THE ROLE OF TOLL-LIKE RECEPTOR 2 IN MODULATION OF BREAST MILK COMPONENTS AND ORAL TOLERANCE

Abstract

Food allergy is a common immune-mediated disease of early life that has increased in incidence over the past three decades. The immaturity of the neonatal immune system makes them prone to the development of allergy. Dietary components are essential for their immune responses to develop normal oral tolerance. A diversity of scientific opinions about breast milk's ability to protect against the development of food allergies might be related to dramatic variations in milk-associated immune mediators (IMs) between mothers. Pattern recognition receptors (PRRs) are one of the multiple components that regulate IM production. Toll-like receptor 2 (TLR2), a PRR that is highly expressed in the mammary gland and immune cells, mediates secretion of both pro and anti-inflammatory IMs, some of which are found in breast milk. The role of maternal TLR2 in regulating breast milk components and infant immune system development is still unknown. We evaluated the impact of maternal TLR2 deficiency in susceptibility to allergic diseases in infants using a cross-fostering model in mice. Milk from TLR2 deficient dams had altered IMs content compared to WT dams’ milk. It failed to induce optimal gastrointestinal integrity and expansion of oral tolerance essential immune cells, including tolerogenic dendritic cells (DCs) and regulatory T cells (Tregs) in pups, thus increasing their susceptibility food sensitization. In humans, a soluble form of TLR2 (sTLR2) was detectable in breast milk, in variable amounts, generally higher than those observed in cow’s milk and baby formulas. sTLR2 was undetectable in mouse milk. Human milk sTLR2 concentrations were lower in homozygous mothers with specific single nucleotide polymorphisms (SNPs) in the TLR2 gene and higher in food allergic mothers. We found that a high level of sTLR2 in milk was associated with an increased incidence of allergies in infants if they were breastfed exclusively for six months regardless of the maternal allergic status. Collectively, our findings and experimental models demonstrate significant associations between maternal TLR2 and food allergy development in infants and the importance of considering both maternal genetic factors and feeding practices.