Artico, M., et al. (2002). "Noradrenergic and cholinergic innervation of the bone marrow." Int J Mol Med 10(1): 77-80.
	Bone marrow is supplied by sensory and autonomic innervation. Although it is well established that hematopoiesis is regulated by cytokines and cell-to-cell contacts, the role played by neuromediators on the proliferation, differentiation and release of hematopoietic cells is still controversial. We studied the innervation of rat femur bone marrow by means of fluorescence histochemistry and immunohistochemistry. Glyoxylic acid-induced fluorescence was used to demonstrate catecholaminergic nerve fibers. The immunoperoxidase method with nickel amplification was applied to detect the distribution of nerve fibers using antibodies against the general neuronal marker PGP 9.5 (neuron-specific cytoplasmic protein), while the cholinacetyltransferase immunoreactivity was studied by immunohistochemistry. Our results show the presence of an extensive network of innervation in the rat bone marrow, providing a morphological basis for the neural modulation of hemopoiesis.

Baron, R. and W. Janig (1988). "Sympathetic and afferent neurons projecting in the splenic nerve of the cat." Neurosci Lett 94(1-2): 109-113.
	Afferent and sympathetic postganglionic nerve cell bodies projecting in the splenic nerve of the cat have been labeled retrogradely with horseradish peroxidase (HRP) in order to study numbers and locations of these neurons. Labeled somata were found bilaterally in dorsal root and sympathetic paravertebral ganglia T3-L2 with a maximum in T10-T13 and in the coeliac superior mesenteric ganglion complex. About 13,200 neurons project into the splenic nerve of the cat, 12,550 being postganglionic and 650 afferent. About 98% of the postganglionic neurons were located in prevertebral and 2% in paravertebral sympathetic ganglia. About 73% of the afferent and 66% of the postganglionic paravertebral neurons were located on the left side. The density of the splenic innervation is about 3-4 times higher than that of the kidneys when normalized to the weight of both organs. It is discussed whether the afferent and sympathetic innervation of the spleen is not only involved in cardiovascular functions but also in regulation of the immune response of this organ.

Berthoud, H. R. and W. L. Neuhuber (2000). "Functional and chemical anatomy of the afferent vagal system." Auton Neurosci 85(1-3): 1-17.
	The results of neural tracing studies suggest that vagal afferent fibers in cervical and thoracic branches innervate the esophagus, lower airways, heart, aorta, and possibly the thymus, and via abdominal branches the entire gastrointestinal tract, liver, portal vein, billiary system, pancreas, but not the spleen. In addition, vagal afferents innervate numerous thoracic and abdominal paraganglia associated with the vagus nerves. Specific terminal structures such as flower basket terminals, intraganglionic laminar endings and intramuscular arrays have been identified in the various organs and organ compartments, suggesting functional specializations. Electrophysiological recording studies have identified mechano- and chemo-receptors, as well as temperature- and osmo-sensors. In the rat and several other species, mostly polymodal units, while in the cat more specialized units have been reported. Few details of the peripheral transduction cascades and the transmitters for signal propagation in the CNS are known. Glutamate and its various receptors are likely to play an important role at the level of primary afferent signaling to the solitary nucleus. The vagal afferent system is thus in an excellent position to detect immune-related events in the periphery and generate appropriate autonomic, endocrine, and behavioral responses via central reflex pathways. There is also good evidence for a role of vagal afferents in nociception, as manifested by affective-emotional responses such as increased blood pressure and tachycardia, typically associated with the perception of pain, and mediated via central reflex pathways involving the amygdala and other parts of the limbic system. The massive central projections are likely to be responsible for the antiepileptic properties of afferent vagal stimulation in humans. Furthermore, these functions are in line with a general defensive character ascribed to the vagal afferent, paraventricular system in lower vertebrates.

