Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Article
  • Published:

An immunoglobulin-like receptor, Allergin-1, inhibits immunoglobulin E–mediated immediate hypersensitivity reactions

Abstract

Anaphylaxis is a life-threatening immediate hypersensitivity reaction triggered by antigen capture by immunoglobulin E (IgE) bound to the high-affinity IgE receptor (FcɛRI) on mast cells. However, the regulatory mechanism of mast cell activation is not completely understood. Here we identify an immunoglobulin-like receptor, Allergin-1, that contains an immunoreceptor tyrosine-based inhibitory motif (ITIM)-like domain, and show it was preferentially expressed on mast cells. Mouse Allergin-1 recruited the tyrosine phosphatases SHP-1 and SHP-2 and the inositol phosphatase SHIP. Coligation of Allergin-1 and FcɛRI suppressed IgE-mediated degranulation of bone marrow–derived cultured mast cells. Moreover, mice deficient in Allergin-1 developed enhanced passive systemic and cutaneous anaphylaxis. Thus, Allergin-1 suppresses IgE-mediated, mast cell–dependent anaphylaxis in mice.

This is a preview of subscription content, access via your institution

Access options

Rent or buy this article

Prices vary by article type

from$1.95

to$39.95

Prices may be subject to local taxes which are calculated during checkout

Figure 1: Molecular characteristics of Allergin-1.
Figure 2: Expression of mouse Allergin-1 protein.
Figure 3: Expression of human Allergin-1 protein.
Figure 4: Signal transduction via ITIM-like motifs of mouse Allergin-1.
Figure 5: Normal development of mast cells in Allergin-1-deficient mice.
Figure 6: Enhanced systemic anaphylaxis in Allergin-1-deficient mice.
Figure 7: Enhanced passive cutaneous anaphylaxis in Allergin-1-deficient mice.

Similar content being viewed by others

Accession codes

Accessions

GenBank/EMBL/DDBJ

References

  1. Sampson, H.A. et al. Second symposium on the definition and management of anaphylaxis: summary report–Second National Institute of Allergy and Infectious Disease/Food Allergy and Anaphylaxis Network symposium. J. Allergy Clin. Immunol. 117, 391–397 (2006).

    Article  PubMed  Google Scholar 

  2. Sampson, H.A. et al. Symposium on the definition and management of anaphylaxis: summary report. J. Allergy Clin. Immunol. 115, 584–591 (2005).

    Article  PubMed  Google Scholar 

  3. Clark, S. & Camargo, C.A. Jr. Epidemiology of anaphylaxis. Immunol. Allergy Clin. North Am. 27, 145–163 (2007).

    Article  PubMed  Google Scholar 

  4. Galli, S.J. Mast cells and basophils. Curr. Opin. Hematol. 7, 32–39 (2000).

    Article  CAS  PubMed  Google Scholar 

  5. Schwartz, L.B. Mast cells: function and contents. Curr. Opin. Immunol. 6, 91–97 (1994).

    Article  CAS  PubMed  Google Scholar 

  6. Kawakami, T. & Galli, S.J. Regulation of mast-cell and basophil function and survival by IgE. Nat. Rev. Immunol. 2, 773–786 (2002).

    Article  CAS  PubMed  Google Scholar 

  7. Dombrowicz, D. et al. Absence of FcɛRI α chain results in upregulation of FcγRIII-dependent mast cell degranulation and anaphylaxis. Evidence of competition between FcɛRI and FcγRIII for limiting amounts of FcR β and γ chains. J. Clin. Invest. 99, 915–925 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Jacoby, W., Cammarata, P.V., Findlay, S. & Pincus, S.H. Anaphylaxis in mast cell-deficient mice. J. Invest. Dermatol. 83, 302–304 (1984).

    Article  CAS  PubMed  Google Scholar 

  9. Miyajima, I. et al. Systemic anaphylaxis in the mouse can be mediated largely through IgG1 and FcγRIII. Assessment of the cardiopulmonary changes, mast cell degranulation, and death associated with active or IgE- or IgG1-dependent passive anaphylaxis. J. Clin. Invest. 99, 901–914 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. Oettgen, H.C. et al. Active anaphylaxis in IgE-deficient mice. Nature 370, 367–370 (1994).

