CD22 - Revision history

Anna Crie: /* Biological roles of GBP-ligand interaction */

2012-01-20T19:56:16Z

Biological roles of GBP-ligand interaction

Anna Crie: /* Biosynthesis of ligands */

2012-01-20T19:54:49Z

Biosynthesis of ligands

Anna Crie: /* Biological roles of GBP-ligand interaction */

2012-01-20T19:51:53Z

Biological roles of GBP-ligand interaction

Anna Crie: /* Biological roles of GBP-ligand interaction */

2012-01-20T19:50:25Z

Biological roles of GBP-ligand interaction

Anna Crie: /* Biological roles of GBP-ligand interaction */

2012-01-20T19:48:21Z

Biological roles of GBP-ligand interaction

Anna Crie: /* Biosynthesis of ligands */

2012-01-20T16:39:07Z

Biosynthesis of ligands

Anna Crie: /* Biological roles of GBP-ligand interaction */

2012-01-20T16:38:40Z

Biological roles of GBP-ligand interaction

Anna Crie: /* Biological roles of GBP-ligand interaction */

2012-01-20T05:10:43Z

Biological roles of GBP-ligand interaction

Anna Crie at 05:08, 20 January 2012

2012-01-20T05:08:24Z

Anna Crie: /* Biological roles of GBP-ligand interaction */

2012-01-20T04:44:42Z

Biological roles of GBP-ligand interaction

@@ Line 30: / Line 30: @@
 Despite the presence of cis ligands, CD22 can interact with trans ligands on opposing cells, and redistribute to the site of cell contact.<ref name="Collins 2004">Collins BE, Blixt O, DeSieno AR, Bovin N, Marth JD, Paulson JC. [http://www.ncbi.nlm.nih.gov/pubmed/15079087 Masking of CD22 by cis ligands does not prevent redistribution of CD22 to sites of cell contact]. ''Proc Natl Acad Sci U S A''. 2004;101(16):6104-9.</ref>  This property is has been implicated in recirculation of B cells in the bone marrow,<ref name="Nitschke 1999">Nitschke L, Floyd H, Ferguson DJ, Crocker PR. [http://www.ncbi.nlm.nih.gov/pubmed/10224292 Identification of CD22 ligands on bone marrow sinusoidal endothelium implicated in CD22-dependent homing of recirculating B cells]. ''J Exp Med''. 1999;189(9):1513-8.</ref>  and is believed to be relevant to innate recognition of self.
-<ref name="Lanoue 2002">Lanoue A, Batista FD, Stewart M, Neuberger MS. [http://www.ncbi.nlm.nih.gov/pubmed/11807774 Interaction of CD22 with alpha2,6-linked sialoglycoconjugates: innate recognition of self to dampen B cell autoreactivity?]. ''Eur J Immunol''. 2002;32(2):348-55.</ref> <ref name="Duong 2010">Duong BH, Tian H, Ota T, Completo G, Han S, Vela JL, Ota M, Kubitz M, Bovin N, Paulson JC, Nemazee D. [http://www.ncbi.nlm.nih.gov/pubmed/20038598 Decoration of T-independent antigen with ligands for CD22 and Siglec-G can suppress immunity and induce B cell tolerance in vivo]. ''J Exp Med''. 2010;207(1):173-87.</ref>  Indeed, Lanoue et al. demonstrated that B cell signaling is suppressed if the antigen is expressed on a cell that contains ligands of CD22. <ref name="Lanoue 2002"/>  Several groups have demonstrated that co-presentation of an antigen and CD22 ligands results in suppressed activation of a B cell.(14-16)
+<ref name="Lanoue 2002">Lanoue A, Batista FD, Stewart M, Neuberger MS. [http://www.ncbi.nlm.nih.gov/pubmed/11807774 Interaction of CD22 with alpha2,6-linked sialoglycoconjugates: innate recognition of self to dampen B cell autoreactivity?]. ''Eur J Immunol''. 2002;32(2):348-55.</ref> <ref name="Duong 2010">Duong BH, Tian H, Ota T, Completo G, Han S, Vela JL, Ota M, Kubitz M, Bovin N, Paulson JC, Nemazee D. [http://www.ncbi.nlm.nih.gov/pubmed/20038598 Decoration of T-independent antigen with ligands for CD22 and Siglec-G can suppress immunity and induce B cell tolerance in vivo]. ''J Exp Med''. 2010;207(1):173-87.</ref>  Indeed, Lanoue et al. demonstrated that B cell signaling is suppressed if the antigen is expressed on a cell that contains ligands of CD22. <ref name="Lanoue 2002"/>  Several groups have demonstrated that co-presentation of an antigen and CD22 ligands results in suppressed activation of a B cell. <ref name="Lanoue 2002"/><ref name="Duong 2010"/><ref name="Courtney 2009">Courtney AH, Puffer EB, Pontrello JK, Yang ZQ, Kiessling LL. [http://www.ncbi.nlm.nih.gov/pubmed/19202057 Sialylated multivalent antigens engage CD22 in trans and inhibit B cell activation]. ''Proc Natl Acad Sci U S A''. 2009;106(8):2500-5.</ref>  In fact, immunization of a mouse with a polymer containing both a T-independent antigen and a high affinity CD22 ligand induces activation and apoptosis of B cells recognizing the antigen, resulting in tolerization of the mouse to subsequent challenge with the antigen.<ref name="Duong 2010"/>  The results suggest that trans ligands of CD22 and other B cell siglecs may serve as markers of self, and that CD22 participates in a mechanism of peripheral tolerance to self-antigens.
 == CFG resources used in investigations ==

