Casein‐specific immunoglobulins in cow's milk allergic patient subgroups reveal a shift to IgA dominance in tolerant patients

Differences in casein‐specific immunoglobulin (Ig) G‐subclass and IgA serum levels between reactive and tolerant patients may hint at the immunopathogenesis during tolerance development in cow's milk allergy (CMA). α ‐, β‐ and κ ‐casein‐specific IgG 1 , IgG 4 , IgE and IgA serum levels were compared in clinically reactive and tolerized IgE‐mediated (n = 15) and non‐IgE‐mediated (n = 14) CMA with delayed gastrointestinal symptoms, using enzyme‐linked immunosorbent assay (ELISA) and immunoblot techniques. The median anti‐casein IgE levels in clinically reactive IgE‐mediated CMA patients (n = 9) were 140‐ to 180‐fold higher than in tolerized patients (n = 6) and 160‐ to 200‐fold higher than in controls (n = 10). Median α ‐, β‐ and κ ‐casein‐specific IgG 1 and IgG 4 levels were nine‐ to 60‐fold higher in reactive patients and five‐ to 60‐fold in tolerized patients. Clinical tolerance in IgE‐mediated CMA was thus associated with decreased casein‐specific IgE, IgG 4 and IgG 1 , whereas serum IgA anti‐ α ‐, β ‐ and κ ‐casein remained practically unaltered. Tolerized cow's milk protein (CMP)‐sensitive atopic dermatitis had, in particular, decreased κ ‐casein‐specific IgG 1 levels, compared with clinically reactive patients. The ELISA levels to immunoblot correlation profile for the α ‐, β ‐ and κ ‐casein‐specific IgE suggested that the IgE‐mediated CMA patients predominantly reacted to tertiary α ‐ and β ‐casein epitopes whereas the IgE in non‐IgE‐mediated patients reacted to linearized α ‐, β ‐ and κ ‐casein epitopes. Clinical tolerance in non‐IgE‐mediated CMA patients (n = 9) was associated with a four‐ to 10‐fold decrease in casein‐specific IgE levels, accompanied by a five‐ to eightfold decrease in IgG 1 and five‐ to 60‐fold decrease in IgG 4 levels, whereas casein‐specific IgA levels remained unaltered. Thus, tolerance in both patient groups was characterized by a generalized decreased humoral immune response to caseins, which induced a functional shift to IgA dominance.