Albumins represent highly cross-reactive animal allergens

Abstract

Albumins from animals are highly cross-reactive allergens for patients suffering from immunoglobulin E (IgE)-mediated allergy. Approximately 20-30% of cat and dog allergic patients show IgE reactivity and mount IgE-mediated allergic reactions to cat and dog albumin. It is astonishing that allergic patients can develop specific IgE responses against animal albumins because these proteins exhibit a more than 70% sequence identity to human serum albumin (HSA) which is the most abundant protein in the blood of the human body. The sequence identity of cat albumin (Fel d 2) and dog albumin (Can f 3) and HSA are 82% and 80%, respectively. Given the high degree of sequence identity between the latter two allergens and HSA one would expect that immunological tolerance would prohibit IgE sensitization to Fel d 2 and Can f 3. Here we discuss two possibilities for how IgE sensitization to Fel d 2 and Can f 3 may develop. One possibility is the failed development of immune tolerance in albumin-allergic patients whereas the other possibility is highly selective immune tolerance to HSA but not to Fel d 2 and Can f 3. If the first assumption is correct it should be possible to detect HSA-specific T cell responses and HSA-containing immune complexes in sensitized patients. In the latter scenario few differences in the sequences of Fel d 2 and Can f 3 as compared to HSA would be responsible for the development of selective T cell and B cell responses towards Fel d 2 as well as Can f 3. However, the immunological mechanisms of albumin sensitization have not yet been investigated in detail although this will be important for the development of allergen-specific prevention and allergen-specific immunotherapy (AIT) strategies for allergy to albumin.

Keywords: albumin; allergen; allergy; antibody; cross-reactivity; epitope; immunoglobulin E (IgE); tolerance.

Figure 1

Phylogenetic tree of albumins from different sources. The numbers on the branch point indicate phylogenetic likelihood, whereas the numbers on the branch line indicate phylogenetic distance to branch point. Generated by Molecular Evolutionary Genetics Analysis software.

Figure 2

(A, B) Alignment of the amino acid sequence of HSA with albumins from other sources. Amino acid numbers are shown on the right and left margin and designations of albumins are given at the right margin, which are from top to bottom: Human, rhesus macaque, cat, dog, donkey, horse, pig, bovine, golden hamster, sheep, rabbit, rat, guinea pig, chicken, and American bullfrog. Amino acids identical to Fel d 2 are shown as dots, dashes indicate gaps. Amino acids are colored according to their chemical properties: Blue – Hydrophobic amino acids (Glycine, Alanine, Proline, Valine, Leucine, Isoleucine, Methionine, Phenylalanine, Tryptophan); Red – Acidic amino acids (Tyrosine, Aspartic acid, Glutamic acid); Yellow – Neutral amino acids (Serine, Threonine, Cysteine, Asparagine, Glutamine); Green – Basic amino acids (Lysine, Arginine, Histidine).

Figure 3

Model of the three-dimensional cat albumin structure. Surface representation of the model of the 3D structure of cat albumin (5yxe) as compared to human serum albumin (1ao6). In total 584 amino acids in Fel d 2 and 588 amino acids in Human serum albumin were aligned. Atoms with RMSD less than 0.972 Å were excluded. White amino acids indicate conservative regions identical to human serum albumin. Differences are represented by red and blue colors, with blue indicating more conserved mutations and red indicating less conserved mutations according to the BLOSUM90 substitution matrix. Arrows indicate the C- and N-terminus.

Figure 4

Possible mechanisms underlying IgE sensitization to albumins. Allergic patients who are allergic to exogenous albumins such as Fel d 2 and Can f 3 may lack IgE auto-sensitization to HSA due to highly selective central and/or peripheral tolerance to HSA (left part). Alternatively, patients with an allergy to exogenous albumins may show IgE- and T-cell cross-reactivity to HSA due to failed tolerance (right part). AIT with albumin-containing vaccines may induce and/or enhance auto-reactivity to HSA.