Cow's Milk

1. Major Allergens

      A number of milk proteins have been identidied as allergenic or immunogenic in humans. Many patients are allergic to more than one milk protein as identidied by skin-test reactivity or by oral challenge. Individuals allergic to cow's milk will often exhibit the presence of IgE antibodies in their serum to goat or sheep's milk. Caseins and β-lactoglobulin are the major allergens in cow's milk. The percentage of persons allergic to individual cow's milk proteins or protein families will vary depending on the method used to define the response. By oral challenge,  β-lactoglobulin produces more positive responses than does casein. When skin tests were employed, casein was slightly more prevalent (63%) than β-lactoglobulin (62%). Although these individual studies show one group of proteins more reative than the other by the method employed, the general consensus is that caseins and β-lactoglobulin are most frequently the cause of allerfic reactions to cow's milk.

      Caseins:  The caseins are a family of chemically related proteins. The frequency of reactivity to individual casein proteins has not been systemically evaluated. αs1-casein has at least five genetic variants. It is a 23-kDa phosphoprotein with sequential mouse epitopes. The amino acid sequence of the protein has been established. Based on the predicated structure, hydrophobic and hydrophilic domains connected by a segment of α-helix have been identified. αs2-casein have varying degrees of posttranslational phosphorylation. Four genetic variants have been identified. β-caseins have one major component with seven genetic variants and eight minor components that are proteolytic fragments of the major component. The molecular weight of the major component is 23,980. Modeling studies indicated that the protein has hydrophobic side chains dispersed over the C-terminal end and center surface of the structure, with a hydrophilic N-terminus. κ-caseins compries two gentic variants. This protein is cleaved at residue 105 to 106 by rennin (chymosin) into two domains. The hydrophobic domain (para-κ-caseins) is not soluble, whereas the polar domain (macropeptide) is extremely soluble.

      β-lactoglobulin:    Whey proteins comprise approximately 20% of milk proteins. The most abundant whey protein is β-lactoglobulin, an 18-kDa protein belonging to the lipocalin family. There are at least six genetic variants of this protein. The primary strcture has been obtained. The complete has been reported and shows 91% sequence homology with ovine β-lactoglobulin.

2. Minor Allergens

      To a lesser degree, the whey proteins α-lactalbumin and bovine serum albumin (BSA) have been implicated in allergic reactions to cow's milk.

      α-lactalbumin:    α-lactalbumin consists of two genetic variants and its molecular weight is approximately 14 kDa. The protein has been cloned and the nucleotide sequence identified. The primary amino acid structure has been setermined. The two genetic variants differ in only one amino acid sequence. Sequence analysis andicates homology to lysozyme. This protein apparently promotes transfer of galactose to glucose to form lactose, the major milk sugar. α-Lactalbumin produces both positive skin tasts and positive oral challenges in significant number of cow's milk-allergic individuals.

      BSA:     BSA can be detected in milk and is identical in characteristics to bovine blood serum albumin. BSA has produced both positive skin tests and oral challenges in some cow's milk-allergic individuals. BSA is a heterogeneous protein with a molecular weight of 67 kDa comprising approximately 1% of the total milk protein.

      Other proteins:    Other milk components may occasionlly be allergenic. These include bovine immunoglobulins (Ig), which comprise less than 2% of the total milk protein, β2-microglobulin, transferrin, lactoferrin, lactoperoxidase, alkaline phosphatase, and catalase. Maillard reaction adducts, which are lactose-protein conjugates, may occasionally act as allergens. A β-lactoglobulin lactose conjugate was shown in one study to be 10 to 100 times more potent in intradermal skin tests than native β-lactoglobulin.

3. Structure-Epitopes

      Although caseins are significant allergens, no data are available regarding their human T- or B-cell epiopes. For αs1-casein, the mouse T- and B-cell epiyopes have been identified as sequential epitopes. Because αs1-casein is the casein subunit that most often interacts with IgE from infants and children with clinically allergic symptoms, it would be helpful to have information regarding its epitopes in human systems. Baldo found that the glycomacropeptide from κ-casein (amino acid residues 106 to 167) and the polypeptide fragment encompassing amino acid residues 99 to 167 reacted with most of the serum in his IgE-blotting study; the latter peptide proved more reactive, and might indicate the presence of an IgE epitope in amino acid sequence 99 to 105.

4. Dose Responses

     The exact quantity of milk protein required to produce sensitization (IgE antibody production) or clinical symptoms is not known. Trace quantities of milk proteins in processed foods may produce symptoms in sensitive individuals. Some infants may develop cow's milk allergy despite breastfeeding. β-Lactoglobulin levels in women's breast milk increased from a based level of 0.0 to 3.5 μg /l (after abstinence from cow's milk ingestion for at least 24 h) to as much as 0.01 to 2.34 μg /l after administration of 400 ml of cow's milk. This may explain the source of sensitization in some stituations. Because β-Lactoglobulin could not be detected in all samples, it may not be the only explanation. Intact proteins, such as BSA, have also been measured in peripheral blood from individuals who have these proteins.