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Important Mammalian Respiratory Allergens Are Lipocalins

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Allergy is an expanding problem in the industrialized countries. Allergenic proteins, the allergens, causing the allergic symptoms are ubiquitous materials in the environment, normally not harmful for individuals not sensitized to them. In contrast, sensitized individuals who have specific immunoglobulin E against the allergen as a result of activation of the immune system can develop immediate, even fatal allergic reactions. Sensitization to indoor allergens, for example to those derived from pets, is often associated with more severe forms of allergic diseases, such as asthma. Recent years have shown that the major mammalian allergens causing respiratory sensitization belong to the lipocalin family of proteins. Reasons for this remain to be fully elucidated but it appears that lipocalin allergens exhibit immunological features that may account for their allergenic capacity.

Introduction

Allergy is a disorder of the immune system which is manifested as inappropriate reactions to ubiquitous materials in the environment such as pollen, house dust mites, or animal dander.1 Allergic reactions are mediated by immunoglobulin E (IgE) antibody. Proteins able to bind IgE are called allergens. They initiate allergic or type I hypersensitivity reactions by cross-linking the antibody on mast cells and basophils. This results in the release of inflammatory mediators and in the symptoms of allergy. Allergic symptoms can arise from different organs, typically from airways, digestive track, and skin. Their severity varies, e.g., from mild rhinitis and itching to a systemic anaphylactic shock. Sensitization, as indicated by the presence of IgE, can be evaluated by measuring serum IgE or by skin prick tests (SPT). Sensitization can also develop without leading to a clinical illness.

The nomenclature of allergens is based on the system introduced by the Allergen Nomenclature Sub-Committee of the International Union of Immunological Societies.2,3 The designation comprises the first three letters of the genus of origin of the allergen, the first letter of the species name, and a running Arabic number. If two species names have identical designations they are distinguished by adding one or more letters, as necessary, to each species designation. Isoallergens sharing an amino acid identity of ≥ 67% are distinguished by a two-digit number after the sequential number of the allergen and the variants with an additional two-digit number. For example, bovine dander allergen Bos d 2.0101 is the variant 01 of the isoallergen 01 of Bos d 2.

Exposure and Sensitization to Animal Allergens

The major respiratory allergens of animals (Table 1), especially from mammals, belong to the lipocalin family of proteins.4,5 While the cat allergen Fel d 1 is an important exception to the rule (see refs. 6,7), another major cat allergen, Fel d 4, was recently reported to be a lipocalin.8 The food allergen Bos d 5 (β-lactoglobulin) also belongs to lipocalins.5

Table 1. Lipocalin allergens.

Table 1

Lipocalin allergens.

Household pets, cats and dogs, are frequently found in homes in the industrialized countries. As the allergens which emanate from these animals tend to stick to clothing, they are commonly found in other indoor environments, such as homes without pets, schools, day care centers, and transport vehicles. The concentrations may be high enough to sensitize and to cause symptoms in sensitized individuals.9 Assessed by skin prick tests (SPT), dogs sensitize 7-15% of individuals in community populations.10,11 The figure can rise up to 56% among asthmatic children.12 Among dog-allergic subjects, sensitization to Can f 1 is detected in 50-70% of the individuals (see refs. 13-15) while the figure for Can f 2 is about 25%.14,15 The prevalence of sensitization to cat among children with asthma is 30-50%.16,17 The predominant cat allergen Fel d 1, not a lipocalin, sensitizes over 90% of cat-allergic individuals.18 Sixty-three percent of cat-allergic individuals had IgE against Fel d 4, a recently discovered lipocalin allergen, typically at low levels.8

Exposure to rodents and to rabbit is a major occupational health problem since 20-30% of workers in laboratory animal facilities become sensitized to animal allergens.19,20 Allergy to rabbit was observed to develop rapidly in laboratory animal workers, as its prevalence was the highest in comparison with sensitization to other animal species within one year of exposure.19 Sixty-six percent of laboratory workers with asthma and rhinitis had IgE against rat Rat n 1.21 In a survey of asthma patients, 35% of them had a positive SPT result with a rabbit dander extract.22 Mice, rats, hamsters, guinea pigs, and gerbils are popular pets, but mouse can also induce allergy in subjects who live in infested apartments. The prevalence of sensitization to mouse was 18% among inner-city children with asthma in a U.S. study.23 Keeping guinea pigs was associated with a more than threefold risk for atopic eczema in comparison with having other pets, such as dogs, cats, or hamsters.24 Seventy to 87% of guinea pig-allergic subjects had IgE reactivity to Cav p 1 while the reactivity to Cav p 2 was about 55%.25