Bertram, C. D., et al. (2018). "Contraction of collecting lymphatics: organization of pressure-dependent rate for multiple lymphangions." Biomech Model Mechanobiol 17(5): 1513-1532.
	The paper describes the extension of a previously developed model of pressure-dependent contraction rate to the case of multiple lymphangions. Mechanical factors are key modulators of active lymphatic pumping. As part of the evolution of our lumped-parameter model to match experimental findings, we have designed an algorithm whereby the time until the next contraction depends on lymphangion transmural pressure in the contraction just completed. The functional dependence of frequency on pressure is quantitatively matched to isobaric contraction experiments on isolated lymphatic segments. When each of several lymphangions is given this ability, a scheme for their coordination must be instituted to match the observed synchronization. Accordingly, and in line with an experiment on an isolated lymphatic vessel segment in which we measured contraction sequence and conduction delay, we took the fundamental principle to be that local timing can be overridden by signals to initiate contraction that start in adjacent lymphangions, conducted with a short delay. The scheme leads to retrograde conduction when the lymphangion chain is pumping against an adverse pressure difference, but antegrade conduction when contractions occur with no or a favourable pressure difference. Abolition of these conducted signals leads to chaotic variation of cycle-mean flow-rate from the chain, diastolic duration in each lymphangion, and inter-lymphangion delays. Chaotic rhythm is also seen under other circumstances. Because the model responds to increasing adverse pressure difference by increasing the repetition rate of contractions, it maintains time-average output flow-rate better than one with fixed repetition rate.

Blum, H. E. (2017). "The human microbiome." Advances in Medical Sciences 62(2): 414-420.
	Until recently, human microbiology was based on the identification of single microbes, such as bacteria, fungi and viruses, frequently isolated from patients with acute or chronic infections. Novel culture-independent molecular biochemical analyses (genomics, transcriptomics, proteomics, metabolomics) allow today to detect and classify the diverse microorganisms in a given ecosystem (microbiota), such as the gastrointestinal tract, the skin, the airway system, the urogenital tract and others, and to assess all genomes in these ecosystems (microbiome) as well as their gene products. These analyses revealed that each individual has its own microbiota that plays a role in health and disease. In addition, they greatly contributed to the recent advances in the understanding of the pathogenesis of a wide range of human diseases. It is to be expected that these new insights will translate into diagnostic, therapeutic and preventive measures in the context of personalized/precision medicine.

Bratton, B. O., et al. (2012). "Neural regulation of inflammation: no neural connection from the vagus to splenic sympathetic neurons." Experimental Physiology 97(11): 1180-1185.
	The ‘inflammatory reflex’ acts through efferent neural connections from the central nervous system to lymphoid organs, particularly the spleen, that suppress the production of inflammatory cytokines. Stimulation of the efferent vagus has been shown to suppress inflammation in a manner dependent on the spleen and splenic nerves. The vagus does not innervate the spleen, so a synaptic connection from vagal preganglionic neurons to splenic sympathetic postganglionic neurons was suggested. We tested this idea in rats. In a preparatory operation, the anterograde tracer DiI was injected bilaterally into the dorsal motor nucleus of vagus and the retrograde tracer Fast Blue was injected into the spleen. On histological analysis 7–9 weeks later, 883 neurons were retrogradely labelled from the spleen with Fast Blue as follows: 89% in the suprarenal ganglia (65% left, 24% right); 11% in the left coeliac ganglion; but none in the right coeliac or either of the superior mesenteric ganglia. Vagal terminals anterogradely labelled with DiI were common in the coeliac but sparse in the suprarenal ganglia, and confocal analysis revealed no putative synaptic connection with any Fast Blue-labelled cell in either ganglion. Electrophysiological experiments in anaesthetized rats revealed no effect of vagal efferent stimulation on splenic nerve activity or on that of 15 single splenic-projecting neurons recorded in the suprarenal ganglion. Together, these findings indicate that vagal efferent neurons in the rat neither synapse with splenic sympathetic neurons nor drive their ongoing activity.

