Skip to main content
SpringerLink
Log in

Carbohydrates as Allergens

  • ALLERGENS (RK BUSH, SECTION EDITOR)
  • Published:
Current Allergy and Asthma Reports Aims and scope Submit manuscript

Abstract

Complex carbohydrates are effective inducers of Th2 responses, and carbohydrate antigens can stimulate the production of glycan-specific antibodies. In instances where the antigen exposure occurs through the skin, the resulting antibody production can contain IgE class antibody. The glycan-stimulated IgE may be non-specific but may also be antigen specific. This review focuses on the production of cross-reactive carbohydrate determinants, the recently identified IgE antibody response to a mammalian oligosaccharide epitope, galactose-alpha-1,3-galactose (alpha-gal), as well as discusses practical implications of carbohydrates in allergy. In addition, the biological effects of carbohydrate antigens are reviewed in setting of receptors and host recognition.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Similar content being viewed by others

Abbreviations

Ab:

Antibody

CRD:

Carbohydrate recognition domains

CCD:

Cross-reactive carbohydrate determinant

DC:

Dendritic cell

Alpha-gal:

Galactose-α-1,3-galactose

GalNAc:

N-acetylgalactosamine

References

Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance

  1. Okano M, Satoskar AR, Nishizaki K, Harn Jr DA. Lacto-N-fucopentaose III found on Schistosoma mansoni egg antigens functions as adjuvant for proteins by inducing Th2-type response. J Immunol. 2001;167:442–50.

    Article  CAS  PubMed  Google Scholar 

  2. Faveeuw C, Mallevaey T, Paschinger K, Wilson IB, Fontaine J, Mollicone R, et al. Schistosome N-glycans containing core alpha 3-fucose and core beta 2-xylose epitopes are strong inducers of Th2 responses in mice. Eur J Immunol. 2003;33:1271–81.

    Article  CAS  PubMed  Google Scholar 

  3. Ishihara H, Takahashi N, Oguri S, Tejima S. Complete structure of the carbohydrate moiety of stem bromelain. An application of the almond glycopeptidase for structural studies of glycopeptides. J Biol Chem. 1979;254:10715–9.

    CAS  PubMed  Google Scholar 

  4. van Kuik JA, Hoffmann RA, Mutsaers JHG, van Halbeek H, Kamerling JP, Vliegenthart JF. A 500-MHz 1H-NMR study on the N-linked carbohydrate of bromelain. Glycoconj J. 1986;3:27–34.

    Article  CAS  Google Scholar 

  5. Cummings RD, Nyame AK. Glycobiology of schistosomiasis. FASEB J. 1996;10:838–48.

    CAS  PubMed  Google Scholar 

  6. Dell A, Haslam SM, Morris HR, Khoo KH. Immunogenic glycoconjugates implicated in parasitic nematode diseases. Biochim Biophys Acta. 1999;1455:353–62.

    Article  CAS  PubMed  Google Scholar 

  7. Wilson IB, Altmann F. Structural analysis of N-glycans from allergenic grass, ragweed and tree pollens: core 1,3-linked fucose and xylose present in all pollens examined. Glycoconj J. 1998;15:1055–70.

    Article  CAS  PubMed  Google Scholar 

  8. Wilson IB. Glycosylation of proteins in plants and invertebrates. Curr Opin Struct Biol. 2002;12:569–77.

    Article  CAS  PubMed  Google Scholar 

  9. Van Die I, Cummings RD. Glycans modulate immune responses in helminth infections and allergy. Chem Immunol Allergy. 2006;90:91–112.

    PubMed  Google Scholar 

  10. van de Vijver KK, Hokke CH, van Remoortere A, Jacobs W, Deelder AM, Van Marck EA. Glycans of Schistosoma mansoni and keyhole limpet haemocyanin induce hepatic granulomas in vivo. Int J Parasitol. 2004;34:951–61.