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 === Biosynthesis of ligands ===
 The ligands of CD22 are predominately the product of a single sialyltransferase, ST6Gal I.  Mice deficient in ST6Gal I express no ligands on B cells resulting in an immuno-deficient phenotype.
-Differences in the specificity of human and murine siglec orthologs/paralogs also reflect adaptations to recognize self-ligands <ref name="Crocker 2007"/><ref name="Varki 2010">Varki, A. [http://www.ncbi.nlm.nih.gov/pubmed/20445087 Colloquium paper: uniquely human evolution of sialic acid genetics and biology]. "Proc Natl Acad Sci U S A''. 2010 May 11;107 Suppl 2:8939-46.</ref>.  In particular, murine CD22 preferentially recognizes NeuGc containing α2-6 sialosides (2) with over 10 fold higher affinity than NeuAc (1), but human CD22 exhibits equal affinity for both, consistent with the fact that mouse B cells preferentially express NeuGc, while human B cells express only NeuAc <ref name="Brinkman 2000">Brinkman-Van der Linden EC, Sjoberg ER, Juneja LR, Crocker PR, Varki N, Varki A. [http://www.ncbi.nlm.nih.gov/pubmed/10722703 Loss of N-glycolylneuraminic acid in human evolution. Implications for sialic acid recognition by siglecs]. .J'' Biol Chem''. 2000 Mar 24;275(12):8633-40.</ref><ref name="Kelm 1994">Kelm S, Schauer R, Manuguerra JC, Gross HJ, Crocker PR. [http://www.ncbi.nlm.nih.gov/pubmed/7696861 Modifications of cell surface sialic acids modulate cell adhesion mediated by sialoadhesin and CD22]. '' Glycoconj J''. 1994 Dec;11(6):576-85.</ref><ref name="Naito 2007">Naito Y, Takematsu H, Koyama S, Miyake S, Yamamoto H, Fujinawa R, Sugai M, Okuno Y, Tsujimoto G, Yamaji T, Hashimoto Y, Itohara S, Kawasaki T, Suzuki A, Kozutsumi Y. [http://www.ncbi.nlm.nih.gov/pubmed/17296732 Germinal center marker GL7 probes activation-dependent repression of N-glycolylneuraminic acid, a sialic acid species involved in the negative modulation of B-cell activation]. '' Mol Cell Biol''. 2007 Apr;27(8):3008-22.</ref><ref name="Blixt 2003">Blixt O, Collins BE, van den Nieuwenhof IM, Crocker PR, Paulson JC. [http://www.ncbi.nlm.nih.gov/pubmed/12773526 Sialoside specificity of the siglec family assessed using novel multivalent probes: identification of potent inhibitors of myelin-associated glycoprotein]. J'' Biol Chem''. 2003 Aug 15;278(33):31007-19.</ref>.  Another difference is that human CD22 exhibits highest affinity for the 6-sulfo-NeuAc&alpha;2-6Galβ1-4GlcNAc (3) <ref name="Blixt 2004"/><ref name="Kimura 2007"/><ref name="CFG">Consortium for Functional Glycomics. [http://www.functionalglycomics.org http://www.functionalglycomics.org].</ref>. Despite these differences, activation of B cells in both species results in down regulation of the highest affinity ligand.  In murine B cells, activation causes de novo synthesis of sialosides with NeuAc instead of NeuGc through down regulation of CMP-sialic acid hydroxylase <ref name="Naito 2007"/>, while in human B cells, differentiation of B cells in germinal centers coincides with loss of the sulfate from the high affinity sulfated ligand (3) <ref name="Kimura 2007"/>.  Recent reports also document that 9-O-acetyl substitutions of sialic acids also play an important role in regulating the association of CD22 with cis ligands, which is an element of specificity conserved across the two species <ref name="Sjoberg 1994">Sjoberg ER, Powell LD, Klein A, Varki A. [http://www.ncbi.nlm.nih.gov/pubmed/18034751 Natural ligands of the B cell adhesion molecule CD22 beta can be masked by 9-O-acetylation of sialic acids]. J'' Cell Biol''. 1994 Jul;126(2):549-62.</ref><ref name="Cariappa 2009">Cariappa A, Takematsu H, Liu H, Diaz S, Haider K, Boboila C, Kalloo G, Connole M, Shi HN, Varki N, Varki A, Pillai S. [http://www.ncbi.nlm.nih.gov/pubmed/19103880 B cell antigen receptor signal strength and peripheral B cell development are regulated by a 9-O-acetyl sialic acid esterase]. J'' Exp Med''. 2009 Jan 16;206(1):125-38.</ref><ref name="Pillai 2009">Pillai S, Cariappa A, Pirnie SP. [http://www.ncbi.nlm.nih.gov/pubmed/19766537 Esterases and autoimmunity: the sialic acid acetylesterase pathway and the regulation of peripheral B cell tolerance]. '' Trends Immunol''. 2009 Oct;30(10):488-93.</ref><ref name="Surolia 2010">Surolia I, Pirnie SP, Chellappa V, Taylor KN, Cariappa A, Moya J, Liu H, Bell DW, Driscoll DR, Diederichs S, Haider K, Netravali I, Le S, Elia R, Dow E, Lee A, Freudenberg J, De Jager PL, Chretien Y, Varki A, Macdonald ME, Gillis T, Behrens TW, Bloch D, Collier D, Korzenik J, Podolsky DK, Hafler D, Murali M, Sands B, Stone JH, Gregersen PK, Pillai S. [http://www.ncbi.nlm.nih.gov/pubmed/20555325 Functionally defective germline variants of sialic acid acetylesterase in autoimmunity]. '' Nature''. 2010 Jul 8;466(7303):243-7.</ref>.