Bratton, B. O., et al. (2012). "Neural regulation of inflammation: no neural connection from the vagus to splenic sympathetic neurons." Exp Physiol 97(11): 1180-1185.
	The 'inflammatory reflex' acts through efferent neural connections from the central nervous system to lymphoid organs, particularly the spleen, that suppress the production of inflammatory cytokines. Stimulation of the efferent vagus has been shown to suppress inflammation in a manner dependent on the spleen and splenic nerves. The vagus does not innervate the spleen, so a synaptic connection from vagal preganglionic neurons to splenic sympathetic postganglionic neurons was suggested. We tested this idea in rats. In a preparatory operation, the anterograde tracer DiI was injected bilaterally into the dorsal motor nucleus of vagus and the retrograde tracer Fast Blue was injected into the spleen. On histological analysis 7-9 weeks later, 883 neurons were retrogradely labelled from the spleen with Fast Blue as follows: 89% in the suprarenal ganglia (65% left, 24% right); 11% in the left coeliac ganglion; but none in the right coeliac or either of the superior mesenteric ganglia. Vagal terminals anterogradely labelled with DiI were common in the coeliac but sparse in the suprarenal ganglia, and confocal analysis revealed no putative synaptic connection with any Fast Blue-labelled cell in either ganglion. Electrophysiological experiments in anaesthetized rats revealed no effect of vagal efferent stimulation on splenic nerve activity or on that of 15 single splenic-projecting neurons recorded in the suprarenal ganglion. Together, these findings indicate that vagal efferent neurons in the rat neither synapse with splenic sympathetic neurons nor drive their ongoing activity.

Browning, K. N., et al. (2017). "The Vagus Nerve in Appetite Regulation, Mood, and Intestinal Inflammation." Gastroenterology 152(4): 730-744.
	Although the gastrointestinal tract contains intrinsic neural plexuses that allow a significant degree of independent control over gastrointestinal functions, the central nervous system provides extrinsic neural inputs that modulate, regulate, and integrate these functions. In particular, the vagus nerve provides the parasympathetic innervation to the gastrointestinal tract, coordinating the complex interactions between central and peripheral neural control mechanisms. This review discusses the physiological roles of the afferent (sensory) and motor (efferent) vagus in regulation of appetite, mood, and the immune system, as well as the pathophysiological outcomes of vagus nerve dysfunction resulting in obesity, mood disorders, and inflammation. The therapeutic potential of vagus nerve modulation to attenuate or reverse these pathophysiological outcomes and restore autonomic homeostasis is also discussed.

