Abstract
Lipocalins represent the most important group of inhalant animal allergens. For some of them, three-dimensional protein structures have been resolved, but their functions are still elusive. Lipocalins generally display a low sequence identity between family members. The characterization of new lipocalin allergens has revealed however that some of them display a high sequence identity to lipocalins from another species. They constitute a new group of potentially cross-reactive molecules which, in addition to serum albumins, may contribute to allergic cross-reactions between animal dander of different species. However, the clinical relevance of cross-reactivity needs to be assessed. Further studies are needed to understand which of these animal lipocalins are the primary allergens and which are cross-reacting molecules. The use of single, well characterized allergens for diagnosis will allow the identification of the sensitizing animal, which is a prerequisite for specific immunotherapy.
Similar content being viewed by others
References
Papers of particular interest, published recently, have been highlighted as: • Of importance •• Of major importance
Radauer C, Bublin M, Wagner S, et al. Allergens are distributed into few protein families and possess a restricted number of biochemical functions. J Allergy Clin Immunol. 2008;121:847–52 e7.
Grzyb J, Latowski D, Strzalka K. Lipocalins–a family portrait. J Plant Physiol. 2006;163:895–915.
•• Flower DR, North ACT, Sansom CE. The lipocalin protein family: structural and sequence overview. Biochim Biophys Acta Protein Struct Mol Enzymol. 2000;1482:9–24. Review based on structure comparisons between lipocalins, but also members of the calycin superfamily.
Flower DR. The lipocalin protein family: structure and function. Biochem J. 1996;318(Pt 1):1–14.
Ganfornina MD, Gutierrez G, Bastiani M, Sanchez D. A phylogenetic analysis of the lipocalin protein family. Mol Biol Evol. 2000;17:114–26.
Sanchez D, Ganfornina MD, Gutierrez G, Marin A. Exon-intron structure and evolution of the Lipocalin gene family. Mol Biol Evol. 2003;20:775–83.
•• Virtanen T, Kinnunen T. Mammalian allergens. Clin Allergy Immunol. 2008;21:201–18. Short descriptions on mammalian allergens.
Morgenstern JP, Griffith IJ, Brauer AW, et al. Amino acid sequence of Fel dI, the major allergen of the domestic cat: protein sequence analysis and cDNA cloning. Proc Natl Acad Sci U S A. 1991;88:9690–4.
Smith W, Butler AJ, Hazell LA, et al. Fel d 4, a cat lipocalin allergen. Clin Exp Allergy. 2004;34:1732–8.
Smith W, O'Neil SE, Hales BJ, et al. Two Newly Identified Cat Allergens: the von Ebner Gland Protein Fel d 7 and the Latherin-Like Protein Fel d 8. Int Arch Allergy Immunol. 2011;156:159–70.
Hilger C, Kohnen M, Grigioni F, et al. Allergic cross-reactions between cat and pig serum albumin. Study at the protein and DNA levels. Allergy. 1997;52:179–87.
Ichikawa K, Vailes LD, Pomes A, Chapman MD. Molecular cloning, expression and modelling of cat allergen, cystatin (Fel d 3), a cysteine protease inhibitor. Clin Exp Allergy. 2001;31:1279–86.
Adedoyin J, Gronlund H, Oman H, et al. Cat IgA, representative of new carbohydrate cross-reactive allergens. J Allergy Clin Immunol. 2007;119:640–5.
Konieczny A, Morgenstern JP, Bizinkauskas CB, et al. The major dog allergens, Can f 1 and Can f 2, are salivary lipocalin proteins: cloning and immunological characterization of the recombinant forms. Immunol. 1997;92:577–86.
Ramadour M, Guetat M, Guetat J, et al. Dog factor differences in Can f 1 allergen production. Allergy. 2005;60:1060–4.
Spitzauer S, Schweiger C, Sperr WR, et al. Molecular characterization of dog albumin as a cross-reactive allergen. J Allergy Clin Immunol. 1994;93:614–27.
Mattsson L, Lundgren T, Everberg H, et al. Prostatic kallikrein: a new major dog allergen. J Allergy Clin Immunol. 2009;123:362–8.
