Discussion
In this study, we found that OVM-specific IgD serum levels increased in egg-allergic patients with increasing tolerable amounts of heated egg, which is consistent with previous reports of OVM-specific IgG4.6 As egg-allergic patients initially become able to ingest cooked egg during acquisition of natural tolerance, our findings suggest that OVM-specific IgD levels are associated with outgrowing egg allergy.
High-affinity, but not low-affinity, IgE is known to cause anaphylaxis.11 We hypothesized that elevated allergen-specific IgD levels are associated with low-affinity allergen-specific IgE levels as children outgrow egg allergy, resulting in hypo-responsiveness to egg allergens. High-affinity IgE antibodies are derived from memory B cells, whereas low-affinity IgE antibodies are derived from naïve B cells. A recent study demonstrated that allergen-specific IgG+ memory B cells prone to isotype switching without further affinity maturation are likely sources of short-lived IgE+ plasmablasts.12 The IgM and IgD constant regions are located in the first immunoglobulin heavy chain constant region gene block, whereas the IgG4 and IgE constant regions are located in the third gene block.13 During class switching from IgM to IgG or IgE, the IgD and IgM constant regions are removed through a looping-out deletion of the heavy chain DNA interposed between the IgM and IgG or IgE S regions.14 Naïve IgM+IgD+ B cells undergo IgM to IgD class switching and become IgD secreting IgD+ plasma cells. Therefore, allergen-specific IgD production might reflect low-affinity allergen-specific IgE production.
The ratio of OVM-specific IgD to OVA-specific IgD, but not that of OVM-specific IgG4 to OVA-specific IgG4, changed depending on the status of egg allergy. Studies show that IgE and IgG4 antibodies bind largely the same sequential epitopes in patients who remained reactive or outgrew their allergy.15, 16 Overlapping binding patterns between IgE and IgG4 support the hypothesis that the differentiation of allergen-specific memory IgG+ B cells may shift from specific IgE producing cells to specific IgG4 producing cells during the development of allergen immune tolerance. As OVM-specific IgD production was preceded by OVA-specific IgD production, our study suggests that different mechanisms regulate allergen-specific IgD production compared to allergen-specific IgG4 production.
A previous study found that OVM-specific IgE is more effective at differentiating clinically reactive egg-allergic patients from those tolerant of heated egg compared to EW- and OVA-specific IgE, suggesting that reactivity to heated egg is dependent on the affinity of OVM-specific IgE.17 Recently, OVM-specific IgE avidity has shown to improve the predictive value for allergy and anaphylaxis to heated hen’s egg.18 OVM-specific IgD levels might reflect the replacement of high-affinity with low-affinity OVM-specific IgE and thereby discriminate intolerant from partially tolerant egg-allergic patients. On the other hand, even if relatively higher levels of OVA-specific IgD were accompanied with the presence of low-affinity of OVA-specific IgE in the CAE group, OVA-specific IgD could not predict outgrowing egg allergy.
Because of the largest AUC in ROC analysis, the ratio of OVM-specific IgE to OVM-specific IgD could be a useful marker to identify high-risk egg-allergic patients capable of ingesting a low-dose of cooked whole egg who might be a good candidate for low-dose OIT. In fact, low-dose OIT with 1/32 of a cooked whole egg has been shown to induce sustained unresponsiveness to 1/32 and 1/2 of a cooked whole egg, with no severe symptoms.19 Japanese food allergy guidelines recommend an oral food challenge test using a low cumulative dose, corresponding to 1/32 of a cooked whole egg in high-risk cases where a small dose may induce symptoms. 7
There are several limitations to this study. First, there was a small number of patients. Second, the sex ratio differed between groups; however, we do not believe that this influences our results as serum total IgD concentrations in adults are affected by age and smoking but not gender.2 Third, all children were only challenged with heated egg and were instructed to avoid egg of any form if they tested positive with less than 2g of boiled EW. Finally, there was a lack of trajectory of specific IgD levels during natural tolerance development. Further studies involving more patients are needed to elucidate the role of allergen-specific IgD in immune tolerance in egg-allergic patients.
In conclusion, OVM-specific IgD production differs from OVM-specific IgG4 as children natural outgrow egg allergy. The ratio of OVM-specific IgE to OVM-specific D is useful in distinguishing egg-sensitized patients with clinically reactive egg allergy from those partially tolerant to egg.