Changes in humoral responses to β ‐lactoglobulin in tolerant patients suggest a particular role for IgG 4 in delayed, non‐IgE‐mediated cow's milk allergy

The major cow's milk allergen β ‐lactoglobulin ( β ‐LG) is relatively resistant to enzymatic degradation and may therefore be involved in non‐immunoglobulin (Ig)E‐mediated cow's milk allergy (CMA) with delayed gastrointestinal symptoms. Serum levels of β ‐LG‐specific IgG 1 , IgG 4 , IgE, and IgA were compared in clinically reactive and tolerized IgE‐mediated and non‐IgE‐mediated CMA with delayed gastrointestinal symptoms (n = 29) and controls (n = 10). Tolerance was associated with decreased β ‐LG‐specific IgE, IgG 1 , and IgG 4 levels in both patient groups. However, the significantly increased β ‐LG‐specific IgG 4 levels in clinically reactive non‐IgE‐mediated CMA patients, and its median 36‐fold reduction in tolerant patients, suggested a possible immunopathological role for IgG 4 in delayed CMA. Similarly, the significantly increased β ‐LG‐specific IgE levels in IgE‐mediated CMA patients were decreased 44‐fold in tolerant patients. The tolerant patients had apparently shifted the humoral immune response from a β ‐LG‐specific IgE‐ and/or IgG 4 ‐dominated immune response to an IgA‐dominated immune response as the IgA/IgE or IgA/IgG 4 ratios increased 90‐ and 15‐fold in tolerant IgE‐mediated‐, and non‐IgE‐mediated CMA patients, respectively. Thus, the marked difference in β ‐LG‐specific Ig ratios suggested a tolerance‐induced inhibition of a Th 2 ‐type of immune response with significantly increased IgA dominance in both CMA patient groups.