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.

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.

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.

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.

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.

Catecholamines and acetylcholine are key regulators of the interaction between microbes and the immune system.

Recent studies suggest that catecholamines (CAs) and acetylcholine (ACh) play essential roles in the crosstalk between microbes and the immune system. Host cholinergic afferent fibers sense pathogen-associated molecular patterns and trigger efferent cholinergic and catecholaminergic pathways that alter immune cell proliferation, differentiation, and cytokine production. On the other hand, microbes have the ability to produce and degrade ACh and also regulate autogenous functions in response to CAs. Understanding the role played by these neurotransmitters in host-microbe interactions may provide valuable information for the development of novel therapies.

Autonomic and inflammatory consequences of posttraumatic stress disorder and the link to cardiovascular disease.

Stress- and anxiety-related disorders are on the rise in both military and general populations. Over the next decade, it is predicted that treatment of these conditions, in particular, posttraumatic stress disorder (PTSD), along with its associated long-term comorbidities, will challenge the health care system. Multiple organ systems are adversely affected by PTSD, and PTSD is linked to cancer, arthritis, digestive disease, and cardiovascular disease. Evidence for a strong link between PTSD and cardiovascular disease is compelling, and this review describes current clinical data linking PTSD to cardiovascular disease, via inflammation, autonomic dysfunction, and the renin-angiotensin system. Recent clinical and preclinical evidence regarding the role of the renin-angiotensin system in the extinction of fear memory and relevance in PTSD-related immune and autonomic dysfunction is also addressed.

Dietary Marine n-3 PUFAs Do Not Affect Stress-Induced Visceral Hypersensitivity in a Rat Maternal Separation Model.

BACKGROUND: Although never evaluated for efficacy, n-3 (ω-3) long-chain polyunsaturated fatty acids (LCPUFAs) are commercially offered as treatment for irritable bowel syndrome (IBS). OBJECTIVE: This study was designed to investigate, in a mast cell-dependent model for visceral hypersensitivity, whether this pathophysiologic mechanism can be reversed by dietary LCPUFA treatment via peroxisome proliferator-activated receptor γ (PPARG) activation. METHODS: Maternally separated rats were subjected to hypersensitivity-inducing acute stress at adult age. Reversal was attempted by protocols with tuna oil-supplemented diets [4% soy oil (SO) and 3% tuna oil (SO-T3) or 3% SO and 7% tuna oil (SO-T7)] and compared with control SO diets (7% or 10% SO) 4 wk after stress. The PPARG agonist rosiglitazone was evaluated in a 1 wk preventive protocol (30 mg · kg⁻¹ · d⁻¹). Erythrocytes were assessed to confirm LCPUFA uptake and tissue expression of lipoprotein lipase and glycerol kinase as indicators of PPARG activation. Colonic mast cell degranulation was evaluated by toluidine blue staining. In vitro, human mast cell line 1 (HMC-1) cells were pretreated with rosiglitazone, eicosapentaenoic acid, or docosahexaenoic acid, stimulated with phorbol 12-myristate 13-acetate (PMA) and calcium ionophore or compound 48/80 and evaluated for tumor necrosis factor α (TNF-α) and ß-hexosaminidase release. RESULTS: Stress led to visceral hypersensitivity in all groups. Hypersensitivity was not reversed by SO-T3 or control treatment [prestress vs. 24 h poststress vs. posttreatment area under the curve; 76 ± 4 vs. 128 ± 12 (P < 0.05) vs. 115 ± 14 and 82 ± 5 vs. 127 ± 16 (P < 0.01) vs. 113 ± 19, respectively]. Comparison of SO-T7 with its control showed similar results [74 ± 6 vs. 103 ± 13 (P < 0.05) vs. 115 ± 17 and 66 ± 3 vs. 103 ± 10 (P < 0.05) vs. 117 ± 11, respectively]. Erythrocytes showed significant LCPUFA uptake in the absence of colonic PPARG activation. Rosiglitazone induced increased PPARG target gene expression, but did not prevent hypersensitivity. Mast cell degranulation never differed between groups. Rosiglitazone and LCPUFAs significantly reduced PMA/calcium ionophore-induced TNF-α release but not degranulation of HMC-1 cells. CONCLUSION: Dietary LCPUFAs did not reverse stress-induced visceral hypersensitivity in maternally separated rats. Although further research is needed, claims concerning LCPUFAs as a treatment option in IBS cannot be confirmed at this point and should be regarded with caution.

The spleen: the forgotten organ in acute kidney injury of critical illness.

