View source for Siglec-8

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=" Kikly 2009">
Kikly, K.K., Bochner, B.S., et al. [http://www.ncbi.nlm.nih.gov/pubmed/10856141 Identification of SAF-2, a novel siglec expressed on eosinophils, mast cells, and basophils.] J Allergy Clin Immunol 105, 1093-100 (2000)</ref>
<ref name="Bochner 2009">Bochner, B.S. [http://www.ncbi.nlm.nih.gov/pubmed/19178537 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 name=" Floyd H  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><ref name=" Tateno 1125">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 name=" Zhang 2007"></ref>. Siglec-8, and its murine 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 name=" Bochner 4307 ">Bochner, B. S. et al. Glycan array screening reveals a candidate ligand for Siglec-8. J Biol Chem 280, 4307-4312 (2005).</ref>
<ref name=" Nutku, E 2003">
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>.

== 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 ==
This section documents what is currently known about Siglec-8, its carbohydrate ligand(s), and how they interact to mediate cell communication. Further information about Siglec-8 can be found in its [http://www.functionalglycomics.org/glycomics/molecule/jsp/viewGbpMolecule.jsp?gbpId=cbp_hum_Itlect_00146&sideMenu=no GBP Molecule Page] in the CFG database.
=== Carbohydrate ligands ===
The high affinity ligand for Siglec-8 has been deduced from glycan microarray screening on the CFG microarray (click [http://www.functionalglycomics.org:80/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_GLYCAN_v3_49_09152004 here] and [http://www.functionalglycomics.org:80/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_GLYCAN_v2_19_02202004 here]) to be NeuAcα2-3(6-SO3)Galβ1-4(Fucα1-3)GlcNAc [6'Su-SLeX] <ref name=" Bochner 4307 ">
</ref><ref name=" Tateno 1125"></ref>

[[File:6pso3slex.jpg]]

For Siglec-F, histologic studies suggest the presence of an &alpha;2,3-linked sialylated glycoprotein ligand expressed by airway epithelium.  Its constitutive expression requires the enzyme St3Gal3.<ref>Guo JP, Brummet ME, Myers AC, Na HJ, Rowland E, Schnaar RL, Zheng T, Zhu Z, Bochner BS. Characterization of expression of glycan ligands for Siglec-F in normal mouse lungs. Am J Respir Cell and Molec Biol 2010 Apr 15 [Epub ahead of print] 2010 and </ref>  Levels of this ligand are increased during allergic pulmonary inflammation.
<ref name=" Zhang 2007">Zhang M, Angata T, Cho JY, Miller M, Broide DH, Varki A. Defining the in vivo function of Siglec-F, a CD33-related Siglec expressed on mouse eosinophils. Blood 2007; 109:4280-7</ref>
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=== Cellular expression of GBP and ligands ===
Siglec-8 is expressed in human eosinophils and mast cells, and weakly in basophils. <ref name=" Kikly 2009"></ref>
<ref name=" Floyd H  2000">Floyd H, Ni J, Cornish AL, Zeng Z, Liu D, Carter KC, Steel J, Crocker PR. Siglec-8: a novel eosinophil-specific member of the immunoglobulin superfamily. J Biol Chem 2000; 275:861-6.</ref><ref>Yokoi H, Myers A, Matsumoto K, Crocker PR, Saito H, Bochner BS. Alteration and acquisition of Siglecs during in vitro maturation of CD34+ progenitors into human mast cells. Allergy 2006; 61:769-76</ref>
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=== Biosynthesis of ligands ===
Constitutive expression in airway epithelium of the putative &alpha;2,3-linked sialylated glycoprotein ligand for Siglec-F requires the enzyme St3Gal3 which has been characterized in
[http://www.functionalglycomics.org/glycomics/molecule/jsp/glycoEnzyme/viewGlycoEnzyme.jsp?gbpId=gt_hum_624&sideMenu=true&pageType=general Human] and
[http://www.functionalglycomics.org/glycomics/molecule/jsp/glycoEnzyme/viewGlycoEnzyme.jsp?gbpId=gt_mou_644&sideMenu=true&pageType=general Mouse].
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=== Structure ===
[[File:Siglec8 SiglecF.jpg]]
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=== Biological roles of GBP-ligand interaction ===
'''In vitro'''
Eosinophil apoptosis. <ref name=" Nutku, E 2003"></ref><ref>Nutku E, Hudson SA, Bochner BS. Mechanism of Siglec-8-induced human eosinophil apoptosis: role of caspases and mitochondrial injury. Biochem Biophys Res Commun 2005; 336:918-24</ref><ref>1Nutku-Bilir E, Hudson SA, Bochner BS. Interleukin-5 priming of human eosinophils alters Siglec-8 mediated apoptosis pathways. Am J Respir Cell Mol Biol 2008; 38:121-4</ref>
Inhibition of mast cell mediator release.<ref>Yokoi H, Choi OH, Hubbard W, Lee H-S, Canning BJ, Lee HH, Ryu S-D, Bickel CA, Hudson SA, MacGlashan DW, Jr., Bochner BS. Inhibition of FcεRI-dependent mediator release and calcium flux from human mast cells by Siglec-8 engagement. J Allergy Clin Immunol 2008; 121:499-505</ref>

