The concept of transmissible immunity from mother to offspring during breastfeeding originated from the classic studies of Paul Ehrlich published in 1892. His experiments showed that offspring of non-immune mother mice nursed by immune foster mothers (but not their own mothers) acquire six weeks of protection from toxin challenge. The anti-toxin (antibody) was present in the mother's milk, passing apparently unhindered across the intestinal wall into the circulation of the newborn (4). Ehrlich hypothesized that this explained how the suckling newborn is so frequently protected from infections during the first year of life. We now know that the neonatal Fc receptor (FcRn) carries the bulk of ingested maternal IgG from the gut lumen across the intestine where it enters the circulation in breastfed offspring. Furthermore, it is established that these passively absorbed maternal antibodies provide neonates with protective immunity to infectious agents at a time prior their own immune competence (5). However, it is appreciated that there are additional complexities in the mechanism of action of maternal antibodies in neonates (6). For example, the breast milk transmission of allergic or autoimmune pathology from mother to child (5;7;8) provides a compelling argument for more detailed understanding of critical mediators of antibody uptake operational in the intestine in neonatal life. This is especially true in the advent of an identified therapeutic target (FcRn) with potential to enhance or prevent delivery of maternal antibodies as a means to improve child health. In the course of our studies to define critical mediators in maternal transmission of resistance from development of asthma, we measured the levels of ingested maternal antibodies in FcRn-deficient and -sufficient offspring nursed by allergic foster mothers. To our surprise, in addition to the expected decrease in the absorption of allergen-specific IgG1 by FcRn-/- compared to FcRn offspring (9), was the virtual absence of absorbed maternal allergen-specific IgA and IgE in breastfed FcRn-/- mice. Experiments performed in rats in the 1970s used radiolabeled antibodies purified from serum of myeloma patients to show intestinal uptake of IgG, but not IgA, IgE, IgM or IgD (10). This provided the foundation for the focused effort that ultimately led to the identification FcRn (11;12). It does not appear that this immune mechanism has been reexamined in foster nursing experiments as a means to quantify levels of maternal IgA or IgE absorbed from breast milk by FcRn-deficient mice. However, it has been proven in many laboratories that FcRn plays no role controlling the half-life of IgA or IgE, despite its critical role in protecting all IgG isotypes from degradation in vivo (9). In this exploratory application, we will resolve what appear to be discordant observations to determine the role for FcRn in absorption of maternal IgA or IgE from the gastrointestinal tract. Thus, we propose:
Aim 1. To determine whether FcRn binds IgA or IgE to facilitate transcytosis and absorption from the gut lumen;
and Aim 2. To determine whether immune complexes provide a scaffold to enhance FcRn-mediated uptake of IgA or IgE in the neonatal gastrointestinal tract.

Public Health Relevance

The neonatal Fc receptor for IgG (FcRn) mediates mother to child transmission of immunity, providing children with protection from infections in early life. Our preliminary data challenge fundamental concepts in the basic understanding of the biology of FcRn, a molecular target with tremendous therapeutic potential to positively impact health in children and adults.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Exploratory/Developmental Grants (R21)
Project #
5R21AI092060-02
Application #
8263746
Study Section
Gastrointestinal Mucosal Pathobiology Study Section (GMPB)
Program Officer
Prabhudas, Mercy R
Project Start
2011-05-15
Project End
2014-04-30
Budget Start
2012-05-01
Budget End
2014-04-30
Support Year
2
Fiscal Year
2012
Total Cost
$192,500
Indirect Cost
$67,500
Name
University of Connecticut
Department
Microbiology/Immun/Virology
Type
Schools of Medicine
DUNS #
022254226
City
Farmington
State
CT
Country
United States
Zip Code
06030