Acute kidney injury (AKI) is an increasing medical burden and is independently associated with mortality. AKI is a common comorbidity in the intensive care unit (ICU), with sepsis-associated AKI seen in almost a quarter of all ICU patients. Due to the high mortality seen in these patients, improved therapeutic options are needed. Data from experimental studies in animals support observations in humans that the host immune response to sepsis and trauma contributes to multiorgan failure and the high morbidity and mortality seen in critically ill patients. The spleen, a major component of the reticuloendothelial system, appears to be a key player in the 'cytokine storm' that develops after infection and trauma, and the resultant systemic inflammation is regulated by the autonomic nervous system. Over the past decade, evidence has suggested that controlling the splenic cytokine response improves tissue function and mortality in sepsis and other inflammatory-mediated diseases. One pathway that controls the response of the spleen to sepsis and trauma is the cholinergic anti-inflammatory pathway, and it may provide a key target for therapeutic intervention. Here, we review this concept and highlight the potential use of ultrasound to stimulate the cholinergic anti-inflammatory pathway and reduce systemic inflammation and disease severity.

Avaliação da variabilidade da frequência cardíaca de idosos diabéticos e não diabéticos / Assessment of heart rate variability in elderly diabetic and nondiabetic patients

INTRODUÇÃO: O cenário de envelhecimento populacional e o aumento das Doenças Crônicas Não Transmissíveis (DCNT) requer o desenvolvimento e validação de métodos diagnóstico e de ferramentas não invasivas para identificação de fatores de risco e estadiamento destas doenças. Entre estes métodos evidencia-se a análise da modulação autonômica do coração por meio da Variabilidade da Frequência Cardíaca (VFC). OBJETIVO: Analisar a variabilidade da frequência cardíaca de idosos diabéticos (DM+) e não diabéticos (DM–) residentes em um município baiano; avaliar a resposta da variabilidade da frequência cardíaca na realização da manobra de levantar-se rapidamente. MÉTODOS: estudo epidemiológico transversal, de abordagem censitária. Desenvolvido com 205 idosos da zona urbana do munícipio de Aiquara-BA, após aplicação os critérios de inclusão e exclusão. Os dados da VFC foram coletados através do monitor Polar RS800CX...

INTRODUCTION: The scenario of population aging and the increase of Chronic Noncommunicable Diseases (NCDs) requires the development and validation of diagnostic methods and non-invasive tools for identification of risk factors and staging of these diseases.Among these methods, the analysis of autonomic modulation of the heart using the Heart Rate Variability (HRV) becomes evident. OBJECTIVE: To analyze the heart rate variability in diabetic (DM+) and nondiabetic (DM–) elderlies residents in a municipality of Bahia, and also to know the response of heart rate variability in performance of the quickly stand up maneuver. METHODS: cross-sectional study of censitary approach. Carried out with 205 elderlies in the urban area of the municipality of Aiquara-BA, after had applied the inclusion and exclusion criteria. HRV data were collected through the Polar RS800CX...

Disfunção autonômica e anticorpos contra receptores anti-m2 e anti-β1 em pacientes chagásicos / Autonomic dysfunction and anti-M2 and anti-β1 receptor antibodies in Chagas disease patients

FUNDAMENTO: A morte súbita é a principal causa de óbito na doença de Chagas, acometendo pacientes mesmo em fases precoces da doença. É reconhecido o comprometimento do sistema nervoso autônomo nessa doença e seu potencial como deflagrador de arritmias malignas quando associado a alterações estruturais ou metabólicas. OBJETIVO: Buscamos identificar, em pacientes chagásicos com função sistólica preservada, o comprometimento do sistema nervoso autônomo e sua associação com anticorpos funcionalmente ativos contra receptores anti-m2 e anti-β1. MÉTODOS: Mediante análise espectral da variabilidade RR durante teste de inclinação passiva, pacientes chagásicos crônicos foram comparados com controles saudáveis pareados por idade. Posteriormente, a associação de disfunção autonômica com anticorpos funcionalmente ativos com ação anti-m2 e anti-β1 foi pesquisada pelo método de Langendorf. RESULTADOS: Observamos que pacientes chagásicos sem disfunção ventricular expressam atividade parassimpática ante um estímulo vagal, porém com menor intensidade em relação aos controles. Pacientes chagásicos com anticorpos anti-m2 ou anti-β1 apresentaram uma redução ainda mais expressiva da resposta vagal durante a arritmia sinusal respiratória, independentemente da presença de lesão estrutural. Entretanto, a associação de ambos promoveu resposta ao estímulo vagal similar aos chagásicos sem a presença dos mesmos. CONCLUSÃO: A menor reserva vagal em pacientes chagásicos com função preservada esteve associada à presença de anticorpos anti-m2 ou anti-β1 funcionalmente ativos, e não à presença de lesão cardíaca estrutural.