+Differences in the specificity of human and murine siglec orthologs/paralogs also reflect adaptations to recognize self-ligands <ref name="Crocker 2007"/><ref name="Varki 2010">Varki, A. [http://www.ncbi.nlm.nih.gov/pubmed/20445087 Colloquium paper: uniquely human evolution of sialic acid genetics and biology]. ''Proc Natl Acad Sci U S A''. 2010 May 11;107 Suppl 2:8939-46.</ref>.  In particular, murine CD22 preferentially recognizes NeuGc containing α2-6 sialosides (2) with over 10 fold higher affinity than NeuAc (1), but human CD22 exhibits equal affinity for both, consistent with the fact that mouse B cells preferentially express NeuGc, while human B cells express only NeuAc <ref name="Brinkman 2000">Brinkman-Van der Linden EC, Sjoberg ER, Juneja LR, Crocker PR, Varki N, Varki A. [http://www.ncbi.nlm.nih.gov/pubmed/10722703 Loss of N-glycolylneuraminic acid in human evolution. Implications for sialic acid recognition by siglecs]. .J'' Biol Chem''. 2000 Mar 24;275(12):8633-40.</ref><ref name="Kelm 1994">Kelm S, Schauer R, Manuguerra JC, Gross HJ, Crocker PR. [http://www.ncbi.nlm.nih.gov/pubmed/7696861 Modifications of cell surface sialic acids modulate cell adhesion mediated by sialoadhesin and CD22]. '' Glycoconj J''. 1994 Dec;11(6):576-85.</ref><ref name="Naito 2007">Naito Y, Takematsu H, Koyama S, Miyake S, Yamamoto H, Fujinawa R, Sugai M, Okuno Y, Tsujimoto G, Yamaji T, Hashimoto Y, Itohara S, Kawasaki T, Suzuki A, Kozutsumi Y. [http://www.ncbi.nlm.nih.gov/pubmed/17296732 Germinal center marker GL7 probes activation-dependent repression of N-glycolylneuraminic acid, a sialic acid species involved in the negative modulation of B-cell activation]. '' Mol Cell Biol''. 2007 Apr;27(8):3008-22.</ref><ref name="Blixt 2003">Blixt O, Collins BE, van den Nieuwenhof IM, Crocker PR, Paulson JC. [http://www.ncbi.nlm.nih.gov/pubmed/12773526 Sialoside specificity of the siglec family assessed using novel multivalent probes: identification of potent inhibitors of myelin-associated glycoprotein]. J'' Biol Chem''. 2003 Aug 15;278(33):31007-19.</ref>.  Another difference is that human CD22 exhibits highest affinity for the 6-sulfo-NeuAc&alpha;2-6Galβ1-4GlcNAc (3) <ref name="Blixt 2004"/><ref name="Kimura 2007"/><ref name="CFG">Consortium for Functional Glycomics. [http://www.functionalglycomics.org http://www.functionalglycomics.org].</ref>. Despite these differences, activation of B cells in both species results in down regulation of the highest affinity ligand.  In murine B cells, activation causes de novo synthesis of sialosides with NeuAc instead of NeuGc through down regulation of CMP-sialic acid hydroxylase <ref name="Naito 2007"/>, while in human B cells, differentiation of B cells in germinal centers coincides with loss of the sulfate from the high affinity sulfated ligand (3) <ref name="Kimura 2007"/>.  Recent reports also document that 9-O-acetyl substitutions of sialic acids also play an important role in regulating the association of CD22 with cis ligands, which is an element of specificity conserved across the two species <ref name="Sjoberg 1994">Sjoberg ER, Powell LD, Klein A, Varki A. [http://www.ncbi.nlm.nih.gov/pubmed/18034751 Natural ligands of the B cell adhesion molecule CD22 beta can be masked by 9-O-acetylation of sialic acids]. J'' Cell Biol''. 1994 Jul;126(2):549-62.</ref><ref name="Cariappa 2009">Cariappa A, Takematsu H, Liu H, Diaz S, Haider K, Boboila C, Kalloo G, Connole M, Shi HN, Varki N, Varki A, Pillai S. [http://www.ncbi.nlm.nih.gov/pubmed/19103880 B cell antigen receptor signal strength and peripheral B cell development are regulated by a 9-O-acetyl sialic acid esterase]. J'' Exp Med''. 2009 Jan 16;206(1):125-38.</ref><ref name="Pillai 2009">Pillai S, Cariappa A, Pirnie SP. [http://www.ncbi.nlm.nih.gov/pubmed/19766537 Esterases and autoimmunity: the sialic acid acetylesterase pathway and the regulation of peripheral B cell tolerance]. '' Trends Immunol''. 2009 Oct;30(10):488-93.</ref><ref name="Surolia 2010">Surolia I, Pirnie SP, Chellappa V, Taylor KN, Cariappa A, Moya J, Liu H, Bell DW, Driscoll DR, Diederichs S, Haider K, Netravali I, Le S, Elia R, Dow E, Lee A, Freudenberg J, De Jager PL, Chretien Y, Varki A, Macdonald ME, Gillis T, Behrens TW, Bloch D, Collier D, Korzenik J, Podolsky DK, Hafler D, Murali M, Sands B, Stone JH, Gregersen PK, Pillai S. [http://www.ncbi.nlm.nih.gov/pubmed/20555325 Functionally defective germline variants of sialic acid acetylesterase in autoimmunity]. '' Nature''. 2010 Jul 8;466(7303):243-7.</ref>.
 === Structure ===

