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.