Date of Award
Fall 2022
Document Type
Dissertation
Degree Name
Doctor of Philosophy (PhD)
Department
Investigative Medicine
First Advisor
Eisenbarth, Stephanie
Abstract
Immunoglobulin A (IgA) is the predominant antibody isotype in the gut, where it regulates commensal flora and neutralizes toxins and pathogens. The function of food-specific IgA in the gut is unknown but is presumed to protect from food allergy. Specifically, it has been hypothesized that food-specific IgA binds ingested allergens and promotes tolerance by immune exclusion; however, the evidence to support this hypothesis is indirect and mixed. While it is known that healthy adults make gut peanut-specific IgA, it is unclear whether children also have gut peanut-specific IgA. We found that in a cohort of non-food allergic infants (n=112), there is detectable stool peanut-specific IgA that is similar to adult quantities of gut peanut-specific IgA. To investigate whether this peanut-specific IgA is associated with peanut tolerance, we examined a separate cohort of atopic children (n=441) and found that gut peanut-specific IgA does not predict protection from development of future peanut allergy in infants, nor does it correlate with concurrent oral tolerance of peanut in older children. In fact, we observed higher plasma peanut IgA in those with peanut allergy. Similarly, egg white-specific IgA was detectable in infant stools and did not predict egg tolerance or outgrowth of egg allergy. Bead-based epitope assay analysis of gut peanut-specific IgA revealed similar epitope specificity between children with peanut allergy and those without; however gut peanut-specific IgA and plasma peanut-specific IgE had different epitope specificities. These findings call into question the presumed protective role of food-specific IgA in food allergy.Even though gut food-specific IgA may not be protective in food allergy, it is still universally made in humans, unlike pathogenic food-specific isotypes, like IgE, which causes food allergy. As such, it is important to understand the mechanisms by which food-specific IgA can be induced to understand how non-pathogenic food responses and potentially augment them to prevent food IgE production. While there is evidence that food requires co-administration with an adjuvant to induce gut food-specific IgA, it is unclear what types of adjuvants can lead to food-specific IgA production. We have previously reported that cholera toxin, a member of the AB5 toxin group, leads to the production of food-specific IgA, but the natural adjuvant(s) that people are exposed to are as yet unknown. We examined other AB5 toxins, intestinal infections, broad-spectrum antibiotics, allergenic adjuvants, TLR7 stimulation with imiquimod, and iNKT cell activation with the synthetic lipid KRN7000 to see whether these stimuli could induce gut peanut-specific IgA. Of these adjuvants, we found that only AB5 toxins, TLR7 stimulation, and iNKT cell activation led to the production of gut peanut-specific IgA. On the surface, it appears that there is not a common factor between these three types of adjuvants, so we examined the cellular mechanisms of imiquimod and KRN7000 to identify whether there are similarities. We determined that both imiquimod and KRN7000 depend on CD4+ T cells to make food-specific IgA. Further, both adjuvants require type 2 conventional dendritic cells (cDC2), but only imiquimod relies on TLR7 expression and only KRN7000 relies on iNKT cells. These findings indicate that AB5 toxins, TLR7 stimulation, and iNKT cell activation can all induce gut peanut-specific IgA through disparate pathways that activate cDC2 dendritic cells and depend on CD4+ T cells.
Recommended Citation
Liu, Elise, "The Role and Production of Gut Food-Specific Immunoglobulin A" (2022). Yale Graduate School of Arts and Sciences Dissertations. 823.
https://elischolar.library.yale.edu/gsas_dissertations/823
