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Blood, 1 March 2004, Vol. 103, No. 5, pp. 1973-1974. This Article Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by van Mirre, E. Articles by Lazarus, A. H. Search for Related Content PubMed PubMed Citation Articles by van Mirre, E. Articles by Lazarus, A. H. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?  Previous Article  |  Table of Contents CORRESPONDENCE To the editor: IVIg-mediated amelioration of murine ITP via FcRIIb is not necessarily independent of SHIP-1 and SHP-1 activity Crow et al1 state that the protective effect of intravenous immunoglobulins (IVIg's) in murine idiopathic thrombocytopenia (ITP) requires FcRIIb but not its signaling molecules Src homology 2 domain-containing inositol polyphosphate phosphatase-1 (SHIP-1), Src homology 2 domain-containing polyphosphate phosphatase-1 (SHP-1), or Bruton tyrosine kinase (Btk). However, SHIP-1 and SHP-1 can replace each other functionally. Thus, the study by Crow et al does not definitely rule out a role for these molecules in the effect of IVIg on murine ITP. Treatment of ITP with IVIg's is nowadays well established. The mechanism of action of IVIg in ITP is considered to be blockade of Fc receptors (FcRs). Indeed, in animal models there is evidence for such a mechanism.2 However, studies in knockout mice have revealed that the mechanism of action of IVIg's in ITP may be more complicated, since mice deficient for the inhibiting Fc receptor, FcRIIb, do not respond to IVIg's when suffering from experimental ITP.3 This absolute requirement of FcRIIb for the efficacy of IVIg's in murine ITP was confirmed in a study published by Crow et al1 in the July 15, 2003, issue of Blood. In that interesting study the authors also report that mice with a single deficiency of molecules involved in signaling via FcRIIb (ie, SHIP-1, SHP-1, and Btk), respond normally to IVIg's when suffering from experimental ITP. The authors concluded that the beneficial effect of IVIg's in this experimental ITP model is mediated via recruitment of as-yet-unknown signaling molecules by FcRIIb. However, we would like to point to another possible explanation for the data of Crow et al. Huang et al4 have published evidence that both SHIP-1 and SHP-1 bind to phosphorylated immunoreceptor tyrosine-based inhibition motifs (ITIMs) in FcRIIb. Furthermore, these authors also show that SHIP-1 and SHP-1 carry out similar functions; as indeed is well known in literature, as summarized by Erneux et al.5 In addition, SHP-1 and SHIP-1 share considerable homology, especially the N-terminal region, which harbors the SH2 domains. As a matter of fact, 24 of the first 107 amino acid residues are identical, yielding 22% identity. The homology of these domains, which have long been known to bind to phosphorylated tyrosine residues in so-called immunoreceptor tyrosine-based activation motifs (ITAMs) and ITIMs, is up to 56%. Thus, it is very well possible that signal transduction via FcRIIb in the absence of SHIP-1 is mediated by SHP-1, and vice versa. Hence, the data in the report by Crow et al in our opinion do not definitely rule out a role of these signaling molecules in the FcRIIb-dependent effects of IVIg's in experimental ITP. In addition, the role of SHIP-2, which has been shown to have inducible expression on monocytes,6 is not taken into account in the study of Crow et al. Thus, it would be interesting to see whether IVIg's are capable of inducing SHIP-2 in cells of the reticulo-endothelial system and whether this has functional consequences for the protective mechanism of action of IVIg's. In conclusion, the experiments by Crow et al do not allow definite conclusions regarding involvement of SHIP-1, SHP-1, SHP-2, and Btk in the intracellular signaling pathways triggered by IVIg's via FcRIIb during ITP. Edwin van Mirre, Annet van Royen, and C. Erik Hack Correspondence: Edwin van Mirre, Department of Immunopathology, Sanquin Research, Plesmanlaan 125, 1066 CX Amsterdam, The Netherlands; e-mail: e.vanmirre{at}sanquin.nl. References Crow AR, Song S, Freedman J, et al. IVIg-mediated amelioration of murine ITP via FcgammaRIIB is independent of SHIP1, SHP-1, and Btk activity. Blood. 