Abstract
Breastfeeding provides defense against infectious disease during early life. The mechanisms underlying this protection are complex but likely include the vast array of immune cells and components, such as immunoglobulins, in milk. Simply characterizing the concentrations of these bioactives, however, provides only limited information regarding their potential relationships with disease risk in the recipient infant. Rather, understanding pathogen and antigen specificity profiles of milk-borne immunoglobulins might lead to a more complete understanding of how maternal immunity impacts infant health and wellbeing. Milk produced by women living in 11 geographically dispersed populations was applied to a protein microarray containing antigens from 16 pathogens, including diarrheagenic E. coli, Shigella spp., Salmonella enterica serovar Typhi, Staphylococcus aureus, Streptococcus pneumoniae, Mycobacterium tuberculosis and other pathogens of global health concern, and specific IgA and IgG binding was measured. Our analysis identified novel disease-specific antigen responses and suggests that some IgA and IgG responses vary substantially within and among populations. Patterns of antibody reactivity analyzed by principal component analysis and differential reactivity analysis were associated with either lower-to-middle-income countries (LMICs) or high-income countries (HICs). Antibody levels were generally higher in LMICs than HICs, particularly for Shigella and diarrheagenic E. coli antigens, although sets of S. aureus, S. pneumoniae, and some M. tuberculosis antigens were more reactive in HICs. Differential responses were typically specific to canonical immunodominant antigens, but a set of nondifferential but highly reactive antibodies were specific to antigens possibly universally recognized by antibodies in human milk. This approach provides a promising means to understand how breastfeeding and human milk protect (or do not protect) infants from environmentally relevant pathogens. Furthermore, this approach might lead to interventions to boost population-specific immunity in at-risk breastfeeding mothers and their infants.
Highlights
Human milk is the gold standard for infant nutrition, during the first 6 months of life [1, 2]
This technical point is raised because the obtained data showed many immunoglobulin A (IgA) responses across all cohorts to antigens from pathogens where there is likely a low risk of exposure. This antibody binding is in part likely cross-reactive and/or polyspecific and might be reduced with more diluted samples. This technical factor may be mitigated by the normalization procedure applied to the data, which accounts for IgA reactivity against components of the E. coli cell-free expression system
Results from this study provide evidence that high-throughput protein array technology can be used to investigate IgA and IgG specificity to a variety of pathogens in human milk underlying substantial infant morbidity and mortality around the world
Summary
Human milk is the gold standard for infant nutrition, during the first 6 months of life [1, 2]. Socioeconomic factors, resources, and myriad other factors modify benefits of breastfeeding, infants who are fed human milk have lower risks for many serious childhood illnesses including infectious diarrheal and respiratory diseases [3, 4]. Derived immune factors and immune cells, many of which have been primed to fend off the pathogens endemic to an infant’s environment, are most certainly important in this regard [17, 18]. These factors include aspects of both innate and acquired immune systems, such as neutrophils, B and T cells, natural killer cells, cytokines, chemokines, complement system components, and immunoglobulins. The immunoglobulins, most of which are present as secretory immunoglobulin A (IgA), are thought to be directed at pathogens with which the mother has had contact, representing a form of dynamic immunological memory [19]
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