e230 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 (1-3). In a group of 44 adult patients selected for their sensitization to both cats and dogs, 61% had IgE antibodies to Can f 6 (3). 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 (4). 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 (5). Both studies confirmed the biological relevance of Can f 6 via basophil activation tests in dog-allergic patients (4, 5).

Environmental Characteristics

Source and tissue

Can f 6 is produced by the submaxillary gland and found in dog dander (2). The gene encoding Can f 6 was amplified from both canine skin and bladder cDNA libraries, but not from tongue or submandibular gland libraries (5).

Clinical Relevance

Disease severity

Can f 6 is a major allergen and key lipocalin driving disease among dog-allergic individuals (1, 6). Sensitization to lipocalins such as Can f 6 is significantly associated with asthma (7). 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 (6). 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) (6). 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) (6). 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 (8).

Molecular Aspects

Allergic Molecules

Can f 6 is a lipocalin protein with a molecular weight of 21 kDa that was identified in 2011 (1, 5). Analysis of individual components within dog dander extract demonstrated positive nasal provocation tests (NPT) results with the allergens Can f 3, Can f 4 and Can f 6, however no association was found with IgE to Can f 1, Can f 2 or Can f 5 (6). Additionally, the presence of IgE to Can f 4 and Can f 6 (together with Can f 3) conferred the greatest risk of a positive nasal challenge test, despite mean IgE levels towards Can f 4 and Can f 6 remaining generally low (6). The authors considered that this finding probably reflected cross-sensitization, as Can f 6 has shown extensive cross-reactivity with cat and horse lipocalins (6). In fact, the primary sequence for Can f 6 is more similar to other mammalian lipocalins than to other dog lipocalins, which may account for the observed co-sensitization and cross-reactivity profiles of Can f 6 (1).

Cross-reactivity

Can f 6 is highly cross-reactive with lipocalins from horse and cat (6), and may contribute with homologous allergens to multisensitization and symptoms in individuals allergic to mammals (5). Can f 6 has a high amino acid identity to Fel d 4 (67%) and to Equ c 1 (57%) (3). Can f 6 and Fel d 4 are capable of inhibiting IgE reactivity to each other at low competitor concentrations (2), and inhibition and cross-inhibition experiments have confirmed cross-reactivity between Can f 6 and Fel d 4 (3). 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 (5). 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 (5).

Compiled By

Author: RubyDuke Communications

Reviewer: Dr. Magnus Borres

Last reviewed: December 2020