Can f 4
Summary
Canis familiaris allergen 4 (Can f 4) is the most abundantly detected allergen in dog fur and a major allergen component of dog hair and dander extracts. Can f 4 has at least two isoforms and is strongly affected by denaturation. These variations in molecular structure may contribute to the highly heterogeneous IgE reactivity (46–81%) seen in studies from different geographical regions. Sensitization to Can f 4 is significantly associated with asthma, and can serve as a marker for clinically relevant dog allergy. Specific IgE tests for Can f 4 became available in 2019 and, when tested in combination with other dog allergens, Can f 4 improves the reliability of dog allergy diagnosis.
Epidemiology
Worldwide distribution
Dog-allergic individuals are sensitive to a number of proteins found in dog hair and dander extracts. Can f 4 is considered a major allergen component of dog dander and is important for over 80% of people with dog allergies for IgE binding. Can f 4 T-cell responses have been shown to be a TH2-deviated memory response in allergenic but not nonallergenic individuals.
An early assessment of recombinant dog allergens noted 60% (15/25) of dog dust-sensitized subjects exhibited IgE reactivity to an “18 kDa component”, later identified as Can f 4, in immunoblotting. In contrast, Mattsson et al. found that only 35% of dog-allergic individuals were sensitized to recombinant Can f 4 (rCan f 4) as examined by ImmunoCAP. In this study, the magnitude of IgE antibody binding to Can f 4 was comparable to that of Can f 1, greater than to Can f 2 and Can f 3, and lower than to Can f 5.
Can f 4 has at least two isoforms, and the overall IgE reactivity of natural Can f 4 depends strongly on the integrity of the allergen’s conformation. Geographic variation in the prevalence of sensitivity to Can f 4 ranges from 46% to 81%, suggesting a difference in reaction to the isoforms.
Clinical Relevance
Disease severity
Sensitization to lipocalins such as Can f 4 is significantly associated with asthma. Sensitization to Can f 4 and Can f 6 can serve as a marker for clinically relevant dog allergy. Kack et al. used nasal provocation tests (NPTs) to demonstrate a positive association between sensitization to dog allergen components and clinical symptoms of dog allergy in children aged 10–18 years. In this study, sensitization to the lipocalins Can f 4 and Can f 6, and to the serum albumin Can f 3, was significantly associated with a positive NPT result in the unadjusted logistic regression analysis. After adjusting for the effect of the other protein groups, only sensitization to lipocalins was shown to be associated with an increased risk for a positive NPT result. Additionally, the likelihood of a positive NPT result increased with sensitization to an increasing number of dog allergen components; multisensitization to all six investigated dog allergen components (Can f 1, Can f 2, Can f 3, Can f 4, Can f 5, and Can f 6) conferred the overall highest risk for a positive reaction.
Diagnostics
In vitro Diagnosis
The clinical utility of specific IgE test to Can f 4 has not been studied extensively since it became available for clinical use in 2019. However, it appears that assessment of Can f 4 in combination with other dog allergens improves the reliability of allergy tests in dog allergy. rCan f 4 displayed close biochemical and immunological similarity to purified natural Can f 4, and bound IgE antibodies from 35% of dog-allergic subjects. Can f 4 may be relevant as an independent sensitizer in dog allergy, however, taken together, the levels of IgE to five dog allergens (Can f 1, Can f 2, Can f 3, Can f 4, and Can f 5) amounted on average to 93% of that to dog dander. rCan f 4 brings the panel of available dog allergens closer to completion and will be important in component-resolved diagnostics in allergy to animal epithelial allergens.
Cross-Reactivity
Can f 4 displays 38-39% sequence identity to bovine and porcine odorant-binding proteins, and 25-29% identity to several known mammalian allergens including Equ c 1, Mus m 1, Rat n 1, and Fel d 4. Despite belonging to the same protein family, Can f 4 showed only 24% and 26% amino acid sequence identity to Can f 1 and Can f 2, respectively.
References
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- Jensen-Jarolim E, Pacios LF, Bianchini R, Hofstetter G, Roth-Walter F. Structural similarities of human and mammalian lipocalins, and their function in innate immunity and allergy. Allergy. 2016;71(3):286-94.
- Rytkönen-Nissinen M, Saarelainen S, Randell J, Häyrinen J, Kalkkinen N, Virtanen T. IgE Reactivity of the Dog Lipocalin Allergen Can f 4 and the Development of a Sandwich ELISA for Its Quantification. Allergy Asthma Immunol Res. 2015;7(4):384-92.
- Rönkä AL, Kinnunen TT, Goudet A, Rytkönen-Nissinen MA, Sairanen J, Kailaanmäki AH, et al. Characterization of human memory CD4(+) T-cell responses to the dog allergen Can f 4. J Allergy Clin Immunol. 2015;136(4):1047-54.e10.
- Saarelainen S, Taivainen A, Rytkönen-Nissinen M, Auriola S, Immonen A, Mäntyjärvi R, et al. Assessment of recombinant dog allergens Can f 1 and Can f 2 for the diagnosis of dog allergy. Clin Exp Allergy. 2004;34(10):1576-82.
- Mattsson L, Lundgren T, Olsson P, Sundberg M, Lidholm J. 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(8):1276-87.
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