Journal
JOURNAL OF THROMBOSIS AND HAEMOSTASIS
Volume 7, Issue 2, Pages 322-329Publisher
WILEY-BLACKWELL
DOI: 10.1111/j.1538-7836.2008.03161.x
Keywords
antigen-presenting cell; anti-platelet antibody; immune thrombocytopenic purpura; macrophage; T cell
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Funding
- Japanese Ministry of Health, Labour and Welfare
- Japanese Ministry of Education, Science, Sports and Culture
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Background: Immune thrombocytopenic purpura (ITP) is an autoimmune disease primarily caused by IgG anti-platelet autoantibodies. Activation of autoreactive CD4(+) T cells upon recognition of cryptic GPIIb/IIIa peptides presented by antigen-presenting cells (APCs) is a critical step for triggering and maintaining the pathogenic anti-platelet autoantibody response. Objectives: We investigated which APCs carry the cryptic peptides of GPIIb/IIIa that activate autoreactive CD4(+) T cells in ITP patients. Methods: GPIIb/IIIa-reactive T-cell lines generated from ITP patients were cultured with autologous freshly isolated splenic macrophages, B cells or dendritic cells. To further investigate how the macrophages presented the antigenic GPIIb/IIIa peptides, we prepared macrophages from the peripheral blood monocytes of the same patients during remission. Results: Macrophages induced the proliferation of GPIIb/IIIa-reactive T-cell lines without an exogenous antigen, but B cells and dendritic cells required GPIIb/IIIa peptides to stimulate the T cells. Macrophages derived from peripheral blood during remission required an exogenous antigen to induce the GPIIb/IIIa-reactive T-cell line response, but could elicit a response without added antigen if they were preincubated with platelets from ITP patients with platelet-associated anti-GPIIb/IIIa antibodies or healthy platelets pretreated with ITP platelet eluates. The T-cell response was inhibited by anti-Fc gamma RI antibody. Finally, cultured macrophages that captured opsonized platelets promoted anti-GPIIb/IIIa antibody production in mixed cultures of autologous GPIIb/IIIa-reactive T-cell lines and B cells. Conclusions: Splenic macrophages that take up opsonized platelets via Fc gamma RI are major APCs for cryptic GPIIb/IIIa peptides, and are central to the maintenance of anti-platelet autoantibody production in ITP patients.
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