Domestic animals able to induce allergy include horse and cow. A population study reported a prevalence of about 13% for a positive SPT with horse dander.11 Two of the characterized horse allergens, Equ c 1 and Equ c 2, are lipocalins. Seventy-six per cent of horse-allergic subjects had IgE to Equ c 1 (see ref. 26) while up to 50% had IgE against Equ c 2.27 Cow epithelium is a potent sensitizer in the farming environment, inducing a variety of symptoms including asthma.28 About 90% of dairy farmers with asthma of bovine origin have IgE against the major respiratory allergen of cow, Bos d 2.29

Lipocalin allergens have also been detected in insects. Exposure to cockroach allergens depends on socioeconomic factors including housing conditions. Sensitization to cockroach is around 40% among inner-city children with asthma.30 Forty to sixty per cent of asthmatic patients with cockroach allergy had IgE to recombinant Bla g 4, a lipocalin allergen.31 Another insect-derived lipocalin allergen is Tria p 1 from the “kissing bug”.32

Immunological Features of Lipocalin Allergens

Although allergens bind IgE by definition, it is basically unknown why the inert environmental substances elicit the process of sensitization, the generation of T helper type 2 (Th2) lymphocytes, which results in the synthesis of allergen-specific IgE by B lymphocytes.33,34 One requirement for a protein to be an allergen is that it is effectively dispersed in the environment. As discussed above, lipocalin allergens are widely encountered in human environments, obviously a result from the fact that lipocalin allergens are present in the dander and excretions of mammals. Another possible factor promoting the allergenic capacity of a protein could be its biological function. Lipocalins are known to exhibit a variety of biological functions (see ref. 35), including an enzyme activity (see ref. 36), which has been suggested to account for the allergenicity of some mite, fungal and pollen allergens.37 The dog allergen Can f 1 has been proposed to be a cysteine protease inhibitor since it exhibits a considerable level of homology with tear lipocalin.38 It can be speculated that like the allergens with enzyme activity (see ref. 37), lipocalin allergens might initially affect cell populations other than the T helper (Th) cells (lymphocytes), the crucial cell population in sensitization. For example, microbial pathogens can deliver signals to dendritic cells through pathogen-associated molecular patterns (PAMPs).39 These signals can result in the polarization of T cell response, but lipocalins, or allergens in general, are not known to contain PAMPs. One endogenous lipocalin, glycodelin, acts on T cells directly. By elevating T cell receptor activation thresholds, glycodelin appears to favor the Th2 deviation of immune response.40,41 Nevertheless, lipocalins are not known to possess a unifying physicochemical property or biological function which could explain their allergenicity.

Since Th cells play a central role in the specific immune response against exogenous substances and are therefore important in sensitization, it is possible that they are involved in determining the allergic capacity of proteins.4,34 When we studied the cellular response against Bos d 2 we observed unexpectedly that the peripheral blood mononuclear cells (PBMC) from highly allergic cow dust-asthmatic patients with positive skin prick test reactions to Bos d 2 proliferated very weakly in vitro upon stimulation with the allergen.42 We have recently verified that the finding was not characteristic for Bos d 2 only since recombinant dog Can f 1 and horse Equ c 1 were also weak stimulants for the PBMCs of dog and horse-allergic patients, respectively (Tuomas Virtanen, to be published). Accordingly, rat Rat n 1 was reported to be weakly stimulatory in vitro.43 In a study with murine cells, we found that Bos d 2 was a weak immunogen for several inbred mouse strains.44 Our recent study suggests that the weak stimulatory capacity of lipocalin allergens can result from their poor recognition by Th cells since the immunodominant T cell epitope of Bos d 2 was observed to be suboptimal for human T cells.45 The finding is interesting because a weak stimulation through T cell receptor is known to favor Th2-type responses.46,47 As lipocalins can exhibit considerable amino acid identity between species, it can be speculated that the presence of endogenous lipocalins could have resulted in the deletion of high-avidity lipocalin allergen-reactive T cells during thymic maturation.4,48 Consequently, the remaining T cell population might recognize exogenous lipocalin allergens weakly, promoting the Th2 deviation of immune response.

IgE antibodies cross-reactive between different allergens can result in symptoms in an individual who encounters an allergen which is able to bind the cross-reactive antibodies but was not their initial inducer. The cross-reactivity of IgE antibodies between non-serum-derived mammalian allergens is poorly known. At the level of allergen extracts, there seems to be cross-reactivity.49,50 It has also been suggested that the major cat and dog allergens have common IgE epitopes.49 In a study with guinea-pig Cav p 1, a 100-fold excess of cat, mouse, and rat allergen preparations were able to cause weak inhibition, less than 10%, in IgE ELISA, pointing to a low-level cross-reactivity.25 A further study suggested that a part of the IgE-binding epitopes of Cav p 1 and 2 are also cross-reactive.51 Inhibition experiments with cow, dog and horse allergen extracts pointed to a possibility that cow dander contains a homolog with cat Fel d 4.8 Most probably it is not the bovine Bos d 2 (see below) since its amino acid identity with Fel d 4 is only 29% (SBNS, Dec. 9, 2004). A monoclonal antibody raised to Bos d 5 (β-lactoglobulin), a bovine food allergen, has been reported to react against human serum retinol-binding protein.52 The core of the epitope sequence, DTDY, is also found in glycodelin, another human lipocalin.

