In 2003, the National Institutes of Health (NIH), Bethesda, MD, USA, launched the NIH Roadmap for Medical Research, marking the renaissance in interdisciplinary research, and outlining new perspectives of cutting-edge 21st century work that crosses disciplines. The ‘interdisciplinary research’, as per the Roadmap, was defined as “integrating the analytical strengths of two or more often disparate scientific disciplines to solve a given biological problem.”The NIH Roadmap may have been the critical catalyst that helped spark the large-scale integrative research expansion, and many interdisciplinary, multidisciplinary research centers and consortia were soon conceived and built. As a result, the interdisciplinary work is no longer considered ‘extravagant’. On the contrary, that type of work is gradually being established as a promising trend that serves as a corrective of the cell-centered reductionism and approach that dominated medical research in the preceding 2-3 decades. Neuroendocrine-immunology bridges neurosciences and immunology and is a bona fide interdisciplinary area that enormously contributed to this new trend. A major goal of BrainImmune is to promote the advancement of neuroendocrine-immunology research. In fulfilling this objective, we highlight certain major advances made in this field in 2015, as discussed here on BrainImmune.
Anatomy & ImmunoPhysiology
Picture left: A representative image of Lyve-1 labeling on whole mount meninges; lymphatic vessels shown in red, blood vessels in green. From ‘Structural and functional features of central nervous system lymphatic vessels’ by Antoine Louveau et al., Nature, 2015, 523:337-41; Credit: Louveau et al. Nature magazine (2015), cf. news.virginia.edu
Perhaps the most stimulating breakthrough in this research area was the discovery of the brain lymphatic systemby Antoine Louveau et al. In the report, published in Nature, the research team led by Antoine Louveau and Jonathan Kipnis of the Center for Brain Immunology and Glia, University of Virginia School of Medicine, VA, USA, found the exact location of lymphatic vessels along the brain dural sinuses.
These vessels represent a previously overlooked pathway that is able to carry both fluid and immune cells from the cerebrospinal fluid, and is connected to the deep cervical lymph nodes. The vessels had ‘gone undiscovered’ for many years, perhaps due to their hidden location.
Thus, it seems that the brain contains lymphatic vessels similar to those found elsewhere in the body. Remarkably, this work is about to break down a major dogma in immunology and autoimmunity research, namely that the brain is an ‘immune privileged’ organ. As eloquently stated by the study’s authors “current dogmas regarding brain tolerance and the immune privilege of the brain should be revisited”.
As we already discussed here, this paradigm shifting-work may provide important insights into the pathogenesis of brain inflammatory/autoimmune diseases such as multiple sclerosis and perhaps Alzheimer’s disease and autism (see more at news.virginia.edu).
Johannes vom Berg et al. reported that in a mouse model of Alzheimer’s disease the brain microglial cells express high levels of IL-12 and IL-23, whereas in humans the authors found high p40 concentrations in the cerebrospinal fluid of AD patients. Notably, higher levels of p40 were detected in individuals with lower cognitive performance. These findings are particularly interesting, as ustekinumab, a drug based on a monoclonal antibody that blocks both IL-12 and IL-23, is already approved for the treatment of psoriasis in humans.
The neuropeptide oxytocin has been associated with social bonding, sociosexual behavior, increased generosityand exerting an anxiolytic action. In 2015 Karen Parker and colleagues from the Stanford University School of Medicine, CA, USA, also demonstrated that low oxytocin levels – both plasma and cerebrospinal fluid (CSF) –predict trait anxiety in children. The authors suggested that patient stratification and the selection of individuals with low plasma oxytocin levels but high anxiety level may improve the prediction of patients most likely to benefit from oxytocin treatment.
Immunology & Neuroendocrine Immunology of Autoimmunity/Inflammation & Arthritis
A study by Iona Schuster and al. from the University of Western Australia indicated thata new TRAIL+ NK cell subset may control autoimmunity & autoreactivity related to viral infections. This work, derived from a murine cytomegalovirus-induced autoimmunity model, establishes a new function of TRAIL-expressing NK cells – in the elimination of activated CD4+ T cells in the salivary gland during viral infection. Thus, NK cells through this mechanism may actually curb and control autoimmunity. The findings may bring new insights into Sjogren’s syndrome and other autoimmune diseases where virus-induced autoimmunity is believed to play a role.
Psychological stress has been linked in the past to the pathogenesis of peptic ulcers, whereas the Helicobacter pylori bacterium appears to be inadequate as a monocausal trigger as the majority of infected people do not develop ulcers.
In 2015, a study by Susan Levenstein and colleagues, from the Aventino Medical Group, Rome, Italy, made available novel data that psychological stress enhances the risk of peptic ulcer, independently of the presence of H. pylori or NSAIDs use. In a prospective study of a population-based Danish cohort, the authors found that psychological stress was associated with increased incidence of peptic ulcer. The risk of developing ulcers in individuals with high stress was doubled when comparing high versus low tertile subjects’ group. The study may serve as a stimulus for further research into the role of stress in the etiopathogenesis of peptic ulcers.
Macrophages are known to be associated with tumor development, and recent evidence indicates that M1-type macrophages restrain cancer advancement, while M2-type accelerate cancer growth.
The subfornical organ is a vascularized structure and a circumventricular organ that lacks a blood–brain barrier. Recent evidence indicates this brain structure may serve as a ‘sensor’ for peripheral inflammation.
In 2015, Shun-Guang Wei and colleagues from the University of Iowa Carver College of Medicine, Iowa City, IA, USA, demonstrated that in rats a microinjection of IL-1β and TNF-α enhanced the brain renin–angiotensin system (RAS) activity and prostaglandin E2 synthesis in the subfornical organ. The study suggests that proinflammatory cytokines acting within the subfornical organ may trigger sympathetic nervous system excitation and/or increase in autonomic and neuro-hormonal output. According to these authors, through these mechanisms, peripheral pro-inflammatory cytokines may drive the chronic hyperactivity of the sympathetic nervous system documented in heart failure or some forms of hypertension.
It seems that these two studies may contribute to a better understanding of skin infections and/or the inflammatory/autoimmune diseases of this organ. They may also help the search for new antimicrobial & antifungal therapeutic agents or approaches.