Seminars in Immunopathology

, Volume 34, Issue 3, pp 353–364 | Cite as

Sialoadhesin in recognition of self and non-self

  • Mariliis Klaas
  • Paul R. CrockerEmail author


The immune system is tightly regulated to maintain an appropriate balance between immune activation and tolerance. Macrophages play a key role in this process since they express many pathogen recognition molecules as well as receptors for ‘self’. Sialoadhesin is a major macrophage receptor that specifically recognizes sialic acid, an abundant component of host glycoconjugates but which can also be found on several human pathogens. In recent years, several studies have demonstrated that sialoadhesin can contribute to the uptake and processing of sialylated pathogens as well as playing an important role in regulating inflammatory and autoimmune responses via recognition of self.


Sialoadhesin Sialic acid Innate immunity Pathogens 


  1. 1.
    Alfoldi J, Di Palma F, Grabherr M, Williams C, Kong L, Mauceli E, Russell P, Lowe CB, Glor RE, Jaffe JD, Ray DA, Boissinot S, Shedlock AM, Botka C, Castoe TA, Colbourne JK, Fujita MK, Moreno RG, ten Hallers BF, Haussler D, Heger A, Heiman D, Janes DE, Johnson J, de Jong PJ, Koriabine MY, Lara M, Novick PA, Organ CL, Peach SE, Poe S, Pollock DD, de Queiroz K, Sanger T, Searle S, Smith JD, Smith Z, Swofford R, Turner-Maier J, Wade J, Young S, Zadissa A, Edwards SV, Glenn TC, Schneider CJ, Losos JB, Lander ES, Breen M, Ponting CP, Lindblad-Toh K (2011) The genome of the green anole lizard and a comparative analysis with birds and mammals. Nature 477:587–591PubMedCrossRefGoogle Scholar
  2. 2.
    An TQ, Tian ZJ, He YX, Xiao Y, Jiang YF, Peng JM, Zhou YJ, Liu D, Tong GZ (2010) Porcine reproductive and respiratory syndrome virus attachment is mediated by the N-terminal domain of the sialoadhesin receptor. Vet Microbiol 143:371–378PubMedCrossRefGoogle Scholar
  3. 3.
    Angata T, Varki A (2002) Chemical diversity in the sialic acids and related alpha-keto acids: an evolutionary perspective. Chem Rev 102:439–469PubMedCrossRefGoogle Scholar
  4. 4.
    Asano K, Nabeyama A, Miyake Y, Qiu CH, Kurita A, Tomura M, Kanagawa O, Fujii S, Tanaka M (2011) CD169-positive Mϕs dominate antitumor immunity by crosspresenting dead cell-associated antigens. Immunity 34:85–95PubMedCrossRefGoogle Scholar
  5. 5.
    Avril T, Wagner ER, Willison HJ, Crocker PR (2006) Sialic acid-binding immunoglobulin-like lectin 7 mediates selective recognition of sialylated glycans expressed on Campylobacter jejuni lipooligosaccharides. Infect Immun 74:4133–4141PubMedCrossRefGoogle Scholar
  6. 6.
    Backer R, Schwandt T, Greuter M, Oosting M, Jungerkes F, Tuting T, Boon L, O'Toole T, Kraal G, Limmer A, den Haan JM (2010) Effective collaboration between marginal metallophilic Mϕs and CD8+ dendritic cells in the generation of cytotoxic T cells. Proc Natl Acad Sci USA 107:216–221PubMedCrossRefGoogle Scholar
  7. 7.
    Banchereau J, Pascual V (2006) Type I interferon in systemic lupus erythematosus and other autoimmune diseases. Immunity 25:383–392PubMedCrossRefGoogle Scholar
  8. 8.
    Barral P, Polzella P, Bruckbauer A, van Rooijen N, Besra GS, Cerundolo V, Batista FD (2010) CD169(+) Mϕs present lipid antigens to mediate early activation of iNKT cells in lymph nodes. Nat Immunol 11:303–312PubMedCrossRefGoogle Scholar
  9. 9.