2003;102: 558-560.[Abstract/Free Full Text] Teeling JL, Jansen-Hendriks T, Kuijpers TW, et al. Therapeutic efficacy of intravenous immunoglobulin preparations depends on the immunoglobulin G dimers: studies in experimental immune thrombocytopenia. Blood. 2001;98: 1095-1099.[Abstract/Free Full Text] Samuelsson A, Towers TL, Ravetch JV. Anti-inflammatory activity of IVIG mediated through the inhibitory Fc receptor. Science. 2001;291: 484-486.[Abstract/Free Full Text] Huang ZY, Hunter S, Kim MK, Indik ZK, Schreiber AD. The effect of phosphatases SHP-1 and SHIP-1 on signaling by the ITIM- and ITAM-containing Fcgamma receptors FcgammaRIIB and FcgammaRIIA. J Leukoc Biol. 2003;73: 823-829.[Abstract/Free Full Text] Erneux C, Govaerts C, Communi D, Pesesse X. The diversity and possible functions of the inositol polyphosphate 5-phosphatases. Biochim Biophys Acta. 1998;1436: 185-199.[Medline] [Order article via Infotrieve] Pengal RA, Ganesan LP, Fang H, Marsh CB, Anderson CL, Tridandapani S. SHIP-2 inositol phosphatase is inducibly expressed in human monocytes and serves to regulate Fcgamma receptor-mediated signaling. J Biol Chem. 2003;278: 22657-22663.[Abstract/Free Full Text]   Response: Response: SHP up or SHIP out van Mirre and colleagues raise interesting questions in their interpretation of our recent paper.1 Our work confirmed that intravenous immunoglobulin (IVIg)–mediated amelioration of murine immune thrombocytopenia (ITP) is absolutely dependent on the inhibitory receptor FcRIIB.2 Although van Mirre et al suggest that IVIg works by competitive blockade of activating FcRs, IVIg had no noticeable effect whatsoever in FcRIIB-deficient mice in our study, suggesting that a purely "competitive" reticuloendothelial system (RES) blockade per se may not significantly contribute to IVIg-mediated amelioration of murine ITP. We further demonstrated that this FcRIIB-mediated reversal of ITP was independent of the individual activities of the phosphatases SHIP-1, SHP-1, and the kinase Btk. van Mirre et al suggest that SHIP-1 and SHP-1 can replace each other functionally and thus a redundancy pathway may exist. In point of fact, we clearly state in our paper that redundancy may exist in the SHIP/SHP families, although since the substrates for SHIP and SHP are markedly different, we would find it difficult to conclude that they can perform the same function. In addition, it has been demonstrated that FcRIIB-mediated inhibitory signaling does not require SHP-1 in both B cells3 and mast cells.4 Experiments with SHIP-1/SHP-1 double knockouts also could not rule out other family members such as SHIP-2/SHP-2 or even another inositol phosphatase, PTEN, which can dramatically down-regulate phagocytosis through the activating receptor alone.5 We hypothesized in our paper that the FcRIIB pathway utilized by IVIg may be different from that found in B cells. In the 2 cell types in which FcRIIB has been extensively studied, namely B cells and mast cells, negative signaling through the immunoreceptor tyrosine-based inhibitory motif (ITIM) involves co-crosslinking with an activating receptor complex. Current data have not established that IVIg-dependent effects on the macrophage FcRIIB require simultaneous interaction with an activating receptor. If co-ligation does occur, some likely candidates for the provision of an activating receptor in mice could be FcRIIIA or FcRI; we have, however, recently shown that IVIg can function independently of the activating receptor FcRIIIA,6 and that IVIg worked well in nonobese