Cascella, M., et al. (2020). Features, Evaluation and Treatment Coronavirus (COVID-19). StatPearls. Treasure Island (FL).
	According to the World Health Organization (WHO), viral diseases continue to emerge and represent a serious issue to public health. In the last twenty years, several viral epidemics such as the severe acute respiratory syndrome coronavirus (SARS-CoV) in 2002 to 2003, and H1N1 influenza in 2009, have been recorded. Most recently, the Middle East respiratory syndrome coronavirus (MERS-CoV) was first identified in Saudi Arabia in 2012. In a timeline that reaches the present day, an epidemic of cases with unexplained low respiratory infections detected in Wuhan, the largest metropolitan area in China's Hubei province, was first reported to the WHO Country Office in China, on December 31, 2019. Published literature can trace the beginning of symptomatic individuals back to the beginning of December 2019. As they were unable to identify the causative agent, these first cases were classified as "pneumonia of unknown etiology." The Chinese Center for Disease Control and Prevention (CDC) and local CDCs organized an intensive outbreak investigation program. The etiology of this illness is now attributed to a novel virus belonging to the coronavirus (CoV) family. On February 11, 2020, the WHO Director-General, Dr. Tedros Adhanom Ghebreyesus, announced that the disease caused by this new CoV was a "COVID-19," which is the acronym of "coronavirus disease 2019". In the past twenty years, two additional coronavirus epidemics have occurred. SARS-CoV provoked a large-scale epidemic beginning in China and involving two dozen countries with approximately 8000 cases and 800 deaths, and the MERS-CoV that began in Saudi Arabia and has approximately 2,500 cases and 800 deaths and still causes as sporadic cases. This new virus seems to be very contagious and has quickly spread globally. In a meeting on January 30, 2020, per the International Health Regulations (IHR, 2005), the outbreak was declared by the WHO a Public Health Emergency of International Concern (PHEIC) as it had spread to 18 countries with four countries reporting human-to-human transmission. An additional landmark occurred on February 26, 2020, as the first case of the disease, not imported from China, was recorded in the United States. Initially, the new virus was called 2019-nCoV. Subsequently, the task of experts of the International Committee on Taxonomy of Viruses (ICTV) termed it the SARS-CoV-2 virus as it is very similar to the one that caused the SARS outbreak (SARS-CoVs). The CoVs have become the major pathogens of emerging respiratory disease outbreaks. They are a large family of single-stranded RNA viruses (+ssRNA) that can be isolated in different animal species.[1] For reasons yet to be explained, these viruses can cross species barriers and can cause, in humans, illness ranging from the common cold to more severe diseases such as MERS and SARS. Interestingly, these latter viruses have probably originated from bats and then moving into other mammalian hosts - the Himalayan palm civet for SARS-CoV, and the dromedary camel for MERS-CoV - before jumping to humans. The dynamics of SARS-Cov-2 are currently unknown, but there is speculation that it also has an animal origin. The potential for these viruses to grow to become a pandemic worldwide seems to be a serious public health risk. Concerning COVID-19, the WHO raised the threat to the CoV epidemic to the "very high" level, on February 28, 2020. Probably, the effects of the epidemic caused by the new CoV has yet to emerge as the situation is quickly evolving. On March 11, as the number of COVID-19 cases outside China has increased 13 times and the number of countries involved has tripled with more than 118,000 cases in 114 countries and over 4,000 deaths, WHO declared the COVID-19 a pandemic. World governments are at work to establish countermeasures to stem possible devastating effects. Health organizations coordinate information flows and issues directives and guidelines to best mitigate the impact of the threat. At the same time, scientists around the world work tirelessly, and information about the transmission mechanisms, the clinical spectrum of disease, new diagnostics, and prevention and therapeutic strategies are rapidly developing. Many uncertainties remain with regard to both the virus-host interaction and the evolution of the epidemic, with specific reference to the times when the epidemic will reach its peak. At the moment, the therapeutic strategies to deal with the infection are only supportive, and prevention aimed at reducing transmission in the community is our best weapon. Aggressive isolation measures in China have led to a progressive reduction of cases in the last few days. In Italy, in geographic regions of the north, initially, and subsequently throughout the peninsula, political and health authorities are making incredible efforts to contain a shock wave that is severely testing the health system. In the midst of the crisis, the authors have chosen to use the "Statpearls" platform because, within the PubMed scenario, it represents a unique tool that may allow them to make updates in real-time. The aim, therefore, is to collect information and scientific evidence and to provide an overview of the topic that will be continuously updated.

Cesta, M. F. (2006). "Normal structure, function, and histology of mucosa-associated lymphoid tissue." Toxicol Pathol 34(5): 599-608.
	The mucosa-associated lymphoid tissue (MALT) initiates immune responses to specific antigens encountered along all mucosal surfaces. MALT inductive sites are secondary immune tissues where antigen sampling occurs and immune responses are initiated. Effector sites, present as diffuse lymphoid tissue along all mucosal surfaces are the sites of IgA transport across the mucosal epithelium. Though there are many differences between inductive sites in various organs, they all contain the same basic compartments-follicles, interfollicular regions, subepithelial dome regions, and follicle-associated epithelium. The morphologic differences between MALT and other secondary lymphoid tissues, between the MALT sites of differing anatomic locations, and species differences among laboratory animals are described. The morphologic changes in MALT associated with aging, route of nutrition, and genetic mutation (i.e., the nude and SCID mutations) are also discussed. MALT tissues comprise the mucosal immune system which can function independently of the systemic immune system and are, therefore, an important and often overlooked aspect of immunopathology.