    Calvert JG, Slade DE, Shields SL, Jolie R, Mannan RM, Ankenbauer RG, Welch SK (2007) CD163 expression confers susceptibility to porcine reproductive and respiratory syndrome viruses. J Virol 81:7371–7379PubMedCrossRefGoogle Scholar
  10. 10.
    Carrasco YR, Batista FD (2007) B cells acquire particulate antigen in a Mϕ-rich area at the boundary between the follicle and the subcapsular sinus of the lymph node. Immunity 27:160–171PubMedCrossRefGoogle Scholar
  11. 11.
    Chen WC, Completo GC, Sigal DS, Crocker PR, Saven A, Paulson JC (2010) In vivo targeting of B-cell lymphoma with glycan ligands of CD22. Blood 115:4778–4786PubMedCrossRefGoogle Scholar
  12. 12.
    Crocker PR, Gordon S (1985) Isolation and characterization of resident stromal Mϕs and hematopoietic cell clusters from mouse bone marrow. J Exp Med 162:993–1014PubMedCrossRefGoogle Scholar
  13. 13.
    Crocker PR, Gordon S (1986) Properties and distribution of a lectin-like hemagglutinin differentially expressed by murine stromal tissue Mϕs. J Exp Med 164:1862–1875PubMedCrossRefGoogle Scholar
  14. 14.
    Crocker PR, Hill M, Gordon S (1988) Regulation of a murine Mϕ haemagglutinin (sheep erythrocyte receptor) by a species-restricted serum factor. Immunology 65:515–522PubMedGoogle Scholar
  15. 15.
    Crocker PR, Gordon S (1989) Mouse Mϕ hemagglutinin (sheep erythrocyte receptor) with specificity for sialylated glycoconjugates characterized by a monoclonal antibody. J Exp Med 169:1333–1346PubMedCrossRefGoogle Scholar
  16. 16.
    Crocker PR, Werb Z, Gordon S, Bainton DF (1990) Ultrastructural localization of a Mϕ-restricted sialic acid binding hemagglutinin, SER, in Mϕ-hematopoietic cell clusters. Blood 76:1131–1138PubMedGoogle Scholar
  17. 17.
    Crocker PR, Kelm S, Dubois C, Martin B, McWilliam AS, Shotton DM, Paulson JC, Gordon S (1991) Purification and properties of sialoadhesin, a sialic acid-binding receptor of murine tissue Mϕs. EMBO J 10:1661–1669PubMedGoogle Scholar
  18. 18.
    Crocker PR, Mucklow S, Bouckson V, McWilliam A, Willis AC, Gordon S, Milon G, Kelm S, Bradfield P (1994) Sialoadhesin, a Mϕ sialic acid binding receptor for haemopoietic cells with 17 immunoglobulin-like domains. EMBO J 13:4490–4503PubMedGoogle Scholar
  19. 19.
    Crocker PR, Clark EA, Filbin M, Gordon S, Jones Y, Kehrl JH, Kelm S, Le Douarin N, Powell L, Roder J, Schnaar RL, Sgroi DC, Stamenkovic K, Schauer R, Schachner M, van den Berg TK, van der Merwe PA, Watt SM, Varki A (1998) Siglecs: a family of sialic-acid binding lectins. Glycobiology 8:vGoogle Scholar
  20. 20.
    Crocker PR, Vinson M, Kelm S, Drickamer K (1999) Molecular analysis of sialoside binding to sialoadhesin by NMR and site-directed mutagenesis. Biochem J 341:355–361PubMedCrossRefGoogle Scholar
  21. 21.
    Crocker PR, Paulson JC, Varki A (2007) Siglecs and their roles in the immune system. Nat Rev Immunol 7:255–266PubMedCrossRefGoogle Scholar
  22. 22.
    Dancourt J, Barlowe C (2010) Protein sorting receptors in the early secretory pathway. Ann Rev Biochem 79:777–802PubMedCrossRefGoogle Scholar
  23. 23.