    Article  CAS  PubMed  Google Scholar 

  11. Tsujimura, Y. et al. Basophils play a pivotal role in immunoglobulin-G-mediated but not immunoglobulin-E-mediated systemic anaphylaxis. Immunity 28, 581–589 (2008).

    CAS  PubMed  Google Scholar 

  12. Kraft, S. & Kinet, J.P. New developments in FcɛRI regulation, function and inhibition. Nat. Rev. Immunol. 7, 365–378 (2007).

    Article  CAS  PubMed  Google Scholar 

  13. Jouvin, M.H. et al. Differential control of the tyrosine kinases Lyn and Syk by the two signaling chains of the high affinity immunoglobulin E receptor. J. Biol. Chem. 269, 5918–5925 (1994).

    CAS  PubMed  Google Scholar 

  14. Li, L. & Yao, Z. Mast cell and immune inhibitory receptors. Cell. Mol. Immunol. 1, 408–415 (2004).

    CAS  PubMed  Google Scholar 

  15. Malbec, O. et al. Fc epsilon receptor I-associated Lyn-dependent phosphorylation of Fcγ receptor IIB during negative regulation of mast cell activation. J. Immunol. 160, 1647–1658 (1998).

    CAS  PubMed  Google Scholar 

  16. Maeda, A., Kurosaki, M., Ono, M., Takai, T. & Kurosaki, T. Requirement of SH2-containing protein tyrosine phosphatases SHP-1 and SHP-2 for paired immunoglobulin-like receptor B (PIR-B)-mediated inhibitory signal. J. Exp. Med. 187, 1355–1360 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Yamashita, Y., Ono, M. & Takai, T. Inhibitory and stimulatory functions of paired Ig-like receptor (PIR) family in RBL-2H3 cells. J. Immunol. 161, 4042–4047 (1998).

    CAS  PubMed  Google Scholar 

  18. Katz, H.R. et al. Mouse mast cell gp49B1 contains two immunoreceptor tyrosine-based inhibition motifs and suppresses mast cell activation when coligated with the high-affinity Fc receptor for IgE. Proc. Natl. Acad. Sci. USA 93, 10809–10814 (1996).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Yotsumoto, K. et al. Paired activating and inhibitory immunoglobulin-like receptors, MAIR-I and MAIR-II, regulate mast cell and macrophage activation. J. Exp. Med. 198, 223–233 (2003).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Kumagai, H. et al. Identification and characterization of a new pair of immunoglobulin-like receptors LMIR1 and 2 derived from murine bone marrow-derived mast cells. Biochem. Biophys. Res. Commun. 307, 719–729 (2003).

    Article  CAS  PubMed  Google Scholar 

  21. Bachelet, I., Munitz, A., Moretta, A., Moretta, L. & Levi-Schaffer, F. The inhibitory receptor IRp60 (CD300a) is expressed and functional on human mast cells. J. Immunol. 175, 7989–7995 (2005).

    Article  CAS  PubMed  Google Scholar 

  22. Jurgens, L., Arndt-Jovin, D., Pecht, I. & Jovin, T.M. Proximity relationships between the type I receptor for Fcɛ (FcɛRI) and the mast cell function-associated antigen (MAFA) studied by donor photobleaching fluorescence resonance energy transfer microscopy. Eur. J. Immunol. 26, 84–91 (1996).

    Article  CAS  PubMed  Google Scholar 

  23. Xu, R., Abramson, J., Fridkin, M. & Pecht, I. SH2 domain-containing inositol polyphosphate 5′-phosphatase is the main mediator of the inhibitory action of the mast cell function-associated antigen. J. Immunol. 167, 6394–6402 (2001).