Chin, J. L., et al. (2013). "Effects of portal hypertension on contractility of rat spleen." European Journal of Pharmacology 721(1): 1-4.
	Portal hypertension induces changes in vascular responses to vasoconstrictors. However, the effects of portal hypertension on splenic contraction have not previously been investigated. In partial portal vein ligated (PVL) and sham-operated rats, we examined the splenic contractile responses to cumulative concentrations of noradrenaline and KCl. In PVL rats, the potency of noradrenaline in producing splenic contraction was significantly increased (pEC50 of 5.88±0.08), as compared to sham (5.40±0.06; p<0.001). In the presence of prazosin (10−8M), there was a significant rightward shift in the noradrenaline concentration response curve but the shift was greater for PVL, so that in the presence of prazosin there was no significant difference between PVL and sham animals in the potency of noradrenaline. Prazosin produced a significantly greater shift of noradrenaline potency in spleen from PVL (pKB of 8.88±0.06) (n=6) than from sham animals (8.51±0.08, n=6), demonstrating that the α1-adrenoceptor mediated component is greater in spleen from PVL. In the presence of prazosin (10−8M) the residual response is non-α1-adrenoceptor mediated, presumably α2-adrenoceptor mediated, and this response did not differ between sham and PVL. The maximum splenic contraction did not significantly differ between sham and PVL rats for either agonist. In conclusion, noradrenaline potency in contracting the rat spleen was significantly increased in tissues from PVL rats. The increased potency of prazosin suggests a greater predominance of α1-adrenoceptors in spleen of PVL rats, as prazosin has lower potency at α2-adrenoceptors.

Christensen, J., et al. (2020). "Repetitive Mild Traumatic Brain Injury Alters Glymphatic Clearance Rates in Limbic Structures of Adolescent Female Rats." Sci Rep 10(1): 6254.
	The glymphatic system is the macroscopic waste clearance system for the central nervous system. Glymphatic dysfunction has been linked to several neurological conditions, including traumatic brain injury (TBI). Adolescents are at particularly high risk for experiencing a TBI, particularly mild TBI (mTBI) and repetitive mTBI (RmTBI); however, glymphatic clearance, and how it relates to behavioral outcomes, has not been investigated in this context. Therefore, this study examined glymphatic function in the adolescent brain following RmTBI. Female adolescent Sprague Dawley rats were subjected to either three mTBIs or sham injuries spaced three days apart. One-day after their final injury, the animals underwent a beam walking task to assess sensorimotor function, and contrast-enhanced MRI to visualize glymphatic clearance rate. Behavioural measures indicated that the RmTBI group displayed an increase in loss of consciousness as well as motor coordination and balance deficits consistent with our previous studies. The contrast-enhanced MRI results indicated that the female adolescent glymphatic system responds to RmTBI in a region-specific manner, wherein an increased influx but reduced efflux was observed throughout limbic structures (hypothalamus, hippocampus, and amygdala) and the olfactory bulb but neither the influx or efflux were altered in the cortical structures (primary motor cortex, insular cortex, and dorsolateral prefrontal cortex) examined. This may indicate a role for an impaired and/or inefficient glymphatic system in the limbic structures and cortical structures, respectively, in the development of post-concussive symptomology during adolescence.

Collado, M. C., et al. (2019). Baby’s First Microbes: The Microbiome of Human Milk. How Fermented Foods Feed a Healthy Gut Microbiota: A Nutrition Continuum. M. A. Azcarate-Peril, R. R. Arnold and J. M. Bruno-Bárcena. Cham, Springer International Publishing: 3-33.
	At the beginning of the twenty-first century, microbiological studies on human milk started to describe the existence of its own microbiota. Hygienically collected milk samples from healthy women contain a relatively low bacterial load consisting mostly of Staphylococcus, Streptococcus, and other Gram-positive bacteria (Corynebacterium, Propionibacterium, Lactobacillus and Bifidobacterium). DNA from strict anaerobic bacteria is also detected in human milk samples. Colostrum and milk bacteria may play a key role in driving the development of the infant gut microbiota, the correct maturation of the infant immune system and the improvement of tolerance mechanisms. A well-balanced human milk microbiota is also relevant for maternal breast health. The origin of human milk bacteria still remains largely unknown. Infant’s oral cavity and maternal skin may contaminate milk. Additionally, selected bacteria of the maternal digestive microbiota may access the mammary glands through oral- and entero-mammary pathways by involving mononuclear cells for their transport. These pathways would provide new opportunities for manipulating maternal-fetal microbiota, reducing the risk of preterm birth or infant diseases.