BACKGROUND: Sudden death is the leading cause of death in Chagas' disease, affecting patients even in the early stages of the disease. The impairment of the autonomic nervous system in this disease has been recognized, as well as its potential as a trigger for malignant arrhythmias when associated with structural or metabolic changes. OBJECTIVE: We sought to identify, in Chagas patients with preserved systolic function, the impairment of the autonomic nervous system and its association with functionally active anti-m2 and anti-β1 receptor antibodies. METHODS: Using spectral analysis of RR variability during passive tilt test, chronic chagasic patients were compared with healthy controls matched for age. Subsequently, the association of autonomic dysfunction with functionally active antibodies with anti-m2 and anti-β1 action was investigated by the Langendorf method. RESULTS: We observed that patients with Chagas disease without ventricular dysfunction express parasympathetic activity against a vagal stimulus, however with less intensity compared to controls. Chagasic patients with anti-m2 or anti-β1 antibodies showed a further significant reduction of the vagal response during respiratory sinus arrhythmia, regardless of the presence of structural lesion. However, the association of both factors promoted response to vagal stimulation similar to that seen in Chagas disease without their presence. CONCLUSION: The lower vagal reserve in Chagas patients with preserved function was associated with functionally active anti-m2 or anti-β1 antibodies, and not with the presence of structural heart lesion.

Autonomic dysfunction and anti-M2 and anti-ß1 receptor antibodies in Chagas disease patients.

BACKGROUND: Sudden death is the leading cause of death in Chagas' disease, affecting patients even in the early stages of the disease. The impairment of the autonomic nervous system in this disease has been recognized, as well as its potential as a trigger for malignant arrhythmias when associated with structural or metabolic changes. OBJECTIVE: We sought to identify, in Chagas patients with preserved systolic function, the impairment of the autonomic nervous system and its association with functionally active anti-m2 and anti-ß1 receptor antibodies. METHODS: Using spectral analysis of RR variability during passive tilt test, chronic chagasic patients were compared with healthy controls matched for age. Subsequently, the association of autonomic dysfunction with functionally active antibodies with anti-m2 and anti-ß1 action was investigated by the Langendorf method. RESULTS: We observed that patients with Chagas disease without ventricular dysfunction express parasympathetic activity against a vagal stimulus, however with less intensity compared to controls. Chagasic patients with anti-m2 or anti-ß1 antibodies showed a further significant reduction of the vagal response during respiratory sinus arrhythmia, regardless of the presence of structural lesion. However, the association of both factors promoted response to vagal stimulation similar to that seen in Chagas disease without their presence. CONCLUSION: The lower vagal reserve in Chagas patients with preserved function was associated with functionally active anti-m2 or anti-ß1 antibodies, and not with the presence of structural heart lesion.

The effects of brain injury on heart rate variability and the innate immune response in critically ill patients.

Brain injury and its related increased intracranial pressure (ICP) may lead to increased vagus nerve activity and the subsequent suppression of innate immunity via the cholinergic anti-inflammatory pathway. This may explain the observed increased susceptibility to infection in these patients. In the present study, we investigated the association between brain injury, vagus nerve activity, and innate immunity. We determined heart rate variability (HRV) as a measure of vagus nerve activity, plasma cytokines, and cytokine production of ex vivo lipopolysaccharide-stimulated whole blood in the first 4 days of admission to the neurological intensive care unit (ICU) in 34 patients with various forms of brain damage. HRV, immune parameters, and the correlations between these measures were analyzed in the entire group of patients and in subgroups of patients with conditions associated with high (intracranial hemorrhage [ICH]) and normal ICP (subarachnoid hemorrhage [SAH] with an extraventricular drain alleviating ICP). Healthy volunteers were used for comparison. HRV total spectral power and ex vivo-stimulated cytokine production were severely depressed in patients compared with healthy volunteers (p<0.05). Furthermore, HRV analysis showed that normalized units of high-frequency power (HFnu, corresponding with vagus nerve activity) was higher, and the low-frequency:high-frequency ratio (LF:HF, corresponding with sympathovagal balance) was lower in patients compared to healthy volunteers (p<0.05). HFnu correlated inversely with ex vivo-stimulated tumor necrosis factor-α (TNF-α) production (r=-0.22, p=0.025). The most pronounced suppression of ex vivo-stimulated cytokine production was observed in the ICH group. Furthermore, in ICH patients, HFnu correlated strongly with lower plasma TNF-α levels (r=-0.73, p=0.002). Our data suggest that brain injury, and especially conditions associated with increased ICP, is associated with vagus nerve-mediated immune suppression.

