Suppression of in vitro megakaryocyte production by antiplatelet autoantibodies from adult patients with chronic ITP

Immune thrombocytopaenic purpura (ITP) is an autoimmune bleeding disease that is rarely fatal. However, in many adults treatment is unsatisfactory, with as much morbidity from the immunosuppressive effects of treatment as from bleeding. Identifying the underlying disease process should help us to identify more targeted therapies and improve not only the treatment but also the quality of life of patients with this disorder.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-2141.2006.06024.x

The pathogenesis of immune thrombocytopaenic purpura.

Chronic immune thrombocytopenia (ITP) is a haematological disorder in which patients predominantly develop skin and mucosal bleeding. Early studies suggested ITP was primarily due to immune-mediated peripheral platelet destruction. However, increasing evidence indicates that an additional component of this disorder is immune-mediated decreased platelet production that cannot keep pace with platelet destruction. Evidence for increased platelet destruction is thrombocytopenia following ITP plasma infusions in normal subjects, in vitro platelet phagocytosis, and decreased platelet survivals in ITP patients that respond to therapies that prevent in vivo platelet phagocytosis; e.g., intravenous immunoglobulin G, anti-D, corticosteroids, and splenectomy. The cause of platelet destruction in most ITP patients appears to be autoantibody-mediated. However, cytotoxic T lymphocyte-mediated platelet (and possibly megakaryocyte) lysis, may also be important. Studies supporting suppressed platelet production include: reduced platelet turnover in over 80% of ITP patients, morphological evidence of megakaryocyte damage, autoantibody-induced suppression of in vitro megakaryocytopoiesis, and increased platelet counts in most ITP patients following treatment with thrombopoietin receptor agonists. This review summarizes data that indicates that the pathogenesis of chronic ITP may be due to both immune-mediated platelet destruction and/or suppressed platelet production. The relative importance of these two mechanisms undoubtedly varies among patients.

https://onlinelibrary.wiley.com/doi/pdf/10.1111/j.1365-2141.2009.07717.x

Pathogenesis of chronic immune thrombocytopenia: increased platelet destruction and/or decreased platelet production.

T cell proliferative responses to platelet membrane GPIIb-IIIa were examined in 14 patients with chronic immune thrombocytopenic purpura (ITP), 7 systemic lupus erythematosus (SLE) patients with or without thrombocytopenia, and 10 healthy donors. Although peripheral blood T cells from all subjects failed to respond to the protein complex in its native state, reduced GPIIb-IIIa stimulated T cells from three ITP patients and one SLE patient with thrombocytopenia, and tryptic peptides of GPIIb-IIIa stimulated T cells from nearly all subjects. The specificity of the responses for GPIIb-IIIa was confirmed by activation of GPIIb-IIIa-primed T cells by a recombinant GPIIbalpha fragment in secondary cultures. Characterization of T cell response induced by modified GPIIb-IIIa showed that the response was restricted by HLA-DR, the responding T cells had a CD4(+) phenotype, and the proliferation was accelerated only in ITP patients, suggesting in vivo activation of these T cells. In vitro IgG anti-GPIIb-IIIa synthesis in PBMC cultures was induced by modified GPIIb-IIIa specifically in ITP patients with platelet-associated anti-GPIIb-IIIa antibody. Anti-GPIIb-IIIa antibody produced in supernatants was absorbed by incubation with normal platelets. In summary, CD4(+) and HLA-DR-restricted T cells to GPIIb-IIIa are involved in production of anti-platelet autoantibody in ITP patients and are related to the pathogenic process in chronic ITP.

/pdf/autoreactive-t-cells-to-platelet-gpiib-iiia-in-immune-3m55dd62ou.pdf

Autoreactive T cells to platelet GPIIb-IIIa in immune thrombocytopenic purpura. Role in production of anti-platelet autoantibody.

Spectrum of Ig Classes, Specificities, and Titers of Serum Antiglycoproteins in Chronic Idiopathic Thrombocytopenic Purpura

Platelet-associated and plasma anti-glycoprotein autoantibodies in chronic ITP

Four patients with acute leukemia received transplants from HLA-mismatched, related donors. Marrow cells that had been depleted of T lymphocytes using a monoclonal anti-T-lymphocyte antibody and rabbit complement were used. In vitro studies showed that 80-97% of the mature T lymphocytes were removed using this procedure. Infusion of the treated marrow was accomplished without complications, and engraftment occurred in each case. Graft-versus-host disease occurred in 3 of the 4 patients. These results show that additional manipulations of the marrow will be required to allow complete T lymphocyte removal from the marrow before the feasibility of this approach in HLA-mismatched patients can be determined.

Renshaw Lw

Papers

Platelet-associated and plasma anti-glycoprotein autoantibodies in chronic ITP

Transplantation of T-lymphocyte-depleted bone marrow between HLA-mismatched individuals.