Creasy, C., et al. (2013). "Thoracic and abdominal lymphatic pump techniques inhibit the growth of S. pneumoniae bacteria in the lungs of rats." Lymphat Res Biol 11(3): 183-186.
	BACKGROUND: Osteopathic physicians utilize manual medicine techniques called lymphatic pump techniques (LPT) to improve lymphatic flow and enhance immunity. Clinical studies report that LPT enhances antibody responses to bacterial vaccines, shortens duration of cough in patients with respiratory disease, and shortens the duration of intravenous antibiotic therapy and hospital stay in patients with pneumonia. The purpose of this study was to identify if thoracic LPT (Th-LPT) or abdominal LPT (Ab-LPT) would reduce Streptococcus pneumoniae colony-forming units (CFU) in the lungs of rats with acute pneumonia. METHODS AND RESULTS: Rats were nasally infected with S. pneumoniae and received either control, sham, Ab-LPT, or Th-LPT once daily for 3 consecutive days. On day 4 post-infection, lungs were removed and bacteria were enumerated. Three daily applications of either Ab-LPT or Th-LPT were able to significantly (p<0.05) reduce the numbers of pulmonary bacteria compared to control and sham. There were no significant differences in the percentage or concentration of leukocytes in blood between groups, suggesting neither Ab-LPT nor Th-LPT release leukocytes into blood circulation. CONCLUSIONS: Our data demonstrate that LPT may protect against pneumonia by inhibiting bacterial growth in the lung; however, the mechanism of protection is unclear. Once these mechanisms are understood, LPT can be optimally applied to patients with pneumonia, which may substantially reduce morbidity, mortality, and frequency of hospitalization.

Da Mesquita, S., et al. (2018). "Functional aspects of meningeal lymphatics in ageing and Alzheimer’s disease." Nature 560(7717): 185-191.
	Ageing is a major risk factor for many neurological pathologies, but its mechanisms remain unclear. Unlike other tissues, the parenchyma of the central nervous system (CNS) lacks lymphatic vasculature and waste products are removed partly through a paravascular route. (Re)discovery and characterization of meningeal lymphatic vessels has prompted an assessment of their role in waste clearance from the CNS. Here we show that meningeal lymphatic vessels drain macromolecules from the CNS (cerebrospinal and interstitial fluids) into the cervical lymph nodes in mice. Impairment of meningeal lymphatic function slows paravascular influx of macromolecules into the brain and efflux of macromolecules from the interstitial fluid, and induces cognitive impairment in mice. Treatment of aged mice with vascular endothelial growth factor C enhances meningeal lymphatic drainage of macromolecules from the cerebrospinal fluid, improving brain perfusion and learning and memory performance. Disruption of meningeal lymphatic vessels in transgenic mouse models of Alzheimer’s disease promotes amyloid-β deposition in the meninges, which resembles human meningeal pathology, and aggravates parenchymal amyloid-β accumulation. Meningeal lymphatic dysfunction may be an aggravating factor in Alzheimer’s disease pathology and in age-associated cognitive decline. Thus, augmentation of meningeal lymphatic function might be a promising therapeutic target for preventing or delaying age-associated neurological diseases.

