Immunopathogenesis of Idiopathic Thrombocytopenic Purpura ITP

40 HEMATOLOGIA l Volumen 7 - Nº 2, 2003

Dr P Imbach CONFERENCIA

University Childrens Hospital Basel, Switzerland HEMATOLOGIA, Vol 7 Nº 2: 40-41 e-mail: paulimbach@unibas ch Mayo-Octubre, 2003

ITP manifests as immune mediated, destructive and related cytokines Platelets (auto)antigen driven thrombocytopenia The etiology of ITP is still unknown T-cell clones and Interleukins, mainly Interleukin-2 Immunologically an antigenic challenge or an au- (IL-2) direct autoreative B-cells to secret (auto) anti- toimmune stimulus induces interaction between an- bodies tigen presenting cells and T-lymphocytes Through In acute ITP specific antibody (eg against signal mechanisms T-cell activation and B-cell anti- Varicella zoster virus) may crossreact with platelet body production occur Regulatory mechanism of T- antigen: molecular mimicry occurs Th or Th ex- 0 2 cells and antiidiotypic antibodies direct the degree and pression with TGF-ß as potent immunosuppressive duration of the physiologic immune response In ITP modulator among the cytokine pattern seems to cor- the immune response and the selftolerance mechanism relate with transient ITP are altered in the presence of an antigen stimulus In chronic ITP autoimmune targets on platelets Mainly 3 elements are involved in the pathophysi- are mostly GPIIb/IIIa with different locations of ology of ITP: the platelet, the cellular and humoral epitopes, GPIb/IX and rarely GPIa/IIa, IV and V Th 1 immune response, the mono-macrocytic phagocytosis pattern and abnormal activation of autoreative B- mediated by Fc-receptors cells characterize autoimmunity in chronic ITP With aberrant immune response circulating and platelet- associated autoantibodies can be detected by capture THE PLATELETS assays (immunoblot-, MAIPA-assay) The sensitivity The platelet function is balancing between inflam- (positive results in patients with ITP) is 49 - 66%, the matory, procoagulant, antithrombic and fibrinolytic specificity (negative results in patients with properties When platelet reactive antibodies are nonimmune thrombocytopenia) is 78 - 95% overwhelming actively the platelet function gets out (Auto-)antibodies have a hypervariable region of balance: bleeding or thrombosis are symptoms of with amino-acid sequences which are specific for each the advanced state of disorder Platelets vary in form, individual antibody and which never before were size, density, age as well as reactivity according to encountered by the host and, therefore, are foreign to polimorphism of major glycoproteins (GPs) Platelets the host who starts to produce neutralizing, regula- trigger the immune response from the first stimulus tory antibody The patients own antidiotypic antibod- to irreversible participation in cell to cell reations In ies or those in IVIG preparations regulate/ ITP mainly the numeric balances are disturbed downmodulate the production of (platelet) antibodies

THE IMMUNE SYSTEM PHAGOCYTOSIS AND FCg-RECEPTORS (FCgR) In ITP the immunopathogenesis of platelets is an- Among the classes of FcγRs the low affinity FcγIIA tibody mediated under the control of T-helper cells with the capacity of IgG and binding and FcγIIIA 1 3 ITP 41 with IgG binding are prominent mediators of platelet events are present in other (auto)immune related 2 clearance in ITP and bind mainly immunocomplexed disorders The mechanism of action of T-cell antibodies High affinity FcγRI which binds monomeric regulatory drugs, of IVIG and other biologic IgG seems to play a minor role in ITP Several therapeutics can be documented by measuring polimorphisms exist for FcγII and III in humans which changes of the different components of the immune alter affinites for antibodies The inhibitory FcγRIIb response leads to co-crosslinking with B-cell receptors resulting In the future, monoclonal antibodies against the in cell inactivation (no phagocytosis) different steps of the immune response (eg anti-T The immunologic characteristics of FcγRs are also cell antibodies, CD20 antibody (rituximab), anti-Fc- important in the context of the immunomodulatory receptor antibodies) may provide specific therapies effect of IVIG treatment: IVIG dimer and multimer in ITP and other immune related disorders seems to block Fc-receptors more actively than monomeric IVIG On the other hand the dimers/ multimers are responsible for marked side effects of REFERENCES IVIG treatment IVIG increase the presence of see Supplement on State-of-the-Art Expert Meeting on ITP J Ped inhibitory FcγRIIB and prevent ITP in a mice model Hematol Oncol 2003 (in press), especially the articles by R The immunopathology of ITP is a model for Kekomäki, A Crow and A Lazarus, J Semple, R McMillan and altered immune response Similar immunopathologic D Cines