    Delputte PL, Vanderheijden N, Nauwynck HJ, Pensaert MB (2002) Involvement of the matrix protein in attachment of porcine reproductive and respiratory syndrome virus to a heparinlike receptor on porcine alveolar Mϕs. J Virol 76:4312–4320PubMedCrossRefGoogle Scholar
  24. 24.
    Delputte PL, Nauwynck HJ (2004) Porcine arterivirus infection of alveolar Mϕs is mediated by sialic acid on the virus. J Virol 78:8094–8101PubMedCrossRefGoogle Scholar
  25. 25.
    Delputte PL, Costers S, Nauwynck HJ (2005) Analysis of porcine reproductive and respiratory syndrome virus attachment and internalization: distinctive roles for heparan sulphate and sialoadhesin. J Gen Virol 86:1441–1445PubMedCrossRefGoogle Scholar
  26. 26.
    Delputte PL, Van Breedam W, Delrue I, Oetke C, Crocker PR, Nauwynck HJ (2007) Porcine arterivirus attachment to the Mϕ-specific receptor sialoadhesin is dependent on the sialic acid-binding activity of the N-terminal immunoglobulin domain of sialoadhesin. J Virol 81:9546–9550PubMedCrossRefGoogle Scholar
  27. 27.
    Delputte PL, Van Gorp H, Favoreel HW, Hoebeke I, Delrue I, Dewerchin H, Verdonck F, Verhasselt B, Cox E, Nauwynck HJ (2011) Porcine sialoadhesin (CD169/Siglec-1) is an endocytic receptor that allows targeted delivery of toxins and antigens to Mϕs. PLoS One 6:e16827PubMedCrossRefGoogle Scholar
  28. 28.
    Duan X, Nauwynck HJ, Favoreel HW, Pensaert MB (1998) Identification of a putative receptor for porcine reproductive and respiratory syndrome virus on porcine alveolar Mϕs. J Virol 72:4520–4523PubMedGoogle Scholar
  29. 29.
    Freeman GJ, Casasnovas JM, Umetsu DT, DeKruyff RH (2010) TIM genes: a family of cell surface phosphatidylserine receptors that regulate innate and adaptive immunity. Immunol Rev 235:172–189PubMedGoogle Scholar
  30. 30.
    Guerry P, Ewing CP, Hickey TE, Prendergast MM, Moran AP (2000) Sialylation of lipooligosaccharide cores affects immunogenicity and serum resistance of Campylobacter jejuni. Infect Immun 68:6656–6662PubMedCrossRefGoogle Scholar
  31. 31.
    Hartnell A, Steel J, Turley H, Jones M, Jackson DG, Crocker PR (2001) Characterization of human sialoadhesin, a sialic acid binding receptor expressed by resident and inflammatory Mϕ populations. Blood 97:288–296PubMedCrossRefGoogle Scholar
  32. 32.
    Hashimoto Y, Suzuki M, Crocker PR, Suzuki A (1998) A streptavidin-based neoglycoprotein carrying more than 140 GT1b oligosaccharides: quantitative estimation of the binding specificity of murine sialoadhesin expressed on CHO cells. J Biochem 123:468–478PubMedCrossRefGoogle Scholar
  33. 33.
    Heikema AP, Bergman MP, Richards H, Crocker PR, Gilbert M, Samsom JN, van Wamel WJ, Endtz HP, van Belkum A (2010) Characterization of the specific interaction between sialoadhesin and sialylated Campylobacter jejuni lipooligosaccharides. Infect Immun 78:3237–3246PubMedCrossRefGoogle Scholar
  34. 34.
    Hoffmann PR, deCathelineau AM, Ogden CA, Leverrier Y, Bratton DL, Daleke DL, Ridley AJ, Fadok VA, Henson PM (2001) Phosphatidylserine (PS) induces PS receptor-mediated macropinocytosis and promotes clearance of apoptotic cells. J Cell Biol 155:649–659PubMedCrossRefGoogle Scholar
  35. 35.
