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The Immunomodulatory role of maternal IgG in infant atopic programming
Project Code: T07033
Allergy and Inflammation Sciences, University of Southampton.
Acute allergic reactions to foods are associated with the development of immunoglobulin E (IgE) antibodies. Symptoms of food allergy most commonly appear in the first 3 years of life and in western communities egg is the commonest allergen in this age group. Symptoms range from urticaria and eczema, angioedema, asthma, rhinitis, vomiting, diarrhoea and failure to thrive, through to life threatening anaphylaxis.
Aims and Objectives
Over the last 10 years it has become apparent that the seeds of allergic disease are sown in very early life and pivotal events may occur during pregnancy. The mother’s nutrition, health and environment as well as the genotype of both the mother and foetus interact to influence the developing immune system which in turn will affect the risk of allergic disease once the baby is born. Amongst a number of modulatory factors that have been identified are immunoglobulin G (IgG) antibodies. IgG is actively transported across the placenta from mother to foetus as a form of passive immune protection which is sustained through the early months of the infant’s life while the baby begins to generate its own IgG antibodies. There is evidence that allergen specific IgG antibodies passed from mother to foetus have a protective role against the development of allergy.
Thus high levels of IgG antibody to cat allergen at birth have been associated with less subsequent cat allergy. Furthermore, mothers receiving rye grass immunotherapy which raises the rye grass specific IgG antibody levels, if continued through pregnancy is associated with less rye grass allergy in the babies. During a previous Food Standards Agency funded grant (T07005) we found that high ovalbumin specific IgG antibodies was associated with a reduced risk of subsequent allergy to ovalbumin and also other allergens over the first year of life.
The above observations are very distinct from those associated with the baby’s own IgG antibodies. There is evidence that those babies who have food and other allergies develop not only increased IgE but also IgG antibody levels. It, therefore, becomes important to understand how and why antenatal exposure to IgG antibody is protective when this is delivered from the mother to the foetus, while the baby’s own generation of IgG antibody is associated with increased susceptibility to allergy. This study has, therefore, been designed to investigate how maternal IgG antibody might regulate the developing foetal immune system in relation to the subsequent development of allergic problems.
A birth cohort was recruited where either the mother or father or a sibling in the family had already shown signs of allergic disease. The mothers during pregnancy were randomised to either a controlled trial of egg avoidance through pregnancy and lactation or to a normal diet as set up during T07005. Over 200 families were recruited and babies have been evaluated in the current study up to 3 years of age for signs and symptoms of allergic disease by clinical history, examination, allergy skin tests and blood sampling. The focus has been to establish whether different forms of ovalbumin specific IgG, which were generated by the mother and transmitted to the foetus, had different effects on allergy outcome. Additionally the way in which ovalbumin has been transmitted from the mother to the foetus across the placenta has been related to outcome as has the affinity of the IgG antibodies for ovalbumin. An attempt has also been made to identify whether and how ovalbumin IgG antibody would block cord blood mononuclear cell (CBMC) proliferative responses to stimulation with ovalbumin. The IgG and IgE binding epitopes of ovalbumin have also been characterised. Finally, the pattern of generation of ovalbumin IgG and IgE postnatally has been related to clinical outcomes.
We have shown that the levels of ovalbumin specific total IgG and ovalbumin specific IgG1 and G4 in the newborn baby’s cord blood correlates closely with the mother’s levels indicating transmission across the placenta. While this has been shown in the past for total IgG and IgG1, it has not previously been shown for IgG4 antibodies. A non allergic outcome in the infants at 6 months of age was related to the lowest and highest cord ovalbumin specific IgG levels. However, longer term non allergic outcomes at 18 months and 3 years were only related to the highest cord specific ovalbumin IgG concentrations. Furthermore, these higher levels of total IgG ovalbumin antibodies were related to higher proportions of IgG4 to IgG1 ovalbumin antibody.
As distinct from the above observations where IgG of maternal origin was protective particularly when IgG4 antibody levels were high, when the infant generated its own IgG antibodies this was strongly associated with subsequent allergy. Thus high levels of ovalbumin specific IgG by 6 and 18 months of age was a strong predictor of an allergy risk. This was primarily related to the IgG1 rather that G4 levels. In a previous long term follow up a raised IgG1 ovalbumin specific antibody was a strong predictor of later asthma.
There were distinct patterns of ovalbumin exposure of the foetus through transplacental transmission. This was either as free ovalbumin or complexed with IgG or a mixture of the two. However, there was no association between a given pattern of exposure and allergic outcome. Furthermore, affinity of the IgG antibody for ovalbumin did not have any relation to allergic outcome. The degree of affinity was inversely related to the concentration of the antibody.
Assessment of the affects of ovalbumin specific IgG in blocking CBMC responses to ovalbumin was compromised by endotoxin contamination of the standard commercially available ovalbumin. Most of the cellular proliferative responses were a consequence of endotoxin contamination and there was no effect of IgG in blocking the response. This relatively new finding, though not the first, suggests that previous studies using commercial ovalbumin should be interpreted taking account of the endotoxin contamination. We have shown that serum containing maternal ovalbumin specific IgG does not block CBMC responses to ovalbumin. Indeed on occasions, the serum enhanced responses. Subsequent experiments have shown that the stimulation was not due to the IgG but to other factors in the serum, likely to be a range of cytokines and perhaps ovalbumin itself. Further studies will be required to elaborate on these findings which must be interpreted with caution. There is the potential that natural endotoxin exposure from egg might explain the apparent protective effect of high maternal ova IgG, and therefore high maternal egg intake on the development of allergy in the infant.
Finally we have shown nine epitope peptide fragments of ovalbumin which bind to ovalbumin specific IgE. Eight of these nine also bound ovalbumin specific IgG. Thus there was one unique IgE binding epitope. Furthermore, we also identified one unique peptide showing high binding to IgG but not IgE.
The most important finding is that the generation of ovalbumin specific IgG and particularly IgG4 rather than IgG1 antibodies in the mother and transported to the foetus is associated with protection against later allergic sensitisation. Whether or not this is a direct blocking effect or an epiphenomenon remains to be established. The potential for endotoxin contamination of native egg to contribute to the effect requires further elaboration but is compatible with the hygiene hypothesis. The overall implication is that it is likely to be preferable to recommend high intakes of allergenic foods during pregnancy rather than to recommend attempts at exclusion. The effects of the IgG antibody in reducing allergy outcome did not appear to be a consequence of suppression of CBMC responses to allergen though these results must be interpreted with caution. Finally the identification of a unique peptide ragment of ovalbumin which exclusively binds to IgG implies that there may be the potential to use this as a means to modulate immune responses without triggering allergy. Further investigations will be required before this can be considered as potential for exploitation.
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