No abstract

The decline in immune function with aging represents a major clinical challenge in many disease conditions. It is manifest in many parameters but is essentially linked to the adaptive immune responses. The prediction would be that abnormalities in both T and B lymphocytes underlie the loss of cellular and humoral capacity, respectively. Somewhat surprisingly, this is not reflected in numerical losses but more in alterations at the population and single cell levels. There is a major reduction in naïve T cells with a proportional increase in memory cells, and also a generally reduced function of these cells. While bone marrow function reduces with age, the most obvious reason for the T cell defects is the severe atrophy of the thymus. This is closely aligned with puberty, thereby implicating a major aetiological role for sex steroids in both thymus and immune system deterioration with age. Accordingly surgical or chemical castration (utilizing luteinizing hormone-releasing hormone) blocks sex steroids resulting in profound rejuvenation of the immune system.

The nervous, endocrine, and immune systems interact to adapt to infection, inflammation, and tissue injury. Neural control is mediated in several ways, one of them being through the neuroendocrine regulation of the secretion of hypothalamic and pituitary hormones. The hormonal effects on the immune system range from the impact of steroidal hormones, which exhibit inhibitory effects over immune functions, to growth hormone, prolactin and neurohypophyseal hormones, known to stimulate and modulate humoral and cellular aspects of the immune system. This review will discuss the mechanisms behind the immunomodulatory role of the neuroendocrine system, including the critically important feedback loops required to maintain balance for these bidirectional interactions and alterations that occur with age.

In essence, normal thymus function involves the production of a broad repertoire of αβT cells capable of responding to foreign antigens with low risk of autoreactivity. Thymic epithelial cells are an essential component of the thymic stromal microenvironment, promoting the growth and export of self-tolerant thymocytes. Autoimmune disease, resulting from a loss of self-tolerance, is clinically and genetically complex, and accordingly has many potential etiological origins. However, it is commonly linked to defects in the thymic epithelial microenvironment. The study of autoimmune-linked thymic stromal dysfunction has indisputably advanced our understanding of T cell tolerance; notably, a field-wide paradigm shift occurred when autoimmune regulator (Aire) was found to drive expression of a multitude of peripheral tissue-restricted antigens in medullary thymic epithelial cells. Many other associations with polygenically controlled autoimmune diseases have been reported but are more difficult to definitively dissect. Paradoxically, immunodeficiency and age-related immunosenescence are also linked with increased autoimmunity. Here we discuss the theoretical basis and the evidence gathered thus far to support these associations.