Can f 6
Summary
Canis familiaris allergen 6 (Can f 6) is a major dog allergen present in dog dander, recognized more frequently by dog-sensitized individuals than Can f 2, Can f 3 and Can f 4. Sensitization to Can f 6 is significantly associated with dog-related rhinitis and asthma, and can serve as a marker for clinically relevant dog allergy. Can f 6 shares extensive co-sensitization and cross-reactivity profiles with other mammalian lipocalins, particularly cat and horse, and contributes with these homologous allergens to multisensitization and respiratory symptoms in individuals allergic to mammals. A specific test for IgE to Can f 6 became available in 2019, marking an important step forwards in the accurate diagnosis of dog allergy.
Epidemiology
Worldwide distribution
Lipocalins represent the most important protein family of the mammalian respiratory allergens, and include the dog allergens Can f 1, Can f 2, Can f 4 and Can f 6. In a group of 44 adult patients selected for their sensitization to both cats and dogs, 61% had IgE antibodies to Can f 6. A study of Chinese children showed that just over half (56%) of the dog-allergic subjects reacted to Can f 6, versus none of the healthy controls, indicating that Can f 6 is a major dog allergen in this pediatric population. Similarly, IgE antibodies to Can f 6 were found in serum from 38% of dog-sensitized children and adults in Sweden, suggesting that Can f 6 is a key dog allergen and more frequently recognized than the allergens Can f 2, Can f 3 and Can f 4. Both studies confirmed the biological relevance of Can f 6 via basophil activation tests in dog-allergic patients.
Clinical Relevance
Disease severity
Can f 6 is a major allergen and key lipocalin driving disease among dog-allergic individuals. Sensitization to lipocalins such as Can f 6 is significantly associated with asthma. However, the clinical utility of a specific IgE test to Can f 6 has not been studied extensively since it became available for clinical use in 2019.
Sensitization to Can f 6 can serve as a marker for clinically relevant dog allergy. In a study of 60 dog-allergic children aged 10–18 years, 86% of patients sensitized to Can f 6 reported dog-related rhinitis (versus 53% of non-sensitized patients, p=0.007), while 64% reported dog-induced asthma (versus 38%, p=0.038). A majority of the patients in this study were sensitized to several components in dog dander, and sensitization to an increasing number of components significantly increased the risk for reported dog-induced asthma and rhinitis (p=0.01). Similarly, a large cross-sectional and longitudinal population-based study demonstrated that molecular polysensitization to cat or dog allergens including Can f 6 predicted an increased likelihood of allergy to cat or dog, versus patients with none or limited sensitizations.
Cross-Reactivity
Can f 6 is highly cross-reactive with lipocalins from horse and cat, and may contribute with homologous allergens to multisensitization and symptoms in individuals allergic to mammals. Can f 6 has a high amino acid identity to Fel d 4 (67%) and to Equ c 1 (57%). Can f 6 and Fel d 4 are capable of inhibiting IgE reactivity to each other at low competitor concentrations, and inhibition and cross-inhibition experiments have confirmed cross-reactivity between Can f 6 and Fel d 4. Dog-allergic subjects sensitized to either rCan f 6, rFel d 4 or nEqu c 1 were 81.6%, 88.6% and 73.8% likely to be sensitized to all three allergens, respectively. Based on sequence similarity and identity between Can f 6, Fel d 4 and Equ c 1, Can f 6 can also be expected to cross-react with the major rodent allergens Mus m 1 and Rat n 1.
References
- Clayton GM, White J, Lee S, Kappler JW, Chan SK. Structural characteristics of lipocalin allergens: Crystal structure of the immunogenic dog allergen Can f 6. PLoS One. 2019;14(9):e0213052.
- Hilger C, Kuehn A, Hentges F. Animal lipocalin allergens. Curr Allergy Asthma Rep. 2012;12(5):438-47.
- Hilger C, Swiontek K, Arumugam K, Lehners C, Hentges F. 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(4):1149-51.
- Wang YJ, Li L, Song WJ, Zhou YJ, Cao MD, Zuo XR, et al. Canis familiaris allergen Can f 6: expression, purification and analysis of B-cell epitopes in Chinese dog allergic children. Oncotarget. 2017;8(53):90796-807.
- Nilsson OB, Binnmyr J, Zoltowska A, Saarne T, van Hage M, Grönlund H. Characterization of the dog lipocalin allergen Can f 6: the role in cross-reactivity with cat and horse. Allergy. 2012;67(6):751-7.
- Käck U, Asarnoj A, Grönlund H, Borres MP, van Hage M, Lilja G, et al. Molecular allergy diagnostics refine characterization of children sensitized to dog dander. J Allergy Clin Immunol. 2018;142(4):1113-20.e9.
- Schoos AM, Kattan JD, Gimenez G, Sampson HA. Sensitization phenotypes based on protein groups and associations to allergic diseases in children. J Allergy Clin Immunol. 2016;137(4):1277-80.
- Asarnoj A, Hamsten C, Wadén K, Lupinek C, Andersson N, Kull I, et al. Sensitization to cat and dog allergen molecules in childhood and prediction of symptoms of cat and dog allergy in adolescence: A BAMSE/MeDALL study. J Allergy Clin Immunol. 2016;137(3):813-21.e7.