    Article  CAS  PubMed  Google Scholar 

  24. Lienard, H., Bruhns, P., Malbec, O., Fridman, W.H. & Daeron, M. Signal regulatory proteins negatively regulate immunoreceptor-dependent cell activation. J. Biol. Chem. 274, 32493–32499 (1999).

    Article  CAS  PubMed  Google Scholar 

  25. Aizawa, S. et al. Hematopoietic supportive function of human bone marrow stromal cell lines established by a recombinant SV40-adenovirus vector. Exp. Hematol. 22, 482–487 (1994).

    CAS  PubMed  Google Scholar 

  26. Jacobs, K.A. et al. A genetic selection for isolating cDNAs encoding secreted proteins. Gene 198, 289–296 (1997).

    Article  CAS  PubMed  Google Scholar 

  27. Pirozzi, G., Terry, R.W., Epstein, D. & Labow, M.A. Identification and characterization of a novel surface antigen gene induced in mast cells activated through the high affinity IgE receptor. J. Immunol. 155, 5811–5818 (1995).

    CAS  PubMed  Google Scholar 

  28. Shibuya, A., Nakahashi-Oda, C. & Tahara-Hanaoka, S. Regulation of immune responses by the activating and inhibitory myeloid-associate immunoglobuline-like receptors (MAIR) (CD300). Immune Netw. 9, 41–45 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  29. Clark, G.J., Ju, X., Tate, C. & Hart, D.N. The CD300 family of molecules are evolutionarily significant regulators of leukocyte functions. Trends Immunol. 30, 209–217 (2009).

    Article  CAS  PubMed  Google Scholar 

  30. Gebhardt, T. et al. Growth, phenotype, and function of human intestinal mast cells are tightly regulated by transforming growth factor β1. Gut 54, 928–934 (2005).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. Royer, B. et al. Inhibition of IgE-induced activation of human mast cells by IL-10. Clin. Exp. Allergy 31, 694–704 (2001).

    Article  CAS  PubMed  Google Scholar 

  32. Hjertson, M. et al. Retinoic acid inhibits in vitro development of mast cells but has no marked effect on mature human skin tryptase- and chymase-positive mast cells. J. Invest. Dermatol. 120, 239–245 (2003).

    Article  CAS  PubMed  Google Scholar 

  33. Ishida, S., Kinoshita, T., Sugawara, N., Yamashita, T. & Koike, K. Serum inhibitors for human mast cell growth: possible role of retinol. Allergy 58, 1044–1052 (2003).

    Article  CAS  PubMed  Google Scholar 

  34. Gebhardt, T. β2-Adrenoceptor-mediated suppression of human intestinal mast cell functions is caused by disruption of filamentous actin dynamics. Eur. J. Immunol. 35, 1124–1132 (2005).

    Article  CAS  PubMed  Google Scholar 

  35. Daeron, M., Malbec, O., Latour, S., Arock, M. & Fridman, W.H. Regulation of high-affinity IgE receptor-mediated mast cell activation by murine low-affinity IgG receptors. J. Clin. Invest. 95, 577–585 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Uehara, T. et al. Inhibition of IgE-mediated mast cell activation by the paired Ig-like receptor PIR-B. J. Clin. Invest. 108, 1041–1050 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Castells, M.C. et al. gp49B1-αvβ3 interaction inhibits antigen-induced mast cell activation. Nat. Immunol. 2, 436–442 (2001).

    Article  CAS  PubMed  Google Scholar 

  38. Zhang, S., Cherwinski, H., Sedgwick, J.D. & Phillips, J.H. Molecular mechanisms of CD200 inhibition of mast cell activation. J. Immunol. 173, 6786–6793 (2004).

