Lactoferrin also inhibits the binding of pathogens to host cells and regulates excess immune responses via blocking pro-inflammatory cytokines and free-radical activity [4,111,112]. Understanding the underlying mechanisms could identify new therapeutic targets and strategies for disease prevention across the lifespan. Keywords:breastfeeding, developmental origins of health and disease, human milk, microbiota, mucosal immunity == INTRODUCTION == Mucosal membranes are composed of specialized ORM-10962 epithelial cells covering a layer of connective tissue that lines the respiratory, digestive, and urinary tracts. The immune system, with its innate and adaptive components, is an essential element of the mucosa, which serves as the body’s first line of defense Rabbit polyclonal to Neuron-specific class III beta Tubulin against pathogens and the first point of contact for establishing tolerance toward innocuous antigens such as food proteins and commensal bacteria [1]. After full gestation, all of the basic mucosal immune elements are in place, but they exist in an immature state characterized by incomplete barrier integrity, deficiency in secretory immunoglobulin A (sIgA), reduced complement activation, and low levels of memory immune cells [2]. Therefore, infants depend on their mother’s milk for passive immunity, and rely on milk and ORM-10962 other exogenous factors to stimulate mucosal immune system development. Besides essential nutrients, human ORM-10962 milk is rich in cytokines, immunoglobulins, growth factors, microbiota, soluble receptors, immune cells, enzymes, lipids, and oligosaccharides [3,4,5]. These components are dynamic and change over time to match the needs of infants throughout lactation. Some factors also have a diurnal rhythm or fluctuate during a single feeding [6]. By the end of pregnancy, the mammary gland starts to produce colostrum, which is especially rich in bioactive factors that provide passive immunity to the neonate [7]. Transitional milk is secreted for about two weeks, followed by mature milk that comprises a thinner fore-milk that becomes fattier toward the end of the feed, referred to as hind-milk [8]. Milk composition is highly variable between women due to several fixed and modifiable factors, including genetics, diet, health status, environmental exposures, infant gestational age, and infant sex [6,8]. It is well established that breastfeeding is protective against infections and immune-mediated diseases, both during and beyond the lactation period [9,10]. For example, recent systematic reviews and meta-analyses have found that breastfed (vs. formula fed) infants have a 31% lower incidence ORM-10962 of diarrhea and a 52% lower risk of mortality due to infectious disease in the first 2 years of life [10]. These effects are particularly critical in low resource settings where the burden of infectious disease is high and the access to clean water for preparing formula is low. In high resource settings, breastfeeding remains important for the prevention of chronic immune-mediated diseases such as asthma (9% reduced risk) and allergic rhinitis (21% reduced risk) [10]. Collectively, this evidence suggests a critical role for human milk in developing the mucosal immune system during early life, which will be the focus of this review. == Box 1. == no caption available == DEVELOPMENT OF THE MUCOSAL IMMUNE SYSTEM == The mucosal immune system includes physical (epithelium) and chemical (mucus) barriers, signaling molecules (e.g. pattern recognition receptors), along with innate immune cells (neutrophils, macrophages, mast cells, natural killer T cells, dendritic cells [DCs]) and adaptive immune cells (B and T cells). These components overlay gastrointestinal, pulmonary, and other mucosal surfaces [11,12]. Structures of the fetal mucosal immune system are fully developedin uteroby week 28; thus, neonates have a responsive but immature immune system at birth [13]. With limited exposure to foreign antigens, the initial immune responses of neonates are essential for facilitating tolerance toward self, maternal, and bacterial antigens. However, they also have reduced functional capacity in some aspects of innate immunity. Thus, during this early developmental period, breastmilk is vital in helping to prevent infection and supporting a smooth transition from fetal to postnatal life as the mucosal immune system matures (Fig.1). == FIGURE 1. == Timeline of innate and adaptive mucosal immune development during gestation and infancy and the bridging role of human milk. (Original). Gut barrier development beingsin uteroand continues until weaning, correlating with a decline in gut permeability and an increased thickness of the mucus layer. Levels of neutrophils increase toward the end of gestation and rapidly decrease.