Mattsson L, Lundgren T, Olsson P, et al. Molecular and immunological characterization of Can f 4: a dog dander allergen cross-reactive with a 23 kDa odorant-binding protein in cow dander. Clin Exp Allergy. 2010;40:1276–87.
Hilger C, Swiontek K, Arumugam K, et al. Identification of a new major dog allergen highly cross-reactive with Fel d 4 in a population of cat- and dog-sensitized patients. J Allergy Clin Immunol. 2012;129:1149–51e2.
Gregoire C, Rosinski-Chupin I, Rabillon J, et al. cDNA cloning and sequencing reveal the major horse allergen Equ c1 to be a glycoprotein member of the lipocalin superfamily. J Biol Chem. 1996;271:32951–9.
Dandeu JP, Rabillon J, Divanovic A, et al. Hydrophobic interaction chromatography for isolation and purification of Equ.cl, the horse major allergen. J Chromatogr. 1993;621:23–31.
Lascombe MB, Gregoire C, Poncet P, et al. Crystal structure of the allergen Equ c 1. A dimeric lipocalin with restricted IgE-reactive epitopes. J Biol Chem. 2000;275:21572–7.
Goubran Botros H, Poncet P, Rabillon J, et al. Biochemical characterization and surfactant properties of horse allergens. Eur J Biochem. 2001;268:3126–36.
Bulone V, Krogstad-Johnsen T, Smestad-Paulsen B. Separation of horse dander allergen proteins by two-dimensional electrophoresis–molecular characterisation and identification of Equ c 2.0101 and Equ c 2.0102 as lipocalin proteins. Eur J Biochem. 1998;253:202–11.
Cabanas R, Lopez-Serrano MC, Carreira J, et al. Importance of albumin in cross–reactivity among cat, dog and horse allergens. J Investig Allergol Clin Immunol. 2000;10:71–7.
Mantyjarvi R, Parkkinen S, Rytkonen M, et al. Complementary DNA cloning of the predominant allergen of bovine dander: a new member in the lipocalin family. J Allergy Clin Immunol. 1996;97:1297–303.
Rautiainen J, Rytkonen M, Syrjanen K, et al. Tissue localization of bovine dander allergen Bos d 2. J Allergy Clin Immunol. 1998;101:349–53.
Ylonen J, Mantyjarvi R, Taivainen A, Virtanen T. IgG and IgE antibody responses to cow dander and urine in farmers with cow-induced asthma. Clin Exp Allergy. 1992;22:83–90.
Rouvinen J, Rautiainen J, Virtanen T, et al. Probing the molecular basis of allergy. Three-dimensional structure of the bovine lipocalin allergen Bos d 2. J Biol Chem. 1999;274:2337–43.
Restani P, Ballabio C, Di Lorenzo C, et al. Molecular aspects of milk allergens and their role in clinical events. Anal Bioanal Chem. 2009;395:47–56.
Walls AF. Newman Taylor AJ, Longbottom JL. Allergy to guinea pigs: I. Allergenic activities of extracts derived from the pelt, saliva, urine and other sources. Clin Allergy. 1985;15:241–51.
Fahlbusch B, Rudeschko O, Schlott B, et al. Further characterization of IgE-binding antigens from guinea pig hair as new members of the lipocalin family. Allergy. 2003;58:629–34.
Fahlbusch B, Rudeschko O, Szilagyi U, et al. Purification and partial characterization of the major allergen, Cav p 1, from guinea pig Cavia porcellus. Allergy. 2002;57:417–22.
Hilger C, Swiontek K, Kler S, et al. Evaluation of 2 new recombinant guinea–pig lipocalins, Cav p 2 and Cav p 3, in the diagnosis of guinea–pig allergy. Clin Exp Allergy. 2011;41:899–908.
Payne AP. The harderian gland: a tercentennial review. J Anat. 1994;185:1–49.
Baker J, Berry A, Boscato LM, et al. Identification of some rabbit allergens as lipocalins. Clin Exp Allergy. 2001;31:303–12.
Price JA, Longbottom JL. Allergy to rabbits. II. Identification and characterization of a major rabbit allergen. Allergy. 1988;43:39–48.
Warner JA, Longbottom JL. Allergy to rabbits. III. Further identification and characterisation of rabbit allergens. Allergy. 1991;46:481–91.
