Primary immune thrombocytopenia: understanding pathogenesis is the key to better treatments
2008; Elsevier BV; Volume: 7; Issue: 2 Linguagem: Inglês
10.1111/j.1538-7836.2008.03258.x
ISSN1538-7933
Autores Tópico(s)Autoimmune Bullous Skin Diseases
ResumoJournal of Thrombosis and HaemostasisVolume 7, Issue 2 p. 319-321 Free Access Primary immune thrombocytopenia: understanding pathogenesis is the key to better treatments B. H. CHONG, B. H. CHONG Haematology Department, St George Hospital, SEALS, and St George Clinical School, University of New South Wales, NSW, AustraliaSearch for more papers by this author B. H. CHONG, B. H. CHONG Haematology Department, St George Hospital, SEALS, and St George Clinical School, University of New South Wales, NSW, AustraliaSearch for more papers by this author First published: 27 January 2009 https://doi.org/10.1111/j.1538-7836.2008.03258.xCitations: 12 Beng H. Chong, Level 2, Pitney Building, St George Hospital, Kogarah, NSW 2217, Australia.Tel.: +61 2 91132010; fax: +61 2 91133998.E-mail: beng.chong@unsw.edu.au AboutSectionsPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat In 1951, W. Harrington infused himself with plasma from a patient with primary immune thrombocytopenia (ITP) and promptly developed transient thrombocytopenia [1]. Since then, it has been widely accepted that ITP is an immune thrombocytopenic disorder in which platelets opsonized by autoantibodies are cleared by macrophages in the reticuloendothelial system. In recent years, many aspects of the pathogenic mechanisms that cause ITP have been elucidated. This article will focus on how an understanding of the pathogenesis of ITP has led to more specific and rational treatments for this disorder. The platelet autoantigens that stimulate autoantibody production by B cells are mainly platelet glycoprotein (GP)IIb–GPIIIa and GPIb–GPIX [2]. Sustained autoantibody production in ITP requires interactions between B cells, T cells and antigen-presenting cells (APCs). Previous work by Kuwana et al. (1998) showed that autoreactive B cells and T cells in ITP respond to cryptic epitopes on GPIIb–GPIIIa fragments, but not to native GPIIb–GPIIIa [3]. In this issue of the journal, Kuwana et al. have identified splenic macrophages as major APCs in patients with ITP [4]. Splenic macrophages capture antibody-coat platelets via Fcgamma receptors (FcγRs). Other investigators have described an over-representation of certain FcγR polymorphisms (FcγRIIa-131H and FcγRIIIa-158V) in ITP patients as compared with healthy controls [5], a finding that suggests a role for FcγR in the pathogenesis of ITP. Membrane GPIIb–GPIIIa and GPIb–GPIX of phagocytosed platelets are processed, and their digested peptides are presented by macrophages to autoreactive human leukocyte antigen (HLA)-restricted CD4+ T cells. T cells become activated when T-cell receptors recognize the HLA-DR/antigenic peptide complex on APCs. They secrete interleukin (IL)-6 and upregulate CD154 expression, exerting helper activity on autoreactive antibody-producing B cells [3, 6-8]. The latter are restricted B-cell clones [9] that undergo proliferation and somatic mutation under antigenic pressure [10]. The autoantibody that they produce binds to platelets, and the opsonized platelets are phagocytosed by mainly splenic macrophages, thus completing the pathogenic loop. Interactions between macrophages, autoreactive T cells and B cells are essential for the maintenance of pathogenic processes in ITP. These cellular interactions are mediated and enhanced by a group of cell surface molecules, that is, T-cell receptor/antigenic peptide–major histocompatibility complex (MHC) complex, B7–CD28–cytotoxic T-lymphocyte antigen-4 (CTLA-4), CD40–CD40L and Fas–FasL [11]. Two essential steps for optimal CD4+ T-cell activation are T-cell receptor interaction with the antigenic peptide–MHC-DR complex, and the interaction between CD28 and B7 on T cells. T-cell activation leads to increased expression of the CD40 ligand (CD154), which binds its receptor, CD40, on B cells [11-13]. This interaction is essential for B-cell proliferation, isotype switching, memory cell generation and autoantibody production. Platelet-associated CD40L can also induce B-cell proliferation [14]. CD154 on T cells and platelets can act cooperatively to stimulate B-cell autoantibody production [11]. Th1/Th2 imbalance leads to autoimmune disease. In active ITP, type 1 cells are increased in number, and there are reductions in the number of Th2 cells and increases in serum levels of IL-2, interferon-gamma and IL-10, but during remission the pattern is skewed towards an increase in the number of Th2 cells [15, 16]. T-cell-mediated platelet lysis may also contribute to platelet destruction in ITP. Olsson et al. [17] found C3+ T cells in patients with active ITP showed increased expression of several cytotoxic genes (the Apo-1/Fas, granzyme A and B and perforin genes) and that CD 14−/CD19− mononuclear cells from six of eight patients lysed autologous platelets in vitro. Furthermore, they demonstrated increased expression of members of the KIR family (KIR3DL1 and KIR3DL2) in patients in remission. This finding suggests that upregulation of KIRs inhibits T-cell cytotoxicity and induces remission in ITP. Studies of platelet turnover in the 1980s showed that in the majority of patients with ITP, platelet production is either reduced or normal [18], which could be due to suppressed megakaryopoiesis or intramedullary platelet destruction. McMillan et al. showed that platelet autoantibodies could decrease platelet production by demonstrating inhibition of megakaryocyte growth and maturation in vitro, using plasma from 12 of 18 patients with chronic ITP, and purified IgG from two patients [19]. This is not unexpected, because platelet autoantigens such as GPIIb–GPIIIa and GPIb–GPIX are expressed on megakaryocytes. In another study, in vitro inhibition of megakaryopoiesis by autoantibodies was also observed in childhood ITP [20]. Despite recent significant advances in our understanding of ITP, the trigger that initiates the autoimmune process is still unknown. There is evidence for an infective