IgE and IgG4 Antibodies to Cow's Milk Components in Children with Eosinophilic Esophagitis: Higher Specific IgG4 Antibodies and IgG4:IgE Ratios Compared with Subjects with IgE-Mediated Food Allergy

Background: Eosinophilic esophagitis (EoE) in adults is characterized by elevated serum IgG4 antibodies (Ab) to whole food allergens with low to negative specific IgE Ab.  The mechanistic involvement of IgG4 Ab in EoE is unclear because these Ab not only are predominately bispecific in vivo and not known to elicit inflammation via Fc binding, but also their appearance is a marker of tolerance during oral immunotherapy (OIT).  Presented is an analysis of specific IgG and IgE Ab to cow’s milk components in children with EoE and to other relevant allergen components in subjects with IgE-mediated food allergy.

Methods: Sera were assayed for specific IgE and IgG4 Ab to cow’s milk components Bos d 4, Bos d 5, Bos d 6 and Bos d 8, galactose-alpha-1,3-galactose (alpha-gal), and/or peanut component Ara h 2 by ImmunoCAP.  Specific pan-IgG and IgG4 Ab to Bos d 5 or alpha-gal were measured by adsorbing serum Ab onto solid-phase Protein G-Sepharose and anti-IgG4-Sepharose respectively, followed by incubation with radiolabeled allergen.  Levels of serum IgG1 (and IgG2) Ab to Bos d 5 and alpha-gal and specific IgG4:IgE ratios were determined.

Results: IgG4 Ab to Bos d 4, Bos d 5, and Bos d 8 were at least 5-fold higher, and specific IgG4:IgE ratios were greater than 100-fold higher in children with EoE as compared with subjects with delayed anaphylaxis to red meat, or peanut anaphylaxis before or after OIT (p<0.001).  Although there was no obvious association between histological remission (<15 eosinophils/hpf) and serology following treatment (i.e., swallowed steroids or cow’s milk elimination diet) in children with EoE, a reduction in serum IgG4 Ab to cow’s milk components and specific IgG4:IgE ratios was observed among those treated with cow’s milk elimination diet.  Focused serology revealed IgG1 and IgG4 Ab to Bos d 5 with low to negative levels of IgE Ab to cow’s milk components in the sera of children with EoE.  In contrast, the antibody response in subjects with delayed anaphylaxis to red meat was dominated by IgE and IgG1 Ab to alpha-gal with low to undetectable levels of IgG4 Ab.

Conclusions: Specific IgG4:IgE ratios to cow’s milk components are very high in children with EoE, and this may explain the lack of positive results for cow’s milk components using the Immuno Solid-phase Allergen Chip (ISAC) microarray test.  Our results are in keeping with a model where the pathology of EoE is not due to allergen-specific IgE Ab, and is more likely to be T cell-mediated.