Mammalian Lipocalin Allergens Causing Respiratory Sensitization

Cat

The cat allergen Fel d 4 (SWISS-PROT accession number Q5VFH6) is the only feline allergen in the lipocalin family. The physicochemical properties of Fel d 4 and other mammalian lipocalin allergens causing respiratory sensitization are shown in Table 2. The allergen was cloned from the submandibular salivary gland.8 mRNA for Fel d 4 was not detected in the other tissues examined, such as the parotid gland, liver, skin, tongue or the anal gland. Isoallergens were not isolated. Fel d 4 exhibits a 67% amino acid identity with the major horse allergen Equ c 1 and a 60% identity with boar salivary lipocalin (the SIB BLAST network service (SBNS) at the Swiss Institute of Bioinformatics, Dec. 9, 2004). The latter is an odorant and pheromone-binding protein, present in the male submaxillary salivary glands but absent in females.53 The amino acid identity of Fel d 4 can be up to 58% with murine major urinary proteins (MUPs) and rat α2u-globulins (SBNS, Dec. 9, 2004). It is 38% with a human putative MUP-like lipocalin.

Table 2. Physicochemical characteristics of mammalian lipocalin allergens causing respiratory sensitization.

Table 2

Physicochemical characteristics of mammalian lipocalin allergens causing respiratory sensitization.

Cow

Bos d 2 (SWISS-PROT Q28133) is the major allergen of cow dander and the only respiratory allergen of cow in the lipocalin family.29,54 Bos d 2 is localized in the secretory cells of the apocrine sweat glands and in the basement membranes of the epithelium and hair follicles.55 Three variants of Bos d 2 have been identified.56 An immunologically related allergen is found in urine.29 The three-dimensional structure of Bos d 2 (Protein Data Bank (PDB) code 1BJ7) was determined with the Pichia pastoris-produced allergen.57,58 It is assumed that Bos d 2 is a pheromone carrier.55 The amino acid identity of Bos d 2 with odorant-binding proteins and other lipocalins from other species is at the level of 30-40% (SBNS, Nov. 19, 2004). The IgE-binding capacity of Bos d 2 is strongly dependent on the intact three-dimensional structure of the allergen.59,60 Studies in cellular immunology incited us to propose a hypothesis on the allergenic capacity of Bos d 2 and other lipocalin allergens (see above).

Dog

Two of the dog allergens, Can f 1 and Can f 2, are lipocalins.14 A third previously unidentified allergen, detected in dog epithelial extract, is probably also a lipocalin.15 Can f 1 (SWISS-PROT O18873) is mainly found in dog saliva.61 It is also present in dog dander but absent or in a low concentration in serum, urine, and feces.61,62 mRNA for Can f 1 has been detected in tongue epithelial tissue but not in skin or liver.14 The human protein which exhibits the highest amino acid identity with Can f 1, 57%, is tear lipocalin, known also as von Ebner's gland protein (SBNS, Nov. 18, 2004). Can f 2 (SWISS-PROT O18874) is present in dog dander and in saliva but urine or feces contain very little of it.61 The mRNA of Can f 2 is predominantly found in the parotid gland. It is expressed to a lesser extent in tongue tissue and not found in skin or liver.14 Can f 2 exhibits amino acid identities with rodent urinary proteins at a level of about 30% (SBNS, Nov. 19, 2004). Both Can f 1 and Can f 2 are available as recombinant proteins.14,15

Guinea Pig

Guinea pig dust contains several allergens which are present in dander, fur, urine, and saliva. 25,63 Two major allergens, Cav p 1 and Cav p 2, are probably lipocalins.25,51 Cav p 1 (SWISS-PROT P83507), found also in urine, was isolated from hair extract.25 Its N-terminal sequence, 14 amino acids, contains the GXW motif and it exhibits a 57% amino acid identity with Mus m 1, the mouse major urinary protein (MUP). Cav p 1 exists in isoforms and may form dimers.51 Cav p 2 (SWISS-PROT P83508) was also isolated from hair extract.51 It exists in isoforms. A sequence of 13 amino acids contains the characteristic GXW motif of lipocalins and shows a 69% identity with bovine Bos d 2.51

