Siglec-8

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Siglec-8 is a human siglec expressed predominantly on eosinophils and mast cells, and is a paradigm for the rapidly evolving sub-family of CD33-related siglecs that are expressed on various white blood cells<ref>Crocker, P. R., Paulson, J. C. & Varki, A. Siglecs and their roles in the immune system. Nat Rev Immunol 7, 255-266 (2007).</ref><ref name="Bochner 2009">Bochner, B. S. Siglec-8 on human eosinophils and mast cells, and Siglec-F on murine eosinophils, are functionally related inhibitory receptors. Clin Exp Allergy 39, 317-324 (2009).</ref><ref>Floyd, H. et al. Siglec-8. A novel eosinophil-specific member of the immunoglobulin superfamily. J Biol Chem 275, 861-866 (2000).</ref>. A characteristic feature of Siglec-8 and most other CD33-related siglecs is a cytoplasmic domain with a single immunoreceptor tyrosine inhibitory motif (ITIM) and a single ITIM-like motif that participate in siglec-mediated regulation of cell signaling and endocytosis. While there is no clear ortholog in mice, Siglec-F has been documented as a functional paralog that has a similar expression pattern on murine leukocytes and similar ligand specificity<ref name="Bochner 2009"/><ref>Tateno, H., Crocker, P. R. & Paulson, J. C. Mouse Siglec-F and human Siglec-8 are functionally convergent paralogs that are selectively expressed on eosinophils and recognize 6'-sulfo-sialyl Lewis X as a preferred
Siglec-8 is a human siglec expressed predominantly on eosinophils and mast cells, and is a paradigm for the rapidly evolving sub-family of CD33-related siglecs that are expressed on various white blood cells<ref>Crocker, P. R., Paulson, J. C. & Varki, A. Siglecs and their roles in the immune system. Nat Rev Immunol 7, 255-266 (2007).</ref><ref name="Bochner 2009">Bochner, B. S. Siglec-8 on human eosinophils and mast cells, and Siglec-F on murine eosinophils, are functionally related inhibitory receptors. Clin Exp Allergy 39, 317-324 (2009).</ref><ref>Floyd, H. et al. Siglec-8. A novel eosinophil-specific member of the immunoglobulin superfamily. J Biol Chem 275, 861-866 (2000).</ref>. A characteristic feature of Siglec-8 and most other CD33-related siglecs is a cytoplasmic domain with a single immunoreceptor tyrosine inhibitory motif (ITIM) and a single ITIM-like motif that participate in siglec-mediated regulation of cell signaling and endocytosis. While there is no clear ortholog in mice, Siglec-F has been documented as a functional paralog that has a similar expression pattern on murine leukocytes and similar ligand specificity<ref name="Bochner 2009"/><ref>Tateno, H., Crocker, P. R. & Paulson, J. C. Mouse Siglec-F and human Siglec-8 are functionally convergent paralogs that are selectively expressed on eosinophils and recognize 6'-sulfo-sialyl Lewis X as a preferred
glycan ligand. Glycobiology 15, 1125-1135 (2005).</ref><ref>Zhang, M. et al. Defining the in vivo function of Siglec-F, a CD33-related Siglec expressed on mouse
glycan ligand. Glycobiology 15, 1125-1135 (2005).</ref><ref>Zhang, M. et al. Defining the in vivo function of Siglec-F, a CD33-related Siglec expressed on mouse
-
eosinophils. Blood 109, 4280-4287 (2007).</ref>. Siglec-8 and its paralog Siglec-F recognize a ligand containing both sialic acid and sulfate (NeuAcα2-3[6S]Galβ1-4G[Fucα1-3]GlcNAc-), a specificity that is distinct from all other siglecs. Ligation of Siglec-8 (or Siglec-F) with antibodies or polymeric ligands induces apoptosis of eosinophils, suggesting a therapeutic approach for treating eosinophil (or mast cell) mediated disease by targeting Siglec-8[13-16]<ref>O'Reilly, M. K. & Paulson, J. C. Siglecs as targets for therapy in immune-cell-mediated disease. Trends Pharmacol Sci 30, 240-248 (2009).</ref><ref>Zimmermann, N. et al. Siglec-F antibody administration to mice selectively reduces blood and tissue
+
eosinophils. Blood 109, 4280-4287 (2007).</ref>. Siglec-8 and its paralog Siglec-F recognize a ligand containing both sialic acid and sulfate (NeuAcα2-3[6S]Galβ1-4G[Fucα1-3]GlcNAc-), a specificity that is distinct from all other siglecs. Ligation of Siglec-8 (or Siglec-F) with antibodies or polymeric ligands induces apoptosis of eosinophils, suggesting a therapeutic approach for treating eosinophil (or mast cell) mediated disease by targeting Siglec-8<ref>O'Reilly, M. K. & Paulson, J. C. Siglecs as targets for therapy in immune-cell-mediated disease. Trends Pharmacol Sci 30, 240-248 (2009).</ref><ref>Zimmermann, N. et al. Siglec-F antibody administration to mice selectively reduces blood and tissue
eosinophils. Allergy 63, 1156-1163 (2008).</ref><ref>Bochner, B. S. et al. Glycan array screening reveals a candidate ligand for Siglec-8. J Biol Chem 280, 4307-
eosinophils. Allergy 63, 1156-1163 (2008).</ref><ref>Bochner, B. S. et al. Glycan array screening reveals a candidate ligand for Siglec-8. J Biol Chem 280, 4307-
4312 (2005).</ref><ref>Nutku, E., Aizawa, H., Hudson, S. A. & Bochner, B. S. Ligation of Siglec-8: a selective mechanism for induction of human eosinophil apoptosis. Blood 101, 5014-5020 (2003).</ref>.
4312 (2005).</ref><ref>Nutku, E., Aizawa, H., Hudson, S. A. & Bochner, B. S. Ligation of Siglec-8: a selective mechanism for induction of human eosinophil apoptosis. Blood 101, 5014-5020 (2003).</ref>.