@@ Line 27: / Line 27: @@
 Following ligation of the BCR with antigen, phosphokinases phosphorylate the BCR complex, which in turn amplifies a signal to activate the cell to proliferate and produce antibody.  As one of the co-receptors of the BCR, CD22 recruits cofactors that modulate the degree of BCR phosphorylation and downstream signaling.  In particular, CD22 recruits the phsophatase SHP-1 that dephosphorylates the BCR complex and suppresses cell signaling. Thus, CD22 is often considered to be a negative regulator of BCR signaling.
-The roles of ligands in BCR signaling have been extensively investigated. <ref name="Tedder 2005"/><ref name="Crocker 2007"/><ref name="Walker 2008"/><ref name="Collins 2006"/><ref name="Naito 2007"/><ref name="Cariappa 2009"/><ref name="Hennet 1998">Hennet T, Chui D, Paulson JC, Marth JD. [http://www.ncbi.nlm.nih.gov/pubmed/9539767 Immune regulation by the ST6Gal sialyltransferase]. ''Proc Natl Acad Sci U S A''. 1998;95(8):4504-9.</ref>
+The roles of ligands in BCR signaling have been extensively investigated. <ref name="Tedder 2005"/><ref name="Crocker 2007"/><ref name="Walker 2008"/><ref name="Collins 2006"/><ref name="Naito 2007"/><ref name="Cariappa 2009"/><ref name="Hennet 1998">Hennet T, Chui D, Paulson JC, Marth JD. [http://www.ncbi.nlm.nih.gov/pubmed/9539767 Immune regulation by the ST6Gal sialyltransferase]. ''Proc Natl Acad Sci U S A''. 1998;95(8):4504-9.</ref>  Siglecs in general, and CD22 in particular, are known to interact with sialylated ligands on the same cell, “in cis”, and on opposing cells, “in trans”.  Although many B cell glycoproteins carry the ligand of CD22, the predominant cis ligands appear to be CD22 itself. <ref name="Hans 2005">Han S, Collins BE, Bengtson P, Paulson JC. [http://www.ncbi.nlm.nih.gov/pubmed/16408005 Homomultimeric complexes of CD22 in B cells revealed by protein-glycan cross-linking]. ''Nat Chem Biol''. 2005;1(2):93-7.</ref>  This is due in part to the fact that CD22 is preferentially concentrated in clathrin coated pits.  Although there is agreement that cis ligand influence CD22 function as a regulator of BCR signaling, there is yet no consensus on the relevance of cis ligands to the constitutive regulation of the BCR. <ref name="Tedder 2005"/><ref name="Walker 2008"/><ref name="Collins 2006"/><ref name="Naito 2007"/><ref name="Cariappa 2009"/>
 Despite the presence of cis ligands, CD22 can interact with trans ligands on opposing cells, and redistribute to the site of cell contact.<ref name="Collins 2004">Collins BE, Blixt O, DeSieno AR, Bovin N, Marth JD, Paulson JC. [http://www.ncbi.nlm.nih.gov/pubmed/15079087 Masking of CD22 by cis ligands does not prevent redistribution of CD22 to sites of cell contact]. ''Proc Natl Acad Sci U S A''. 2004;101(16):6104-9.</ref>  This property is has been implicated in recirculation of B cells in the bone marrow,<ref name="Nitschke 1999">Nitschke L, Floyd H, Ferguson DJ, Crocker PR. [http://www.ncbi.nlm.nih.gov/pubmed/10224292 Identification of CD22 ligands on bone marrow sinusoidal endothelium implicated in CD22-dependent homing of recirculating B cells]. ''J Exp Med''. 1999;189(9):1513-8.</ref>  and is believed to be relevant to innate recognition of self.

