Allergen Profile, Dog, IgE With Component Reflex

Unlike cat allergy, which is almost entirely attributable to sensitization to its major allergen, Fel d 1, the sensitization profile for dog allergy is more heterogeneous.^15,16 A number of allergen molecules have been described in dogs (Canis familiaris).² Can f 1, Can f 2, Can f 4 and Can f 6 belong to the lipocalin family; Can f 3 is a serum albumin; and Can f 5 is a prostatic kallikrein from male dog urine.^2,17 Most children sensitized to dog dander have IgE to more than one dog allergen molecule,¹⁸ and polysensitization to dog allergens is a better predictor of dog allergy than sensitization to dog dander extract. The production of allergens varies between dog breeds and anatomical sites, as well as between individual dogs of the same breed, introducing variability in natural extracts in terms of source, sampling, processing and ultimately standardization and minimum allergen levels for accurate diagnosis.¹⁹ Can f 1 and Can f 5 have been classified as major allergens as their sensitization frequencies in dog dander sensitized patients are about 55% and 70%, respectively.^20-21 While Can f 2 and Can f 3 are considered minor allergens (< 50% sensitization rate),^20-25 the measurement of sIgE to these components has been shown to add diagnostic value.^16-21

Can f 1

Can f 1 is a lipocalin protein produced by the salivary glands of dogs.¹⁵ Can f 1 cross-reactivity with the human tear lipocalin has been reported.^15,26 Can f 1 also displays some cross-reactivity with cat component Fel d 7^27-29 and may contribute to symptoms in cat as well in dog-allergic patients. The most prominent component positivity in dog sensitized individuals in most studies is Can f 1.^29,30 However, other studies have found that the rates of sensitization to Can f 5 was higher than Can f 1.^22,23,31

In a study in Swedish adults, Can f 1 and cat allergen Fel d 1 were the most common allergens from furry pets, both in healthy participants and in patients with asthma.³² A recent study found that 64% of dog dander sensitized individuals were Can f 1 IgE positive, with 32% of those individuals monosensitized to Can f 1.²⁵ In Can f 1 sensitized individuals, sensitization to cat may be excluded by a negative test to Fel d 1.²⁸

A large European study of more than 700 children eight years old and younger (the ABAMSE/MeDALL study) reported that sIgE reactivity to the five dog allergen molecules tested (Can f 1, Can f 2, Can f 3, Can f 5 and Can f 6) increased with age.³³ This study found that sIgE to Can f 1 was superior to sIgE to dog allergen extract in diagnosing dog allergy. This study also found that sIgE reactivity to Can f 1 in childhood predicted the development of dog allergy in adolescence significantly better than IgE reactivity to dog allergen extract. Furthermore, IgE reactivity to Can f 1 was the only parameter that independently could predict future symptoms to dog.³³ Individuals who are double sensitized to cat and dog had an increasing prevalence of the cross-reactive lipocalins Can f 1 and Fel d 7.³⁴ Although these lipocalins were not reliable markers for genuine sensitization, the comparison of sIgE levels may help to diagnose and find a primary sensitizer.³⁴

Can f 2

Due to their structural similarity, the lipocalins Can f 2, Can f 6 and Fel d 4 exhibit immune cross-reactivity.^21,29 High IgE levels to Can f 2 is associated with asthma severity in dog dander sensitized children.³⁵ Can f 1 and Can f 2 have common epitopes and most of the patients allergic to Can f 2 are co-sensitized to Can f 1.²⁵ Sensitization to Can f 2 without Can f 1 sensitization is very rare.^{6,22,25,36-38} Because Can f 2 has little sequence identity or cross-reactivity to proteins of other mammals, sIgE to this protein suggests dog-specific sensitization.³⁷ Structures of Can f 2 and Equ c 1 are quite similar; however, they do not show cross-reactivity.²¹ Asthmatic children sensitized to Can f 2 have been shown to be at a greater risk of having more severe symptoms.^6,39 Due to their structural similarity, the lipocalins Can f 2, Can f 6 and Fel d 4 exhibit immune cross-reactivity.^17,29
 

Can f 3

Can f 3, dog serum albumin, is a highly cross-reactive minor allergen detected in 15% to 35% of dog-sensitized patients.^7,20 Serum albumins are abundant in saliva and dander and are highly cross-reactive molecules, although they are generally considered to be minor allergens.^30,40 Allergic sensitization to furry animals may be induced not only by direct/indirect exposure but also by a cross-reaction mechanism involving some families of allergenic proteins. Cross sensitization to other furry animals via initial allergy to Can f 3 may play a role in the progression to polysensitization and clinical allergies to other animals. Uriarte et al. found that sensitization to albumins was associated with more severe respiratory symptoms.³⁸ In a recent study of adults with dog extract IgE > 0.35 kUa/L, ³⁰ IgE values of Can f 3 were significantly higher in those with than in those without asthma. Similar results were observed in a study of children with dog sensitization.¹⁸

Can f 4

Can f 4 is the most abundantly detected allergen in dog fur and a major allergen component of dog hair and dander extracts.^19,41 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% to 81%) seen in studies from different geographical regions.¹⁹ Can f 4 T-cell responses have been shown to be a TH2-deviated memory response in allergenic but not nonallergenic individuals.⁴¹

