recruitment of neuraminidase-1 at platelet membrane, trigger platelet desialylation. Desialylated platelets are recognized by the Ashwell-Morell receptor expressed on hepatocytes, leading to their removal from circulation and to the production of TPO, the major growth factor of megakaryocytes. In the bone marrow there is an autoimmune response against megakaryocytes that express similar GP as platelets and are thus recognized by antiplatelet antibodies and exposed to CDC and ADCP. Of note, bone marrow also represents a niche for autoreactive plasma cells. CD8 cytotoxic T cells can mediate cytotoxicity against platelets; however, due to the necessity of a close cell contact, this phenomenon probably takes place in the spleen rather than in the blood. Moreover, there is a recruitment of CTL into the bone marrow where they participate to the immune response against megakaryocytes. Overall, the autoimmune response is favored by a loss of tolerance, supported by a deficiency of Tregs in the spleen, the blood and the bone marrow. ADCC = antibody-dependent cellular cytotoxicity; ADCP = antibody-dependent cellular phagocytosis; AMR = Ashwell-Morell receptor; BAFF = B-cell activating factor; CD = cluster of differentiation; CDC = complement-dependent cytotoxicity; CMC = cytotoxic T lymphocyte-mediated cytotoxicity; cMpl = thrombopoietin receptor; CR = complement receptor; CTL = cytotoxic T cell; FcγR = Fc gamma receptor; GP = glycoprotein; ICOS = inducible T-cell costimulator; ICOS-L = ICOS ligand; IL = interleukin; ITP = immune thrombocytopenia; JAK = janus kinase; MAC = membrane attack complex; MEK = megakaryocyte; MHC = major histocompatibility complex; mRNA = messenger RNA; PD-1 = programmed cell death protein 1 (CD279); PD-L1 = programmed cell death ligand 1 (CD274); STAT = signal transducer and activator of transcription; Tc = cytotoxic T cell; TCR = T-cell receptor; TFH = T follicular helper cell; Th = helper T cell; TPO = thrombopoietin; Treg = regulatory T cell.