A critical review of IgG immunoglobulins and food allergy—implications in systemic health

Townsend Letter for Doctors and Patients, August-Sept, 2003 by Raymond M. Suen, Shalima Gordon

Supporting evidence from Yoshida et al. demonstrate that IgG4 is not only elevated in milk allergic children, for example, but diagnostic of milk allergy in atopic children independent of IgE. (18) In another study, milk-specific IgG4 in particular, IgG4 to casein, has been shown to be diagnostic of milk allergy causing eczema in adults. (19) In an elegant study by Eysink et al. atopy could be correctly classified in 75.4% of young children studied with or without eczema, through identification of high levels of IgG to certain foods. In particular, high levels of IgG antibodies to egg, milk, orange, and a mixture of wheat and rice, were identified in atopic children compared to nonatopic children. Further, this elevation served as a positive predictor of increased IgE antibodies to inhalant allergens, namely cat, dog, and house dust mite. The investigators of this study conclude that the association drawn from these results may clearly identify children with an increased risk of developing future allergic disease. (20)

Other reports demonstrating the importance of IgG antibodies in food allergies include IgG-mediated allergy to casein and other milk proteins, which has been implicated in the development and progression of infantile autism. (21) Furthermore, one study involving rheumatoid arthritis, showed a decrease in gluten-specific IgG serum levels which correlated with an improvement in the symptoms of this disease in 40% of subjects placed on a gluten-free diet, compared to a 4% improvement in a control group, over a one-year period. (22)

The evidence from the above research suggests that IgG4 antibodies may act as sensitizing as well as blocking antibodies. This dual role of IgG4, anaphylactic or blocking antibody, lends weight to defining IgG4 subtypes 4a and 4b, as described by Halpern and Scott in their review, "Non-IgE mediated mechanisms in food allergy," whereby exposure to an allergen may lead to the production of the anaphylactic or nonanaphylactic/blocking subtype, which may depend on genetic predisposition and environmental factors. (23) It is interesting to note that there is some structural homology between IgG4a, IgG1 and IgG3 immunoglobulins, and between IgG4b and IgG2. (24) IgG subclass antibodies and their role in the pathogenesis of food allergic disease deserves considerable attention. Chronicity of antigen exposure, a hyperactive mucosal immune system and/or an increased permeability to macromolecules, are factors to consider influential in IgG4 subclass expression and progression of disease.

A distinguishing feature of IgG4 is its inability to activate the classical complement pathway. This supports the role of IgG4 as a blocking antibody. In a study of egg hypersensitivity, Nakagawa draws our attention to IgG1 involvement in clinical egg hypersensitivity, suggesting that increased IgG4 reduces the effect of complement-fixing antibodies like IgG1; a good prognostic sign, as he suggests. (25) This is further supported by Van Der Zee, who shows that IgG4 antibodies inhibit complement activation of IgG1 antibodies, probably through competitive binding for related antigenic determinants. (26)