2015 – Major Advances in Neuroendocrine Immunology

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 21^st 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 system by 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).

Neuroscience & Neuroimmunology

A Nature Medicine study indicates, perhaps for the first time, that interleukin (IL)-23, a keynote pro-inflammatory cytokine, might contribute to the pathogenesis of Alzheimer’s disease (AD). It is known that IL-12 and IL-23 share a common subunit (p40).

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.

In 2015 more evidence emerged that fibromyalgia is a neuropathic syndrome affecting small sensory and sympathetic nerve fibers causing pain, paresthesias and autonomic dysfunction. Dr. Manuel Martínez-Lavín, an established expert in the field has summarized for BrainImmune the growing body of evidence that fibromyalgia is associated with sympathetic nervous system dysautonomia and represents a ‘sympathetically maintained neuropathic pain syndrome’. He argues that in fibromyalgia the “dysautonomia is characterized by relentless sympathetic hyperactivity accompanied by sympathetic hypo-reactivity to different stressors”.

The neuropeptide oxytocin has been associated with social bonding, sociosexual behavior, increased generosity and 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.

Interestingly, in a previous study, Valsamma Eapen et al. from University of New South Wales, Sydney, Australia, reported that women with low oxytocin levels in the postpartum have a history of bad mother-to-daughter bonding, and may also struggle to bond with their own children.

Immunology & Neuroendocrine Immunology of Autoimmunity/Inflammation & Arthritis

A study by Iona Schuster and al. from the University of Western Australia indicated that a 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.

Sex hormones such as estrogens and testosterone are known to exert a protective effect in rheumatoid arthritis (RA). In 2015, Annica Andersson and colleagues from the University of Gothenburg, Gothenburg, Sweden, demonstrated that a specific ‘signature’ of estrogens’ effect on the migration of the highly pathogenic Th17 cells is perhaps a key mechanism contributing to the protective role of estradiol in RA. The researchers found that estrogen enhances the migration of Th17 in early arthritis to the lymph nodes but reduces Th17 migration to joints in established arthritis. The study may also help elucidate the mechanism behind the sexual dimorphism in rheumatoid arthritis.

In another 2015 study, Rebeca Jimeno et al. showed that vasoactive intestinal peptide (VIP) drives the activity of T cells towards the T regulatory (Treg) cell phenotype, and at the same time, reduces the pathogenic profile of Th17 cells. As VIP is present in the microenvironment of the joint, the study suggests that VIP may possess a therapeutic potential in the early phase of RA by increasing the Treg/Th17 ratio.

Takayasu’s arteritis (TA) is a rare large vessel granulomatous vasculitis, affecting mostly middle-aged women, typically in Asia, South America and the Mediterranean countries. In 2015, David Saadoun and colleagues from the Pierre and Marie Curie University, Paris, France, were perhaps the first to reveal that Th1 and Th17 cells and cytokine pathways may drive systemic inflammation in Takayasu arteritis. Importantly, the researchers found a glucocorticoid resistance of Th17 cells in this condition.

Stress & Stress-Immune Interactions

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.

In 2015, Jun-Fang Qin and colleagues, from the School of Medicine, Nankai University, China, reported that in a mouse model of breast cancer, social isolation stress induced an increase in the number of M2 macrophages inside the tumor tissue. In their in vitro studies, the authors found that the stress hormone adrenaline (epinephrine) was able to stimulate the transformation from the M1-type to M2-type macrophage phenotype. Importantly, the researchers also found β2-adrenoceptors and the human M2 macrophages marker CD163 in tissues obtained from breast cancer patients. The study substantiates previous work linking stress and cancer development.

Cardiology

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.

In another 2015 study, Naghmeh Nikkheslat and colleagues, from the Institute of Psychiatry, King`s College London, UK, demonstrated that patients with coronary heart disease (CHD) and depression had high levels of C-reactive protein (CRP) and interleukin (IL)-6, combined with low cortisol levels and glucocorticoid receptor (GR) mRNA. Importantly, these patients also had less functional ability of the GR to respond to glucocorticoids. The researcher suggested that in patients that had both CHD and depression, the level of endogenous cortisol is insufficient to limit inflammation, as the result of the hypoactivity of the hypothalamus-pituitary-adrenal (HPA) axis, and GR resistance.

Dermatology

In 2014, Lorena Riol-Blanco et al. published in Nature a study providing the first evidence that TRPV1⁺ sensory neurons are able to trigger IL-23 production by dendritic cells (DCs) in the skin. They linked this process to induction of IL-17 and IL-22 release by resident T cells, and the aggravation of psoriasis-like inflammation in a rodent model of this disease. Remarkably, they also found that 75% of skin DCs are in direct contact to sensory nerves.

In 2015, a new report in Immunity, by Sakeen Kashem et al. went further to show that in the murine skin the cross-talk between sensory nociceptive neurons, IL-23-producing CD301b⁺ DCs and IL-17A-producing γδ T cells is required for the establishment of candidiasis resistance. Interestingly, they found that the calcitonin gene related peptide (CGRP) released by TRPV1+ sensory nerves, may drive IL-23 production by DCs, and thus, in turn, up-regulate the IL-17 production by γδ T cells.

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.