Sensitization to Can f 4 is significantly associated with asthma and can serve as a marker for clinically relevant dog allergy.^18,42-44 High Can f 4 IgE levels are associated with asthma severity in dog dander sensitized children.³⁵ Sensitization to Can f 4 and Can f 6 and increasing levels of IgE to Can f 1 has been associated with a positive nasal challenge.³⁵ Furthermore, higher IgE levels to the lipocalins Can f 2, Can f 4 and Can f 6 were found in children with troublesome asthma compared to the rest of the study population.³⁵ These findings are in line with previous studies that have shown that lipocalins are associated with asthma.^39,42 In a population-based sample of 313 adults sensitized to dog dander, subjects with asthma had higher IgE levels of Can f 3, Can f 4 and Can f 6.³⁰

Can f 5

Can f 5 is a prostatic kallikrein that was original isolated from the urine of male dogs.³¹ Since this protein is produced in significant quantities only by non-neutered, male dogs,⁴⁵ it has been suggested that mono-sensitization to Can f 5 may correlate with allergic sensitivity to male and not female dogs.^20,47 Antibodies to Can f 5 have been found in up to 70% of patients with dog allergy^{22,23,31,38,45,48} and approximately a third of Can f 5-positive, dog dander-sensitized patients did not have antibodies to Can f 1, Can f 2 or Can f 3.⁴⁵

No patterns of Can f 5 cross-reactivity to allergens from other furry animals have been identified. However, cross-reactivity to human prostate-specific antigen, the major allergen in seminal plasma, has been reported.^7,49,50 Some studies have implicated sensitization to Can f 5 in cases of human seminal plasma allergy.^51-53

In a population-based study on 963 19-year-olds where associations with asthma symptoms, diagnosis and treatment were examined, Perzanowski et al. found that IgE antibodies to Can f 5 (and Fel d 1) were each associated with current asthma.⁵⁴ Sensitization to Can f 5 was also recently measured among children with severe asthma who, compared with children with controlled asthma, had an IgE response to more than 3 animal-derived allergen molecules, of which Can f 5 was one.^6,39

Käck and colleagues suggested that monosensitization to Can f 5 was inversely related to the positive nasal provocation test.¹⁸ A recent study found that sIgE levels to Can f 5 were higher in subjects with than those without allergic rhinitis, while it did not differ between subjects with and without asthma.³⁰ In this study, monosensitization to Can f 5 was more common in those without than in those with asthma. However, a recent study of a Korean population found that IgE to Can f 5 was significantly higher in asthmatics than in non-asthmatics.⁵⁵ In a study of 294 children and adults with suspected allergic rhinoconjunctivitis, patients sensitized to dogs only exhibited Can f 5 as the most common allergen, whereas in patients sensitized to both dogs and cats, Can f 1 was the dominant allergen followed by Can f 5 and Can f 6.³⁴ The authors suggest that a comparison of IgE levels may indicate which animal is the primary sensitizer and that sensitization to dog appeared to be a result of cross-reactivity with cats in 48% of the cases.

Can f 6

Can f 6 is produced by the submaxillary gland and found in dog dander.⁵⁷ Due to their structural similarity, the lipocalins Can f 2, Can f 6 and Fel d 4 exhibit immune cross-reactivity.^{17,29,41,56-58} Among minor allergens (Can f 2, Can f 3, Can f 4 and Can f 6), sensitization to Can f 6 has been reported to be the most common.^18,30 Several studies have confirmed the biological relevance of Can f 6 via basophil activation tests in dog-allergic patients.^59,60

In a group of 44 adult patients selected for their sensitization to both cats and dogs, 61% had IgE antibodies to Can f 6.⁵⁹ A study of Chinese children showed that 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.⁶⁰ 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 4.⁶⁰ In a study of 60 dog-allergic children aged 10 to 18 years, 86% of patients sensitized to Can f 6 reported dog-related rhinitis (versus 53% of non-sensitized patients), while 64% reported dog-induced asthma (versus 38%).¹⁸ 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).¹⁸ 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.³³

High IgE levels to Can f 6 is associated with asthma severity in dog dander sensitized children.³⁵ In a recent study of adults with dog extract IgE > 0.35 kUa/L, IgE values of Can f 6 were significantly higher in those with than in those without asthma.³⁰ Similar results were observed in a study of children with dog sensitization.¹⁸ In a recent Spanish study of patients with dog sensitization, positivity to Can f 6 was significantly associated with symptoms when in contact with dogs.³¹ Moreover, patients in contact with cats and dogs were sensitized to more dog allergens, in particular Can f 6, than patients not in contact with cats and dogs.³¹

Sensitization to Multiple Components

Multiple sensitization to cat and dog allergens during childhood has been associated to the development of subsequent allergy to dogs and cats.^30,33,34 Sensitization to two or more cat, dog and horse allergen components has been associated with severe respiratory symptoms (severe asthma and rhinitis).^22,38,30,55 Poly-sensitization to multiple cat or dog components has been shown to be a risk marker for asthma in children and has been associated with increased bronchial inflammation in severe asthmatic children and young adults.^{6,22,39,61,62} A cross-sectional cohort study in 269 children found that asthma was significantly associated with sensitization to members of the lipocalin protein family.⁶² Nordlund et al. reported that a specific IgE response in children to more than three animal-derived components was more common among uncontrolled severe asthmatics compared to children with controlled asthma.³⁹ A recent study of unselected adults revealed that sensitization, particularly poly-sensitization, to furry animal allergen components is an important predictor of severity and clinical outcomes of asthma.⁶³ Another recent study found that double-sensitization to cat and dog, cat and horse and polysensitization were associated with an increasing prevalence of the cross-reactive lipocalins Fel d 4/Can f 6/Equ c 1 and Fel d 7/Can f 1. Although these lipocalins were not reliable markers for genuine sensitization, the comparison of sIgE levels may help to diagnose and find a primary sensitizer.³⁴