The maternal-neonatal neuro-immune interface: are there long-term implications for inflammatory or stress-related disease?

Abstract

Inflammatory stimuli reliably elicit hypothalamic-pituitary-adrenal (HPA) activation, and it is now established that the immune and HPA systems are mutually regulatory and that their interactions partly determine stress effects on immune function. What has not been extensively investigated, however, is the interactive nature of the development of the endocrine and immune systems and whether this might alter predisposition to inflammatory disease or stress-related pathologies. Increasing attention is now being focused on the role of early life environments determining long-term predisposition to disease, and a role for the HPA axis in disease predisposition is emerging. Stress generally refers to the condition where coping with actual or perceived stimuli alters the homeostatic state of the organism. The classic stress response involves the activation of central and peripheral catecholamine systems and HPA responses. Increased glucocorticoid levels are thought to protect the organism, both by providing energy substrates to deal with immediate environmental demands and by blocking potentially harmful overreaction by the immune system and other stress-reactive systems (1). However, to avoid immunosuppression and degenerative pathologies associated with increased glucocorticoid levels, the HPA stress response must terminate efficiently once the environmental demands are removed (2). Consequently, disturbances in endocrine-immune interactions upset the normal regulatory homeostatic balance and alter susceptibility to a variety of disease states associated with immune dysregulation (3). The physiological impact of stress is variable across individuals, and susceptibility to stress apparently depends on attributes of the organism, such as genetic endowment and age, and experiential factors, such as previous stress experiences, and early life events (4, 5). Indeed, the endocrine and immune systems and the CNS all respond to environmental pressures during development, and the interactive nature of these systems suggests that alterations in one system could have developmental consequences for the others and potential long-term implications for disease vulnerability. Plasticity in most developing physiological systems is thought to be of adaptive importance, enabling an organism to better meet the demands of the environment in which it matures and will most likely reside. However, the short-term reorganization or re-setting of regulatory systems to deal with immediate demands may also have long-term consequences for normal physiological function, thereby predisposing an organism to pathology. This may particularly be the case when the environmental pressures differ between development and adulthood. A number of epidemiological studies have indicated that nutritional factors early in life have long-term implications for cardiovascular and metabolic disease in adulthood. Most data suggest that maternal nutrition and limited intrauterine growth are responsible for reorganizing metabolic regulation and results in metabolic and cardiovascular pathologies in adult life (6). The concept of “perinatal programming” is not new and has long been investigated in neuroendocrine development of both the adrenal and the gonadal axes (see review, ref. 7). Immune responses, too, are influenced by early life experiences, and it has been suggested that pathogen exposure during development is important for the developing immune repertoire and that too little activation may be associated with the development of allergy (8). Available data also indicate that there are long-term consequences following endocrine-immune interactions during the first week of life. Thus, the administration of steroids during antigen exposure alters the development of immune tolerance (9), and immune challenge during the first week of life is associated with altered endocrine development (10, 11). These data demonstrate the interactive nature of both the immune and the neuroendocrine systems during development and show that these interactions can alter both immune and endocrine function in the long term. Maternal factors represent some of the most salient environmental influences altering endocrine development (12–14). Indeed, there is an extensive literature detailing both prenatal and postnatal influences on the development of the HPA axis. It is also well established that immune factors passed in utero and also to the neonate via milk have a direct impact on the its immunocompetence (15, 16). However, evidence examining the neuro-immune interface and maternal factors is limited.