Food allergy is defined as an adverse clinical reaction due to an immune-mediated hypersensitivity response resulting from the ingestion of a food. A wide variety of foods have been shown to produce allergic reactions including cow’s milk; chicken eggs; legumes; fish and shellfish; and cereals. (1) Depending on the speed of onset of symptoms, less than 45 minutes to 2 hours to days, immediate and delayed food allergies have been described throughout the literature encompassing a variety of gastrointestinal, respiratory, and cutaneous pathologies. (2) The inflammatory response is the common theme to all allergic pictures and is characterized by the release of chemical mediators, vasodilation, increased vascular permeability, edema, and tissue damage.

The role of IgE in Type I immediate hypersensitivity allergic reactions is well understood in the scientific literature. In classic Type I IgE-mediated hypersensitivity, food-specific IgE antibodies bind to Fc[epsilon]RI and Fc[epsilon]RII receptors on the cell membranes of mast cells, basophils, macrophages, monocytes, lymphocytes, eosinophils and platelets. Inflammatory mediators including histamine, serotonin, and tumor necrosis factor alpha, are released and induce symptoms upon exposure of these bound antibodies with food antigens that have penetrated the protective intestinal mucosal barrier. It is generally understood that symptoms of an IgE-mediated allergy manifest within 2 hours of consumption of the culpable food. Classical atopic symptoms include; urticaria, eczema, respiratory and nasal symptoms, and gastrointestinal distress. In the gut specifically, mast cell degranulation and mediator release promotes muscle contraction, stimulates pain fibers, increases mucus production, recruits inflammatory cells, and increases permeability to macromolecules, the latter of which may perpetuate a vicious cycle of food antigen exposure and symptoms. (3) Specific IgE has a half-life of only 1-2 days in circulation, however, exhibits residual activity on mast cells of about 2 weeks with late phase reactions and inflammatory changes. (4)

It is strongly argued in the scientific literature that allergic reactions may occur independent of antigen-specific IgE. High affinity receptors for IgG (FcgammaRI), on human mast cells and basophils, are activated in immediate hypersensitivity reactions, following receptor aggregation through IgG binding. IgG-mediated immediate hypersensitivity results in degranulation, with the release of histamine and arachidonic acid metabolites. (5) Okayama et al. have demonstrated that the mediator profile through activation of FcgammaRI receptors on human mast cells, is qualitatively indistinguishable from responses stimulated through FcepsilonRI, the high affinity receptor for IgE. (6) in addition, FcgammaRI receptor expression on mast cells is up regulated by IFN-gamma, allowing for recruitment of mast cells through IgG-dependent mechanisms into the IFN-gamma-rich inflammatory locus. (7-9) IgG-mediated immediate hyper-sensitivity, also known as IgG-mediated anaphylaxis, is not a new concept in allergy research. In conventional circles, anaphylaxis denotes an immediate hyper-sensitivity reaction to an allergen, exclusively mediated by IgE antibodies. Hence, the foundation of the skin-scratch testing method, which detects IgE-induced histamine release through a wheal-and-flare response from antigen provocation, and IgE RAST quantification. However, as early as the 1970’s, Parish demonstrated the presence of anaphylactic IgG antibodies in human sera. (10) Halpern et al. later suggested that this IgG anaphylactic antibody is indeed a subtype of IgG4. Further studies from Bryant et al. and Pepys have shown that IgG anaphylactic antibody activity could not be removed through precipitation with anti-IgE but only by precipitation with anti-IgG, clearly indicating a novel mechanism for mast cell recruitment into inflammation. (11,12) However, the potential for IgG4 to inhibit, or block IgE-mediated anaphylaxis is a clearly established theme in this line of research, and some authors argue a correlation between increased IgE levels and IgG4 in atopic patients, where IgG4 is thought to hamper antigen binding to cell-bound IgE which would otherwise promote a much stronger allergic reaction. Moreover, the basic principle behind allergen immunotherapy (IT), is oral or intradermal administration of the allergen to induce the development of a systemic immune response, including the production of systemic blocking antibodies. In an update on immunotherapy, “Immunotherapy update: mechanisms of action,” Greenberger concludes that the reduction of allergic symptoms, specifically of allergic rhinitis and asthma, reflect changes in the cytokine and immunoglobulin profile from intradermal allergen provocation. Most notably, intradermal grass injection resulted in a profound increase in antiallergen IgG (2-10 fold), IgG4 (10-100 fold), a decline in antiallergen IgE antibodies, reduced numbers of nasal or bronchial mast cells and eosinophils, down-regulation of T-helper 2-lymphocytes and IL-4, and a lack of increase in interferon gamma. (13) This study clearly establishes IgG4 as a blocking antibody. Furthermore, in a study involving 42 children with malabsorption disorders, those demonstrating high levels of IgG antibodies to ovalbumin (Anti-OA) showed significantly lower serum concentrations of OA at both 2 and 8 hours after oral OA administration, compared to children with lower anti-OA levels. The researchers conclude that the high levels of IgG antibodies to ovalbumin demonstrate blocking capacity in the circulation. Such antibodies in the intestinal secretions and in the gut wall would limit the quantity of antigen that can penetrate the mucosa and enter circulation. (14) However, other studies show elevated IgG4 in symptomatic atopic patients without a concomitant rise in IgE levels. (15-17)

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.