den Dunnen, J., et al. (2012). "IgG opsonization of bacteria promotes Th17 responses via synergy between TLRs and FcgammaRIIa in human dendritic cells." Blood 120(1): 112-121.
	Dendritic cells (DCs) are essential in inducing adaptive immune responses against bacteria by expressing cytokines that skew T-cell responses toward protective Th17 cells. Although it is widely recognized that induction of these cytokines by DCs involves activation of multiple receptors, it is still incompletely characterized which combination of receptors specifically skews Th17-cell responses. Here we have identified a novel role for FcgammaRIIa in promoting human Th17 cells. Activation of DCs by bacteria opsonized by serum IgG strongly promoted Th17 responses, which was FcgammaRIIa-dependent and coincided with enhanced production of selected cytokines by DCs, including Th17-promoting IL-1beta and IL-23. Notably, FcgammaRIIa stimulation on DCs did not induce cytokine production when stimulated individually, but selectively amplified cytokine responses through synergy with TLR2, 4, or 5. Importantly, this synergy is mediated at 2 different levels. First, TLR-FcgammaRIIa costimulation strongly increased transcription of pro-IL-1beta and IL-23p19. Second, FcgammaRIIa triggering induced activation of caspase-1, which cleaves pro-IL-1beta into its bioactive form and thereby enhanced IL-1beta secretion. Taken together, these data identified cross-talk between TLRs and FcgammaRIIa as a novel mechanism by which DCs promote protective effector Th17-cell responses against bacteria.

Druzd, D., et al. (2017). "Lymphocyte Circadian Clocks Control Lymph Node Trafficking and Adaptive Immune Responses." Immunity 46(1): 120-132.
	Lymphocytes circulate through lymph nodes (LN) in search for antigen in what is believed to be a continuous process. Here, we show that lymphocyte migration through lymph nodes and lymph occurred in a non-continuous, circadian manner. Lymphocyte homing to lymph nodes peaked at night onset, with cells leaving the tissue during the day. This resulted in strong oscillations in lymphocyte cellularity in lymph nodes and efferent lymphatic fluid. Using lineage-specific genetic ablation of circadian clock function, we demonstrated this to be dependent on rhythmic expression of promigratory factors on lymphocytes. Dendritic cell numbers peaked in phase with lymphocytes, with diurnal oscillations being present in disease severity after immunization to induce experimental autoimmune encephalomyelitis (EAE). These rhythms were abolished by genetic disruption of T cell clocks, demonstrating a circadian regulation of lymphocyte migration through lymph nodes with time-of-day of immunization being critical for adaptive immune responses weeks later.

Dupont, G., et al. (2019). "Our current understanding of the lymphatics of the brain and spinal cord." Clin Anat 32(1): 117-121.
	The lymphatic system, segregated from the blood vascular system, is an essential anatomical route along which interstitial fluid, solutes, lipids, immune cells, and cellular debris, are conveyed. However, the way these mechanisms operate within the cranial compartment is mostly unknown. Herein, we review current understanding of the meningeal lymphatics, described anatomically over a century ago yet still poorly understood from a functional standpoint. We will delineate the cellular mechanisms by which the meningeal lymphatics are formed and discuss their unique anatomy. Furthermore, this review will discuss the recently-coined "glymphatic system" and the manner by which cerebrospinal fluid (CSF) and interstitial fluid (ISF) are exchanged and thus drained by the meningeal lymphatic vasculature as a key route for conveying cellular waste, solutes, and immune traffic to the deep cervical lymph nodes. The clinical relevance of the meningeal lymphatics will also be described, as they are relevant to various common defects of the lymphatic system. Clin. Anat. 32:117-121, 2019. (c) 2018 Wiley Periodicals, Inc.

Fanelli, V., et al. (2020). "Acute kidney injury in SARS-CoV-2 infected patients." Crit Care 24(1): 155.
	