    Article  PubMed  Google Scholar 

  11. Cervi L, MacDonald AS, Kane C, Dzierszinski F, Pearce EJ. Cutting edge: dendritic cells copulsed with microbial and helminth antigens undergo modified maturation, segregate the antigens to distinct intracellular compartments, and concurrently induce microbe-specific Th1 and helminth-specific Th2 responses. J Immunol. 2004;172:2016–20.

    Article  CAS  PubMed  Google Scholar 

  12. Pearce EJ, Kane CM, Sun J, Taylor J, McKee AS, Cervi L. Th2 response polarization during infection with the helminth parasite Schistosoma mansoni. Immunol Rev. 2004;201:117–26.

    Article  CAS  PubMed  Google Scholar 

  13. Tawill S, Le Goff L, Ali F, Blaxter M, Allen JE. Both free-living and parasitic nematodes induce a characteristic Th2 response that is dependent on the presence of intact glycans. Infect Immun. 2004;72:398–407.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  14. Figdor CG, van Kooyk Y, Adema GJ. C-type lectin receptors on dendritic cells and Langerhans cells. Nat Rev Immunol. 2002;2:77–84.

    Article  CAS  PubMed  Google Scholar 

  15. Janeway Jr CA, Medzhitov R. Innate immune recognition. Ann Rev Immunol. 2002;20:197–216.

    Article  CAS  Google Scholar 

  16. Aalberse RC, Koshte V, Clemens JG. Immunoglobulin E antibodies that crossreact with vegetable foods, pollen, and Hymenoptera venom. J Allergy Clin Immunol. 1981;68:356–64.

    Article  CAS  PubMed  Google Scholar 

  17. Weber A, Schroder H, Thalberg K, Marz L. Specific interaction of IgE antibodies with a carbohydrate epitope of honey bee venom phospholipase A2. Allergy. 1987;42:464–70.

    Article  CAS  PubMed  Google Scholar 

  18. Tretter V, Altmann F, Kubelka V, Marz L, Becker WM. Fucose-α-1,3-linked to the core region of glycoprotein N-glycans creates an important epitope for IgE from honeybee venom allergic individuals. Int Arch Allergy Immunol. 1993;102:259–66.

    Article  CAS  PubMed  Google Scholar 

  19. Kochuyt AM, Van Hoeyveld EM, Stevens EA. Prevalence and clinical relevance of specific immunoglobulin E to pollen caused by sting-induced specific immunoglobulin E to cross-reacting carbohydrate determinants in Hymenoptera venoms. Clin Exp Allergy. 2005;35:441–7.

    Article  CAS  PubMed  Google Scholar 

  20. van der Veen MJ, van Ree R, Aalberse RC, Akkerdaas J, Koppelman SJ, Jansen HM, et al. Poor biologic activity of cross-reactive IgE-directed to carbohydrate determinants of glycoproteins. J Allergy Clin Immunol. 1997;100:327–34.

    Article  PubMed  Google Scholar 

  21. van Ree R, Aalberse RC. Pollen-vegetable food crossreactivity: serological and clinical relevance of crossreactive IgE. J Clin Immunoass. 1993;16:124–30.

    Google Scholar 

  22. Aalberse RC, van Ree R. Crossreactive carbohydrate determinants. Clin Rev Allergy Immunol. 1997;15:375–87.

    Article  CAS  PubMed  Google Scholar 

  23. Mari A. IgE to cross-reactive carbohydrate determinants: analysis of the distribution and appraisal of the in vivo and in vitro reactivity. Int Arch Allergy Immunol. 2002;129:286–95.

    Article  CAS  PubMed  Google Scholar 

  24. Wicklein D, Linder B, Moll H, Kolarich D, Altmann F, Becker WM, et al. Carbohydrate moieties can induce mediator release: a detailed characterization of two major timothy grass pollen allergens. Biol Chem. 2004;385:397–407.