    Ip CW, Kroner A, Crocker PR, Nave KA, Martini R (2007) Sialoadhesin deficiency ameliorates myelin degeneration and axonopathic changes in the CNS of PLP overexpressing mice. Neurobiol Dis 25:105–111PubMedCrossRefGoogle Scholar
  36. 36.
    Jacobs BC, van Doorn PA, Schmitz PI, Tio-Gillen AP, Herbrink P, Visser LH, Hooijkass H, van der Meche FG (1996) Campylobacter jejuni infections and anti-GM1 antibodies in Guillain–Barre syndrome. Ann Neurol 40:181–187PubMedCrossRefGoogle Scholar
  37. 37.
    Jones C, Virji M, Crocker PR (2003) Recognition of sialylated meningococcal lipopolysaccharide by siglecs expressed on myeloid cells leads to enhanced bacterial uptake. Mol Micro 49:1213–1225CrossRefGoogle Scholar
  38. 38.
    Junt T, Moseman EA, Iannacone M, Massberg S, Lang PA, Boes M, Fink K, Henrickson SE, Shayakhmetov DM, Di Paolo NC, van Rooijen N, Mempel TR, Whelan SP, von Andrian UH (2007) Subcapsular sinus Mϕs in lymph nodes clear lymph-borne viruses and present them to antiviral B cells. Nature 450:110–114PubMedCrossRefGoogle Scholar
  39. 39.
    Kelm S, Schauer R, Manuguerra JC, Gross HJ, Crocker PR (1994) Modifications of cell surface sialic acids modulate cell adhesion mediated by sialoadhesin and CD22. Glycoconj J 11:576–585PubMedCrossRefGoogle Scholar
  40. 40.
    Kelm S, Schauer R, Crocker PR (1996) The Sialoadhesins–a family of sialic acid-dependent cellular recognition molecules within the immunoglobulin superfamily. Glycoconj J 13:913–926PubMedCrossRefGoogle Scholar
  41. 41.
    Kelm S, Brossmer R, Isecke R, Gross HJ, Strenge K, Schauer R (1998) Functional groups of sialic acids involved in binding to siglecs (sialoadhesins) deduced from interactions with synthetic analogues. Eur J Biochem 225:663–672CrossRefGoogle Scholar
  42. 42.
    Kirchberger S, Majdic O, Steinberger P, Bluml S, Pfistershammer K, Zlabinger G, Deszcz L, Kuechler E, Knapp W, Stockl J (2005) Human rhinoviruses inhibit the accessory function of dendritic cells by inducing sialoadhesin and B7-H1 expression. J Immunol 175:1145–1152PubMedGoogle Scholar
  43. 43.
    Kobsar I, Oetke C, Kroner A, Wessig C, Crocker P, Martini R (2006) Attenuated demyelination in the absence of the Mϕ-restricted adhesion molecule sialoadhesin (Siglec-1) in mice heterozygously deficient in P0. Mol Cell Neurosci 31:685–691PubMedCrossRefGoogle Scholar
  44. 44.
    Louwen R, Heikema A, van Belkum A, Ott A, Gilbert M, Ang W, Endtz HP, Bergman MP, Nieuwenhuis EE (2008) The sialylated lipooligosaccharide outer core in Campylobacter jejuni is an important determinant for epithelial cell invasion. Infect Immun 76:4431–4438PubMedCrossRefGoogle Scholar
  45. 45.
    May AP, Robinson RC, Vinson M, Crocker PR, Jones EY (1998) Crystal structure of the N-terminal domain of sialoadhesin in complex with 3′ sialyllactose at 1.85 A resolution. Mol Cell 1:719–728PubMedCrossRefGoogle Scholar
  46. 46.
    McGaha TL, Chen Y, Ravishankar B, van Rooijen N, Karlsson MC (2011) Marginal zone Mϕs suppress innate and adaptive immunity to apoptotic cells in the spleen. Blood 117:5403–5412PubMedCrossRefGoogle Scholar
  47. 47.