Garibotti M, Navarrini A, Pisanelli AM, Pelosi P. Three odorant-binding proteins from rabbit nasal mucosa. Chem Senses. 1997;22:383–90.
• Cavaggioni A, Mucignat-Caretta C. Major urinary proteins, [α]2U-globulins and aphrodisin. Biochim Biophys Acta Protein Struct Mol Enzymol. 2000;1482:218–28. Comprehensive review on MUP biology.
Robertson DH, Cox KA, Gaskell SJ, et al. Molecular heterogeneity in the Major Urinary Proteins of the house mouse Mus musculus. Biochem J. 1996;316:265–72.
Bush RK. Mechanism and epidemiology of laboratory animal allergy. ILAR J. 2001;42:4–11.
Matsui EC, Eggleston PA, Buckley TJ, et al. Household mouse allergen exposure and asthma morbidity in inner-city preschool children. Ann Allergy Asthma Immunol. 2006;97:514–20.
Phipatanakul W, Eggleston PA, Wright EC, et al. Mouse allergen. II. The relationship of mouse allergen exposure to mouse sensitization and asthma morbidity in inner-city children with asthma. J Allergy Clin Immunol. 2000;106:1075–80.
Ferrari E, Breda D, Longhi R, et al. In search of a vaccine for mouse allergy: significant reduction of Mus m 1 allergenicity by structure-guided single-point mutations. Int Arch Allergy Immunol. 2012;157:226–37.
Bayard C, Holmquist L, Vesterberg O. Purification and identification of allergenic alpha (2u)-globulin species of rat urine. Biochim Biophys Acta. 1996;1290:129–34.
Gordon S, Tee RD, Stuart MC, Newman Taylor AJ. Analysis of allergens in rat fur and saliva. Allergy. 2001;56:563–7.
Gordon S, Tee RD, Newman Taylor AJ. Analysis of the allergenic composition of rat dust. Clin Exp Allergy. 1996;26:533–41.
Phillips JF, Lockey RF. Exotic pet allergy. J Allergy Clin Immunol. 2009;123:513–5.
Lim DL, Chan RM, Wen H, et al. Anaphylaxis after hamster bites–identification of a novel allergen. Clin Exp Allergy. 2004;34:1122–3.
Torres JA. Pastor–Vargas C, de las Heras M, et al. An odorant-binding protein as a new allergen from Siberian hamster (Phodopus sungorus). Int Arch Allergy Immunol. 2012;157:109–12.
Arruda LK, Vailes LD, Hayden ML, et al. Cloning of cockroach allergen, Bla g 4, identifies ligand binding proteins (or calycins) as a cause of IgE antibody responses. J Biol Chem. 1995;270:31196–201.
Tan YW, Chan SL, Ong TC, et al. Structures of 2 major allergens, Bla g 4 and Per a 4, from cockroaches and their IgE binding epitopes. J Biol Chem. 2009;284:3148–57.
Paddock CD, McKerrow JH, Hansell E, et al. Identification, cloning, and recombinant expression of procalin, a major triatomine allergen. J Immunol. 2001;167:2694–9.
Hilger C, Bessot JC, Hutt N, et al. IgE-mediated anaphylaxis caused by bites of the pigeon tick Argas reflexus: cloning and expression of the major allergen Arg r 1. J Allergy Clin Immunol. 2005;115:617–22.
Marshall N, Liebhaber M, Dyer Z, Saxon A. The prevalence of allergic sensitization to Triatoma protracta (Heteroptera: Reduviidae) in a Southern California, USA, community. J Med Entomol. 1986;23:117–24.
Paesen GC, Adams PL, Harlos K, et al. Tick histamine-binding proteins: isolation, cloning, and three-dimensional structure. Mol Cell. 1999;3:661–71.
Kleine-Tebbe J, Heinatz A, Gräser I, et al. Bites of the European pigeon tick (Argas reflexus): risk of IgE-mediated sensitizations and anaphylactic reactions. J Allergy Clin Immunol. 2006;117:190–5.
• Tegoni M, Pelosi P, Vincent F, et al. Mammalian odorant binding proteins. Biochim Biophys Acta Protein Struct Mol Enzymol. 2000;1482:229–40. Comprehensive review on OBP function and structure.
