oa Editorial [Exploring Neural-Immune System Interactions]

The high prevalence of insomnia represents a large economical burden to society giving rise to reduced productivity, accidents, behavioural and cognitive consequences, and possibly association with increased disease risk. Epidemiological data increasingly implicate insomnia as a predictor of cardiovascular and non-cardiovascular disease mortality, particularly in aged people. It is already accepted that persons deprived of sleep are more susceptible to infections, and that infectious porcesses seem to increase somnolence. In the review by Dr. Cardinali, the reciprocal influences of sleep and the immune system have been evaluated. Specifically, this review addresses whether the immune system causes changes in sleep, and whether sleep might have a role in the modulation of the immune system with possible consequences for disease risk. Finally, the multiple organ dysfunction syndrome (MODS) in which disordered sleep and disordered immune function co-occur has been considered, providing strong evidences for a role of sleep in the regulation of the immune system and possibly in mediating increases in the risk infectious disease and inflammatory disorders in these populations. Different diseases such as Alzheimer's disease (AD), multiple sclerosis (MS) and stroke have important inflammatory and immune components and an anti-inflammatory and/or immunotherapeutic approach might be considered. Although it has become increasingly recognized that inflammation may be important in the neuropathological damage that occurs in AD, unlike MS the inflammation in AD seems to arise from inside the central nervous system (CNS) with little or no involvement of lymphocytes or monocytes beyond their normal surveillance of the brain. The inflammatory cytopathology (microgliosis, astrocytosis, complement activation, increased cytokine expression and acute phase response), is thought to represent a secondary response to early accumulation of Amyloid beta (Aβ) in the brain. Dr. Cacabelos in his review shows that histamine, a pleiotropic factor, plays a main role in neuroimmune regulation. This biogenic amine shows age- and sex-dependent changes in the CNS, and is significantly altered, together with interleukin 1beta (IL-1β) and tumor necrosis factor alfa (TNF-α), in AD and other neurodegenerative disorders in which neuroinflammation appears to be an aggravating phenotype. Dr. Leszek suggests that a long-term activation of the innate immune system in AD patients might trigger an inflammatory cascade that converges in cytoskeletal alterations like intracellular aggregation of the microtubule-associated protein tau into filamentous inclusions. Because appearance of tau-aggregate bearing lesions correlates with both cognitive decline and neurodegeneration, in this review it has been suggested that novel therapeutic approaches must rely on regulation of endogenous inflammatory pathways, identification of early markers of neuronal deterioration and a combination treatment involving immune modulation and anti-inflammatory therapies. MS is an inflammatory disease of the CNS characterized by perivascular cuffs of mononuclear cells that include both lymphocytes and macrophages. This infiltration leads to damage of the myelin sheath and the underlying axon. In the initial stages of the disease, inflammation is the prominent process, causing relapsing-remitting MS (RRMS), the most common form of the disease. Dr. Fernandez-Novoa points out the importance of studying the genetic risk for developing MS. In the conclusions she points out that the HLA-DRB1*15 gene appears to be the most important genetic marker for disease susceptibility. Damage to the CNS usually has a much more profound effect on the individual, since brain and spinal cord repair is limited, and persistent functional deficits still remain following disease and injury. Dr. Lombardi analyzes recent strategies used in brain damage repair and tries to answer some basic answers: are stem cells for neurons and glia present in the human CNS? If so, cane they migrate from germinal centres to the sites of injury? Will growth-factor therapy prove to be effective and well tolerated as a means of protecting cells from injury? Can adult CNS be made amenable to axon regeneration? Will the implantation of neurons and glia restore the structure and function of the adult human CNS? Stroke is a major cause of death and disability throughout the world. Its pathophysiology is complex and includes excitotoxicity, inflammatory pathways, oxidative damage, ionic imbalances, apoptosis and other cell death mechanisms, angiogenesis, and neuroprotection. Inflammation plays an important role in the development of atherosclerosis and is increasingly believed to contribute to reperfusion injury and delayed ischemia in the brain after stroke. Evidence is now beginning to emerge that lymphocytes may have a greater and earlier involvement during stroke, opening the door for novel and highly specific targets for diagnosing, management, treatment, and prevention strategies for both stroke and vascular disease. Dr. Jordan has summarized the role of adhesive molecules and inflammatory mediators in different experimental models of cerebral ischemia, their approaches and effects in therapy and neuroprotection, and has critically reviewed recent treatment strategies in the management of acute ischemic stroke. During ageing both neuroendocrine and immune systems are affected and the altered homeostasis contributes to an increase in morbidity and mortality. Dr. De la Fuente suggests that several immune functions can be used as markers of biological age and predictors of longevity. This hypothesis has been confirmed in several murine models of premature aging of neuroimmunomodulation such as poor response to stress, anxiety, depression or loss of estrogens. In this review special attention has been paid on obesity and immune system and it has been suggested that obese individuals compared to normal subjects of the same chronological age, are prematurely aged, supporting the hypothesis that obesity can be considered a model of premature senescence. The review by Dr. Maletic discusses the role of aberrant neuroimmune functioning in chronic pain disorders. Pain activates a complex adaptive response that includes endocrine, autonomic and immune components. When appropriate, this response reestablishes homeostasis. However, in the context of chronic pain dysregulated immune, autonomic and endocrine responses contribute to peripheral and central sensitization, a phenomena emblematic of chronic pain. Excessive neuroimmune interactions in the vicinity are associated with increased immune/inflammatory signalling in the dorsal horn and supraspinal pain-process circuitry, the so-called “pain-matrix”. The role of immune system as a meta-homeostatic entity that coordinates interactions of emotion- and stress-modulating brain circuitry with endocrine and autonomic systems is also discussed. As we learn more about how central nervous and endocrine systems influence immunologically based disorders and how immune system affects CNS functioning, there may be a need to redefine the nature of some diseases, and, thus, develop novel strategies for therapeutic and personalized interventions.