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Blood, 1 January 2007, Vol. 109, No. 1, pp. 1-2. This Article Full Text (PDF) Alert me when this article is cited 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 CrossRef Citing Articles via Google Scholar Google Scholar Articles by Egmond, M. v. Search for Related Content PubMed Articles by Egmond, M. v. Related Collections Related Article in Blood Online Social Bookmarking                   What's this? Next Article  IMMUNOBIOLOGY Comment on Kanamaru et al, page 203 FcRI: a case of multiple personality disorder? Marjolein van Egmond VU UNIVERSITY MEDICAL CENTER AMSTERDAM IgA and its receptor FcRI have multifaceted anti-inflammatory, noninflammatory, and proinflammatory functions. In this issue of Blood, Kanamaru and colleagues introduce a new level of complexity by showing that monomeric targeting of FcRI can induce apoptosis in monocytes. Immunoglobulin A (IgA) is the most prominent antibody (Ab) class present in mucosal areas. The specific characteristics of these sites, as a vast interface that separates the interior of the body and the outside world, require a tight balance between mounting an effective immunologic defense against pathogenic microorganisms, and avoiding responses against commensal microbial and environmental antigens. In general, IgA is—erroneously—considered a noninflammatory Ab without activating properties, but one which helps to neutralize adherence of microorganisms to the mucosal wall and virus entry.1 This notion, however, holds true only for IgA that is present in mucosal secretions (secretory IgA [SIgA]), which consists of a dimeric IgA molecule, J chain, and secretory component (SC). SIgA is presumably a poor opsonin due to blockage of the receptor-binding site on IgA by the SC,2 which precludes activation of immune cells. In contrast, invading Escherichia coli bacteria that are opsonized with serum IgA are vigorously ingested by FcRI-expressing phagocytes like neutrophils and Kupffer cells.3 Thus, IgA can be involved in either noninflammatory or proinflammatory responses. View larger version (71K): [in this window] [in a new window]   FcRI can initiate 3 different outcomes depending on the mode of interaction with its ligand. (1) Cross-linking of FcRI (eg, via IgA-opsonized bacteria) results in a heavily phosphorylated (p) FcR chain ITAM, which engages Syk and leads to activation. (2) Weak phosphorylation of FcR chain ITAM after monomeric FcRI targeting recruits SHP-1, hereby eliciting an inhibitory signal. SHP-1 also seems to suppress apoptosis. (3) In the presence of additional (unknown) signals, monomeric triggering of FcRI results in apoptosis of monocytes. Although the signaling pathway has not been elucidated, FcR -chain ITAM is critically involved in this process as well.   The mode of interaction between serum IgA and FcRI adds a next level of duality. Cross-linking of the receptor (multimeric aggregation with complexed serum IgA) initiates superoxide production, release of cytokines, phagocytosis, and antigen presentation. However, FcRI targeting with monomeric serum IgA triggers inhibitory signals.4 Interestingly, both activating and inhibitory signals depend on the immunoreceptor tyrosine-based activation (ITAM) motif of the associating FcR chain by either Syk phosphorylation or recruitment of SHP-1, respectively. Kanamaru and colleagues now describe yet another intricacy as they report that monomeric occupancy of FcRI can lead to apoptosis, which is also dependent on FcR chain ITAM. Downstream signaling proteins have not yet been identified, but apoptosis seems to be suppressed by SHP-1. Furthermore, apoptosis induction presumably requires a second signal, as monomeric targeting of FcRI triggers programmed cell death only in low-serum conditions. In high-serum conditions, inhibitory signals are initiated. This makes sense, as blood cells are continuously in contact with monomeric serum IgA, and apoptosis needs to be suppressed in order to circumvent unwarranted death of circulating monocytes. The authors hypothesize that IgA-induced apoptosis may come into play in inflammatory sites where stress conditions and ischemia can provide ample additional signals. As such, it can be envisioned that this process may help to limit disproportionate inflammatory reactions. Although it is currently unclear to what extent this phenomenon will play a role in physiologic or pathologic situations, it remains intriguing that 1 receptor can trigger at least 3 different outcomes depending on the mode of interaction with its ligand (see figure). Finally, the authors demonstrate that development of FcRI-transfected mast cell tumors can effectively be prevented by monomeric triggering of FcRI with anti-FcRI Fabs, and propose that this may constitute a new approach for treating tumors. Since most malignancies do not express FcRI, this treatment modality will be limited. Still, as myeloid precursor cells express FcRI,5 patients with acute or chronic myeloid leukemia may benefit from this approach. In conclusion, these findings emphasize once more the complexity of IgA-FcRI–mediated immune responses, which extend far beyond the old-fashioned concept of IgA as merely a noninflammatory protector by forming an "antiseptic" coating of the mucosal wall. Footnotes The author declares no competing financial interests. References Janeway CA, Travers P, Walport M, Shlomchik MJ. Immunobiology: the Immune System in Health and Disease. 2005; 6th ed. New York NY Garland Science Publishing. Herr AB, Ballister ER, Bjorkman PJ. Insights into IgA-mediated immune responses from the crystal structures of human FcRI and its complex with IgA1-Fc. Nature 2003; 423:614–620.[CrossRef][Medline] [Order article via Infotrieve] van Egmond M, van Garderen E, van Spriel AB, et al. FcRI-positive liver Kupffer cells: reappraisal of the function of immunoglobulin A in immunity. Nat Med 2000; 6:680–685.[CrossRef][Medline] [Order article via Infotrieve] Pasquier B, Launay P, Kanamaru Y, et al. Identification of FcRI as an inhibitory receptor that controls inflammation: dual role of FcR ITAM. Immunity 2005; 22:31–42.[Medline] [Order article via Infotrieve] Otten MA, Rudolph E, Dechant M, et al. Immature neutrophils mediate tumor cell killing via IgA but not IgG Fc receptors. J Immunol 2005; 174:5472–5480.[Abstract/Free Full Text] CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? Related Article in Blood Online: IgA Fc receptor I signals apoptosis through the FcR ITAM and affects tumor growth Yutaka Kanamaru, Houda Tamouza, Séverine Pfirsch, Delphine El Mehdi, Claudine Guérin-Marchand, Marina Pretolani, Ulrich Blank, and Renato C. Monteiro Blood 2007 109: 203-211. [Abstract] [Full Text] [PDF] This Article Full Text (PDF) Alert me when this article is cited 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 CrossRef Citing Articles via Google Scholar Google Scholar Articles by Egmond, M. v. Search for Related Content PubMed Articles by Egmond, M. v. Related Collections Related Article in Blood Online Social Bookmarking                   What's this?

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