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IgG4 antibodies to cow’s milk proteins are strongly associated with pediatric Eosinophilic Esophagitis

Published online: April 17, 2018

Eosinophilic esophagitis (EoE) is an inflammatory disease of the esophagus that has increased in prevalence over the last two decades and is considered a form of food allergy. It is more common in males than females and affects both children and adults. The evidence for food as a cause of the disease comes largely from the success of food avoidance, with elimination of one or more foods often sufficient to achieve disease remission. Current data do not support a central role for specific IgE, an antibody that is classically associated with allergic disease, in EoE disease pathogenesis. However, recent reports in adults suggested that another antibody isoptype, IgG4, may be important in EoE. Although IgG4 has often been associated with antigen-specific tolerance, it has a well-established relationship with allergic disease and the possibility that these antibodies could be pathogenic is suggested by the high levels of this antibody isotype found in IgG4-related disease.    

On this backdrop the group of Platts-Mills, Erwin and colleagues set out to investigate food-specific serum IgG4 responses in children with EoE. As recently published in The Journal of Allergy and Clinical Immunology (JACI) they initially assessed specific IgG4 to dominant proteins in foods often associated with EoE, ie – milk, wheat, soy, egg and peanut, in 30 children with EoE. Those tests showed that the highest IgG4 responses were to three major cow’s milk proteins (α-lactalbumin, β-lactoglobulin, and caseins) and to gluten. Thus, they focused on these proteins in an extended analysis that included a total of 71 children with EoE and that included analysis of specific IgE to the same proteins. Because the ‘normal’ levels of IgG4 to these food proteins are not well defined in the general population they also collaborated with the Viva birth cohort to obtain serum of mid-adolescent age children whose mothers had been recruited during pregnancy and who were not ‘enriched’ for allergic disease. The study design allowed the investigators to compare the prevalence and levels of specific IgG4 to α-lactalbumin, β-lactoglobulin, caseins and gluten in children with EoE and control children, and to further investigate the effect of age, gender and dairy consumption on the specific IgG4 responses to cow’s milk proteins and gluten.

The findings reveal that specific IgG4, particularly to major cow’s milk proteins, were present at higher levels in children with EoE than in control children. These measurements of IgG4 and IgE antibodies to milk proteins showed that many of the sera had as much as 10,000 times as great IgG4 as the levels of IgE antibodies. This is consistent with published results in adults and confirms that IgG4 is a more pronounced feature than IgE antibodies in children with EoE. The association of high-titer specific IgG4 (ie, ≥ 10 µg/mL) to all three major cow’s milk proteins was strongly associated with EoE, achieving odds ratios from 9.2 to 14.8 in a logistic regression analysis adjusted for age, gender and dairy consumption. There was also a trend toward a stronger association in boys than girls, an interesting suggestion given the known gender-bias in EoE. The study did not address whether the high levels of these IgG4 antibodies are mechanistically involved in the pathogenesis of EoE, but future studies can be designed to address this possibility, and also the possibility that measuring food-specific IgG4 could help to identify subjects with a high risk of EoE prior to esophagoscopy.  
The Journal of Allergy and Clinical Immunology (JACI) is an official scientific journal of the AAAAI, and is the most-cited journal in the field of allergy and clinical immunology.