'''In vivo (for Siglec-F)'''
Antibody administration to mice causes selective depletion of eosinophils in blood and gastrointestinal tissues via apoptosis.<ref>Zimmermann N, McBride ML, Yamada Y, Hudson SA, Jones C, Cromie KD, Crocker PR, Rothenberg ME, Bochner BS. Siglec-F antibody administration to mice selectively reduces blood and tissue eosinophils. Allergy 2008; 63:1156-63</ref>  They are also effective in reversing some sequelae of mouse models of eosinophilic gastroenteritis and asthma.<ref>Song DJ, Cho JY, Miller M, Strangman W, Zhang M, Varki A, Broide DH. Anti-Siglec-F antibody inhibits oral egg allergen induced intestinal eosinophilic inflammation in a mouse model. Clin Immunol 2009; 131:157-69</ref><ref>Song DJ, Cho JY, Lee SY, Miller M, Rosenthal P, Soroosh P, Croft M, Zhang M, Varki A, Broide DH. Anti-Siglec-F antibody reduces allergen-induced eosinophilic inflammation and airway remodeling. J Immunol 2009; 183:5333-41</ref>
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== 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 [http://www.functionalglycomics.org/glycomics/search/jsp/landing.jsp?query=Siglec-8&maxresults=20 CFG database search results for Siglec-8].

=== Glycan profiling ===
Glycan structure analysis has been conducted by the CFG for [http://www.functionalglycomics.org/glycomics/common/jsp/samples/searchSample.jsp?5=Human&15=&10=&9=Eosinophils+&operation=refine&templateKey=2&12=CellType&submit=submit human ] and [http://www.functionalglycomics.org/glycomics/common/jsp/samples/searchSample.jsp?5=Mouse&15=&10=&9=Eosinophils+&operation=refine&templateKey=2&12=CellType&submit=submit mouse] eosinophils.

=== Glycogene microarray ===
Analysis has been conducted on glycosyltransferase expression using the glycogene microarray for [http://www.functionalglycomics.org/static/coreE/flash/search.swf?maExpKey=100393 murine eosinophils] that relates to the enzymes required for expression of cis ligands of Siglec-F on these cells. Probes for human Siglec-8 and mouse Siglec-F have been included on all four versions of the CFG glycogene microarray.

=== Knockout mouse lines ===
Mice deficient in Siglec-F have normal blood and bone marrow eosinophils at baseline, but develop exaggerated bone marrow, blood and lung eosinophilia after allergen sensitization and challenge. <ref name=" Zhang 2007"></ref>
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=== Glycan array ===
The discovery of the [http://www.functionalglycomics.org:80/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_GLYCAN_v3_49_09152004 ligand for Siglec-8] [http://www.functionalglycomics.org:80/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_GLYCAN_v2_19_02202004] and its murine paralog, [http://www.functionalglycomics.org:80/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_GLYCAN_v3_47_10132004 Siglec-F ] [http://www.functionalglycomics.org:80/glycomics/HServlet?operation=view&sideMenu=no&psId=primscreen_GLYCAN_v2_58_07262004], was made by investigator-initiated resource requests for glycan array analysis and carbohydrate compounds. To see all glycan array results for Siglec-8, click [http://www.functionalglycomics.org/glycomics/search/jsp/result.jsp?query=siglec-8&cat=coreh here].

== Related GBPs ==
hSiglec-3 (CD33), Siglec-5, Siglec-6 [http://www.functionalglycomics.org/glycomics/search/jsp/landing.jsp?query=siglec-6&maxresults=20 (CFG data)], Siglec-7 [http://www.functionalglycomics.org/glycomics/search/jsp/landing.jsp?query=siglec-7&maxresults=20 (CFG data)], Siglec-9 [http://www.functionalglycomics.org/glycomics/search/jsp/landing.jsp?query=siglec-9&maxresults=20 (CFG data)], Siglec-10 [http://www.functionalglycomics.org/glycomics/search/jsp/landing.jsp?query=siglec-10&maxresults=20 (CFG data)], Siglec-11, Siglec-F [http://www.functionalglycomics.org/glycomics/search/jsp/landing.jsp?query=siglec-F&maxresults=20 (CFG data)], Siglec-E [http://www.functionalglycomics.org/glycomics/search/jsp/landing.jsp?query=siglec-E&maxresults=20 (CFG data)], Siglec-G [http://www.functionalglycomics.org/glycomics/search/jsp/landing.jsp?query=siglec-G&maxresults=20 (CFG data)].

== References ==
<references/>

== Acknowledgements ==
The CFG is grateful to the following PIs for their contributions to this wiki page: Bruce Bochner, Paul Crocker, James Paulson, Ron Schnaar