Papes F, Logan DW, Stowers L. The vomeronasal organ mediates interspecies defensive behaviors through detection of protein pheromone homologs. Cell. 2010;141:692–703.
Chamero P, Marton TF, Logan DW, et al. Identification of protein pheromones that promote aggressive behaviour. Nat. 2007;450:899–902.
Zhou Y, Jiang L, Rui L. Identification of MUP1 as a regulator for glucose and lipid metabolism in mice. J Biol Chem. 2009;284:11152–9.
Yusifov TN, Abduragimov AR, Gasymov OK, Glasgow BJ. Endonuclease activity in lipocalins. Biochem J. 2000;347:815–9.
•• Salo PiM, Sever ML, Zeldin DC. Indoor allergens in school and day care environments. Journal of Allergy and Clinical Immunology. 2009;124:185–92.e9. Review summarizing data from indoor allergen exposure studies in relation to asthma and allergy.
•• Virtanen T, Kinnunen T, Rytkonen–Nissinen M. Mammalian lipocalin allergens–insights into their enigmatic allergenicity. Clin Exp Allergy. 2012;42:494–504. Review analyzing the different molecular features inherant to lipocalins in an attempt to explain their allergenicity.
Royer PJ, Emara M, Yang C, et al. The mannose receptor mediates the uptake of diverse native allergens by dendritic cells and determines allergen-induced T cell polarization through modulation of IDO activity. J Immunol. 2010;185:1522–31.
Wojnar P, Lechner M, Merschak P, Redl B. Molecular cloning of a novel lipocalin-1 interacting human cell membrane receptor using phage display. J Biol Chem. 2001;276:20206–12.
Fluckinger M, Merschak P, Hermann M, et al. Lipocalin-interacting–membrane–receptor (LIMR) mediates cellular internalization of [β]-lactoglobulin. Biochimica et Biophysica Acta (BBA) –. Biomembr. 2008;1778:342–7.
Emara M, Royer PJ, Mahdavi J, et al. Retagging identifies dendritic cell-specific intercellular adhesion molecule-3 (ICAM3)–grabbing non–integrin (DC–SIGN) protein as a novel receptor for a major allergen from house dust mite. J Biol Chem. 2012;287:5756–63.
Saarelainen S, Rytkonen-Nissinen M, Rouvinen J, et al. Animal-derived lipocalin allergens exhibit immunoglobulin E cross–reactivity. Clin Exp Allergy. 2008;38:374–81.
Madhurantakam C, Nilsson OB, Uchtenhagen H, et al. Crystal structure of the dog lipocalin allergen Can f 2: implications for cross-reactivity to the cat allergen Fel d 4. J Mol Biol. 2010;401:68–83.
Nilsson OB, Binnmyr J, Zoltowska A, et al. Characterization of the dog lipocalin allergen Can f 6: the role in cross-reactivity with cat and horse. Allergy. 2012;67:751–7.
Platts-Mills TAE. The role of indoor allergens in chronic allergic disease. J Allergy Clin Immunol. 2007;119:297–302.
• Hauser M, Roulias A, Ferreira F, Egger M. Panallergens and their impact on the allergic patient. Allergy Asthma Clin Immunol. 2010;6:1. Description and classification of plant allergen families.
Egger M, Hauser M, Mari A, et al. The role of lipid transfer proteins in allergic diseases. Curr Allergy Asthma Rep. 2010;10:326–35.
Waterhouse AM, Procter JB, Martin DM, et al. Jalview Version 2–a multiple sequence alignment editor and analysis workbench. Bioinforma. 2009;25:1189–91.
Acknowledgment
Projects of C.H. and A.K. are supported by the Ministry of Higher Education and Research of Luxembourg. The authors thank Arnaud Müller for his assistance on the lipocalin alignment figure.
Disclosure
No potential conflicts of interest relevant to this article were reported.
Author information
Authors and Affiliations
Corresponding author
Rights and permissions
About this article
Cite this article
Hilger, C., Kuehn, A. & Hentges, F. Animal Lipocalin Allergens. Curr Allergy Asthma Rep 12, 438–447 (2012). https://doi.org/10.1007/s11882-012-0283-2
Published:
Issue Date:
DOI: https://doi.org/10.1007/s11882-012-0283-2