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Interactions between nociceptors and mammalian immune cells are complex; however, most promote tissue repair and homeostasis, adaptive immune responses, or Type 2 immunity and inflammation. Nociceptors inhibit histotoxic, collateral damage-causing immune responses and promote tissue repair chiefly through the secretion of the calcitonin gene-related peptide (CGRP) neuropeptide. Nociceptors promote adaptive immunity by fine-tuning dendritic cell functions, through innervation of secondary lymphoid organs, and by communicating with B lymphocytes. Nociceptors can regulate Type 2 immunity inflammation by secreting neuropeptides or glutamate. While the primary role of nociceptors is to maintain tissue homeostasis, their actions can promote pathological conditions if unchecked. Nociceptor functions are themselves modulated by immune cell actions, forming numerous feed-forward and feed-back loops. The peripheral nervous system is being increasingly recognized as a regulator of immune responses at steady-state and in response to infections, cancer, tissue injury, and other challenges. In particular, nociceptors, a population of somatosensory neurons that confer the sensation of itch or pain, can exert both pro- and anti-inflammatory effects. Developing a better understanding of nociceptors as conductors of immune responses is at the forefront of neuroimmunology research. Nociceptors have emerged as master regulators of immune responses in both homeostatic and pathologic settings; however, their seemingly contradictory effects on the functions of different immune cell subsets have been a source of confusion. Nevertheless, work by many groups in recent years has begun to identify patterns of the modalities and consequences of nociceptor-immune system communication. Here, we review recent findings of how nociceptors affect immunity and propose an integrated concept whereby nociceptors are neither inherently pro- nor anti-inflammatory. Rather, we propose that nociceptors have the role of a rheostat that, in a context-dependent manner, favors tissue homeostasis and fine-tunes immunity by preventing excessive histotoxic inflammation, promoting tissue repair, and potentiating anticipatory and adaptive immune responses. [ABSTRACT FROM AUTHOR]

The brain-centric view of neurodegenerative diseases has been challenged by new discoveries related to the neuroimmune axis. Recent reports describe signatures of immune dysfunction that may perpetuate symptoms of neurodegeneration. Signatures of neurodegenerative diseases may go hand-in-hand with accelerated aging of the mammalian immune system; indeed, markers of immune exhaustion have been reported to increase with disease progression for certain pathologies. Harnessing the immune system by means of active vaccination, or by targeting inhibitory immune checkpoints might boost the homing of reparative immune cells (monocyte-derived macrophages and regulatory T cells) into the brain to fight disease. The immune system is vital for proper brain function. Neurodegenerative diseases can emerge as a result of prolonged immune dysregulation. Therefore, boosting peripheral immune cell functions might ultimately promote brain repair and help fight neurodegeneration. Reciprocal communication between the brain and the immune system is essential for maintaining lifelong brain function. This interaction is mediated, at least in part, by immune cells recruited from both the circulation and niches at the borders of the brain. Here, we describe how immune exhaustion and senescence, even if not primary causative factors, can accelerate neurodegenerative diseases. We emphasize the role of a compromised peripheral immune system in driving neurodegeneration and discuss strategies for harnessing peripheral immunity to effectively treat neurodegenerative diseases, including the underlying mechanisms and opportunities for clinical translation. Specifically, we highlight the potential of boosting the immune system by blocking inhibitory checkpoint molecules to harness reparative immune cells in helping the brain to fight against neurodegeneration. [ABSTRACT FROM AUTHOR]

Narcolepsy with cataplexy (NT1) is a rare hypothalamic disorder that presents with a dysregulation of the sleep–wake cycle (i.e., excessive daytime sleepiness and sleep and cataplectic attacks) and other motor, cognitive, psychiatric, metabolic, and autonomic disturbances, with putative autoimmune pathogenesis. Pediatric acute-onset neuropsychiatric syndrome (PANS) is a clinically heterogeneous disorder that presents with acute-onset obsessive–compulsive symptoms and/or a severe eating restriction, with concomitant cognitive, behavioral, or affective symptoms caused by infections and other environmental triggers provoking an inflammatory brain response, which evolves into a chronic or progressive neuroimmune disorder. In this study, we present the case of a 13-year-old boy with vocal tics and syncopal-like episodes, eventually diagnosed as NT1 and PANS, and from this we discuss the hypothesis that both NT1 and PANS might belong to the same immunological spectrum, resulting in comparable imbalances in key neurotransmitter axes (i.e., orexinergic and dopaminergic), with conceptual and operational implications, especially with regards to the pharmacological tretament • Highlights (3-5). • Pediatric acute-onset neuropsychiatric syndrome (PANS) and Narcolepsy type 1 (NT1) are two distinctive neurological diseases that begin during developmental age. • PANS and NT1 have a neuroimmune pathogenesis involving different neurotransmitter axes. • NT1 and PANS may belong to the same immunological spectrum, resulting in involvement of different neurotransmitter axes, respectively orexinergic and dopaminergic. [ABSTRACT FROM AUTHOR]

Sydenham's chorea (SC), an autoimmune disorder affecting the central nervous system, is a pivotal diagnostic criterion for acute rheumatic fever. Primarily prevalent in childhood, especially in developing countries, SC manifests with involuntary movements and neuropsychiatric symptoms. Predominantly occurring between ages 5 and 15, with a female bias, SC may recur, particularly during pregnancy or estrogen use. The autoimmune response affecting the basal ganglia, notably against dopamine, underlies the pathophysiology. Clinical management necessitates an integrated approach, potentially involving immunomodulatory therapies. To address discrepancies in SC management, a survey was conducted across Italy, targeting specialists in neurology, pediatrics, child neuropsychiatry, and rheumatology. Of the 51 responding physicians, consensus favored hospitalization for suspected SC, with broad support for laboratory tests and brain MRI. Treatment preferences showed agreement on oral prednisone and IVIG, while opinions varied on duration and plasmapheresis. Haloperidol emerged as the preferred symptomatic therapy. Post-SC penicillin prophylaxis and steroid therapy gained strong support, although opinions differed on duration. Follow-up recommendations included neuropsychological and cardiological assessments. Despite offering valuable insights, broader and more studies are needed in order to guide treatment decisions in this well-known yet challenging complication of acute rheumatic fever, which continues to warrant scientific attention and concerted clinical efforts. • Sydenham's Chorea is a major concern, especially in children from developing countries, with long-term neuropsychiatric challenges. • We surveyed 51 clinicians via an online questionnaire, revealing current diagnostic and therapeutic practices for SC. • Physicians agreed on hospitalization and prefer MRI as the primary neuroimaging technique for diagnosing SC in children. • Treatment preferences varied, influenced by side effects and disease severity, showing differing clinical judgments. • Findings highlight the need for standardized treatment guidelines to enhance SC management, especially in Italy. [ABSTRACT FROM AUTHOR]

Skin-innervating sensory neurons recognize a diverse array of exogenous and endogenous stimuli, including pathogens, allergens, tissue-derived alarmins, and immune-derived cytokines. Neuropeptides derived from sensory neurons signal to immune cells in the skin to promote or dampen innate immune responses to external insults. Sensory neurons influence the mode and magnitude of antigen-specific adaptive cutaneous immune responses by altering dendritic cell activation, migration, and priming of naïve T cells. Dendritic cell populations in mouse skin and skin-draining lymph nodes express mRNAs of numerous neuropeptide receptor genes, presenting ample opportunities for future investigation into neuronal control of cutaneous immunity. Skin-innervating sensory neurons detect noxious stimuli and release neuropeptides to control and shape mammalian innate and adaptive immune responses to external insults. Peripheral sensory neurons recognize diverse noxious stimuli, including microbial products and allergens traditionally thought to be targets of the mammalian immune system. Activation of sensory neurons by these stimuli leads to pain and itch responses as well as the release of neuropeptides that interact with their cognate receptors expressed on immune cells, such as dendritic cells (DCs). Neuronal control of immune cell function through neuropeptide release not only affects local inflammatory responses but can impact adaptive immune responses through downstream effects on T cell priming. Numerous neuropeptide receptors are expressed by DCs but only a few have been characterized, presenting opportunities for further investigation of the pathways by which cutaneous neuroimmune interactions modulate host immunity. [ABSTRACT FROM AUTHOR]

'Neuroinflammation', one of the hallmarks of many neurodegenerative diseases, causes inadvertent damage to neuronal tissue due to the immune system's response to the underlying pathology. The role of the immune system in the development and progression of many neurodegenerative diseases remains elusive, with conflicting evidence in similar model systems. Due to the complexity of the immune system's involvement and the limitations of preclinical models, indiscriminate targeting of any single immune cell population could lead to inadvertent effects in neurodegenerative disease. The concept of cellular immunotherapy and personalized immunotherapeutic approaches is becoming feasible with current technological advancements, and might provide a new avenue for treating neurodegenerative diseases. We draw a compelling analogy between the immune system's role in neurodegeneration and a construction crew, underscoring the potential of cellular immunotherapies (especially T cell-based) to remodel and repair the central nervous system (CNS). We advocate for the development of personalized immunotherapies that leverage advanced technologies such as single-cell V(D)J sequencing and chimeric antigen receptor T (CAR-T) cell therapy. These approaches could transform the immune system from an inadvertent enabler of neurodegeneration to a precise tool for restoring the CNS: a novel strategy to combat neurodegenerative diseases. Neurodegenerative disorders present major challenges to global health, exacerbated by an aging population and the absence of therapies. Despite diverse pathological manifestations, they share a common hallmark, loosely termed 'neuroinflammation'. The prevailing dogma is that the immune system is an active contributor to neurodegeneration; however, recent evidence challenges this. By analogy with road construction, which causes temporary closures and disruptions, the immune system's actions in the central nervous system (CNS) might initially appear destructive, and might even cause harm, while aiming to combat neurodegeneration. We propose that the application of cellular immunotherapies to coordinate the immune response towards remodeling might pave the way for new modes of tackling the roadblocks of neurodegenerative diseases. [ABSTRACT FROM AUTHOR]

Evolution has created complex mechanisms to sense environmental danger and protect tissues, with the nervous and immune systems playing pivotal roles. These systems work together, coordinating local and systemic reflexes to restore homeostasis in response to tissue injury and infection. By sharing receptors and ligands, they influence the pathogenesis of various diseases. Recently, a less-explored aspect of neuroimmune communication has emerged: the release of neuropeptides from immune cells and cytokines/chemokines from sensory neurons. This article reviews evidence of this unique neuroimmune interplay and its impact on the development of allergy, inflammation, itch, and pain. We highlight the effects of this neuroimmune signaling on vital processes such as host defense, tissue repair, and inflammation resolution, providing avenues for exploration of the underlying mechanisms and therapeutic potential of this signaling. [ABSTRACT FROM AUTHOR]

The immune system classically consists of 2 lines of defense, innate and adaptive, both of which interact with one another effectively to protect us against any pathogenic threats. Importantly, there is a diverse subset of cells known as innate-like T cells that act as a bridge between the innate and adaptive immune systems and are pivotal players in eliciting inflammatory immune responses. A growing body of evidence has demonstrated the regulatory impact of these innate-like T cells in central nervous system (CNS) diseases and that such immune cells can traffic into the brain in multiple pathological conditions, which can be typically attributed to the breakdown of the blood-brain barrier. However, until now, it has been poorly understood whether innate-like T cells have direct protective or causative properties, particularly in CNS diseases. Therefore, in this review, our attention is focused on discussing the critical roles of 3 unique subsets of unconventional T cells, namely, natural killer T cells, γδ T cells, and mucosal-associated invariant T cells, in the context of CNS diseases, disorders, and injuries and how the interplay of these immune cells modulates CNS pathology, in an attempt to gain a better understanding of their complex functions. [ABSTRACT FROM AUTHOR]

The immune system protects the host from infection and works to heal damaged tissue after infection or injury. There is increasing evidence that the immune system and the nervous system work in concert to achieve these goals. The sensory nervous system senses injury, infection, and inflammation, which results in a direct pain signal. Direct activation of peripheral sensory nerves can drive an inflammatory response in the skin. Immune cells express receptors for numerous transmitters released from sensory and autonomic nerves, which allows the nervous system to communicate directly with the immune system. This communication is bidirectional because immune cells can also produce neurotransmitters. Both innate and adaptive immune cells respond to neuronal signaling, but T cells appear to be at the helm of neuroimmune communication. [ABSTRACT FROM AUTHOR]

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Over the last two decades, neuroimmunologic disorders of childhood have been increasingly described, phenotyped, and treated. These disorders remain rare in the general population and while sharing common therapeutic interventions due to their immune pathophysiology, are heterogeneous with regard to presentation and risk of recurrence. As such, the impact of these disorders on the developing brain has come into the forefront of emerging research in pediatric neuroimmunology. Investigations into the singular impact of monophasic disease on long-term development and the impact of early and aggressive disease-modifying therapy in relapsing conditions are quickly becoming areas of ripe investigation as the field's most optimal way to treat and monitor these conditions over time. Although critically important in evaluating the developing brain, research has been heterogeneous among these diseases and limited by small cohort size. This narrative review details the role of common neuroimmunologic disorders in long-term neurological and cognitive outcomes in children as they develop. [ABSTRACT FROM AUTHOR]

Ketogenic diets (KDs) are safe and tolerable in people with multiple sclerosis (MS). While many patient-reported and clinical benefits are noted, the sustainability of these diets outside of a clinical trial is unknown. Evaluate patient perceptions of the KD following intervention, determine the degree of adherence to KDs post-trial, and examine what factors increase the likelihood of KD continuation following the structured diet intervention trial. Sixty-five subjects with relapsing MS previously enrolled into a 6-month prospective, intention-to-treat KD intervention. Following the 6-month trial, subjects were asked to return for a 3-month post-study follow-up, at which time patient reported outcomes, dietary recall, clinical outcome measures, and laboratory values were repeated. In addition, subjects completed a survey to evaluate sustained and attenuated benefits following completion of the intervention phase of the trial. Fifty-two subjects (81%) returned for the 3-month post-KD intervention visit. Twenty-one percent reported continued adherence to a strict KD and an additional 37% reported adhering to a liberalized, less restrictive form of the KD. Those subjects with greater reductions in body mass index (BMI) and fatigue at 6-months on-diet were more likely to continue on KD following trial completion. Using intention-to-treat analysis, patient-reported and clinical outcomes at 3-months post-trial remained significantly improved from baseline (pre-KD), though the degree of improvement was slightly attenuated relative to outcomes at 6-months on KD. Regardless of diet type following the KD intervention, dietary patterns shifted toward greater protein and polyunsaturated fats and less carbohydrate/added sugar consumption. Following the 6-month KD intervention study, the majority of subjects elected to continue on KD, though many pursued a more liberal limit for carbohydrate restriction. Those who experienced a greater reduction in BMI or fatigue were more likely to continue with strict KD. The 6-month KD intervention induced persistent changes to dietary habits in the months following study completion. Registered on Clinicaltrials.gov under registration number NCT03718247, posted on Oct 24, 2018. First patient enrollment date: Nov 1, 2018. Link: https://clinicaltrials.gov/ct2/show/NCT03718247?term=NCT03718247&draw=2&rank=1. [ABSTRACT FROM AUTHOR]

The skin is a barrier organ populated by many types of skin-resident immune cells and sensory neurons. It has become increasingly appreciated that neuroimmune interactions are an important component of inflammatory diseases such as atopic dermatitis and allergic contact dermatitis. Neuropeptides secreted from nerve terminals play an important role in mediating cutaneous immune cell function, and soluble mediators derived from immune cells interact with neurons to induce itch. In this review article, we will explore emerging research describing neuronal effector functions on skin immune cells in mouse models of atopic and contact dermatitis. We will also discuss the contributions of both specific neuronal subsets and secreted immune factors to itch induction and the associated inflammatory processes. Finally, we will explore how treatment strategies have emerged around these findings and discuss the relationship between scratching and dermatitis. [ABSTRACT FROM AUTHOR]

Neuroinflammation has been linked to depression; however, neuroinflammatory biomarkers in the cerebrospinal fluid (CSF) have not previously been thoroughly investigated in a large group of patients with recent-onset depression compared with healthy control subjects. We conducted an individually matched case-control study comparing patients with recent-onset depression (ICD-10: F32) to control subjects. Primary outcomes were CSF white cell count (WCC), CSF-to-serum albumin ratio, CSF total protein, and immunoglobulin G (IgG) index. Secondary outcomes were CSF WCC differential count and CSF neutrophil-to-lymphocyte, CSF-to-serum IgG, and CSF-to-plasma glucose ratios. Linear models adjusting for sex and age were applied. We included 106 patients with recent-onset depression (84.0% outpatients) and 106 healthy control subjects. Patients had 18% higher CSF WCC relative to control subjects (relative mean difference [MD]: 1.18; 95% CI: 1.02–1.40; p =.025). CSF WCC differed with depression symptomatology (p =.034), and patients with severe depression (n = 29) had 43% higher CSF WCC relative to control subjects (MD: 1.43; 95% CI: 1.13–1.80, p =.003). Two (1.9%) patients and no controls (0.0%) had CSF WCC above the normal range (>5 × 106/L). No significant differences between groups were observed regarding CSF-to-serum albumin ratio (MD: 1.07; 95% CI: 0.97–1.18; p =.191), CSF total protein (MD: 1.01; 95% CI: 0.94–1.09; p =.775), or IgG index (MD: 1.05; 95% CI: 0.97–1.15; p =.235). Regarding secondary outcomes, the proportion of CSF neutrophils was lower among patients (MD: 0.22; 95% CI: 0.08–0.59; p =.003) relative to control subjects, whereas the remaining outcomes were not significantly different (all p >.06). Patients had higher CSF WCC relative to control subjects, indicating increased neuroimmunologic activation, particularly for severe depression. [ABSTRACT FROM AUTHOR]

Late adolescence is a period of dynamic change in the brain as humans learn to navigate increasingly complex environments. In particular, prefrontal cortical (PFC) regions undergo extensive remodeling as the brain is fine-tuned to orchestrate cognitive control over attention, reasoning, and emotions. Late adolescence also presents a uniquely vulnerable period as neurodevelopmental illnesses, such as schizophrenia, become evident and worsen into young adulthood. Challenges in early development, including prenatal exposure to infection, may set the stage for a cascade of maladaptive events that ultimately result in aberrant PFC connectivity and function before symptoms emerge. A growing body of research suggests that activation of the mother's immune system during pregnancy may act as a disease primer, in combination with other environmental and genetic factors, contributing to an increased risk of neurodevelopmental disorders, including schizophrenia. Animal models provide an invaluable opportunity to examine the course of brain and behavioral changes in offspring exposed to maternal immune activation (MIA). Although the vast majority of MIA research has been carried out in rodents, here we highlight the translational utility of the nonhuman primate (NHP) as a model species more closely related to humans in PFC structure and function. In this review, we consider the protracted period of brain and behavioral maturation in the NHP, describe emerging findings from MIA NHP offspring in the context of rodent preclinical models, and lastly explore the translational relevance of the NHP MIA model to expand understanding of the etiology and developmental course of PFC pathology in schizophrenia. [ABSTRACT FROM AUTHOR]

• A population of brain-resident regulatory T cells is found in the human and mouse brain. • Brain-resident regulatory T cells can produce immunosuppressive and repair-orientated mediators. • Brain-resident regulatory T cells can protect during neuropathologies. Regulatory T cells (Tregs) control inflammation and maintain immune homeostasis. The well-characterised circulatory population of CD4+Foxp3+ Tregs is effective at preventing autoimmunity and constraining the immune response, through direct and indirect restraint of conventional T cell activation. Recent advances in Treg cell biology have identified tissue-resident Tregs, with tissue-specific functions that contribute to the maintenance of tissue homeostasis and repair. A population of brain-resident Tregs, characterised as CD69+, has recently been identified in the healthy brain of mice and humans, with rapid population expansion observed under a number of neuroinflammatory conditions. During neuroinflammation, brain-resident Tregs have been proposed to control astrogliosis through the production of amphiregulin, polarize microglia into neuroprotective states, and restrain inflammatory responses by releasing IL-10. While protective effects for Tregs have been demonstrated in a number of neuroinflammatory pathologies, a clear demarcation between the role of circulatory and brain-resident Tregs has been difficult to achieve. Here we review the state-of-the-art for brain-resident Treg population, and describe their potential utilization as a therapeutic target across different neuroinflammatory conditions. [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD) is a common, chronic-relapsing inflammatory skin disease with significant disease burden. Genetic and environmental trigger factors contribute to AD, activating 2 of our largest organs, the nervous system and the immune system. Dysregulation of neuroimmune circuits plays a key role in the pathophysiology of AD, causing inflammation, pruritus, pain, and barrier dysfunction. Sensory nerves can be activated by environmental or endogenous trigger factors, transmitting itch stimuli to the brain. On stimulation, sensory nerve endings also release neuromediators into the skin, contributing again to inflammation, barrier dysfunction, and itch. In addition, dysfunctional peripheral and central neuronal structures contribute to neuroinflammation, sensitization, nerve elongation, and neuropathic itch, thus chronification and therapy resistance. Consequently, neuroimmune circuits in skin and central nervous system may be targets to treat pruritus in AD. Cytokines, chemokines, proteases, lipids, opioids, and ions excite/sensitize sensory nerve endings, which not only induces itch but further aggravates/perpetuates inflammation, skin barrier disruption, and pruritus as well. Thus, targeted therapies for neuroimmune circuits as well as pathway inhibitors (eg, kinase inhibitors) may be beneficial to control pruritus in AD either in systemic and/or in topical form. Understanding neuroimmune circuits and neuronal signaling will optimize our approach to control all pathological mechanisms in AD, inflammation, barrier dysfunction, and pruritus. [ABSTRACT FROM AUTHOR]

Baló's concentric sclerosis (BCS) is a rare variant of multiple sclerosis characterized by unique pathological features of alternating demyelination and preserved myelin. To describe two cases of BCS, radiological and pathological findings and its clinical course. We report two distinct cases of BCS that presented with unique MRI findings suggestive of BCS, but with different clinical courses and responses to treatment. The first case demonstrated substantial recovery following corticosteroid therapy, while the second case, initially suspected to be a malignant tumour, showed improvement after surgical intervention and immunoglobulin therapy. These cases highlight the variability in presentation and course of BCS, underscoring the challenges in diagnosis and the importance of considering BCS in the differential diagnosis of demyelinating and tumefactive lesions. The cases also emphasize the potential for favourable outcomes with appropriate management, challenging the traditional view of BCS as uniformly severe. [ABSTRACT FROM AUTHOR]

Every year, 10 million people develop dementia, the most common of which is Alzheimer's disease (AD). To date, there is no way to prevent cognitive decline and therapies are limited. This review provides a neuroimmunological perspective on the progression of AD, and discusses the immune-targeted therapies that are in preclinical and clinical trials that may impact the development of this disease. Specifically, we look to the role of the NLRP3 inflammasome, its triggers in the brain and how its activation can contribute to the progression of dementia. We summarise the range of inhibitors targeting the NLRP3 inflammasome and its downstream pathways that are under investigation, and discuss future therapeutic perspectives for this devastating condition. [Display omitted] • The NLRP3 inflammasome is a multi-protein complex, activated by a range of factors from cell stress to crystal formation. • NLRP3 inflammasome activity is found in Alzheimer's disease, where it has a key role in disease progression. • Many different therapeutic approaches to prevent NLRP3 inflammasome signalling are currently in preclinical and clinical trials. • With no way to stop cognitive decline, immune-targeted therapies may provide a new outlook for people with dementia. [ABSTRACT FROM AUTHOR]

The nervous and immune systems are highly developed, and each performs specialized physiological functions. However, they work together, and their dysfunction is associated with various diseases. Specialized molecules, such as neurotransmitters, cytokines, and more general metabolites, are essential for the appropriate regulation of both systems. Tryptophan, an essential amino acid, is converted into functional molecules such as serotonin and kynurenine, both of which play important roles in the nervous and immune systems. The role of kynurenine metabolites in neurodegenerative and psychiatric diseases has recently received particular attention. Recently, we found that hyperactivity of the kynurenine pathway is a critical risk factor for septic shock. In this review, we first outline neuroimmune interactions and tryptophan derivatives and then summarized the changes in tryptophan metabolism in neurological disorders. Finally, we discuss the potential of tryptophan derivatives as therapeutic targets for neuroimmune disorders. • TRP and its derivatives play regulatory roles in the neuroimmune system. • KYN metabolism undergoes dramatic alterations in response to various stimuli, including infection. • The brain is susceptible to QA toxicity during sepsis. • Targeting TRP derivatives has therapeutic potential for neuroimmune disorders. [ABSTRACT FROM AUTHOR]

Natural killer (NK) cells are innate lymphoid cells with robust antitumor functions rendering them promising therapeutic tools against malignancies. Despite constituting a minor fraction of the immune cells infiltrating tumors in the brain, insights into their role in central nervous system (CNS) pathophysiology are emerging. The challenges posed by a profoundly immunosuppressive microenvironment as well as by tumor resistance mechanisms necessitate exploring avenues to enhance the therapeutic potential of NK cells in both primary and metastatic brain malignancies. In this review, we summarize the role of NK cells in the pathogenesis of tumors in the brain and discuss the avenues investigated to harness their anticancer effects against primary and metastatic CNS tumors, including sources of therapeutic NK cells, combinations with other treatments, and novel engineering approaches for augmenting their cytotoxicity. We also highlight relevant preclinical evidence and clinical trials of NK cell-based therapies. Natural killer (NK) cell therapies are finding their way as promising tools for more effective treatment of brain tumors. Their unique physiology makes NK cells particularly suited for this role, offering two major advantages: independence from antigen presentation by MHC molecules, and safety for allogeneic use. Advances in culturing techniques, supplying combinations of growth factors and/or engineered feeder layer cells, support vigorous NK cell expansion. These approaches offer the advantages of an off-the-shelf product, easier to genetically engineer without compromising treatment efficacy. NK cells demonstrated good safety but modest clinical activity. The concurrent application of traditional and innovative strategies, such as specific antigen targeting with chimeric antigen receptors (CARs), stimulation with activating cytokines, creation of small bispecific and trispecific killer cell engager (BiKE and TriKE) multidomain molecules, and sensitization of malignant cells through combinatorial treatments, offers new avenues to achieve better efficacy. In contrast to CAR-T cells, NK cells lend themselves to off-the-shelf applications owing to their favorable safety profile and retained efficacy in an allogeneic setting. Thus, they promise benefits in terms of treatment standardization, timeliness, and cost. [ABSTRACT FROM AUTHOR]

Microglia, the resident immune cells of the central nervous system (CNS), are poised to respond to neuropathology. Microglia play multiple roles in maintaining homeostasis and promoting inflammation in numerous disease states. The study of microglial innate immune programs has largely focused on exploring neurodegenerative disease states with the use of genetic targeting approaches. Our understanding of how microglia participate in immune responses against pathogens is just beginning to take shape. Here, we review existing animal models of CNS infection, with a focus on how microglial physiology and inflammatory processes control protozoan and viral infections of the brain. We further discuss how microglial participation in over-exuberant immune responses can drive immunopathology that is detrimental to CNS health and homeostasis. Microglia, the primary immune cell population in the brain, play distinct roles in development and homeostasis. To study them during neuroinflammatory states, researchers use experimental paradigms such as an inducible-cre system and pharmacological antagonism of the colony stimulating factor 1 receptor (CSF1R) with its antagonist PLX5622. Microglia are poised to respond to key signals for inflammation, damage, and infection in the central nervous system (CNS). They are able to promote inflammation via the release of proinflammatory cytokines and potentially serve as functional antigen-presenting cells (APCs) during infection. Understanding the specific roles of microglia in experimental infection models will allow us to gain a deeper knowledge on how important microglia-induced inflammation is for combatting neurotropic pathogens, while also recognizing that this inflammation may cause significant damage to other cell types in the CNS. [ABSTRACT FROM AUTHOR]

Pain is a hallmark symptom associated with intestinal inflammation. Two related articles published in Cell by Zhang et al. and by Yang et al. now report how sensory neurons in the gut, the most heavily innervated organ in the human body, flag bacterial pathogens to shape the composition of the gut microbiome and to trigger immunoregulatory mechanisms. [ABSTRACT FROM AUTHOR]

• Chronic orofacial pain is a highly prevalent and clinically relevant condition. • Social, psychological and biological factors may all facilitate and modulate the orofacial pain process. • Pain, negative emotions, insomnia and stress-related cortical activity promote a feedforward neural network. • Cortical, subcortical and cerebellar areas disrupt the homeostatic state which may result in pain chronicity. • An interdisciplinary therapeutic strategy based on a biopsychosocial model is essential for effective pain management. Pain is a multidimensional experience comprising sensory-discriminative, affective-motivational, and cognitive-evaluative dimensions. Clinical and research findings have demonstrated a complex interplay between social burdens, individual coping strategies, mood states, psychological disorders, sleep disturbances, masticatory muscle tone, and orofacial musculoskeletal pain. Accordingly, current classification systems for orofacial pain require psychosocial assessments to be an integral part of the multidimensional diagnostic process. Here, we review evidence on how psychosocial and biological factors may generate and perpetuate musculoskeletal orofacial pain. Specifically, we discuss studies investigating a putative causal relationship between stress, bruxism, and pain in the masticatory system. We present findings that attribute brain structures various roles in modulating pain perception and pain-related behavior. We also examine studies investigating how the nervous and immune system on cellular and molecular levels may account for orofacial nociceptive signaling. Furthermore, we review evidence pointing towards associations between orofacial musculoskeletal pain and neuroendocrine imbalances, sleep disturbances, and alterations of the circadian timing system. We conclude with several proposals that may help to alleviate orofacial pain in the future. [ABSTRACT FROM AUTHOR]

Sarcoidosis is a disease characterized by non-caseating granulomas that can involve the central nervous system as neurosarcoidosis. This challenging disease is currently managed with high dose steroids, and sometimes the addition of infliximab. Other TNA-alpha inhibitors have not been studied as rigorously. We discovered ten neurosarcoidosis patients who were on an alternative TNA-alpha inhibitor, adalimumab. Eight patients had a positive response clinically and radiographically to adalimumab. [ABSTRACT FROM AUTHOR]

Post-acute sequelae of COVID-19 (PASC), or Long COVID, is a chronic condition following acute SARS-CoV-2 infection. Symptoms include exertion fatigue, respiratory issues, myalgia, and neurological manifestations such as 'brain fog,' posing concern for their debilitating nature and potential role in other neurological disorders. However, the underlying potential pathogenic mechanisms of the neurological complications of PASC is largely unknown. Herein, we investigated differences in antigen-specific T cell responses from the peripheral blood towards SARS-CoV-2, latent viruses, or neuronal antigens in 14 PASC individuals with neurological manifestations (PASC-N) versus 22 individuals fully recovered from COVID-19. We employed Activation Induced Marker (AIM), ICS and FluoroSpot assays to determine the specificity and magnitude of CD4+ and CD8+ T cell responses towards SARS-CoV-2 (Spike and rest of proteome), latent viruses (CMV, EBV), and several neuronal antigens. Overall, we observed similar antigen-specific T cell frequencies and cytokine effector T cell responses between PASC donors compared to recovered controls for all antigens tested (viral or autoantigen) in both CD4+ and CD8+ T cell compartments. Our findings suggest that PASC-N does not appear to be associated with changes in antigen-specific T cell responses towards a subset of disease-relevant targets, but more studies in a larger cohort are needed to confirm these unaltered responses. [ABSTRACT FROM AUTHOR]

[Display omitted] Itch is a common symptom that can greatly diminish quality of life. Histamine is a potent endogenous pruritogen, and while antihistamines are often the first-line treatment for itch, in conditions like chronic spontaneous urticaria (CSU), many patients remain symptomatic while receiving maximal doses. Mechanisms that drive resistance to antihistamines are poorly defined. Signaling of the alarmin cytokine IL-33 in sensory neurons is postulated to drive chronic itch by inducing neuronal sensitization to pruritogens. Thus, we sought to determine if IL-33 can augment histamine-induced (histaminergic) itch. Itch behavior was assessed in response to histamine after IL-33 or saline administration. Various stimuli and conditional and global knockout mice were utilized to dissect cellular mechanisms. Multiple existing transcriptomic data sets were evaluated, including single-cell RNA sequencing of human and mouse skin, microarrays of isolated mouse mast cells at steady state and after stimulation with IL-33, and microarrays of skin biopsy samples from subjects with CSU and healthy controls. IL-33 amplifies histaminergic itch independent of IL-33 signaling in sensory neurons. Mast cells are the top expressors of the IL-33 receptor in both human and mouse skin. When stimulated by IL-33, mouse mast cells significantly increase IL-13 levels. Enhancement of histaminergic itch by IL-33 relies on a mast cell– and IL-13–dependent mechanism. IL-33 receptor expression is increased in lesional skin of subjects with CSU compared to healthy controls. Our findings suggest that IL-33 signaling may be a key driver of histaminergic itch in mast cell–associated pruritic conditions such as CSU. [ABSTRACT FROM AUTHOR]

• Multifocal motor neuropathy is associated with the HLA class II HLA-DRB1*15:01-DQB1*06:02 and HLA-DRB1*12:01-DQB1*03:01 haplotypes. • Patients with MMN carrying either of these haplotypes do not have a distinct disease course. • The associations could serve as a genetic tag for other disease associated regions on chromosome 6, including the MHC class III region. • Though a direct link though antigen presentation seems unlikely, these associations imply the role of T cells in the specific inflammation underlying MMN. To gain further insight in the immunopathology underlying multifocal motor neuropathy (MMN) by exploring the association between MMN and the human leukocyte antigen (HLA) class II DRB1, DQB1, and DQA loci in depth and by correlating associated haplotypes to detailed clinical and anti-ganglioside antibody data. We performed high-resolution HLA-class II typing for the DRB1, DQB1, and DQA1 loci in 126 well-characterized MMN patients and assessed disease associations with haplotypes. We used a cohort of 1305 random individuals as a reference for haplotype distribution in the Dutch population. The DRB1*15:01-DQB1*06:02 haplotype (OR 1.6 [95% CI 1.1–2.2], p < 0.05) and the DRB1*12:01-DQB1*03:01 haplotype (OR 2.7 [95% CI 1.2–5.5], p < 0.05) were more frequent in patients with MMN than in controls. These haplotypes were not associated with disease course, response to treatment or anti-ganglioside antibodies. MMN is associated with the DRB1*15:01-DQB1*06:02 and DRB1*12:01-DQB1*03:01 haplotypes. These HLA molecules or gene variants in their immediate vicinity may promote the specific inflammatory processes underlying MMN. [ABSTRACT FROM AUTHOR]

The etiology of psychotic disorders is still unknown, but in a subgroup of patients symptoms might be caused by an autoimmune reaction. In this study, we tested patterns of autoimmune reactivity against potentially novel hippocampal antigens. Serum of a cohort of 621 individuals with psychotic disorders and 257 controls were first tested for reactivity on neuropil of rat brain sections. Brain reactive sera (67 diseased, 27 healthy) were further tested for antibody binding to glutamic acid decarboxylase (GAD) isotype 65 and 67 by cell-based assay (CBA). A sub-cohort of 199 individuals with psychotic disorders and 152 controls was tested for the prevalence of anti-nuclear antibodies (ANA) on HEp2-substrate as well as for reactivity to double-stranded DNA, ribosomal P (RPP), and cardiolipin (CL). Incubation of rat brain with serum resulted in unidentified hippocampal binding patterns in both diseased and control groups. Upon screening with GAD CBA, one of these patterns was identified as GAD65 in one individual with schizophrenia and also in one healthy individual. Two diseased and two healthy individuals had low antibody levels targeting GAD67 by CBA. Antibody reactivity on HEp-2-substrate was increased in patients with schizoaffective disorder, but only in 3 patients did antibody testing hint at a possible diagnosis of systemic lupus erythematosus. Although reactivity of serum to intracellular antigens might be increased in patients with psychotic disorder, no specific targets could be identified. GAD antibodies are very rare and do not seem increased in serum of patients with psychotic disorders. [ABSTRACT FROM AUTHOR]

• Microglia depletion in neonatal rats induced decreases in neonatal cell genesis. • Microglia depletion decreased cell genesis in male, but not female, hippocampus. • Microglia depletion decreased cell genesis in amygdala and cortex of both sexes. • Microglia loss led to increased mitotic cells and hippocampal volume in adolescence. • Microglia thus both support neonatal cell genesis and limit later-life cell genesis. Microglia, the innate immune cells of the brain, regulate brain development through many processes such as synaptic pruning, supporting cell genesis and phagocytosing living and dying cells. There are sex differences in these same developmental processes throughout the brain, thus microglia may contribute to brain sex differences. We examined whether microglia support a known sex difference in neonatal hippocampal neurogenesis and whether juvenile hippocampal neurogenesis was impacted by the loss of neonatal microglia. We used central infusion of liposomal clodronate to selectively deplete microglia and found decreased cell genesis in the male, but not female, dentate gyrus and hippocampus. We found that loss of microglia decreased cell genesis in the cortex and amygdala of both males and females. We assessed the expression of several cytokines and growth factors that have previously been shown to support cell genesis. We found that expression of Il1b and Tnf were decreased in the hippocampus due to microglia depletion however, there were no sex differences in the expression of any immune genes. In adolescence, there was an increase in the number of mitotic cells in the subgranular zone of the dentate gyrus of previously microglia depleted rats however, the number of newly-born neurons was unchanged in the adolescent animals. We also sought to determine whether there was a sex difference in the number of progenitor cells in the dentate gyrus in the neonatal period. We found no sex differences in the number of progenitor cells. Overall, these studies show that microglia are important for regulating region-specific sex differences in cell genesis in the developing brain. [ABSTRACT FROM AUTHOR]

• Nociceptor sensory neurons sense pathogen-derived products. • Nociceptors release context-dependent neuropeptides affecting infection outcome. • Neuro-immune interactions regulate pain, inflammation and shape immune response. • Specialized pro-resolving lipid mediators (SPMs) are not immunosuppressive. • Vagus nerve produces SPMs affecting host response against infections. Clinically, a variety of micro-organisms cause painful infections. Before seen as bystanders in the context of infections, recent studies have demonstrated that, as immune cells, nociceptors can sense pathogen-derived products. Nociceptors and immune cells, therefore, have evolved to communicate with each other to control inflammatory and host responses against pathogens in a complementary way. This interaction is named as neuroimmune communication (or axon-axon immune reflex) and initiates after the release of neuropeptides, such as CGRP and VIP by neurons. By this neurogenic response, nociceptors orchestrate the activity of innate and adaptive immune cells in a context-dependent manner. In this review, we focus on how nociceptors sense pathogen-derived products to shape the host response. We also highlight the new concept involving the resolution of inflammation, which is related to an active and time-dependent biosynthetic shift from pro-inflammatory to pro-resolution mediators, the so-called specialized pro-resolving lipid mediators (SPMs). At very low doses, SPMs act on specific receptors to silence nociceptors, limit pain and neurogenic responses, and resolve infections. Furthermore, stimulation of the vagus nerve induces SPMs production to regulate immune responses in infections. Therefore, harnessing the current understanding of neuro-immune communication and neurogenic responses might provide the bases for reprogramming host responses against infections through well balanced and effective immune response and inflammation resolution. [ABSTRACT FROM AUTHOR]

Introduction: N-methyl-d-aspartate receptor antibody (NMDAR-Ab) encephalitis consensus criteria has recently been defined. We aimed to examine the prevalence of NMDAR-Ab encephalitis in patients with first episode psychosis (FEP) and treatment resistant schizophrenia (TRS) on clozapine, using clinical investigations, antibody testing and to retrospectively apply diagnostic consensus criteria.Methods: Adult (18-65 years old) cases of FEP meeting inclusion criteria were recruited over three years and assessed using the Structured Clinical Interview for DSM-IV disorders (SCID). NMDAR-Ab was identified using a live cell-based assay (L-CBA). Seropositive cases were clinically investigated for features of encephalitis including neuro-imaging, EEG and CSF where possible. Serum was retested using immunohistochemistry (IHC) as part of diagnostic criteria guidelines. A cohort of patients with TRS was also recruited.Results: 112 FEP patients were recruited over 3 years. NMDAR-Ab seroprevalence was 4/112 (3.5%) cases. One case (<1%) was diagnosed with definite NMDAR-Ab encephalitis and treated with immunotherapy. One of the three other seropositive cases met criteria for probable encephalitis. However all three were ultimately diagnosed with mood disorders with psychotic features. None have developed neurological features at three year follow up. 1/100 (1%) of patients with TRS was 100 patients with TRS were recruited. One case (1%) seropositive for NMDAR-Ab but did not meet criteria for encephalitis.Conclusions: NMDAR-Ab encephalitis as defined by consensus guidelines occured rarely in psychiatric services in this study. Further studies are needed to establish pathogenicity of serum NMDAR-Ab antibodies. Psychiatric services should be aware of the clinical features of encephalitis. [ABSTRACT FROM AUTHOR]

Depression has been associated with increased inflammatory proteins, but changes in circulating immune cells are less well defined. We used multiparametric flow cytometry to count 14 subsets of peripheral blood cells in 206 depression cases and 77 age- and sex-matched controls (N = 283). We used univariate and multivariate analyses to investigate the immunophenotypes associated with depression and depression severity. Depression cases, compared with controls, had significantly increased immune cell counts, especially neutrophils, CD4+ T cells, and monocytes, and increased inflammatory proteins (C-reactive protein and interleukin-6). Within-group analysis of cases demonstrated significant associations between the severity of depressive symptoms and increased myeloid and CD4+ T-cell counts. Depression cases were partitioned into 2 subgroups by forced binary clustering of cell counts: the inflamed depression subgroup (n = 81 out of 206; 39%) had increased monocyte, CD4+, and neutrophil counts; increased C-reactive protein and interleukin-6; and more severe depression than the uninflamed majority of cases. Relaxing the presumption of a binary classification, data-driven analysis identified 4 subgroups of depression cases, 2 of which (n = 38 and n = 100; 67% collectively) were associated with increased inflammatory proteins and more severe depression but differed in terms of myeloid and lymphoid cell counts. Results were robust to potentially confounding effects of age, sex, body mass index, recent infection, and tobacco use. Peripheral immune cell counts were used to distinguish inflamed and uninflamed subgroups of depression and to indicate that there may be mechanistically distinct subgroups of inflamed depression. [ABSTRACT FROM AUTHOR]

Dental caries continue to represent a major problem which, if left untreated, will cause irreversible pulpitis. Root canal treatment constitutes one potential treatment intended to preserve teeth afflicted with irreversible pulpitis. During root canal treatment, pain or swelling, referred to as flare-ups, can occur at any point in the process. To analyze the molecular aspect of the phenomenon of flare-up in vital dental pulp tissue following mechanical and bacterial trauma (extirpation and lipopolysaccharide [LPS] induction respectively) through a neurological approach, based on the expression of NaV-1.7 in neuron cells, and HSP-70, TNF-α in macrophage cells. This laboratory experimental study was conducted using 15 Spraque Dawley rats as subjects which were divided into three groups of five subjects: a control group, a pulp tissue extirpation group and an LPS induction followed by extirpation of pulp tissue group. Test samples were collected from the apical field of the mandibular incisor and subsequently examined using immunohistochemical methods. There were significant differences in NaV1.7, HSP70 and TNFα expression between the treatment groups. While a marked increase in the expression of HSP70 occurred, both Nav1.7, and TNFα expression decreased significantly. Extirpating the dental pulp tissue will induce a more pronounced flare-up response from the molecules of the pulp tissue in vital teeth than those in inflamed vital pulp tissue. [ABSTRACT FROM AUTHOR]

Understanding neuroimmunological disorders is essential for developing new diagnostic and therapeutic strategies. Rodent models have provided valuable insights, but are sometimes equated with their human counterparts. Here, we summarize how novel technologies may enable an improved human-focused view of immune mechanisms. Recent studies have applied these new technologies to the brain parenchyma, its surrounding cerebrospinal fluid, and peripheral immune compartments. Therapeutic interventions have also facilitated translational understanding in a reverse way. However, with improved technology, access to patient samples remains a rate-limiting step in translational research. We anticipate that next-generation neuroimmunology is likely to integrate, in the immediate future, diverse technical tools for optimal diagnosis, prognosis, and treatment of neuroimmunological disorders. Autoimmune diseases of the nervous system, particularly multiple sclerosis (MS), are only partly mimicked by commonly used animal models such as experimental autoimmune encephalomyelitis (EAE). Translational studies in patients are mostly based on: autopsy or biopsy material, cerebrospinal fluid (CSF), or peripheral blood. Disease-specific findings considerably depend on the compartment being analyzed. The advent of various immunotherapies has significantly enhanced our knowledge of phase-specific immunopathological mechanisms in the field of neuroimmunology; we can further learn (immune)pathogenesis from successful and unsuccessful therapeutic interventions. MS is specifically associated with complex alterations of various immune cells and parenchymal cells, contributing to the view that changes in immune regulatory networks can initiate and perpetuate the disease. Comparative, unbiased, and multidimensional high-resolution approaches are needed (e.g., using single cell transcriptomics) to reveal key pathogenic signatures in a compartment-specific manner in human nervous system autoimmunity. Orphan diseases such as Rasmussen encephalitis (RE) and Susac syndrome (SuS) can serve as paradigmatic disease entities to dissect defined mechanisms in comparison with more prevalent disorders. [ABSTRACT FROM AUTHOR]

XMEN (X-linked immunodeficiency with magnesium defect, Epstein-Barr virus (EBV), and N-linked glycosylation defect) disease results from loss-of-function mutations in MAGT1, a protein that serves as a magnesium transporter and a subunit of the oligosaccharyltransferase (OST) complex. MAGT1 deficiency disrupts N-linked glycosylation, a critical regulator of immune function. XMEN results in recurrent EBV infections and a propensity for EBV-driven malignancies. Although XMEN is recognized as a systemic congenital disorder of glycosylation (CDG), its neurological involvement is rare and poorly characterized. Two young men, ages 32 and 33, are described here with truncating mutations in MAGT1 , progressive behavioral changes, and neurodegenerative symptoms. These features manifested well into adulthood. Both patients still presented with many of the molecular and clinical hallmarks of the typical XMEN patient, including chronic EBV viremia and decreased expression of NKG2D. While previously unrecognized, XMEN may include prominent and disabling CNS manifestations. How MAGT1 deficiency directly or indirectly contributes to neurodegeneration remains unclear. Elucidating this mechanism may contribute to the understanding of neurodegeneration more broadly. [ABSTRACT FROM AUTHOR]

This study included 51 patients with muscle-specific kinase antibody-positive myasthenia gravis (MuSK-MG) from a Japanese multicenter survey to examine clinical features and outcomes. Median onset age was 37 years and female predominance was observed. All patients developed generalized symptoms and almost all (50/51) patients had bulbar symptoms. About half of the patients met the criteria for refractory MG. The refractory group had a lower age of onset, higher severity scores, and higher maximum daily doses of oral prednisolone compared to the nonrefractory group. The outcomes for MuSK-MG patients in Japan are not favorable, indicating the need for more aggressive treatment. • MuSK-MG was more common in females. • In MuSK-MG, female patients developed the disease at younger age than male patients. • All MuSK-MG cases were generalized MG, with almost all experiencing bulbar palsy. • The outcomes of patients with MuSK-MG in Japan were unfavorable. [ABSTRACT FROM AUTHOR]

Neuro-immune interactions are not only vital for the control of neurotropic pathogens, but also appear to influence brain development and homeostasis. During immune surveillance, T cells can patrol the CNS-associated border regions to sense pathogenic alterations. While access to the CNS parenchyma is restricted in the steady state, various disease processes can initiate parenchymal T cell CNS invasion. However, to breach the glia limitans, T cells must become reactivated within the meningeal spaces. T cells cannot sense native antigens (Ags), but instead recognize small processed peptides bound to MHC molecules and presented on the surface of Ag-presenting cells (APCs). In this review, we focus on (CD4+) T cell–CNS interactions that are dependent on Ag recognition. We discuss the potential paths and mechanisms of T cell entry into the CNS, in particular with respect to CNS-resident APCs, which present CNS-derived Ag in the absence of inflammation. There is an abundant immune cell landscape at interfaces of the healthy CNS. Our understanding of its function is still evolving. Specific macrophage and dendritic cell subsets are found in distinct CNS compartments. Whether these region-specific differences in cell composition translate into specific functions remains to be determined. Primed T cells, regardless of their Ag specificity, can enter the CNS parenchyma via the leptomeninges, where they need to become reactivated in an Ag-specific manner. Parenchymal microglia and border-associated macrophages are dispensable for T cell reactivation. CNS conventional dendritic cells sample, process, and present CNS Ag in the steady- state, thereby licensing encephalitogenic T cells to invade the parenchyma. [ABSTRACT FROM AUTHOR]

• There is a fall in cytokine levels during treatment of elderly psychiatric in-patients. • Fall in cytokine levels during treatment is associated with self-reported clinical improvement amongst elderly psychiatric in-patients. • Fall in cytokine levels during treatment of elderly psychiatric in-patients does not correlate with diagnoses. Immunological abnormalities have been demonstrated in several psychiatric disorders. Predominantly, studies have focused on younger adults, and research on elderly psychiatric in-patients is scant. In this naturalistic study, we investigated changes in cytokine levels during the treatment of diagnostically unselected elderly psychiatric in-patients, and whether these changes could be related to clinical outcomes. Clinical variables, demographic data, lifestyle data, and blood samples, including 27 plasma cytokines representing a broad spectrum of inflammatory mediators, were collected from 81 patients, 60 years and older, at admission and discharge. A subgroup of 49 patients also completed a self-reported clinical, psychiatric status form, indicating their level of recovery during hospitalisation. Statistical analyses demonstrated that a broad range of cytokines fell during treatment, and the fall was associated with clinical improvement, irrespective of psychiatric and somatic diagnoses. Exploiting cytokines as biomarkers of clinical traits might to be of limited use in a general population of elderly psychiatric in-patients as the field stands now. [ABSTRACT FROM AUTHOR]