    Article  CAS  PubMed  Google Scholar 

  25. Jin C, Hantusch B, Hemmer W, Stadlmann J, Altmann F. Affinity of IgE and IgG against cross-reactive carbohydrate determinants on plant and insect glycoproteins. J Allergy Clin Immunol. 2008;121:185–90.

    Article  CAS  PubMed  Google Scholar 

  26. Chung CH, Mirakhur B, Chan E, Le QT, Berlin J, Morse M, et al. Cetuximab-induced anaphylaxis and IgE specific for galactose-α-1,3-galactose. N Engl J Med. 2008;358:1109–17.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  27. Commins SP, Satinover SM, Hosen J, Mozena J, Borish L, Lewis BD, et al. Delayed anaphylaxis, angioedema, or urticaria after consumption of red meat in patients with IgE antibodies specific for galactose-α-1,3-galactose. J Allergy Clin Immunol. 2009;123:426–33.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  28. Kennedy JK, Stallings AP, Platts-Mills TAE, Oliveira W, Workman LT, James HR, et al. Galactose-alpha-1,3-galactose and delayed anaphylaxis, angioedema, and urticaria in children. Pediatrics. 2013;131:1545–52. This study presents data related to tick bites inducing the IgE Ab response to alpha-gal. The report is the first example of a response to an ectoparasite giving rise to an important form of food allergy. The results also document that tick bites can induce high titers of IgE antibodies to a single oligosaccharide epitope.

    Article  Google Scholar 

  29. Van Nunen SA, O’Connor KS, Clarke LR, et al. An association between tick bite reactions and red meat allergy in humans. Med J Aust. 2009;190:510–1. As early as 2007, Dr. van Nunen had recognized patients who developed allergic reactions to meat after being bitten by ticks in the bush north of Sydney. She reported those cases in abstract form to the Australasian Society of Clinical Immunology & Allergy and published her findings after the connection with alpha-gal was described.

    PubMed  Google Scholar 

  30. Mullins RJ, James H, Platts-Mills TA, Commins S. Relationship between red meat allergy and sensitization to gelatin and galactose-α-1,3-galactose. J Allergy Clin Immunol. 2012;129:1334–42.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  31. Jacquenet S, Moneret-Vautrin DA, Bihain BE. Mammalian meat-induced anaphylaxis: clinical relevance of anti-galactose-alpha-1,3-galactose IgE confirmed by means of skin tests to cetuximab. J Allergy Clin Immunol. 2009;124:603–5.

    Article  CAS  PubMed  Google Scholar 

  32. Morisset M, Richard C, Astier C, et al. Anaphylaxis to pork kidney is related to IgE antibodies specific for galactose-alpha-1,3-galactose. Allergy. 2012;67:699–704. The data emphasize the wide range of mammalian foods that are eaten in Europe, which includes not only horse, goat, and rabbit meat but also kidneys, stomach, and other organs. In the USA, venison, bear, and squirrel are common, but they are less common causes of reactions.

    Article  CAS  PubMed  Google Scholar 

  33. Jappe U. Update on meat allergy: α-Gal: a new epitope, a new entity? Hautarzt. 2012;63:299–306.

    Article  CAS  PubMed  Google Scholar 

  34. Hamsten C, Tran TA, Starkhammar M, Brauner A, Commins SP, Platts-Mills TA, et al. Red meat allergy in Sweden: association with tick sensitization and B-negative blood groups. J Allergy Clin Immunol. 2013;132:1431–4.

    Article  PubMed Central  PubMed  Google Scholar 

  35. Gonzalez-Quintela A, Dam Laursen AS, Vidal C, Skaaby T, Gude F, Linneberg A. IgE antibodies to alpha-gal in the general adult population: relationship with tick bites, atopy, and cat ownership. Clin Exp Allergy. 2014;44:1061–8. The prevalence of sIgE to alpha-gal has not been a lingering question. The prevalence of alpha-gal sIgE antibodies in two general adult European populations (Denmark and Spain) was found to be 5.5 and 8.1 %, respectively. The presence of alpha-gal sIgE antibodies was associated with a history of tick bites, atopy, and cat ownership.

