Inhalant Mammal-Derived Lipocalin Allergens and the Innate Immunity.

Tuomas Virtanen

doi:10.3389/falgy.2021.824736

Abstract

A major part of important mammalian respiratory allergens belongs to the lipocalin family of proteins. By this time, 19 respiratory mammalian lipocalin allergens have been registered in the WHO/IUIS Allergen Nomenclature Database. Originally, lipocalins, small extracellular proteins (molecular mass ca. 20 kDa), were characterized as transport proteins but they are currently known to exert a variety of biological functions. The three-dimensional structure of lipocalins is well-preserved, and lipocalin allergens can exhibit high amino acid identities, in several cases more than 50%. Lipocalins contain an internal ligand-binding site where they can harbor small principally hydrophobic molecules. Another characteristic feature is their capacity to bind to specific cell-surface receptors. In all, the physicochemical properties of lipocalin allergens do not offer any straightforward explanations for their allergenicity. Allergic sensitization begins at epithelial barriers where diverse insults through pattern recognition receptors awaken innate immunity. This front-line response is manifested by epithelial barrier-associated cytokines which together with other components of immunity can initiate the sensitization process. In the following, the crucial factor in allergic sensitization is interleukin (IL)-4 which is needed for stabilizing and promoting the type 2 immune response. The source for IL-4 has been searched widely. Candidates for it may be non-professional antigen-presenting cells, such as basophils or mast cells, as well as CD4+ T cells. The synthesis of IL-4 by CD4+ T cells requires T cell receptor engagement, i.e., the recognition of allergen peptides, which also provides the specificity for sensitization. Lipocalin and innate immunity-associated cell-surface receptors are implicated in facilitating the access of lipocalin allergens into the immune system. However, the significance of this for allergic sensitization is unclear, as the recognition by these receptors has been found to produce conflicting results. As to potential adjuvants associated with mammalian lipocalin allergens, the hydrophobic ligands transported by lipocalins have not been reported to enhance sensitization while it is justified to suppose that lipopolysaccharide plays a role in it. Taken together, type 2 immunity to lipocalin allergens appears to be a harmful immune response resulting from a combination of signals involving both the innate and adaptive immunities.

Highlights

Allergic diseases constitute a serious health problem in westernized countries
Among other type 2 response-promoting factors released from stressed or dying cells upon exposure to allergen extracts are, for example, uric acid and Charcot-Leyden crystals, trefoil factors and extracellular ATP [248, 249]. Because such a large proportion of mammalian inhalant allergens are lipocalins, it is attractive to concur with the idea that lipocalin allergens possess specific properties which account for their allergenicity
These properties still largely remain hidden, there are cues to trace and clarify. It appears presumable for the time being that the allergenicity of lipocalin allergens hardly depends on only one factor, as is the case with type 2 immunity in general: No single switch is recognized for Th2 immunity

Summary

INTRODUCTION

Allergic diseases constitute a serious health problem in westernized countries. Their development appears to be associated with modern life style, such as the use of antibiotics, high-level hygiene, the lack of exposure to farming-related microbes, or certain infections [1, 2]. As owning pets is very common, exposure to pet allergens does not require a direct contact with pets; the allergens are widely present in homes without pets, schools, day care centers and other environments, at levels able to sensitize, and cause symptoms [6, 7] It is estimated, for example, that about half of the households in Great Britain have either at least one cat or dog [8]. Mammalian inhalant allergens are especially associated with severe allergic disorders, including asthma [7, 13] They are mainly found in a few protein families which are lipocalins, serum albumins, and secretoglobins [14]. The group taking up the lipocalin-ligand complex in TABLE 1 | Physicochemical characteristics and sensitization rates of mammal-derived inhalant lipocalin allergensa. Bos d 2 Can f 1 Can f 2 Can f 4 Can f 6 Cav p 1 Cav p 2 Cav p 3 Cav p 6 Equ c 1 Equ c 2g

4.6–5.3 No Yes

Findings

DISCUSSION