or inflammatory event in the initiation of ITP. Helicobacter pylori infection causes ITP in some patients [21]. An immune thrombocytopenia similar to ITP occurs in some patients with hepatitis C and HIV/AIDS. It has been proposed that infection initiates and perpetuates autoimmunity by molecular mimicry and cross-reactivity [11]. An antigen on an infective agent may have a molecular structure similar to a platelet antigen and thereby induce the production of a cross-reacting antibody. Alternatively, the infective process may degrade platelet glycoproteins (e.g. GPIIb–GPIIIa) to expose cryptic epitopes that initiate the immune response and antibody production. The mechanisms of drug action in ITP have been recently clarified with new data on the pathogenesis of ITP. Immunosuppressive agents, including corticosteroids, azathioprine, cyclophosphamide and vinca alkaloids, have been used for many years to treat ITP without precise knowledge of how they modulate immune function in this disease. Corticosteroids (e.g. prednisone and dexamethasone), which are commonly used as first-line therapy, suppress the functions of immune cells (macrophages, T cells and B cells) [22] that play key roles in the pathogenesis of ITP [3, 4, 11]. Unfortunately, corticosteroids have other metabolic and cellular actions that result in many unwanted adverse effects. Furthermore, they do not usually give a durable response, probably because they suppress but do not eliminate the pathogenic autoreactive B-cell or T-cell clones. Other immunosuppressive drugs effective in ITP do not cause as wide a range of systemic effects as corticosteroids, but they may also produce significant toxicity. For example, azathioprine, a prodrug that is converted to a purine analog in vivo, inhibits DNA synthesis and proliferation of T and B cells and causes bone marrow suppression and neutropenia. A more selective imunosuppressant, mycophenolate mofetil (MMF), selectively inhibits T-cell and B-cell proliferation by blocking inosine monophosphate dehydrogenase, a key enzyme in the lymphocyte purine synthesis pathway [22]. MMF produces a good platelet response in patients with ITP, with fewer side-effects [23]. Another specific imunosuppressant is the chimeric anti-CD20 monoclonal antibody rituximab, which selectively depletes CD20+ B cells. A recent meta-analysis of over 300 patients with ITP who were given rituximab showed an impressive overall response rate of 62.5% (platelets > 50 × 109 L−1) [24], with a proportion of patients having a durable response, presumably due to deletion of the pathogenic B-cell clone. Rituximab is well tolerated, although there is, occasionally, an increased risk of potentially serious infection. To avoid the increased risk of infection associated with immunosuppressive agents, a clinician may choose to use drugs that target other mechanisms in the pathogenesis of ITP, such as intravenous immunoglobulin (IVIg), anti-D immunoglobulin and thrombopoietin (TPO) mimetic agents. IVIg and anti-D immunoglobulin exert their action by blockade of FcγRs, thus preventing macrophage uptake of opsonized platelets. Both of these drugs are generally well tolerated, with mild and reversible adverse effects such as headache, nausea, vomiting, mild hemolysis and, rarely, aseptic meningitis [25]. Splenectomy removes a major source of macrophages/APCs and autoreactive T and B cells involved in both autoantibody production and platelet destruction [3, 4, 11, 15]. Not surprisingly, it gives a long-term complete response rate of 66% [26]. The surgery itself is associated with a small amount of short-term morbidity, for example wound infection, and mortality. Unfortunately, it also removes an important immune organ that protects the individual from infection by capsulated bacteria such as meningococci and pneumococci, which can cause life-threatening sepsis in the occasional patient. The compounds romiplostim and elthrombopag are TPO mimetic agents that induce megakaryocyte proliferation and differentiation, and consequently increase platelet production. Romiplostim is a fusion protein consisting of a non-homologous c-mpl binding peptide and an Fc domain that prolongs its plasma half-life [25, 26]. Elthrombopag is a small molecule that, like TPO, binds to c-mpl. TPO mimetic agents have been shown in recent clinical trials to be highly efficacious in the treatment of ITP patients, with a response rate of > 80%, contrary to expectations that the increased number of platelets produced would be rapidly opsonized and cleared by macrophages, or that platelet production was already maximally stimulated in ITP. These agents cause mild and few adverse effects [26, 27]. The reasons for the good response to TPO mimetics are incompletely understood. Although increased platelet production may result in increased platelet destruction, a TPO mimetic agent may alter the steady state to a new equilibrium with a higher blood platelet count. Other new targeted drug therapies are under development or at various stages in clinical trials. For example, injection of a humanized monoclonal antibody against CD40 ligand has been shown to produce a good platelet response in a patient with refractory ITP [8]. Similarly, infusion of an antibody against FcR1II has also been shown to be effective in ITP [28]. One goal of future treatment is the eradication of the autoreactive B-cell and/or T-cell clones that perpetuate the disease. Future research to characterize these clones may enable the development of specific agents that can eliminate them, to provide a cure for the disease. Over the years, many investigators have contributed to our understanding of the pathogenesis of ITP. The article by Kawana et al. [4] in this issue of the journal provides a valuable contribution to our overall understanding of this condition. Knowledge of the pathogenesis of ITP is the key to the development of novel, better and targeted therapies for patients, in particular those with refractory disease. Acknowledgements The author wishes to thank his colleague Szu-hee Lee for his critical review of the manuscript. 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