Spinal tumor necrosis factor alpha neutralization reduces peripheral inflammation and hyperalgesia and suppresses autonomic responses in experimental arthritis: a role for spinal tumor necrosis factor alpha during induction and maintenance of peripheral inflammation.

OBJECTIVE: In addition to the sensitization of pain fibers in inflamed tissues, the increased excitability of the spinal cord is an important mechanism of inflammatory pain. Furthermore, spinal neuronal excitability has been suggested to play a role in modulating peripheral inflammation. This study was undertaken to test the hypothesis that spinal actions of the proinflammatory cytokine tumor necrosis factor alpha (TNFalpha) add significantly to both hyperalgesia and maintenance of peripheral inflammation. METHODS: Rats with antigen-induced arthritis (AIA) were treated intrathecally with the TNFalpha-neutralizing compound etanercept continuously during the complete time course of AIA, which was 3 days for the acute phase and 21 days for the chronic phase. During this time, inflammation and pain-related behavior were monitored. Since a role for autonomic control of inflammation was proposed, measures from heart rate time series were obtained in the acute phase. Findings were compared with those in vehicle-treated animals and in animals receiving etanercept intraperitoneally. RESULTS: Spinally administered etanercept acutely reduced pain-related behavior, attenuated both the development and the maintenance of inflammation, and was superior to systemic administration. Parameters indicating autonomic modulation showed a shift toward a sympathetically dominated state in vehicle-treated animals, which was prevented by intrathecal etanercept. CONCLUSION: Our findings indicate that spinal TNFalpha plays an important role in both pain signaling and modulation of peripheral inflammation. Thus, neutralizing this cytokine at the spinal site not only represents a putative therapeutic option for different pain syndromes, but may be directly used to attenuate peripheral inflammation.

Circadian cardiac autonomic function in perinatally HIV-infected preschool children

The 24-h heart rate variability and QT-interval adaptation was investigated in perinatally HIV-infected preschool children classified according to immunological status in order to assess autonomic function at early stages of infection. Thirty-five perinatally HIV-infected and clinically stable children (4.8 ± 0.3 years) were enrolled after approval of the study by the University Hospital Pedro Ernesto Ethics Committee and written informed parental consent was obtained. The children were classified according to peripheral CD4+ count (cells/µL) as follows: group 1, N = 11 (≥1000); group 2, N = 7 (≥500 and <1000); group 3, N = 17 (<500). Left ventricular ejection fraction (>55%), 24-h RR interval variability (RRV) indexes (NN, SDANN, SDNN index, r-MSSD) and 24-h QT and Bazett-corrected QT (QTc) were determined, and groups were matched for age, body surface area, and left ventricular ejection fraction, reducing biases in RRV. The peak differences (∆) between the highest and lowest RRV and QT indexes were extracted from nocturnal (1 am-6 am) and daytime (1 pm-6 pm) hourly assessed segments, respectively. Pearson’s correlation (r) and Kruskal-Wallis ANOVA were used to compare groups. CD4+ count correlated positively with ∆NN (r = 0.45; P = 0.003). There were no significant differences in daytime NN among groups. Nighttime SDNN index (P = 0.01), nighttime r-MSSD (P = 0.003), ∆NN (P = 0.01), ∆SDNN index (P = 0.03) and ∆r-MSSD (P = 0.004) were significantly lower in group 3 than in the other groups. Expected nighttime QTc-interval lengthening was not observed in all groups. In perinatally HIV-infected preschool children with preserved left ventricular systolic function, parasympathetic-mediated autonomic dysfunction parallels immune status, impairing both RRV and circadian QTc interval adaptation.

Influenza virus- and cytokine-immunoreactive cells in the murine olfactory and central autonomic nervous systems before and after illness onset.

Influenza virus invades the olfactory bulb (OB) and enhances cytokine mRNAs therein at the time of illness onset. Here we show that viral antigen immunoreactivity co-localized with glial markers in the OB but could not be detected in other brain areas. Interleukin 1beta- and tumor necrosis factor alpha-immunoreactivity co-localized with neuronal markers in olfactory and central autonomic systems, and the number of cytokine-immunoreactive neurons increased at the time of illness onset [15 h post-inoculation (PI)] but not before (10 h PI). These results suggest that the OB virus influences the brain cytokines and therefore the onset of illness.

Autoantibodies in complex regional pain syndrome bind to a differentiation-dependent neuronal surface autoantigen.