diabetic–severe combined immunodeficient mice,7 which have a defective FcRI.8 It is important to focus not only on SHIPs and SHPs, but to consider the contribution of other regions of FcRIIB in terms of IVIg function. In particular, FcRIIB-dependent inhibitory effects (promotion of apoptosis) have been demonstrated to occur independent of the entire FcRIIB cytoplasmic tail and may therefore utilize the transmembrane region (or the extracellular portion) for initiating inhibitory effects.9,10 We questioned whether IVIg might induce FcRIIB to recruit the gamma chain, a signaling mediator which interacts with transmembrane regions and is required for function of both FcRI and FcRIII. However, we found that IVIg ameliorated murine ITP in mice expressing the human FcRIIA in the absence of the gamma chain (A. R. C. and A. H. L., unpublished observations, October 2003). In conclusion, the mechanism underlying IVIg-mediated FcRIIB-dependent amelioration of murine ITP remains elusive and may involve an as-yet-unappreciated biochemical mechanism distinct from that of B cells or mast cells. Andrew R. Crow, Seng Song, John Freedman, Cheryl D. Helgason, R. Keith Humphries, Katherine A. Siminovitch, and Alan H. Lazarus Correspondence: Alan H. Lazarus, Transfusion Medicine Research, St Michael's Hospital, 30 Bond St, Toronto, ON, Canada M5B 1W8; e-mail: lazarusa{at}smh.toronto.on.ca. References Crow AR, Song S, Freedman J, et al. IVIg-mediated amelioration of murine ITP via FcRIIB is independent of SHIP1, SHP-1, and Btk activity. Blood. 2003;102: 558-560.[Abstract/Free Full Text] Samuelsson A, Towers TL, Ravetch JV. Anti-inflammatory activity of IVIG mediated through the inhibitory Fc receptor. Science. 2001;291: 484-486.[Abstract/Free Full Text] Ono M, Okada H, Bolland S, et al. Deletion of SHIP or SHP-1 reveals two distinct pathways for inhibitory signaling. Cell. 1997;90: 293-301.[CrossRef][Medline] [Order article via Infotrieve] Ono M, Bolland S, Tempst P, Ravetch J. Role of the inositol phosphatase SHIP in negative regulation of the immune system by the receptor FcRIIB. Nature. 1996;383: 263-266.[CrossRef][Medline] [Order article via Infotrieve] Kim JS, Peng X, De PK, Geahlen RL, Durden DL. PTEN controls immunoreceptor (immunoreceptor tyrosine-based activation motif) signaling and the activation of Rac. Blood. 2002;99: 694-697.[Abstract/Free Full Text] Crow AR, Song S, Freedman J, Lazarus AH. IVIg versus an FcR blocking monoclonal antibody (2.4G2) in the treatment of ITP: evidence for different pathways of protection in a murine model [abstract]. Blood. 2003;102: 86a. Crow AR, Song S, Semple JW, Freedman J, Lazarus AH. IVIg inhibits reticuloendothelial system function and ameliorates murine passive-immune thrombocytopenia independent of anti-idiotype reactivity. Br J Haematol. 2001;115: 679-686.[CrossRef][Medline] [Order article via Infotrieve] Gavin AL, Tan PS, Hogarth PM. Gain-of-function mutations in FcRI of NOD mice: implications for the evolution of the Ig superfamily. EMBO J. 1998;17: 3850-3857.[CrossRef][Medline] [Order article via Infotrieve] Pearse RN, Kawabe T, Bolland S, et al. SHIP recruitment attenuates FcRIIB-induced B cell apoptosis. Immunity. 1999;10: 753-760.[CrossRef][Medline] [Order article via Infotrieve] Xu Y, Szalai AJ, Zhou T, et al. FcRs modulate cytotoxicity of anti-Fas antibodies: implications for agonistic antibody-based therapeutics. J Immunol. 2003; 171: 562-568.[Abstract/Free Full Text] CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    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 Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by van Mirre, E. Articles by Lazarus, A. H. Search for Related Content PubMed PubMed Citation Articles by van Mirre, E. Articles by Lazarus, A. H. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?

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