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This Article Full Text (PDF) e-Letter: Submit a Response Alert me when this article is cited Alert me when e-Letters are posted Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by McKenzie, S. E. Search for Related Content PubMed Articles by McKenzie, S. E. Related Collections Related Article in Blood Online Social Bookmarking                         What's this?  Previous Article  |  Table of Contents  |  Next Article  Blood, 15 July 2003, Vol. 102, No. 2, pp. 417 The biology and treatment of ITP: what's next? Immune thrombocytopenic purpura (ITP) is the result of 2 pathologic processes: loss of tolerance to self-antigen accompanied by sustained autoantibody production, and antibody effector mechanisms that destroy platelets in excess of their production. There is a considerable challenge to hematologists treating the chronic, severe, refractory subset of patients. IVIG has many putative mechanisms of action in treating ITP. These include "blockade" of phagocytic Fc receptors, anti-idiotype effects, reduction of antibody production, reduced survival of the autoantibody in the circulation (Hansen and Balthasar, Blood. 2002;100:2087-2093), and, finally, stimulation of inhibitory FcRIIb. In this issue, Crow and colleagues (page 558) follow up on the seminal observations of Samuelsson et al (Science. 2001;291:484-486) concerning how IVIG's efficacy in ITP depends on the inhibitory FcRIIb on macrophages. FcRIIb counters the phagocytic signal provided by the activating Fc receptors (I/ and IIIa/ in mice; I/, IIIa/, and IIA in humans) on splenic macrophages. Crow et al confirm that IVIG's effects in vivo depend on expression of FcRIIb. They then explore the potential downstream signals of FcRIIb used in B cells and mast cells that would explain IVIG's role in macrophages. Using germ line knockout of SHIP1, SHP1, or BTK in their ITP mouse model, Crow and colleagues found IVIG to be effective despite the absence of these individual signaling molecules. Functional redundancy among the known phosphatase families, or an as-yet undiscovered mechanism specific to macrophages, may explain their observations. The mechanism sought by Crow et al may yield new molecular targets for therapy. Equally of interest to the field is the mechanism by which IVIG increases FcRIIb expression in the first place. Current data favor an indirect effect, in which IVIG causes a subset of splenic cells to secrete one or more substances— perhaps cytokines—that act on the phagocyte to increase the relative proportion of inhibitory FcRIIb versus phagocytic Fc receptors. Elucidation of this pathway may also yield new molecular targets of therapy. There are unanswered questions in the development of the ITP autoantibodies and in the antibody effector mechanisms. How is tolerance broken? Do dendritic cells, B cells, macrophages, or platelets themselves present antigen? Is there an intrinsic genetic predisposition for loss of tolerance and sustained autoantibody production? Are there genetic differences, for example in the Fc receptor endowment, that have an impact on disease course or response to therapy? Now that Fc receptor crystal structures have been solved, will small molecule inhibitors of IgG ligand binding be useful? Can we block receptor signaling, as this family of activating receptors prefers lipid microdomains (rafts) in which to initiate signals via members of the src and syk protein tyrosine kinase families? Will additional ways be discovered to alter the balance of activating and inhibitory receptors to allow platelets to survive in circulation? The next step in the biology and therapy of ITP is more precise understanding of the origins of the disease and the promise of molecularly targeted therapy. Steven E. McKenzie Cardeza Foundation for Hematologic Research CiteULike    Connotea    Del.icio.us    Digg    Facebook    Reddit    Technorati    Twitter    What's this? Related Article in Blood Online: IVIg-mediated amelioration of murine ITP via FcRIIB is independent of SHIP1, SHP-1, and Btk activity Andrew R. Crow, Seng Song, John Freedman, Cheryl D. Helgason, R. Keith Humphries, Katherine A. Siminovitch, and Alan H. Lazarus Blood 2003 102: 558-560. [Abstract] [Full Text] [PDF] This article has been cited by other articles: S. E. McKenzie The yin and yang of Fc{gamma} receptors in ITP Blood, February 1, 2008; 111(3): 971 - 972. [Full Text] [PDF] This Article Full Text (PDF) e-Letter: Submit a Response Alert me when this article is cited Alert me when e-Letters are posted Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by McKenzie, S. E. Search for Related Content PubMed Articles by McKenzie, S. E. Related Collections Related Article in Blood Online Social Bookmarking                         What's this?

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