@@ Line 22: / Line 22: @@
 <br>
 === Biological roles of GBP-ligand interaction ===
- CD22 is a co-receptor of the membrane IgM B cell receptor (BCR), and regulates BCR signaling via immunoreceptor tyrosine inhibitory motifs (ITIMs) in its cytoplasmic domain.<ref name="Tedder 2005">Tedder TF, Poe JC, Haas KM. [http://www.ncbi.nlm.nih.gov/pubmed/16227086 CD22: a multifunctional receptor that regulates B lymphocyte survival and signal transduction]. ''Adv Immunol''. 2005;88:1-50.</ref><ref name="Crocker 2007"/><ref name="Walker 2008">Walker JA, Smith KG. [http://www.ncbi.nlm.nih.gov/pubmed/18067554 CD22: an inhibitory enigma]. ''Immunology''. 2008;123(3):314-25.</ref><ref name="Nitschke 2009">Nitschke L. [http://www.ncbi.nlm.nih.gov/pubmed/19594633 CD22 and Siglec-G: B-cell inhibitory receptors with distinct functions]. ''Immunol Rev''. 2009;230(1):128-43.</ref>
 CD22 is predominately localized in clathrin-coated pits on the surface of the cell, where it mediates constitutive recycling to endocytic compartments.<ref name="Collins 2006">Collins BE, Smith BA, Bengtson P, Paulson JC. . [http://www.ncbi.nlm.nih.gov/pubmed/16369536 Ablation of CD22 in ligand-deficient mice restores B cell receptor signaling]. ''Nat Immunol''. 2006;7(2):199-206.</ref><ref name="Grewal 2006">Grewal PK, Boton M, Ramirez K, Collins BE, Saito A, Green RS, Ohtsubo K, Chui D, Marth JD. [http://www.ncbi.nlm.nih.gov/pubmed/16782884 ST6Gal-I restrains CD22-dependent antigen receptor endocytosis and Shp-1 recruitment in normal and pathogenic immune signaling]. ''Mol Cell Biol''. 2006;26(13):4970-81.</ref><ref name="O'Reilly 2011">O'Reilly MK, Tian H, Paulson JC. [http://www.ncbi.nlm.nih.gov/pubmed/21178016 CD22 is a recycling receptor that can shuttle cargo between the cell surface and endosomal compartments of B cells]. ''J Immunol''. 2011;186(3):1554-63.</ref>
 Following ligation of the BCR with antigen, phosphokinases phosphorylate the BCR complex, which in turn amplifies a signal to activate the cell to proliferate and produce antibody.  As one of the co-receptors of the BCR, CD22 recruits cofactors that modulate the degree of BCR phosphorylation and downstream signaling.  In particular, CD22 recruits the phsophatase SHP-1 that dephosphorylates the BCR complex and suppresses cell signaling. Thus, CD22 is often considered to be a negative regulator of BCR signaling.
@@ Line 32: / Line 33: @@
 Despite the presence of cis ligands, CD22 can interact with trans ligands on opposing cells, and redistribute to the site of cell contact.<ref name="Collins 2004">Collins BE, Blixt O, DeSieno AR, Bovin N, Marth JD, Paulson JC. [http://www.ncbi.nlm.nih.gov/pubmed/15079087 Masking of CD22 by cis ligands does not prevent redistribution of CD22 to sites of cell contact]. ''Proc Natl Acad Sci U S A''. 2004;101(16):6104-9.</ref>  This property is has been implicated in recirculation of B cells in the bone marrow,<ref name="Nitschke 1999">Nitschke L, Floyd H, Ferguson DJ, Crocker PR. [http://www.ncbi.nlm.nih.gov/pubmed/10224292 Identification of CD22 ligands on bone marrow sinusoidal endothelium implicated in CD22-dependent homing of recirculating B cells]. ''J Exp Med''. 1999;189(9):1513-8.</ref>  and is believed to be relevant to innate recognition of self.
 <ref name="Lanoue 2002">Lanoue A, Batista FD, Stewart M, Neuberger MS. [http://www.ncbi.nlm.nih.gov/pubmed/11807774 Interaction of CD22 with alpha2,6-linked sialoglycoconjugates: innate recognition of self to dampen B cell autoreactivity?]. ''Eur J Immunol''. 2002;32(2):348-55.</ref> <ref name="Duong 2010">Duong BH, Tian H, Ota T, Completo G, Han S, Vela JL, Ota M, Kubitz M, Bovin N, Paulson JC, Nemazee D. [http://www.ncbi.nlm.nih.gov/pubmed/20038598 Decoration of T-independent antigen with ligands for CD22 and Siglec-G can suppress immunity and induce B cell tolerance in vivo]. ''J Exp Med''. 2010;207(1):173-87.</ref>  Indeed, Lanoue et al. demonstrated that B cell signaling is suppressed if the antigen is expressed on a cell that contains ligands of CD22. <ref name="Lanoue 2002"/>  Several groups have demonstrated that co-presentation of an antigen and CD22 ligands results in suppressed activation of a B cell.(14-16)
 <ref name="Lanoue 2002"/><ref name="Duong 2010"/><ref name="Courtney 2009">Courtney AH, Puffer EB, Pontrello JK, Yang ZQ, Kiessling LL. [http://www.ncbi.nlm.nih.gov/pubmed/19202057 Sialylated multivalent antigens engage CD22 in trans and inhibit B cell activation]. 'Proc Natl Acad Sci U S A''. 2009;106(8):2500-5.</ref>  In fact, immunization of a mouse with a polymer containing both a T-independent antigen and a high affinity CD22 ligand induces activation and apoptosis of B cells recognizing the antigen, resulting in tolerization of the mouse to subsequent challenge with the antigen.<ref name="Duong 2010"/>  The results suggest that trans ligands of CD22 and other B cell siglecs may serve as markers of self, and that CD22 participates in a mechanism of peripheral tolerance to self-antigens.