Complex regional pain syndrome, which is characterised by pain and trophic disturbances, develops frequently after peripheral limb trauma. There is an increasing evidence of an involvement of the immune system in CRPS, and recently we showed that CRPS patients have autoantibodies against nervous system structures. Therefore we tested the sera of CRPS patients, neuropathy patients and healthy volunteers for surface-binding autoantibodies to primary cultures of autonomic neurons and differentiated neuroblastoma cell lines using flow cytometry. Thirteen of 30 CRPS patients, but none of 30 healthy controls and only one of the 20 neuropathy sera had specific surface binding to autonomic neurons (p<0.001). The majority of the sera reacted with both sympathetic and myenteric plexus neurons. Interestingly, 6/30 CRPS sera showed binding to undifferentiated SH-SY5Y neuroblastoma cells. However, differentiation of SH-SY5Y into a cholinergic phenotype induced a surface antigen, which is recognised by 60% of CRPS sera (18/30), but not by controls (p<0.001). Our data show that about 30-40% of CRPS patients have surface-binding autoantibodies against an inducible autonomic nervous system autoantigen. These data support an autoimmune hypothesis in CRPS patients. Further studies must elucidate origin and function of these autoantibodies in CRPS.

Splenic nerve is required for cholinergic antiinflammatory pathway control of TNF in endotoxemia.

The autonomic nervous system maintains homeostasis through its sympathetic and parasympathetic divisions. During infection, cells of the immune system release cytokines and other mediators that cause fever, hypotension, and tissue injury. Although the effect of cytokines on the nervous system has been known for decades, only recently has it become evident that the autonomic nervous system, in turn, regulates cytokine production through neural pathways. We have previously shown that efferent vagus nerve signals regulate cytokine production through the nicotinic acetylcholine receptor subunit alpha7, a mechanism termed "the cholinergic antiinflammatory pathway." Here, we show that vagus nerve stimulation during endotoxemia specifically attenuates TNF production by spleen macrophages in the red pulp and the marginal zone. Administration of nicotine, a pharmacological agonist of alpha7, attenuated TNF immunoreactivity in these specific macrophage subpopulations. Synaptophysin-positive nerve endings were observed in close apposition to red pulp macrophages, but they do not express choline acetyltransferase or vesicular acetylcholine transporter. Surgical ablation of the splenic nerve and catecholamine depletion by reserpine indicate that these nerves are catecholaminergic and are required for functional inhibition of TNF production by vagus nerve stimulation. Thus, the cholinergic antiinflammatory pathway regulates TNF production in discrete macrophage populations via two serially connected neurons: one preganglionic, originating in the dorsal motor nucleus of the vagus nerve, and the second postganglionic, originating in the celiac-superior mesenteric plexus, and projecting in the splenic nerve.

Inflammatory markers and negative mood symptoms following exercise withdrawal.

OBJECTIVE: Physical inactivity is associated with elevated inflammatory markers, but little is known about the time trajectories of reduced physical activity and inflammatory markers. Changes in inflammatory markers in response to withholding regular aerobic exercise were prospectively examined and correlated with increased negative mood symptoms and fatigue that accompany exercise withdrawal. METHODS: Participants with regular exercise habits (N=40, mean age of 31.3+/-7.5 years, 55% women) were randomized to aerobic exercise withdrawal or to continue regular exercise for 2 weeks. Protocol adherence was documented using ambulatory actigraphy. Inflammatory markers (interleukin-6, C-reactive protein, fibrinogen and soluble intercellular adhesion molecule-1) were assessed at weekly intervals. Negative mood was measured with the Profile of Mood States (POMS) and the Beck Depression Inventory (BDI), and fatigue with the Multidimensional Fatigue Inventory (MFI). Autonomic nervous system activity was examined using heart rate variability-based indices. RESULTS: Changes in inflammatory markers did not differ between exercise withdrawal and control groups (multivariate p interaction=0.25). Exercise withdrawal resulted in increased negative mood symptoms and fatigue from baseline to day 14 compared to controls (p DeltaPOMS=0.008, p DeltaBDI=0.002; p DeltaMFI=0.003), but these responses were not associated with changes in inflammatory markers (p-values >0.10). Inflammatory markers were also not correlated with autonomic nervous system dysregulation (p-values >0.10). CONCLUSION: Inflammatory markers were not increased following 2 weeks of exercise withdrawal. Negative mood symptoms and fatigue were not accounted for by changes in inflammatory markers. Compensatory feedback mechanisms may operate among healthy individuals to promote resilience from the effects of reduced exercise.