Nutritionally mediated programming of the developing immune system

Abstract

A growing body of evidence highlights the importance of a mother's nutrition from preconception through lactation in programming the emerging organ systems and homeostatic pathways of her offspring. The developing immune system may be particularly vulnerable. Indeed, examples of nutrition-mediated immune programming can be found in the literature on intra-uterine growth retardation, maternal micronutrient deficiencies, and infant feeding. Current models of immune ontogeny depict a "layered" expansion of increasingly complex defenses, which may be permanently altered by maternal malnutrition. One programming mechanism involves activation of the maternal hypothalamic-pituitary-adrenal axis in response to nutritional stress. Fetal or neonatal exposure to elevated stress hormones is linked in animal studies to permanent changes in neuroendocrine-immune interactions, with diverse manifestations such as an attenuated inflammatory response or reduced resistance to tumor colonization. Maternal malnutrition may also have a direct influence, as evidenced by nutrient-driven epigenetic changes to developing T regulatory cells and subsequent risk of allergy or asthma. A 3rd programming pathway involves placental or breast milk transfer of maternal immune factors with immunomodulatory functions (e.g. cytokines). Maternal malnutrition can directly affect transfer mechanisms or influence the quality or quantity of transferred factors. The public health implications of nutrition-mediated immune programming are of particular importance in the developing world, where prevalent maternal undernutrition is coupled with persistent infectious challenges. However, early alterations to the immune system, resulting from either nutritional deficiencies or excesses, have broad relevance for immune-mediated diseases, such as asthma, and chronic inflammatory conditions like cardiovascular disease.

Figure 1

Developmental timeline of immune cells, organs, and effector functions. Lighter shading indicates stem cell homing to site; darker shading indicates primary site of hematopoiesis at given developmental stage. Timing of early-, middle-, and late-hematopoietic stem cells is not yet well defined in humans. Shading indicates relative maturation of organs (i.e. primordial, populated by progenitors, mature) and cell populations (i.e. cell counts and activity). For maternal antibodies, shading indicates increasing transfer efficiency; adult concentrations of IgM, IgG1, IgG3, and IgG4 are attained by 1–2 y, whereas IgG2 and IgA do not reach adult concentrations until puberty.

Figure 2

Hypothesized associations between maternal malnutrition and the emerging immune system.