    Article  CAS  PubMed  Google Scholar 

  36. Sekiya K, Fukutomi Y, Nakazawa T, Taniguchi M, Akiyama K. Delayed anaphylactic reaction to mammalian meat. J Investig Allergol Clin Immunol. 2012;22:446–7.

    CAS  PubMed  Google Scholar 

  37. Lee JH, Kim JH, Kim TH, Kim SC. Delayed mammalian meat-induced anaphylaxis confirmed by skin test to cetuximab. J Dermatol. 2013;40:577–8.

    Article  PubMed  Google Scholar 

  38. Ebo DG, Faber M, Sabato V, Leysen J, Gadisseur A, Bridts CH, et al. Sensitization to the mammalian oligosaccharide galactose-alpha-1,3-galactose (alpha-gal): experience in a Flemish case series. Acta Clin Belg. 2013;68:206–9.

    Article  CAS  PubMed  Google Scholar 

  39. Hamsten C, Starkhammar M, Tran TA, Johansson M, Bengtsson U, Ahlén G, et al. Identification of galactose-α-1,3-galactose in the gastrointestinal tract of the tick Ixodes ricinus; possible relationship with red meat allergy. Allergy. 2013;68:549–52. Initial demonstration of alpha-gal as a moiety present in ticks. These findings provide direct support for the view that antigens within the tick are the cause of the IgE Ab response after tick bites.

    Article  CAS  PubMed  Google Scholar 

  40. Spiro RG, Bhoyroo VD. Occurrence of α-D-galactosyl residues in the thyroglobulins from several species. Localization in the saccharide chains of the complex carbohydrate units. J Biol Chem. 1984;259:9858–66.

    CAS  PubMed  Google Scholar 

  41. Macher BA, Galili U. The Galα1,3Galβ1,4GlcNAc-R (α-Gal) epitope: a carbohydrate of unique evolution and clinical relevance. Biochim Biophys Acta. 2008;1780:75–88.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  42. Paschinger K, Fabini G, Schuster D, Rendić D, Wilson IB. Definition of immunogenic carbohydrate epitopes. Acta Biochim Pol. 2005;52:629–32.

    CAS  PubMed  Google Scholar 

  43. Koike C, Fung JJ, Geller DA, Kannagi R, Libert T, Luppi P, et al. Molecular basis of evolutionary loss of the alpha 1,3-galactosyltransferase gene in higher primates. J Biol Chem. 2002;22:10114–20.

    Article  Google Scholar 

  44. Larsen RD, Rivera-Marrero CA, Ernst LK, Cummings RD, Lowe JB. Frameshift and nonsense mutations in a human genomic sequence homologous to a murine UDP-Gal:beta-D-Gal(1,4)-D-GlcNAc alpha(1,3)-galactosyltransferase cDNA. J Biol Chem. 1990;265:7055–61.

    CAS  PubMed  Google Scholar 

  45. Galili U, Mandrell RE, Hamadeh RM, Shohet SB, Griffiss JM. Interaction between human natural anti-alpha-galactosyl immunoglobulin G and bacteria of the human flora. Infect Immun. 1988;56:1730–7.

    CAS  PubMed Central  PubMed  Google Scholar 

  46. Springer GF, Horton RE. Blood group isoantibody stimulation in man by feeding blood group-active bacteria. J Clin Invest. 1969;48:1280–91.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  47. Galili U, Macher BA, Buehler J, Shohet SB. Human natural anti-alpha-galactosyl IgG. II. The specific recognition of alpha (1–3)-linked galactose residues. J Exp Med. 1985;162:573–82.