Horse

Two allergens, Equ c 1 and Equ c 2, out of the more than ten horse dander proteins binding IgE are lipocalins, although additional lipocalin allergens may be present in dander.26,27 Equ c 1 (SWISS-PROT Q95182) is found in high concentrations in saliva while urine contains little of it.64 The protein has been cloned from sublingual salivary glands. Its mRNA is expressed at about 100-fold higher level in sublingual salivary glands than in submaxillary salivary glands or liver.65 The crystal structure of Equ c 1 (PDB 1EW3) has been resolved.66 The allergen shows about a 50% amino acid identity with rodent major urinary proteins (see ref. 65) and identities close to 40% with a human putative MUP-like lipocalin and human lipocalin 9 (SBNS, Nov. 26, 2004). The amino acid identity with a salivary lipocalin from pig is 61% (SBNS, Nov. 26, 2004). Equ c 1 is found in several isoforms.67 It exhibits a surfactant-like property.68 The horse dander allergen Equ c 2 was identified as two isoforms, Equ c 2.0101 (SWISS-PROT P81216) and Equ c 2.0102 (SWISS-PROT P81217), with slightly different isoelectric points.27 The N-terminal sequencing of a 29 amino-acid fragment showed that the allergen is a lipocalin since it contained the conserved GXW motif of lipocalins and had a 44% identity with bovine Bos d 2. The amino acid compositions of the allergens are also compatible with lipocalins67 The nomenclature of horse allergens has been clarified by Goubran Botros et al.68

Mouse

Mus m 1, the mouse major urinary protein, MUP6 in the SWISS-PROT data bank (P02762), accounts for the major part of the IgE-binding capacity of the crude male urine.69 The allergen is also present in serum and pelt.69 MUPs are mainly produced in liver, although forms of MUPs are expressed constitutively in the exocrine glands of mice and rats.70 Several hormones contribute to MUP synthesis, and the synthesis is influenced by androgens and is sex-dependent.70 Mouse MUPs are encoded by numerous genes (see ref. 71), and up to 15 MUPs have been detected in male mouse urine.72 Male urine contains the allergen in about a fourfold higher concentration than female urine.69 The structure of mouse MUP (PDB 1MUP) has been resolved.73 It has been produced as a recombinant protein in Pichia pastoris.74 Rodent MUPs function as odorant-binding proteins which are involved in territory marking and in the endocrine priming of female conspecifics.70 Mouse and rat MUPs have an amino acid identity of about 65%.70 As discussed above, the homology of rodent MUPs with cat Fel d 4 and horse Equ c 1 is considerable. The amino acid identity of Mus m 1 is 40% with human putative MUP-like lipocalin (SBNS, Dec. 15, 2004).

Rabbit

The tentatively named major allergen of rabbit, Ory c 1, is a glycoprotein with a molecular mass of 17-18 kDa.75,76 Its aminoterminal sequence with the GXW motif and with a 72% homology with rabbit odorant-binding protein-II suggests that it is a lipocalin.76 Ory c 1 is found in saliva, slightly less in fur, and in low amounts in dander.75-77 It is absent from urine.77 Another rabbit allergen, tentatively named as Ory c 2, has a molecular mass of 21 kDa.76 Its amino-terminal sequence also shows high homology with rabbit odorant-binding protein-II.76 It is present in several source materials.77

Rat

Rat n 1 (SWISS-PROT P02761), also known as rat MUP, is closely related to mouse Mus m 1, as discussed above. Like the mouse, adult male rats excrete more MUPs (about six times) in urine than females.78 Rat urine was previously considered to contain two distinct allergens, rat urinary prealbumin and α2u-globulin. As these strongly cross-reactive proteins (see ref. 21) were found to be isoforms of α2u-globulin (see ref. 79), it would be better to name prealbumin as Rat n 1.01 and α2u-globulin as Rat n 1.02.48 α2u-globulin has been produced in vitro.80 The structure of the protein (PDB 2A2U) has been resolved by X-ray crystallography.73

Concluding Remarks

Allergenicity is a property shared by a number of animal lipocalins. Neither the molecular structure nor biologic activity has provided definite clues for the allergenicity of lipocalins. Allergenicity of a protein can be verified conclusively only immunologically, i.e., by showing its capacity to induce sensitization. We have proposed that the allergenicity of lipocalin allergens is related to the adaptation of the immune system to the presence of endogenous lipocalins. The weak capacity of lipocalin allergens to induce the proliferation of PBMCs and the suboptimal character of the immunodominant T cell epitope of Bos d 2 suggest that the recognition of a lipocalin allergen by Th cells can be involved in promoting the development of the Th2-deviated immune response. Although the mapping of T cell epitopes is a laborious process, on the practical level their identification may allow to design new modalities of allergen immunotherapy, based on natural or optimized allergen peptides.81,82

Acknowledgements

The work was supported by Kuopio University Hospital (project # 5021605) and the Academy of Finland (contract # 205871).

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