The role of autoreactive T-cells in the pathogenesis of idiopathic thrombocytopenic purpura.
Idiopathic thrombocytopenic purpura (ITP) is an autoimmune disease mediated by antiplatelet autoantibodies. The major target of these autoantibodies is a platelet membrane glycoprotein, GPIIb-IIIa, which is a receptor for fibrinogen and other ligands. We recently identified CD4+ T-cells autoreactive to GPIIb-IIIa in ITP patients. These T-cells are considered pathogenic because they help B-cells produce antibodies that bind to normal platelet surfaces. GPIIb-IIIa-reactive T-cells respond to chemically reduced and tryptic peptides of GPIIb-IIIa but not to native GPIIb-IIIa, indicating that the epitopes they recognize are "cryptic" determinants generated at a subthreshold level by the processing of native GPIIb-IIIa under normal circumstances. Although GPIIb-IIIa-reactive T-cells are also detected in healthy individuals, they are activated in vivo only in ITP patients. Activation of GPIIb-IIIa-specific T-cells and the subsequent production of pathogenic anti-GPIIb-IIIa antibodies can be induced by functional antigen-presenting cells in the spleen that present cryptic GPIIb-IIIa peptides to these T-cells. The pathogenic process of ITP can be explained as a continuous loop in which B-cells produce antiplatelet autoantibodies, splenic macrophages phagocytose antibody-coated platelets and present GPIIb-IIIa-derived cryptic peptides, and GPIIb-IIIa-reactive CD4+ T-cells exert their helper activity. Further studies examining the mechanisms that induce the processing and presentation of cryptic peptides derived from the platelet antigen at disease onset will clarify how the pathogenic autoantibody response in ITP is initiated.
Kuwana
Masataka
M
Institute for Advanced Medical Research, Department of Internal Medicine, Keio University School of Medicine, Tokyo, Japan. kuwanam@sc.itc.keio.ac.jp
Ikeda
Yasuo
Y
D015551:Autoimmunity; D018984:Epitopes, T-Lymphocyte / Q000276:immunology; D006801:Humans; D019039:Platelet Glycoprotein GPIIb-IIIa Complex / Q000276:immunology; D016553:Purpura, Thrombocytopenic, Idiopathic / Q000209:etiology / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*
D018984:Epitopes, T-Lymphocyte; D019039:Platelet Glycoprotein GPIIb-IIIa Complex