@@ Line 22: / Line 22: @@
 <br>
 === Biological roles of GBP-ligand interaction ===
-<br>
+ CD22 is a co-receptor of the membrane IgM B cell receptor (BCR), and regulates BCR signaling via immunoreceptor tyrosine inhibitory motifs (ITIMs) in its cytoplasmic domain.<ref name="Tedder 2005">Tedder TF, Poe JC, Haas KM. [http://www.ncbi.nlm.nih.gov/pubmed/16227086 CD22: a multifunctional receptor that regulates B lymphocyte survival and signal transduction]. ''Adv Immunol''. 2005;88:1-50.</ref><ref name="Crocker 2007"/><ref name="Walker 2008">Walker JA, Smith KG. [http://www.ncbi.nlm.nih.gov/pubmed/18067554 CD22: an inhibitory enigma]. ''Immunology''. 2008;123(3):314-25.</ref><ref name="Nitschke 2009">Nitschke L. [http://www.ncbi.nlm.nih.gov/pubmed/19594633 CD22 and Siglec-G: B-cell inhibitory receptors with distinct functions]. ''Immunol Rev''. 2009;230(1):128-43.</ref>
 == CFG resources used in investigations ==

← Older revision		Revision as of 05:08, 20 January 2012
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−	CD22 is predominantly expressed on B cells and is well documented as a regulator of B cell receptor (BCR) signaling<ref name="Crocker 2007">Crocker PR, Paulson JC, Varki A. [http://www.ncbi.nlm.nih.gov/pubmed/17380156 Siglecs and their roles in the immune system]. ''Nat Rev Immunol'' 2007 Apr;7(4):255-66. Review.</ref>. It is one of four siglecs that are highly conserved among mammals. This paradigm is unique among the siglecs in that the cytoplasmic domain has six conserved tyrosine motifs, including three immunoreceptor tyrosine inhibitory motifs (ITIM), one ITIM-like motif, and a growth factor receptor bound protein2 (GRB2) motif. These tyrosine motifs are involved in regulation of BCR signaling and also mediate its constitutive clathrin mediated endocytosis, an activity believed to be tied to its regulation of cell signaling. The preferred glycan ligand of CD22 differs significantly in humans and mice<ref name="Crocker 2007"/><ref name="Kimura 2007">Kimura N, Ohmori K, Miyazaki K, Izawa M, Matsuzaki Y, Yasuda Y, Takematsu H, Kozutsumi Y, Moriyama A, Kannagi R. [http://www.ncbi.nlm.nih.gov/pubmed/17728258 Human B-lymphocytes express alpha2-6-sialylated 6-sulfo-N-acetyllactosamine serving as a preferred ligand for CD22/Siglec-2]. J'' Biol Chem''. 2007 Nov 2;282(44):32200-7.</ref><ref name="Blixt 2004">Blixt O, Head S, Mondala T, Scanlan C, Huflejt ME, Alvarez R, Bryan MC, Fazio F, Calarese D, Stevens J, Razi N, Stevens DJ, Skehel JJ, van Die I, Burton DR, Wilson IA, Cummings R, Bovin N, Wong CH, Paulson JC. [http://www.ncbi.nlm.nih.gov/pubmed/15563589 Printed covalent glycan array for ligand profiling of diverse glycan binding proteins]. ''Proc Natl Acad Sci U S A''. 2004 Dec 7;101(49):17033-8.