    Medzhitov R, Janeway CA Jr (2002) Decoding the patterns of self and nonself by the innate immune system. Science 296:298–300PubMedCrossRefGoogle Scholar
  48. 48.
    Miyake Y, Asano K, Kaise H, Uemura M, Nakayama M, Tanaka M (2007) Critical role of Mϕs in the marginal zone in the suppression of immune responses to apoptotic cell-associated antigens. J Clin Invest 117:2268–2278PubMedCrossRefGoogle Scholar
  49. 49.
    Monteiro VG, Lobato CS, Silva AR, Medina DV, de Oliveira MA, Seabra SH, de Souza W, DaMatta RA (2005) Increased association of Trypanosoma cruzi with sialoadhesin positive mice Mϕs. Parasitol Res 97:380–385PubMedCrossRefGoogle Scholar
  50. 50.
    Munday J, Floyd H, Crocker PR (1999) Sialic acid binding receptors (siglecs) expressed by Mϕs. J Leukoc Biol 66:705–711PubMedGoogle Scholar
  51. 51.
    Nath D, van der Merwe PA, Kelm S, Bradfield P, Crocker PR (1995) The amino-terminal immunoglobulin-like domain of sialoadhesin contains the sialic acid binding site. Comparison with CD22. J Biol Chem 270:26184–26191PubMedCrossRefGoogle Scholar
  52. 52.
    Nimmerjahn F, Ravetch JV (2011) FcgammaRs in health and disease. Curr Top Microbiol Immunol 350:105–125PubMedCrossRefGoogle Scholar
  53. 53.
    Oetke C, Vinson MC, Jones C, Crocker PR (2006) Sialoadhesin-deficient mice exhibit subtle changes in B- and T-cell populations and reduced immunoglobulin M levels. Mol Cell Biol 26:1549–1557PubMedCrossRefGoogle Scholar
  54. 54.
    Pape KA, Catron DM, Itano AA, Jenkins MK (2007) The humoral immune response is initiated in lymph nodes by B cells that acquire soluble antigen directly in the follicles. Immunity 26:491–502PubMedCrossRefGoogle Scholar
  55. 55.
    Pascual V, Farkas L, Banchereau J (2006) Systemic lupus erythematosus: all roads lead to type I interferons. Curr Opin Immunol 18:676–682PubMedCrossRefGoogle Scholar
  56. 56.
    Perry VH, Crocker PR, Gordon S (1992) The blood–brain barrier regulates the expression of a Mϕ sialic acid-binding receptor on microglia. J Cell Sci 101:201–207PubMedGoogle Scholar
  57. 57.
    Phan TG, Grigorova I, Okada T, Cyster JG (2007) Subcapsular encounter and complement-dependent transport of immune complexes by lymph node B cells. Nat Immunol 8:992–1000PubMedCrossRefGoogle Scholar
  58. 58.
    Pulliam L, Sun B, Rempel H (2004) Invasive chronic inflammatory monocyte phenotype in subjects with high HIV-1 viral load. J Neuroimmunol 157:93–98PubMedCrossRefGoogle Scholar
  59. 59.
    Rempel H, Calosing C, Sun B, Pulliam L (2008) Sialoadhesin expressed on IFN-induced monocytes binds HIV-1 and enhances infectivity. PLoS One 3:e1967PubMedCrossRefGoogle Scholar
  60. 60.
    Revilla C, Poderoso T, Martinez P, Alvarez B, Lopez-Fuertes L, Alonso F, Ezquerra A, Dominguez J (2009) Targeting to porcine sialoadhesin receptor improves antigen presentation to T cells. Vet Res 40:14PubMedCrossRefGoogle Scholar
  61. 61.
    Schadee-Eestermans IL, Hoefsmit EC, van de Ende M, Crocker PR, van den Berg TK, Dijkstra CD (2000) Ultrastructural localisation of sialoadhesin (siglec-1) on Mϕs in rodent lymphoid tissues. Immunobiology 202:309–325PubMedCrossRefGoogle Scholar
  62. 62.
