Mechanisms of immune platelet destruction in ITP are obscure. Macrophages may participate in platelet destruction since inhibition of splenic function is therapeutic. We developed a method to directly test macrophage participation in immune platelet reactions. Monocytes armed with antiplatelet ITP- or allo-antibodies against platelet membrane glycoproteins (GPs) Ib, IIb, and IIIa, when exposed to platelets, secreted arachidonic acid metabolites [leukotrienes, and hydroxyeicosanoic acids (HETEs)], but did not form cytokines. Monocyte responses can be used to further assess disease mechanisms and to evaluate therapeutic agents in ITP. There has been no reliable serologic test for antiplatelet antibodies in ITP. By coating polystyrene beads with purified platelet membrane GPs that react with ITP antibodies followed by 125I-antiglobulin, we found positive reactions in 64% of ITP sera; an additional 30% are platelet-bound. Antibodies were often multiple, directed against GPIb, IIb, IIIA, and IIb/IIIa heterodimer. This provides not only effective serologic diagnosis, but also insight into structural aspects of ITP epitopes. We found that Igs in over 90% of normal sera react with a 95 kD platelet protein on Western blot, which by amino acid sequencing was an N-terminal fragment of vinculin; and that Igs in 60% react with talin. These antibodies have complicated diagnosis of immune disorders but are not disease-associated; they can be used to study functions and structure of the major cytoskeletal proteins. We defined a new autoimmune platelet disorder caused by an autoantibody to platelet GPIIb/IIIa that inhibits platelet aggregation by preventing fibrinogen binding. This antibody potentially can be developed for pharmacologic use as a potent """"""""anti-platelet"""""""" agent. Posttransfusion purpura, a disease almost exclusively of women, which we described initially, was further elucidated by finding that microparticulate platelet antigen (Ag) from transfused platelets that coats autologous Ag-free platelets as an Ag-Ab complex to cause thrombocytopenia.
| Jin, Lin; Long, Lingyun; Green, Michael A et al. (2009) The alpha-fetoprotein enhancer region activates the albumin and alpha-fetoprotein promoters during liver development. Dev Biol 336:294-300 |