    Article  CAS  PubMed  Google Scholar 

  48. Galili U, Buehler J, Shohet SB, Macher BA. The human natural anti-Gal IgG. III. The subtlety of immune tolerance in man as demonstrated by crossreactivity between natural anti-Gal and anti-B antibodies. J Exp Med. 1987;165:693–704.

    Article  CAS  PubMed  Google Scholar 

  49. Galili U, Rachmilewitz EA, Peleg A, Flechner I. A unique natural human IgG antibody with anti-alpha-galactosyl specificity. J Exp Med. 1984;160:1519–31.

    Article  CAS  PubMed  Google Scholar 

  50. Tangvoranuntakul P, Gagneux P, Diaz S, Bardor M, Varki N, Varki A. Human uptake and incorporation of an immunogenic nonhuman dietary sialic acid. Proc Natl Acad Sci U S A. 2003;100:12045–50.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  51. Jefferis R. Glycosylation as a strategy to improve antibody-based therapeutics. Nat Rev Drug Discov. 2009;8:226–34.

    Article  CAS  PubMed  Google Scholar 

  52. Mohiuddin MM, Ogawa H, Yin DP, Galili U. Tolerance induction to a mammalian blood group-like carbohydrate antigen by syngeneic lymphocytes expressing the antigen, II: tolerance induction on memory B cells. Blood. 2003;102:229–36.

    Article  CAS  PubMed  Google Scholar 

  53. Babbitt BP, Allen PM, Matsueda G, Haber E, Unanue ER. Binding of immunogenic peptides to Ia histocompatibility molecules. Nature. 1985;317:359–61.

    Article  CAS  PubMed  Google Scholar 

  54. Unanue ER in therapeutic immunology, eds Austen KF, Burakoff SJ, Rosen FS, Strom TB, Blackwell Publishing, 2001.

  55. Speir JA, Abdel-Motal UM, Jondal M, Wilson IA. Crystal structure of an MHC class I presented glycopeptide that generates carbohydrate-specific CTL. Immunity. 1999;10:51–61.

    Article  CAS  PubMed  Google Scholar 

  56. Cobb BA, Wang Q, Tzianabos AO, Kasper DL. Polysaccharide processing and presentation by the MHCII pathway. Cell. 2004;117:677–87.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  57. Dudler T, Altmann F, Carballido JM, Blaser K. Carbohydrate-dependent, HLA class II-restricted, human T cell response to the bee venom allergen phospholipase A2 in allergic patients. Eur J Immunol. 1995;25:538–42.

    Article  CAS  PubMed  Google Scholar 

  58. Cretin N, Bracy J, Hanson K, Iacomini J. The role of T cell help in the production of antibodies specific for Gal alpha 1-3Gal. J Immunol. 2002;168:1479–83.

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

These studies are primarily funded by NIH grants: K08-AI-1085190.

Compliance with Ethics Guidelines

ᅟ

Conflict of Interest

Scott P. Commins declares that these studies are primarily funded by NIH grants: K08-AI-1085190, that he is a consultant for Sanofi, and that he receives royalties from UpToDate.

Human and Animal Rights and Informed Consent

This article does not contain any studies with human or animal subjects performed by any of the authors.

Author information

Authors and Affiliations

  1. Departments of Internal Medicine and Pediatrics, Divisions of Allergy, Asthma and Immunology and Gastroenterology, University of Virginia Health System, PO Box 801355, Charlottesville, VA, 22908, USA

    Scott P. Commins

Authors
  1. Scott P. Commins
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Scott P. Commins.

Additional information

This article is part of the Topical Collection on Allergens

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Commins, S.P. Carbohydrates as Allergens. Curr Allergy Asthma Rep 15, 492 (2015). https://doi.org/10.1007/s11882-014-0492-y

Download citation

  • Published:

  • DOI: https://doi.org/10.1007/s11882-014-0492-y

Keywords

Search

Navigation