Diagnosis and Rationale for Action against Cow's Milk Allergy (DRACMA) Guidelines update - III - Cow's milk allergens and mechanisms triggering immune activation

Abstract

Background: The immunopathogenesis of cow's milk protein allergy (CMPA) is based on different mechanisms related to immune recognition of protein epitopes, which are affected by industrial processing.

Purpose: The purpose of this WAO DRACMA paper is to: (i) give a comprehensive overview of milk protein allergens, (ii) to review their immunogenicity and allergenicity in the context of industrial processing, and (iii) to review the milk-related immune mechanisms triggering IgE-mediated immediate type hypersensitivity reactions, mixed reactions and non-IgE mediated hypersensitivities.

Results: The main cow's milk allergens - α-lactalbumin, β-lactoglobulin, serum albumin, caseins, bovine serum albumins, and others - may determine allergic reactions through a range of mechanisms. All marketed milk and milk products have undergone industrial processing that involves heating, filtration, and defatting. Milk processing results in structural changes of immunomodulatory proteins, leads to a loss of lipophilic compounds in the matrix, and hence to a higher allergenicity of industrially processed milk products. Thereby, the tolerogenic capacity of raw farm milk, associated with the whey proteins α-lactalbumin and β-lactoglobulin and their lipophilic ligands, is lost.

Conclusion: The spectrum of immunopathogenic mechanisms underlying cow's milk allergy (CMA) is wide. Unprocessed, fresh cow's milk, like human breast milk, contains various tolerogenic factors that are impaired by industrial processing. Further studies focusing on the immunological consequences of milk processing are warranted to understand on a molecular basis to what extent processing procedures make single milk compounds into allergens.

Keywords: Allergy; Beta-lactoglobulin; Cow's milk; Food allergy; Pasteurization.

Fig. 2

Molecular milk allergens. Left panel, Whey proteins: apo-α-lactalbumin, apo-β-lactoglobulin, apo-serum albumin and apo-lactoferrin may occur as monomers, or oligomers. Binding of ligands in the holo-variants of these proteins may change their oligomeric state and tolerogenic potency. Below each molecule the pdb accession number is given. Bovine immunoglobulins are not illustrated. Right panel, Caseins: Schematic model of a casein micelle according to Ref. , consisting of all caseins. Usually, α-s1-, α-s2-, and β-caseins cluster around amorphic calcium phosphate, thereby assembling nanoclusters, while κ-casein is found on the border zone. Processing may change the protein tertiary and quaternary structures as well as the composition of a micelle

Fig. 1

Milk processing changes the 3D structure of whey proteins. Top: Cow's milk is an essential food and needs to be distributed to the people around the world. Therefore, milk processing aims at a) avoiding zoonotic infections of the consumer, and b) making milk products transportable and expanding their shelf life time. Milk processing plants are equipped to fulfill these needs and deliver safe products suited for all tastes and demands, from milk, to infant formula, and many more. Bottom: The major whey proteins are beta-lactoglobulin (50%–65% of all whey proteins) (colored dark red) and alpha-lactalbumin (10–12%) (colored orange). Derived from the dairy cow, these proteins are conformationally intact, and emulsified together with lipophilic compounds and vitamins in raw farm milk. Several processing steps in a dairy plant significantly impair the 3D-structure of whey proteins, their homo- and heteromeric aggregation state, the composition of all hydrophilic and lipophilic milk constituents, and thereby change the immunogenicity and allergenicity of milk

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