Revision as of 22:48, 22 April 2010

Siglec-8 is a human siglec expressed predominantly on eosinophils and mast cells, and is a paradigm for the rapidly evolving sub-family of CD33-related siglecs that are expressed on various white blood cells[1][2][3]. A characteristic feature of Siglec-8 and most other CD33-related siglecs is a cytoplasmic domain with a single immunoreceptor tyrosine inhibitory motif (ITIM) and a single ITIM-like motif that participate in siglec-mediated regulation of cell signaling and endocytosis. While there is no clear ortholog in mice, Siglec-F has been documented as a functional paralog that has a similar expression pattern on murine leukocytes and similar ligand specificity[2][4][5]. Siglec-8 and its paralog Siglec-F recognize a ligand containing both sialic acid and sulfate (NeuAcα2-3[6S]Galβ1-4G[Fucα1-3]GlcNAc-), a specificity that is distinct from all other siglecs. Ligation of Siglec-8 (or Siglec-F) with antibodies or polymeric ligands induces apoptosis of eosinophils, suggesting a therapeutic approach for treating eosinophil (or mast cell) mediated disease by targeting Siglec-8[6][7][8][9].

Contents

CFG Participating Investigators contributing to the understanding of this paradigm

Participating Investigators (PIs) of the CFG have made major contributions to the understanding of the biology of Siglec-8 and its murine paralog, Siglec-F. These include: Bruce Bochner, Nicolai Bovin, Paul Crocker, James Paulson, Ronald Schnaar, Ajit Varki

Progress toward understanding this GBP paradigm

Carbohydrate ligands


Cellular expression


Structure


Biological roles of GBP-ligand interaction


CFG resources used in investigations

The best examples of CFG contributions to this paradigm are described below, with links to specific data sets. For a complete list of CFG data and resources relating to this paradigm, see the CFG database search results for Siglec-8.

Glycan profiling

Glycan structure analysis has been conducted by the CFG for human and mouse eosinophils.

Glycogene microarray

Analysis has been conducted on glycosyltransferase expression using the glycogene microarray for murine eosinophils.

Knockout mouse lines


Glycan array

The discovery of the ligand for siglec-8 and its murine paralog, Siglec-F, was made by investigator-initiated resource requests for glycan array analysis and carbohydrate compounds.

Related GBPs

hSiglec-3 (CD33), Siglec-5, Siglec-6, Siglec, 7, Siglec-9, Siglec-10, Siglec-11, Siglec-F, Siglec-E, Siglec-G

References

  1. Crocker, P. R., Paulson, J. C. & Varki, A. Siglecs and their roles in the immune system. Nat Rev Immunol 7, 255-266 (2007).
  2. 2.0 2.1 Bochner, B. S. Siglec-8 on human eosinophils and mast cells, and Siglec-F on murine eosinophils, are functionally related inhibitory receptors. Clin Exp Allergy 39, 317-324 (2009).
  3. Floyd, H. et al. Siglec-8. A novel eosinophil-specific member of the immunoglobulin superfamily. J Biol Chem 275, 861-866 (2000).
  4. Tateno, H., Crocker, P. R. & Paulson, J. C. Mouse Siglec-F and human Siglec-8 are functionally convergent paralogs that are selectively expressed on eosinophils and recognize 6'-sulfo-sialyl Lewis X as a preferred glycan ligand. Glycobiology 15, 1125-1135 (2005).
  5. Zhang, M. et al. Defining the in vivo function of Siglec-F, a CD33-related Siglec expressed on mouse eosinophils. Blood 109, 4280-4287 (2007).
  6. O'Reilly, M. K. & Paulson, J. C. Siglecs as targets for therapy in immune-cell-mediated disease. Trends Pharmacol Sci 30, 240-248 (2009).
  7. Zimmermann, N. et al. Siglec-F antibody administration to mice selectively reduces blood and tissue eosinophils. Allergy 63, 1156-1163 (2008).
  8. Bochner, B. S. et al. Glycan array screening reveals a candidate ligand for Siglec-8. J Biol Chem 280, 4307- 4312 (2005).
  9. Nutku, E., Aizawa, H., Hudson, S. A. & Bochner, B. S. Ligation of Siglec-8: a selective mechanism for induction of human eosinophil apoptosis. Blood 101, 5014-5020 (2003).

Acknowledgements

The CFG is grateful to the following PIs for their contributions to this wiki page:

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