SECTION 5 - SLEEP DISORDERS

Immunomodulation, Neuroendocrinology and Sleep

Background

Both the neuroendocrine output arm and the immune stimulus arm of brain-immune communications affect sleep. Relevant immune factors include the broad family of immune molecules termed cytokines that include interleukins (IL), chemokines and other immune products that allow immune cells to communicate. Cytokines are pleiotropic, both affecting and originating from many other cells and organs than simply those of the immune system, and they are key communicator molecules that affect many aspects of nervous system and neuroendocrine system function. Resultant sleep alterations induced by cytokines probably affect the course of and susceptibility to a variety of diseases including infectious, inflammatory/ autoimmune and endocrine). Reciprocal interactions between neuroendocrine and immune factors and sleep include the following:

> Immune molecules alter sleep architecture.

> Sleep deprivation alters neuroendocrine and immune responses.

> Immune system activation and neuroendocrine responses alter sleep.

> Sleep quality probably affects the course of and susceptibility to infectious disease.

During infection, patterns of cytokines produced depend on a combination of host responses and specific pathogens to which the host is exposed. Many cytokines affect sleep, each individually in different ways (e.g. IL-1, -2, -15, -18, TNF, Interferon). Different combinations of cytokines expressed during infection may have different overall effects on sleep.

Genetic factors that determine sleep patterns interact with environmental factors to contribute to final effects on disease outcome. Genetic host factors in interaction with environmental factors influence the set point of neuroendocrine stress response and cytokine production patterns that interact with cytokine patterns produced in response to different pathogens/antigens.

Control of complex phenotypes such as sleep is likely to have the same characteristics as other complex phenotypes, including behavior or complex illnesses such as inflammation/arthritis. Thus, it is likely that many genes, each with small effect (polygenic/multigenic), regulate different aspects of sleep. Inheritance of sleep phenotypes could therefore be additive as in other complex phenotypes, and hence depend not on single genes but on inherited regions of DNA. Finally, such complex phenotypes often exhibit large environmental variance. Thus an important area of study will be to address and dissect gene-environment interactions and to systematically assess the effect of environmental factors on genetic factors in sleep phenotypes and disease outcome. Potential environmental variables that could be examined in the context of defined genetic backgrounds impacting on sleep include: 1) relative effects of different neuroendocrine and neural stress response pathways; 2) effects, pathways and mechanisms of different pathogen and cytokine exposures; and 3) early developmental factors (maternal-infant interactions).

Progress In The Last 5 Years

- Progress has been made in identifying individual and interfacing effects of different cytokines on sleep architecture and identifying interactions between the individual components of the hormonal stress response system (including CRH and cortisol) and the neuronal stress response system (including sympathetic nervous system responses).

- Progress has included genetic linkage and segregation analysis of linkage regions to identify molecules that affect infectious, cytokine, and sleep interactions. In addition, knock-out animal models and inbred strains have been used to elucidate the role of individual immune and endocrine molecules in sleep.

- Short-term sleep deprivation is associated with complex altered immune responses but the influence on disease outcome is unclear. There is some evidence that sleep loss and chronic sleep restriction may be associated, in addition to cytokines, with other inflammatory markers (e.g., C-reactive protein) that could impact the development and severity of cardiovascular disease as well as daytime sleepiness and fatigue in sleep disorders.

Research Recommendations

- Identify the effects of interactions between the neuroendocrine and immune systems on sleep phenotype and disease outcome in defined genetic models. These studies should identify the molecular and cellular mechanisms and neuroanatomical pathways of these interactions and their effects on sleep architecture, sleep responses to cytokines, and infectious disease outcome.

- Further define the role of sleep, sleep deprivation and chronic sleep restriction on host defense. Human studies are needed to determine the extent to which sleep disturbance and sleep deprivation are related to markers of nonspecific inflammatory responses (e.g., leukocytes, cytokines, c-reactive protein). Studies are needed in transgenic or knock-out animals, including linkage and segregation studies, to identify the functional significance to infection resistance and susceptibility of candidate genes in linkage regions or of newly discovered cytokines, candidate neurohormones, or other molecules.

- Study the biology of the relationships among cytokines, neuroendocrine function and sleep, including studies of the relationships of the neuroendocrine stress response and cytokine induction of sleep in animal models and human studies. Analysis of gene-environment interactions and of sleep responses to infectious agents in genetically manipulated animal models is relevant to the question of how sleep alters disease susceptibility and outcome. Specific pharmacological agents (e.g. specific cytokine or neuroendocrine antagonists/agonists) will be useful to assess the effects of specific neurotransmitters/neurohormones/interleukins/ cytokines on sleep phenotypes.

- Conduct genetic studies to identify neuroendocrine and immune genes relevant to sleep phenotypes. Approaches to identify potential candidate genes of interest could include animal studies utilizing candidate gene knock-out and transgenic animals, expression microarrays, and linkage and segregation studies including congenics studies. Studies in humans and animals could include sequencing of candidate genes and phenotype characterization of subjects with candidate gene mutations or of transgenic or knock-out animal models.

- Conduct animal and human studies to integrate circadian biology and homeostatic sleep regulation with cytokine biology. This approach could include both in vitro and in vivo studies.