Cow's Milk and Immune Function in the Respiratory Tract: Potential Mechanisms

Abstract

During the last decades, the world has witnessed a dramatic increase in allergy prevalence. Epidemiological evidence shows that growing up on a farm is a protective factor, which is partly explained by the consumption of raw cow's milk. Indeed, recent studies show inverse associations between raw cow's milk consumption in early life and asthma, hay fever, and rhinitis. A similar association of raw cow's milk consumption with respiratory tract infections is recently found. In line with these findings, controlled studies in infants with milk components such as lactoferrin, milk fat globule membrane, and colostrum IgG have shown to reduce respiratory infections. However, for ethical reasons, it is not possible to conduct controlled studies with raw cow's milk in infants, so formal proof is lacking to date. Because viral respiratory tract infections and aeroallergen exposure in children may be causally linked to the development of asthma, it is of interest to investigate whether cow's milk components can modulate human immune function in the respiratory tract and via which mechanisms. Inhaled allergens and viruses trigger local immune responses in the upper airways in both nasal and oral lymphoid tissue. The components present in raw cow's milk are able to promote a local microenvironment in which mucosal immune responses are modified and the epithelial barrier is enforced. In addition, such responses may also be triggered in the gut after exposure to allergens and viruses in the nasal cavity that become available in the GI tract after swallowing. However, these immune cells that come into contact with cow's milk components in the gut must recirculate into the blood and home to the (upper and lower) respiratory tract to regulate immune responses locally. Expression of the tissue homing-associated markers α4β7 and CCR9 or CCR10 on lymphocytes can be influenced by vitamin A and vitamin D3, respectively. Since both vitamins are present in milk, we speculate that raw milk may influence homing of lymphocytes to the upper respiratory tract. This review focuses on potential mechanisms via which cow's milk or its components can influence immune function in the intestine and the upper respiratory tract. Unraveling these complex mechanisms may contribute to the development of novel dietary approaches in allergy and asthma prevention.

Keywords: allergies; asthma; barrier functioning; gut–lung axis; immune regulation; raw cow’s milk; respiratory syncytial virus; upper airways.

Figure 1

Potential mechanisms of cow’s milk-induced immune homeostasis in the upper respiratory tract. In the oropharynx, raw cow’s milk components can contribute to immune homeostasis via different mechanisms. First, bovine IgG can bind and possibly even neutralize bacteria, viruses, or allergens. Immune complexes are transported over the epithelial barrier by neonatal Fc receptor (FcRn) or transported via M-like cells to reach the mucosal tissue in the Waldeyer’s ring. The immune complexes can bind to FcγRII on antigen-presenting cells (APCs), leading to phagocytosis and clearance of the pathogens—as well as antigen presentation to (regulatory) T cells. Second, sialylated oligosaccharides may function as decoy receptors for viruses in the lumen of the oropharynx, preventing viral adhesion. Further, the expression of tight junction proteins can be enhanced by several milk components, thus strengthening the mucosal barrier against breaching by allergens and pathogens. Finally, several milk components contribute to immune regulation by inducing the differentiation into tolerogenic dendritic cells (tol. DC) and immunoregulatory T cells (Tregs). In this way, raw cow’s milk can promote a local microenvironment that contributes to immune homeostasis in the upper airways.

Figure 2

Mechanisms involved in the gut-lung axis linked to milk components. TLR signaling by microbiota in the gut results in improved airway immunity although the exact mechanism in this gut–lung axis is unknown. Microbiota, specifically Bifidobacteria, may ferment sialylated oligosaccharides present in cow’s milk into short-chain fatty acids (SCFAs), which are taken up into the circulation. Cow’s milk contains vitamin A, vitamin D3, and 1,25-hydroxyvitamin D3. Vitamin A and vitamin D3 can be taken up by epithelial and dendritic cells (DCs) and converted by the enzymes RALDH and 1α-hydroxylase into retinoic acid (RA) and 1,25-hydroxyvitamin D3, respectively. However, the majority of vitamin D3 is taken up into the systemic and converted into its active form in the kidneys. In the lamina propria, RA may induce expression of gut homing markers CCR9 and α4β7 on T cells and CCR9 on B cells directly or prime DC to induce the expression of these markers in the mesenteric lymph node (MLN). 1,25-hydroxyvitamin D3 may induce the expression of homing marker CCR10 on T and B cells directly or indirectly via vitamin D3-primed DC (VitD3 DC). In addition, 1,25-hydroxyvitamin D3 downregulates the expression of CCR9 on lymphocytes in a direct way. Lymphocytes expressing CCR9 have a homing capacity toward the small intestine, while lymphocytes expressing CCR10 have a homing potential toward the colon and respiratory tract, providing a potential mechanism of the gut–lung axis.