</ref>. While both recognize the sequence ~~Siaa~~-2-~~6Galb~~-1-4GlcNAc expressed abundantly on B cells, murine CD22 prefers Neu5Gc (not found in humans) over Neu5Ac, while human CD22 exhibits highest affinity for sulfated sialoside, ~~Neu5Aca~~-2-~~6Galb~~-1-4[6S]GlcNAc, demonstrating significant evolution of ligand specificity with conservation of function. Although CD22 recognizes ligands on the same cell in ''cis'', it also binds to ligands in ''trans'' if expressed on adjacent contacting cells. A major area of investigation is to understand the relative roles of ''cis'' and ''trans'' ligands in CD22 function.	+	CD22 is predominantly expressed on B cells and is well documented as a regulator of B cell receptor (BCR) signaling<ref name="Crocker 2007">Crocker PR, Paulson JC, Varki A. [http://www.ncbi.nlm.nih.gov/pubmed/17380156 Siglecs and their roles in the immune system]. ''Nat Rev Immunol'' 2007 Apr;7(4):255-66. Review.</ref>. It is one of four siglecs that are highly conserved among mammals. This paradigm is unique among the siglecs in that the cytoplasmic domain has six conserved tyrosine motifs, including three immunoreceptor tyrosine inhibitory motifs (ITIM), one ITIM-like motif, and a growth factor receptor bound protein2 (GRB2) motif. These tyrosine motifs are involved in regulation of BCR signaling and also mediate its constitutive clathrin mediated endocytosis, an activity believed to be tied to its regulation of cell signaling. The preferred glycan ligand of CD22 differs significantly in humans and mice<ref name="Crocker 2007"/><ref name="Kimura 2007">Kimura N, Ohmori K, Miyazaki K, Izawa M, Matsuzaki Y, Yasuda Y, Takematsu H, Kozutsumi Y, Moriyama A, Kannagi R. [http://www.ncbi.nlm.nih.gov/pubmed/17728258 Human B-lymphocytes express alpha2-6-sialylated 6-sulfo-N-acetyllactosamine serving as a preferred ligand for CD22/Siglec-2]. J'' Biol Chem''. 2007 Nov 2;282(44):32200-7.</ref><ref name="Blixt 2004">Blixt O, Head S, Mondala T, Scanlan C, Huflejt ME, Alvarez R, Bryan MC, Fazio F, Calarese D, Stevens J, Razi N, Stevens DJ, Skehel JJ, van Die I, Burton DR, Wilson IA, Cummings R, Bovin N, Wong CH, Paulson JC. [http://www.ncbi.nlm.nih.gov/pubmed/15563589 Printed covalent glycan array for ligand profiling of diverse glycan binding proteins]. ''Proc Natl Acad Sci U S A''. 2004 Dec 7;101(49):17033-8.</ref>. While both recognize the sequence Siaα-2-6Galβ-1-4GlcNAc expressed abundantly on B cells, murine CD22 prefers Neu5Gc (not found in humans) over Neu5Ac, while human CD22 exhibits highest affinity for sulfated sialoside, Neu5Acα-2-6Galβ-1-4[6S]GlcNAc, demonstrating significant evolution of ligand specificity with conservation of function. Although CD22 recognizes ligands on the same cell in ''cis'', it also binds to ligands in ''trans'' if expressed on adjacent contacting cells. A major area of investigation is to understand the relative roles of ''cis'' and ''trans'' ligands in CD22 function.

