Crow et al1 state that the protective effect of intravenous immunoglobulins (IVIg’s) in murine idiopathic thrombocytopenia (ITP) requires FcγRIIb 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 Fcγ receptors (FcγRs). 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, FcγRIIb, do not respond to IVIg’s when suffering from experimental ITP. 3 This absolute requirement of FcγRIIb 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 FcγRIIb (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 FcγRIIb. 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 FcγRIIb. 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