    Seyerl M, Kirchberger S, Majdic O, Seipelt J, Jindra C, Schrauf C, Stockl J (2010) Human rhinoviruses induce IL-35-producing Treg via induction of B7-H1 (CD274) and sialoadhesin (CD169) on DC. Eur J Immunol 40:321–329PubMedCrossRefGoogle Scholar
  63. 63.
    Steiniger B, Barth P, Herbst B, Hartnell A, Crocker PR (1997) The species-specific structure of microanatomical compartments in the human spleen: strongly sialoadhesin-positive Mϕs occur in the perifollicular zone, but not in the marginal zone. Immunology 92:307–316PubMedCrossRefGoogle Scholar
  64. 64.
    Van Breedam W, Van Gorp H, Zhang JQ, Crocker PR, Delputte PL, Nauwynck HJ (2010) The M/GP(5) glycoprotein complex of porcine reproductive and respiratory syndrome virus binds the sialoadhesin receptor in a sialic acid-dependent manner. PLoS Pathog 6:e1000730PubMedCrossRefGoogle Scholar
  65. 65.
    van der Kuyl AC, van den Burg R, Zorgdrager F, Groot F, Berkhout B, Cornelissen M (2007) Sialoadhesin (CD169) expression in CD14+ cells is upregulated early after HIV-1 infection and increases during disease progression. PLoS One 2:e257PubMedCrossRefGoogle Scholar
  66. 66.
    Van Gorp H, Van Breedam W, Delputte PL, Nauwynck HJ (2008) Sialoadhesin and CD163 join forces during entry of the porcine reproductive and respiratory syndrome virus. J Gen Virol 89:2943–2953PubMedCrossRefGoogle Scholar
  67. 67.
    Van Gorp H, Van Breedam W, Delputte PL, Nauwynck HJ (2009) The porcine reproductive and respiratory syndrome virus requires trafficking through CD163-positive early endosomes, but not late endosomes, for productive infection. Arch Virol 154:1939–1943PubMedCrossRefGoogle Scholar
  68. 68.
    Vanderheijden N, Delputte PL, Favoreel HW, Vandekerckhove J, Van Damme J, van Woensel PA, Nauwynck HJ (2003) Involvement of sialoadhesin in entry of porcine reproductive and respiratory syndrome virus into porcine alveolar Mϕs. J Virol 77:8207–8215PubMedCrossRefGoogle Scholar
  69. 69.
    Varki A (2008) Sialic acids in human health and disease. Trends Mol Med 14:351–360PubMedCrossRefGoogle Scholar
  70. 70.
    Vinson M, van der Merwe PA, Kelm S, May A, Jones EY, Crocker PR (1996) Characterization of the sialic acid-binding site in sialoadhesin by site-directed mutagenesis. J Biol Chem 271:9267–9272PubMedCrossRefGoogle Scholar
  71. 71.
    Wu C, Rauch U, Korpos E, Song J, Loser K, Crocker PR, Sorokin LM (2009) Sialoadhesin-positive Mϕs bind regulatory T cells, negatively controlling their expansion and autoimmune disease progression. J Immunol 182:6508–6516PubMedCrossRefGoogle Scholar
  72. 72.
    York MR, Nagai T, Mangini AJ, Lemaire R, van Seventer JM, Lafyatis R (2007) A Mϕ marker, Siglec-1, is increased on circulating monocytes in patients with systemic sclerosis and induced by type I interferons and toll-like receptor agonists. Arthritis Rheum 56:1010–1020PubMedCrossRefGoogle Scholar
  73. 73.
    Zou Z, Chastain A, Moir S, Ford J, Trandem K, Martinelli E, Cicala C, Crocker P, Arthos J, Sun PD (2011) Siglecs Facilitate HIV-1 Infection of Mϕs through Adhesion with Viral Sialic Acids. PLoS One 6:e24559PubMedCrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2012

Authors and Affiliations

  1. 1.Division of Cell Signalling and Immunology, College of Life SciencesUniversity of DundeeDundeeUK

Personalised recommendations