	[[Image:SiglecCD22.jpg\|right\|alt text]]		[[Image:SiglecCD22.jpg\|right\|alt text]]

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 === Biological roles of GBP-ligand interaction ===
 Differences in the specificity of human and murine siglec orthologs/paralogs also reflect adaptations to recognize self-ligands <ref name="Crocker 2007"/><ref name="Varki 2010">Varki, A. [http://www.ncbi.nlm.nih.gov/pubmed/20445087 Colloquium paper: uniquely human evolution of sialic acid genetics and biology]. "Proc Natl Acad Sci U S A''. 2010 May 11;107 Suppl 2:8939-46.</ref>.  In particular, murine CD22 preferentially recognizes NeuGc containing α2-6 sialosides (2) with over 10 fold higher affinity than NeuAc (1), but human CD22 exhibits equal affinity for both, consistent with the fact that mouse B cells preferentially express NeuGc, while human B cells express only NeuAc <ref name="Brinkman 2000">Brinkman-Van der Linden EC, Sjoberg ER, Juneja LR, Crocker PR, Varki N, Varki A. [http://www.ncbi.nlm.nih.gov/pubmed/10722703 Loss of N-glycolylneuraminic acid in human evolution. Implications for sialic acid recognition by siglecs]. .J'' Biol Chem''. 2000 Mar 24;275(12):8633-40.</ref><ref name="Kelm 1994">Kelm S, Schauer R, Manuguerra JC, Gross HJ, Crocker PR. [http://www.ncbi.nlm.nih.gov/pubmed/7696861 Modifications of cell surface sialic acids modulate cell adhesion mediated by sialoadhesin and CD22]. '' Glycoconj J''. 1994 Dec;11(6):576-85.</ref><ref name="Naito 2007">Naito Y, Takematsu H, Koyama S, Miyake S, Yamamoto H, Fujinawa R, Sugai M, Okuno Y, Tsujimoto G, Yamaji T, Hashimoto Y, Itohara S, Kawasaki T, Suzuki A, Kozutsumi Y. [http://www.ncbi.nlm.nih.gov/pubmed/17296732 Germinal center marker GL7 probes activation-dependent repression of N-glycolylneuraminic acid, a sialic acid species involved in the negative modulation of B-cell activation]. '' Mol Cell Biol''. 2007 Apr;27(8):3008-22.</ref><ref name="Blixt 2003">Blixt O, Collins BE, van den Nieuwenhof IM, Crocker PR, Paulson JC. [http://www.ncbi.nlm.nih.gov/pubmed/12773526 Sialoside specificity of the siglec family assessed using novel multivalent probes: identification of potent inhibitors of myelin-associated glycoprotein]. J'' Biol Chem''. 2003 Aug 15;278(33):31007-19.</ref>.  Another difference is that human CD22 exhibits highest affinity for the 6-sulfo-NeuAcα2-6Galβ1-4GlcNAc (3) <ref name="Blixt 2004"/><ref name="Kimura 2007"/><ref name="CFG">Consortium for Functional Glycomics. [http://www.functionalglycomics.org http://www.functionalglycomics.org].</ref>. Despite these differences, activation of B cells in both species results in down regulation of the highest affinity ligand.  In murine B cells, activation causes de novo synthesis of sialosides with NeuAc instead of NeuGc through down regulation of CMP-sialic acid hydroxylase <ref name="Naito 2007"/>, while in human B cells, differentiation of B cells in germinal centers coincides with loss of the sulfate from the high affinity sulfated ligand (3) <ref name="Kimura 2007"/>.  Recent reports also document that 9-O-acetyl substitutions of sialic acids also play an important role in regulating the association of CD22 with cis ligands, which is an element of specificity conserved across the two species <ref name="Sjoberg 1994">Sjoberg ER, Powell LD, Klein A, Varki A. [http://www.ncbi.nlm.nih.gov/pubmed/18034751 Natural ligands of the B cell adhesion molecule CD22 beta can be masked by 9-O-acetylation of sialic acids]. J'' Cell Biol''. 1994 Jul;126(2):549-62.</ref><ref name="Cariappa 2009">Cariappa A, Takematsu H, Liu H, Diaz S, Haider K, Boboila C, Kalloo G, Connole M, Shi HN, Varki N, Varki A, Pillai S. [http://www.ncbi.nlm.nih.gov/pubmed/19103880 B cell antigen receptor signal strength and peripheral B cell development are regulated by a 9-O-acetyl sialic acid esterase]. J'' Exp Med''. 2009 Jan 16;206(1):125-38.</ref><ref name="Pillai 2009">Pillai S, Cariappa A, Pirnie SP. [http://www.ncbi.nlm.nih.gov/pubmed/19766537 Esterases and autoimmunity: the sialic acid acetylesterase pathway and the regulation of peripheral B cell tolerance]. '' Trends Immunol''. 2009 Oct;30(10):488-93.</ref><ref name="Surolia 2010">Surolia I, Pirnie SP, Chellappa V, Taylor KN, Cariappa A, Moya J, Liu H, Bell DW, Driscoll DR, Diederichs S, Haider K, Netravali I, Le S, Elia R, Dow E, Lee A, Freudenberg J, De Jager PL, Chretien Y, Varki A, Macdonald ME, Gillis T, Behrens TW, Bloch D, Collier D, Korzenik J, Podolsky DK, Hafler D, Murali M, Sands B, Stone JH, Gregersen PK, Pillai S. [http://www.ncbi.nlm.nih.gov/pubmed/20555325 Functionally defective germline variants of sialic acid acetylesterase in autoimmunity]. '' Nature''. 2010 Jul 8;466(7303):243-7.</ref>.