    Article  CAS  PubMed  Google Scholar 

  39. Masuda, A., Nakamura, A., Maeda, T., Sakamoto, Y. & Takai, T. Cis binding between inhibitory receptors and MHC class I can regulate mast cell activation. J. Exp. Med. 204, 907–920 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Ujike, A. et al. Modulation of immunoglobulin (Ig)E-mediated systemic anaphylaxis by low-affinity Fc receptors for IgG. J. Exp. Med. 189, 1573–1579 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Daheshia, M., Friend, D.S., Grusby, M.J., Austen, K.F. & Katz, H.R. Increased severity of local and systemic anaphylactic reactions in gp49B1-deficient mice. J. Exp. Med. 194, 227–234 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  42. Ono, M., Bolland, S., Tempst, P. & Ravetch, J.V. Role of the inositol phosphatase SHIP in negative regulation of the immune system by the receptor FcγRIIB. Nature 383, 263–266 (1996).

    Article  CAS  PubMed  Google Scholar 

  43. Bruhns, P., Marchetti, P., Fridman, W.H., Vivier, E. & Daeron, M. Differential roles of N- and C-terminal immunoreceptor tyrosine-based inhibition motifs during inhibition of cell activation by killer cell inhibitory receptors. J. Immunol. 162, 3168–3175 (1999).

    CAS  PubMed  Google Scholar 

  44. Daeron, M. et al. The same tyrosine-based inhibition motif, in the intracytoplasmic domain of FcγRIIB, regulates negatively BCR-, TCR-, and FcR-dependent cell activation. Immunity 3, 635–646 (1995).

    Article  CAS  PubMed  Google Scholar 

  45. Mukai, K. et al. Basophils play a critical role in the development of IgE-mediated chronic allergic inflammation independently of T cells and mast cells. Immunity 23, 191–202 (2005).

    Article  CAS  PubMed  Google Scholar 

  46. Obata, K. et al. Basophils are essential initiators of a novel type of chronic allergic inflammation. Blood 110, 913–920 (2007).

    Article  CAS  PubMed  Google Scholar 

  47. Matozaki, T., Murata, Y., Okazawa, H. & Ohnishi, H. Functions and molecular mechanisms of the CD47-SIRPα signalling pathway. Trends Cell Biol. 19, 72–80 (2009).

    Article  CAS  PubMed  Google Scholar 

  48. Blanchard, M.M. & Nowotny, V. High-throughput rapid yeast DNA extraction. Application to yeast artificial chromosomes as polymerase chain reaction templates. Genet. Anal. Tech. Appl. 11, 7–11 (1994).

    Article  CAS  PubMed  Google Scholar 

  49. Saito, H., Kato, A., Matsumoto, K. & Okayama, Y. Culture of human mast cells from peripheral blood progenitors. Nat. Protocols 1, 2178–2183 (2006).

    Article  CAS  PubMed  Google Scholar 

  50. Oda, H. et al. RhoH plays critical roles in FcɛRI-dependent signal transduction in mast cells. J. Immunol. 182, 957–962 (2009).

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We thank T. Honjo, H. Karasuyama and K. Mukai for discussions and S. Mitsuishi for secretarial assistance. Supported by the Ministry of Education, Science and Culture of Japan and the Program for Promotion of Fundamental Studies in Health Science of the National Institute of Biomedical Innovation.

Author information

Authors and Affiliations

Authors

Contributions

K.H., S.S., A.F., H.T. and T.S. did experiments and analyzed data; S.S. and K.S. contributed to experimental design and data interpretation; S.T.-H. designed and did experiments, analyzed data and wrote the paper; and A.S. supervised the overall project and wrote the paper.

Corresponding authors

Correspondence to Satoko Tahara-Hanaoka or Akira Shibuya.

Ethics declarations

Competing interests

A.F., H.T., T.S. and S.S. are an employees of Ono Pharmaceutical.

Supplementary information

Supplementary Text and Figures

Supplementary Figures 1–4 and Table 1 (PDF 242 kb)

Rights and permissions

Reprints and permissions

About this article

Cite this article

Hitomi, K., Tahara-Hanaoka, S., Someya, S. et al. An immunoglobulin-like receptor, Allergin-1, inhibits immunoglobulin E–mediated immediate hypersensitivity reactions. Nat Immunol 11, 601–607 (2010). https://doi.org/10.1038/ni.1886

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/ni.1886

This article is cited by

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing