Disrupted autonomic pathways in spinal cord injury: Implications for the immune regulation.

Spinal Cord Injury (SCI) disrupts critical autonomic pathways responsible for the regulation of the immune function. Consequently, individuals with SCI often exhibit a spectrum of immune dysfunctions ranging from the development of damaging pro-inflammatory responses to severe immunosuppression. Thus, it is imperative to gain a more comprehensive understanding of the extent and mechanisms through which SCI-induced autonomic dysfunction influences the immune response. In this review, we provide an overview of the anatomical organization and physiology of the autonomic nervous system (ANS), elucidating how SCI impacts its function, with a particular focus on lymphoid organs and immune activity. We highlight recent advances in understanding how intraspinal plasticity that follows SCI may contribute to aberrant autonomic activity in lymphoid organs. Additionally, we discuss how sympathetic mediators released by these neuron terminals affect immune cell function. Finally, we discuss emerging innovative technologies and potential clinical interventions targeting the ANS as a strategy to restore the normal regulation of the immune response in individuals with SCI.

Antibody Testing for Suspected Autoimmune Autonomic Dysfunction and Small Fiber Neuropathies.

SUMMARY: Autonomic dysfunction and small fiber neuropathies are heterogeneous disorders with a wide array of potential etiologies. As with other neurologic diseases, autoantibodies specific to neural tissue, either in the setting of cancer or systemic autoimmunity, may cause autonomic abnormalities. Given the complex and varied functions of the autonomic nervous system, however, the presentation of these conditions may be quite variable. This, in addition to pitfalls of autonomic testing especially for the novice, can lead to inaccuracies in recognizing and characterizing these conditions. We now have a large number of autoantibodies available for testing with more in the pipeline thanks to unprecedented developments in the field of neuroimmunology. Those have been very helpful in uncovering potentially treatable mechanisms of autonomic disease, but also pose a challenge to the clinician given their multiplicity and variable specificity. Growing knowledge regarding autoimmune autonomic implications and the autonomic specificities of each antibody, in addition to the increasing attention to the relevance of antibody titers are of utmost importance for clinicians concerned with autonomic neurology. This review attempts to shed a light on the frequently encountered antibodies in relation to autonomic dysfunction.

Neuroimmune interactions in cardiovascular diseases.

Our body is continuously in contact with external stimuli that need a fine integration with the internal milieu in order to maintain the homoeostasis. Similarly, perturbations of the internal environment are responsible for the alterations of the physiological mechanisms regulating our main functions. The nervous system and the immune system represent the main interfaces between the internal and the external environment. In carrying out these functions, they share many similarities, being able to recognize, integrate, and organize responses to a wide variety of stimuli, with the final aim to re-establish the homoeostasis. The autonomic nervous system, which collectively refers to the ensemble of afferent and efferent neurons that wire the central nervous system with visceral effectors throughout the body, is the prototype system controlling the homoeostasis through reflex arches. On the other hand, immune cells continuously patrol our body against external enemies and internal perturbations, organizing acute responses and forming memory for future encounters. Interesting to notice, the integration of the two systems provides a further unique opportunity for fine tuning of our body's homoeostasis. In fact, the autonomic nervous system guides the development of lymphoid and myeloid organs, as well as the deployment of immune cells towards peripheral tissues where they can affect and control several physiological functions. In turn, every specific immune cell type can contribute to regulate neural circuits involved in cardiovascular function, metabolism, and inflammation. Here, we review current understanding of the cross-regulation between these systems in cardiovascular diseases.

Neural Control of Immunity in Hypertension: Council on Hypertension Mid Career Award for Research Excellence, 2019.

The nervous system and the immune system share the common ability to exert gatekeeper roles at the interfaces between internal and external environment. Although interaction between these 2 evolutionarily highly conserved systems has been recognized for long time, the investigation into the pathophysiological mechanisms underlying their crosstalk has been tackled only in recent decades. Recent work of the past years elucidated how the autonomic nervous system controls the splenic immunity recruited by hypertensive challenges. This review will focus on the neural mechanisms regulating the immune response and the role of this neuroimmune crosstalk in hypertension. In this context, the review highlights the components of the brain-spleen axis with a focus on the neuroimmune interface established in the spleen, where neural signals shape the immune response recruited to target organs of high blood pressure.

Ganglionic Acetylcholine Receptor Antibodies and Autonomic Dysfunction in Autoimmune Rheumatic Diseases.

Autonomic neuropathy has been reported in autoimmune rheumatic diseases (ARD) including Sjögren's syndrome, systemic sclerosis, rheumatoid arthritis, and systemic lupus erythematosus. However, the pathophysiological mechanism underlying autonomic dysfunction remains unknown to researchers. On the other hand, autoimmune autonomic ganglionopathy (AAG) is an acquired immune-mediated disorder, which causes dysautonomia that is mediated by autoantibodies against ganglionic acetylcholine receptors (gAChRs). The purpose of this review was to describe the characteristics of autonomic disturbance through previous case reports and the functional tests used in these studies and address the importance of anti-gAChR antibodies. We have established luciferase immunoprecipitation systems to detect antibodies against gAChR in the past and determined the prevalence of gAChR antibodies in various autoimmune diseases including AAG and rheumatic diseases. Autonomic dysfunction, which affects lower parasympathetic and higher sympathetic activity, is usually observed in ARD. The anti-gAChR antibodies may play a crucial role in autonomic dysfunction observed in ARD. Further studies are necessary to determine whether anti-gAChR antibody levels are correlated with the severity of autonomic dysfunction in ARD.

Autonomic regulation of T-lymphocytes: Implications in cardiovascular disease.

The nervous and immune systems both serve as essential assessors and regulators of physiological function. Recently, there has been a great interest in how the nervous and immune systems interact to modulate both physiological and pathological states. In particular, the autonomic nervous system has a direct line of communication with immune cells anatomically, and moreover, immune cells possess receptors for autonomic neurotransmitters. This circumstantial evidence is suggestive of a functional interplay between the two systems, and extensive research over the past few decades has demonstrated neurotransmitters such as the catecholamines (i.e. dopamine, norepinephrine, and epinephrine) and acetylcholine have potent immunomodulating properties. Furthermore, immune cells, particularly T-lymphocytes, have now been found to express the cellular machinery for both the synthesis and degradation of neurotransmitters, which suggests the ability for both autocrine and paracrine signaling from these cells independent of the nervous system. The details underlying the functional interplay of this complex network of neuroimmune communication are still unclear, but this crosstalk is suggestive of significant implications on the pathogenesis of a number of autonomic-dysregulated and inflammation-mediated diseases. In particular, it is widely accepted that numerous forms of cardiovascular diseases possess imbalanced autonomic tone as well as altered T-lymphocyte function, but a paucity of literature exists discussing the direct role of neurotransmitters in shaping the inflammatory microenvironment during the progression or therapeutic management of these diseases. This review seeks to provide a fundamental framework for this autonomic neuroimmune interaction within T-lymphocytes, as well as the implications this may have in cardiovascular diseases.

Complex regional pain syndrome: a focus on the autonomic nervous system.

PURPOSE: Although autonomic features are part of the diagnostic criteria for complex regional pain syndrome (CRPS), the role of the autonomic nervous system in CRPS pathophysiology has been downplayed in recent years. The purpose of this review is to redress this imbalance. METHODS: We focus in this review on the contribution of the autonomic nervous system to CRPS pathophysiology. In particular, we discuss regional sympathetic and systemic autonomic disturbances in CRPS and the mechanisms which may underlie them, and consider links between these mechanisms, immune disturbances and pain. RESULTS: The focused literature research revealed that immune reactions, alterations in receptor populations (e.g., upregulation of adrenoceptors and reduced cutaneous nerve fiber density) and central changes in autonomic drive seem to contribute to regional and systemic disturbances in sympathetic activity and to sympathetically maintained pain in CRPS. CONCLUSIONS: We conclude that alterations in the sympathetic nervous system contribute to CRPS pathology. Understanding these alterations may be an important step towards providing appropriate treatments for CRPS.

Immune and autonomic nervous system interactions in multiple sclerosis: clinical implications.

Multiple sclerosis is characterized by a wide spectrum of clinical manifestations, among which dysfunction of the autonomic nervous system represents an important cause of multiple sclerosis-related disability. The aim of this review is to provide an overview of autonomic dysfunction in people with multiple sclerosis, and to discuss the interactions between the immune and autonomic nervous systems and the effects of these interactions on various aspects of multiple sclerosis. Autonomic dysfunction in people with multiple sclerosis can be demonstrated clinically and on a molecular level. Clinically, it can be demonstrated by measuring autonomic symptoms with the Composite Autonomic Symptom Score (COMPASS-31), and neurophysiologically, with different autonomic nervous system tests. Both symptomatic and objectively determined autonomic dysfunction can be associated with increased risk of multiple sclerosis disease activity. Further supporting these clinical observations are molecular changes in immune cells. Changes in the sympathetic autonomic system, such as different expression of dopaminergic and adrenergic receptors on immune cells, or modulation of the cholinergic anti-inflammatory pathway over different subunits of the nicotinic acetylcholine receptor in the peripheral immune system, may mediate different effects on multiple sclerosis disease activity.

Autonomic involvement in Guillain-Barré syndrome: an update.

BACKGROUND: Guillain-Barré syndrome (GBS), an inflammatory, usually demyelinating polyradiculopathy, is characterized by ascending symmetrical limb weakness, sensory disturbances, and absent or reduced deep tendon reflexes. There is extensive literature suggesting that GBS is associated with autonomic dysfunction in up to two-thirds of patients. However, it is interesting that there is still no consensus amongst medical professionals regarding whether GBS patients should be routinely screened for autonomic nervous system (ANS) neuropathy. This is an important issue, as the mortality rate from presumed ANS abnormalities now exceeds that of respiratory failure. Given the long interval since this literature was last comprehensively reviewed, an update on this topic is warranted. METHODS: A PubMed search yielded 193 results with the terms "GBS or Guillain-Barré syndrome and autonomic symptoms" and 127 results with the terms "GBS or Guillain-Barré syndrome and dysautonomia." RESULTS: This review will summarize the current literature involving GBS and autonomic dysfunction in terms of presentation, management, and a brief discussion of prognosis. We also examine prospective approaches that may be helpful and update a proposed management plan.

Bioelectronic Approaches to Control Neuroimmune Interactions in Acute Kidney Injury.

Recent studies have shown renal protective effects of bioelectric approaches, including ultrasound treatment, electrical vagus nerve stimulation, and optogenetic brainstem C1 neuron stimulation. The renal protection acquired by all three modalities was lost in splenectomized mice and/or α7 subunit of the nicotinic acetylcholine receptor-deficient mice. C1 neuron-mediated renal protection was blocked by ß2-adrenergic receptor antagonist. These findings indicate that all three methods commonly, at least partially, activate the cholinergic anti-inflammatory pathway, a well-studied neuroimmune pathway. In this article, we summarize the current understanding of neuroimmune axis-mediated kidney protection in preclinical models of acute kidney injury by these three modalities. Examination of the differences among these three modalities might lead to a further elucidation of the neuroimmune axis involved in renal protection and is of interest for developing new therapeutic approaches.

Needleless Transcutaneous Neuromodulation Accelerates Postoperative Recovery Mediated via Autonomic and Immuno-Cytokine Mechanisms in Patients With Cholecystolithiasis.

BACKGROUND: Postsurgical gastrointestinal disturbance is clinically characterized by the delayed passage of flatus and stool, delayed resumption of oral feeding, dyspepsia symptoms, and postsurgical pain. This study was designed 1) to evaluate the effects of needleless transcutaneous neuromodulation (TN) on postoperative recovery; 2) to investigate mechanisms of the TN involving autonomic functions in postoperative patients after removal of the gallbladder. METHODS: Sixty patients scheduled for laparoscopic cholecystectomy (LC) were randomized to TN (n = 30) and sham-TN (n = 30). TN was performed via acupoints ST36 and PC6 for 30 min twice daily from 24 hours before surgery to 72 hours after surgery. Sham-TN was performed using the same parameters at nonacupoints. RESULTS: 1) Compared to sham-TN, TN shortened time to first flatulence (38.9 ± 4.0 vs. 24.9 ± 2.4 hour, p = 0.004) and time to defecation (63.1 ± 4.5 vs. 42.5 ± 3.1 hour, p < 0.001). 2) Compared to sham-TN, TN increased the percentage of normal pace-making activity (66.2 ± 2.2 vs. 73.8 ± 2.3%, p = 0.018). 3) TN enhanced vagal activity. Compared to that 24 hours before surgery, surgery decreased vagal activity (HF) (0.41 ± 0.02 vs. 0.34 ± 0.02, p = 0.043) 3 hours after the operation. Compared to sham-TN, TN increased HF (0.45 ± 0.02 vs. 0.52 ± 0.02, p = 0.045) 72 hours after the operation. Further, HF was negatively correlated with time to defecation and serum norepinephrine. 4) Surgery increased serum IL-6 (1.1 ± 0.1 before surgery vs. 2.9 ± 0.7 pg/mL, p = 0.041) 72 hours after the operation, which was reduced to baseline by TN (0.9 ± 0.1). CONCLUSIONS: In conclusion, the proposed needleless TN accelerates postoperative recovery after LC, possibly mediated via the autonomic and immune-cytokine mechanisms. Needleless and self-administrable TN may be an easy-to-implement and low-cost complementary therapy for postoperative recovery.

Ageing, the autonomic nervous system and arrhythmia: From brain to heart.

An ageing myocardium possesses significant electrophysiological alterations that predisposes the elderly patient to arrhythmic risk. Whilst these alterations are intrinsic to the cardiac myocytes, they are modulated by the cardiac autonomic nervous system (ANS) and consequently, ageing of the cardiac ANS is fundamental to the development of arrhythmias. A systems-based approach that incorporates the influence of the cardiac ANS could lead to better mechanistic understanding of how arrhythmogenic triggers and substrates interact spatially and temporally to produce sustained arrhythmia and why its incidence increases with age. Despite the existence of physiological oscillations of ANS activity on the heart, pathological oscillations can lead to defective activation and recovery properties of the myocardium. Such changes can be attributable to the decrease in functionality and structural alterations to ANS specific receptors in the myocardium with age. These altered ANS adaptive responses can occur either as a normal ageing process or accelerated in the presence of specific cardiac pathologies, such as genetic mutations or neurodegenerative conditions. Targeted intervention that seek to manipulate the ageing ANS influence on the myocardium may prove to be an efficacious approach for the management of arrhythmia in the ageing population.

Anti-inflammatory and autonomic effects of electroacupuncture in a rat model of diet-induced obesity.

OBJECTIVE: To study the effect of electroacupuncture (EA) on the cholinergic anti-inflammatory pathway (CAP) by measurement of vagal activity in rats with high-fat diet (HFD)-induced obesity. METHODS: Diet-induced obesity (DIO) was induced in 30 rats by feeding them a HFD for 12 weeks. A further 10 rats fed normal food comprised the lean diet (LD) control group. DIO rats were further subdivided into three groups that received a HFD only (HFD group, n=10), a HFD plus electroacupuncture (HFD+EA group, n=10) or a HFD plus minimal acupuncture (HFD+MA group, n=10). EA and MA treatments were continued for 8 weeks. Heart rate variability (HRV) was used to measure the function of the autonomic nervous system before and after treatment. ELISA was used to determine acetylcholine (ACh) and tumour necrosis factor (TNF)-α levels in the serum. Real-time PCR was used to assess the mRNA expression of α7-subtype nicotinic acetylcholine cholinergic receptors (α7nAChRs) and TNF-α in the mesenteric white adipose tissues (MWAT). RESULTS: EA but not MA significantly reduced rats' bodyweight. No difference was found in the low frequency (LF), high frequency (HF) and the balance between LF and HF (LF/HF) components of HRV before treatment. After the EA intervention, HF was elevated and LF/HF was reduced in the HFD+EA group comparedwith the HFD group. TNF-α in the serum and MWAT were increased in the HFD group, but were reduced in the HFD+EA group. Furthermore, EA promoted expression of α7nAChRs and ACh in the MWAT. There was no difference between the HFD and HFD+MA groups for any indices. CONCLUSIONS: EA enhanced vagal activity, promoted ACh release and activated α7nAChRs in the MWAT, leading to inhibition of proinflammatory cytokine production.

Neural Regulation of Bone and Bone Marrow.

Bones provide both skeletal scaffolding and space for hematopoiesis in its marrow. Previous work has shown that these functions were tightly regulated by the nervous system. The central and peripheral nervous systems tightly regulate compact bone remodeling, its metabolism, and hematopoietic homeostasis in the bone marrow (BM). Accumulating evidence indicates that the nervous system, which fine-tunes inflammatory responses and alterations in neural functions, may regulate autoimmune diseases. Neural signals also influence the progression of hematological malignancies such as acute and chronic myeloid leukemias. Here, we review the interplay of the nervous system with bone, BM, and immunity, and discuss future challenges to target hematological diseases through modulation of activity of the nervous system.

The interplay between neuroendocrine activity and psychological stress-induced exacerbation of allergic asthma.

Psychological stress is recognized as a key factor in the exacerbation of allergic asthma, whereby brain responses to stress act as immunomodulators for asthma. In particular, stress-induced enhanced type 2 T-helper (Th2)-type lung inflammation is strongly associated with asthma pathogenesis. Psychological stress leads to eosinophilic airway inflammation through activation of the hypothalamic-pituitary-adrenal pathway and autonomic nervous system. This is followed by the secretion of stress hormones into the blood, including glucocorticoids, epinephrine, and norepinephrine, which enhance Th2 and type 17 T-helper (Th17)-type asthma profiles in humans and rodents. Recent evidence has shown that a defect of the µ-opioid receptor in the brain along with a defect of the peripheral glucocorticoid receptor signaling completely disrupted stress-induced airway inflammation in mice. This suggests that the stress response facilitates events in the central nervous and endocrine systems, thus exacerbating asthma. In this review, we outline the recent findings on the interplay between stress and neuroendocrine activities followed by stress-induced enhanced Th2 and Th17 immune responses and attenuated regulatory T (Treg) cell responses that are closely linked with asthma exacerbation. We will place a special focus on our own data that has emphasized the continuity from central sensing of psychological stress to enhanced eosinophilic airway inflammation. The mechanism that modulates psychological stress-induced exacerbation of allergic asthma through neuroendocrine activities is thought to involve a series of consecutive pathological events from the brain to the lung, which implies there to be a "neuropsychiatry phenotype" in asthma.

How stress contributes to autoimmunity-lessons from Sjögren's syndrome.

A large body of clinical evidence on the association between stressful life events and autoimmune diseases suggests that stress may play an important role in the pathogenesis of these disorders. In this article, we discuss the effects of stress, not on the immune system but on specific cell populations against which the autoimmune reactivity is directed. Using Sjögren's syndrome as a model autoimmune disease, we review the role of stress in the initiation and perpetuation of autoimmune reactivity. We present data that reveal the effects of stress on salivary gland epithelial cells, suggesting that stress can become immunogenic through its various effects on salivary gland epithelium.

[The interface between the immune system and autonomic nervous system].

  The nervous system and the immune system are two major systems in human body. Although it was revealed these two systems correlated, the control of immune cell dynamics by the nervous system has come to draw a lot of attention at the present time. Recent advances in basic and preclinical science reveal that reflex neural circuits inhibit the production of cytokines and inflammation in several animal models. One well-characterized cytokine-inhibiting mechanism, termed the "inflammatory reflex", is dependent upon vagus nerve stimulation that inhibits cytokine production and attenuates the inflammation. And the mechanism for controlling lymphocyte trafficking becomes clear, and molecular basis of immune regulation by the nervous system was reported. On the other hand, the nervous system is protected from the invasion of harmful agents by the barrier. However, there are neuroimmunological disorders, which is associated with autoimmunity, tumor immunity, and infection immunity. Autoimmune autonomic ganglionopathy (AAG) is an acquired immune-mediated disorder that leads to widespread autonomic manifestations, in which autoantibodies to ganglionic nicotinic acetylcholine receptors play a central role. Previously, we elucidated the prevalence of extra-autonomic manifestations in patients with AAG. It is necessary to establish the new systems for the detection of autoantibodies to other subunits of acetylcholine receptor.

Long-term cardiovascular autonomic and clinical changes after immunoglobulin G immunoadsorption therapy in autoimmune autonomic ganglionopathy.

: A 63-year-old male was diagnosed with autoimmune autonomic ganglionopathy based on the finding of plasma antibodies to the nicotinic acetylcholine receptor (nAChR) of autonomic ganglia. He complained of mouth and eye dryness, dysphagia, severe constipation, erectile dysfunction, urgency, frequent urination, habitual orthostatic syncope and presyncope. A remarkable symptomatic orthostatic hypotension without changes in heart rate was present. We here describe the 3-year time course of the changes in spectral indices of cardiovascular autonomic control LF/HF and LFSAP, dysautonomia symptoms intensity and anti-nAChR antibodies following repetitive selective immunoadsorptions. During the follow-up, the reduction of anti-nAChR antibodies produced by immunoadsorption was associated with a diminished orthostatic hypotension, a restored capability to increase LF/HF, LFSAP and norepinephrine in upright position, a decline in the intensity of autonomic symptoms and an improvement of life quality. Spectral parameters LF/HF and LFSAP may represent noninvasive, low-cost biomarkers suitable for autoimmune autonomic ganglionopathy patients' clinical follow-up.