The nervous and immune systems are classically studied as two separate entities. However, their interactions are crucial for maintaining barrier functions at tissues constantly exposed to the external environment. We focus here on the role of neuronal signaling in regulating the immune system at two major barriers: the skin and respiratory tract. Barrier tissues are heavily innervated by sensory and autonomic nerves, and are densely populated by resident immune cells, allowing rapid, coordinated responses to noxious stimuli, as well as to bacterial and fungal pathogens. Neural release of neurotransmitters and neuropeptides allows fast communication with immune cells and their recruitment. In addition to maintaining homeostasis and fighting infections, neuroimmune interactions are also implicated in several chronic inflammatory conditions such as atopic dermatitis (AD), chronic obstructive pulmonary disease (COPD), and asthma. Barrier tissues, such as the respiratory tract and skin, are major sites where swift communication between the peripheral nervous system and immune system occurs. Recent insights have uncovered the molecular mechanisms by which nerves regulate tissue-resident immune cells, including innate lymphoid cells (ILCs) and mast cells. Bacterial, fungal, and parasitic pathogens can directly signal to peripheral sensory nerves to induce neuroimmune interactions during infection of barrier tissues. Neuroimmune interactions are involved in the exacerbation of many chronic inflammatory diseases, including asthma, COPD, AD, and psoriasis. Immune cells in the lungs and skin can be positively or negatively modulated by the nervous system, depending on the type of peripheral sensory or autonomic nerves – representing neuroimmune regulatory switches. [ABSTRACT FROM AUTHOR]

Diverse disturbances in immune-endocrine circuitries are involved in the development and aggravation of several chronic metabolic diseases (CMDs), including obesity, diabetes, and metabolic syndrome. The chronic inflammatory syndrome observed in CMDs culminates in dysregulated immune responses with low microbial killing efficiency, by means low host innate immune response, and loss of ability to eliminate the pathogens, which results in a high prevalence of infectious diseases, including pneumonia, tuberculosis, and sepsis. Herein, we review evidence pointing out PPARγ as a putative player in immune-endocrine disturbances related to increased risk of infections in CMDs. Cumulated evidence indicates that PPARγ activation modulates host cells to control inflammation during CMDs because of PPARγ agonists have anti-inflammatory and pro-resolutive properties, increasing host ability to eliminate pathogen, modulating hormone production, and restoring glucose and lipid homeostasis. As such, we propose PPARγ as a putative therapeutic adjuvant for patients with CMDs to favor a better infection control. [ABSTRACT FROM AUTHOR]

Disorders of the central nervous system (CNS) have many etiologies compounded by limited options for treatment. The lack of successful treatments for these disorders stems from the difficulty of gaining effective access to the CNS through the blood–brain barrier, and the irreplaceable nature of neurons. Here, we review recent advances in the field of neuroimmunology and discuss novel strategies for targeting microglia, meningeal lymphatics, and the peripheral immune system that may lead to successful treatment of a broad range of CNS disorders. In the future, it will be important to continue to explore the vast communications between the CNS and the immune system to map out dysfunctions that attribute to diseases such as chronic neuroinflammation, autoimmunity, CNS injury, and more. The conception of CNS immune privilege has been redefined with discovery of the meningeal lymphatic system. Meningeal lymphatics offer a conduit between the CNS and periphery, with implications in neurological dysfunction seen in AD, aging, and multiple sclerosis. Under defined conditions, hematopoietic-derived macrophages can replace CNS-resident microglia in the long term, demonstrating their feasibility as a cell-therapy approach. Manipulating peripheral immune cells with novel approaches can target neuroimmune interactions without the complications of penetrating the CNS. [ABSTRACT FROM AUTHOR]

Highlights • Maternal Immune activation (MIA) is associated with increased risk for various neurodevelopmental and neurodegenerative disorders. • MIA acts synergistically with genetic and environmental factors for neurodevelopmental disorders. • MIA results in altered immunological milieu for the developing brain. • MIA results in diverse alterations in neuron number, structure and function in different brain regions. • Global and specific epigenetic mechanisms have a potential to explain the diverse changes associated with MIA. Abstract The developing brain is sensitive to a variety of insults. Epidemiological studies have identified prenatal exposure to infection as a risk factor for a range of neurological disorders, including autism spectrum disorder and schizophrenia. Animal models corroborate this association and have been used to probe the contribution of gene-environment interactions to the etiology of neurodevelopmental disorders. Here we review the behavior and brain phenotypes that have been characterized in MIA offspring, including the studies that have looked at the interaction between maternal immune activation and genetic risk factors for autism spectrum disorder or schizophrenia. These phenotypes include behaviors relevant to autism, schizophrenia, and other neurological disorders, alterations in brain anatomy, and structural and functional neuronal impairments. The link between maternal infection and these phenotypic changes is not fully understood, but there is increasing evidence that maternal immune activation induces prolonged immune alterations in the offspring's brain which could underlie epigenetic alterations which in turn may mediate the behavior and brain changes. These concepts will be discussed followed by a summary of the pharmacological interventions that have been tested in the maternal immune activation model. [ABSTRACT FROM AUTHOR]

Abstract The human olfactory system is a mucosal surface and a major portal of entry for respiratory and neurotropic pathogens into the body. Understanding how the human nasopharynx-associated lymphoid tissue (NALT) halts the progression of pathogens into the lower respiratory tract or the central nervous system is key for developing effective cures. Although traditionally mice have been used as the gold-standard model for the study of human nasal diseases, mouse models present important caveats due to major anatomical and functional differences of the human and murine olfactory system and NALT. We summarize the NALT anatomy of different animal groups that have thus far been used to study host-pathogen interactions at the olfactory mucosa and to test nasal vaccines. The goal of this review is to highlight the strengths and limitations of each animal model of nasal immunity and to identify the areas of research that require further investigation to advance human health. Highlights • The human olfactory system is a first line of defense against pathogens. • The immune responses of the olfactory mucosa against microbiota and pathogens are poorly understood. • This review summarizes the different invertebrate and vertebrate animal models available to understand nasal host-microbe interactions. • An evaluation of strengths and weaknesses of each model is provided. [ABSTRACT FROM AUTHOR]

Abstract The expression of elements of the cholinergic system has been demonstrated in non-neuronal cells, such as immune cells, where acetylcholine modulates innate and adaptive responses. However, the study of the non-neuronal cholinergic system has focused on lymphocyte cholinergic mechanisms, with less attention to its role of innate cells. Considering this background, the aims of this review are 1) to review information regarding the cholinergic components of innate immune system cells; 2) to discuss the effect of cholinergic stimuli on cell functions; 3) and to describe the importance of cholinergic stimuli on host immunocompetence, in order to set the base for the design of intervention strategies in the biomedical field. Highlights • Cholinergic system and innate cells • Neuroimmunomodulation by cholinergic agents • Innate immune cells and neuroimmunomodulation [ABSTRACT FROM AUTHOR]