High Levels of IgG4 Antibodies to Foods During Infancy Are Associated With Tolerance to Corresponding Foods Later in Life

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Tomicić S, Norrman G, Fälth-Magnusson K, Jenmalm MC, Devenney I, Böttcher MF. Pediatr Allergy Immunol. 2009;20(1):35–41PURPOSE OF THE STUDY. To examine the serum and salivary antibody responses to food-elimination diets and to identify immunologic parameters related to oral tolerance.STUDY POPULATION. Prospective study of 89 children <2 years of age with eczema.METHODS. Children with eczema were examined at 3 time points, that is, at enrollment, after a 6-week treatment period, and at 4.5 years of age. Treatment included topical emollients and/or steroids for all children and a 6-week egg- and/or milk-elimination diet for 60 of the 89 children in the cohort of children who were diagnosed with an allergy to 1 or both foods. Laboratory data included skin-prick testing (SPT) to food allergens; total and specific serum immunoglobulin E (IgE) levels; serum IgA, IgG1, and IgG4 antibodies to ovalbumin and β-lactoglobulin; total IgA levels; and saliva IgA levels. At study completion, children were categorized as being egg or milk tolerant if the food was reintroduced into the diet after passage of a challenge in the clinic or at home.RESULTS. Of the 89 participating children, 60 were prescribed elimination diets that were based on SPT results, as follows: 24 egg, 11 milk, and 25 both. At study completion (4.5 years of age), 37 of 49 previously egg-allergic and 11 of 36 previously milk-allergic children were considered to be tolerant. Children who were egg or milk tolerant at 4.5 years of age had significantly higher levels of ovalbumin- or β-lactoglobulin–specific IgG4 at enrollment, respectively. Tolerant children also had higher food-specific IgG4/IgE ratios at 4.5 years. The highest IgG4/IgE ratios were found in children who had circulating milk- and/or egg-specific IgE antibodies but negative SPT results at enrollment. There was no significant difference between total or food-specific IgE levels at enrollment between the tolerant and nontolerant groups; however, children in the tolerant group had significantly lower food-specific IgE antibodies at 4.5 years, compared with those in the nontolerant group. There were no significant differences in total IgA, saliva IgA, or food-specific IgA levels between groups at enrollment or at 4.5 years.CONCLUSIONS. High food-specific IgG4 antibodies at <2 years of age and high IgG4/IgE ratios were related to oral tolerance to milk and egg at 4.5 years of age.REVIEWER COMMENTS. This study demonstrates that early immunologic markers may be indicators of oral tolerance acquisition among a subset of children with eczema and milk and/or egg allergy. These data may be useful in conjunction with other measures such as serum-specific IgE levels, history of past reactions, and SPT to predict future oral tolerance acquisition. One weakness of the study was the fact that participants did not undergo a diagnostic food challenge to confirm clinical reactivity at enrollment, and recommendations for food elimination were made on the basis of SPT results. It is likely that elimination diets were prescribed for some participants who were actually clinically tolerant at enrollment despite having a positive SPT result. Future studies to determine the utility of immunologic markers should confirm clinical reactivity by performing a diagnostic food challenge or confirming a convincing history of past reactions.