Gautron, L., et al. (2013). "Neuronal and nonneuronal cholinergic structures in the mouse gastrointestinal tract and spleen." J Comp Neurol 521(16): 3741-3767.
	Accumulating evidence demonstrates that acetylcholine can directly modulate immune function in peripheral tissues including the spleen and gastrointestinal tract. However, the anatomical relationships between the peripheral cholinergic system and immune cells located in these lymphoid tissues remain unclear due to inherent technical difficulties with currently available neuroanatomical methods. In this study, mice with specific expression of the tdTomato fluorescent protein in choline acetyltransferase (ChAT)-expressing cells were used to label preganglionic and postganglionic cholinergic neurons and their projections to lymphoid tissues. Notably, our anatomical observations revealed an abundant innervation in the intestinal lamina propria of the entire gastrointestinal tract principally originating from cholinergic enteric neurons. The aforementioned innervation frequently approached macrophages, plasma cells, and lymphocytes located in the lamina propria and, to a lesser extent, lymphocytes in the interfollicular areas of Peyer's patches. In addition to the above innervation, we observed labeled epithelial cells in the gallbladder and lower intestines, as well as Microfold cells and T-cells within Peyer's patches. In contrast, we found only a sparse innervation in the spleen consisting of neuronal fibers of spinal origin present around arterioles and in lymphocyte-containing areas of the white pulp. Lastly, a small population of ChAT-expressing lymphocytes was identified in the spleen including both T- and B-cells. In summary, this study describes the variety of cholinergic neuronal and nonneuronal cells in a position to modulate gastrointestinal and splenic immunity in the mouse.

Grüneboom, A., et al. (2019). "A network of trans-cortical capillaries as mainstay for blood circulation in long bones." Nature Metabolism 1(2): 236-250.
	Closed circulatory systems underlie the function of vertebrate organs, but in long bones their structure is unclear although they constitute the exit route for bone marrow (BM) leukocytes. To understand neutrophil migration from BM, we studied the vascular system of murine long bones. Here, in a mouse model, we show that hundreds of capillaries originate in BM, traverse cortical bone perpendicularly along the shaft and connect to the periosteal circulation. Structures similar to these trans-cortical vessels (TCVs) also exist in human limb bones. TCVs express arterial or venous markers and transport neutrophils. Furthermore, over 80% of arterial and 59% of venous blood passes through TCVs. Genetic and drug-mediated modulation of osteoclast count and activity leads to substantial changes in TCV numbers. In a murine model of chronic arthritic bone inflammation, new TCVs develop within weeks. Our data indicate that TCVs are a central component of the closed circulatory system in long bones and may represent an important route for immune cell export from BM.

Helmink, B. A., et al. (2020). "B cells and tertiary lymphoid structures promote immunotherapy response." Nature 577(7791): 549-555.
	Treatment with immune checkpoint blockade (ICB) has revolutionized cancer therapy. Until now, predictive biomarkers(1-10) and strategies to augment clinical response have largely focused on the T cell compartment. However, other immune subsets may also contribute to anti-tumour immunity(11-15), although these have been less well-studied in ICB treatment(16). A previously conducted neoadjuvant ICB trial in patients with melanoma showed via targeted expression profiling(17) that B cell signatures were enriched in the tumours of patients who respond to treatment versus non-responding patients. To build on this, here we performed bulk RNA sequencing and found that B cell markers were the most differentially expressed genes in the tumours of responders versus non-responders. Our findings were corroborated using a computational method (MCP-counter(18)) to estimate the immune and stromal composition in this and two other ICB-treated cohorts (patients with melanoma and renal cell carcinoma). Histological evaluation highlighted the localization of B cells within tertiary lymphoid structures. We assessed the potential functional contributions of B cells via bulk and single-cell RNA sequencing, which demonstrate clonal expansion and unique functional states of B cells in responders. Mass cytometry showed that switched memory B cells were enriched in the tumours of responders. Together, these data provide insights into the potential role of B cells and tertiary lymphoid structures in the response to ICB treatment, with implications for the development of biomarkers and therapeutic targets.

Hodge, L. M., et al. (2010). "Lymphatic pump treatment mobilizes leukocytes from the gut associated lymphoid tissue into lymph." Lymphat Res Biol 8(2): 103-110.
	BACKGROUND: Lymphatic pump techniques (LPT) are used clinically by osteopathic practitioners for the treatment of edema and infection; however, the mechanisms by which LPT enhances lymphatic circulation and provides protection during infection are not understood. Rhythmic compressions on the abdomen during LPT compress the abdominal area, including the gut-associated lymphoid tissues (GALT), which may facilitate the release of leukocytes from these tissues into the lymphatic circulation. This study is the first to document LPT-induced mobilization of leukocytes from the GALT into the lymphatic circulation. METHODS AND RESULTS: Catheters were inserted into either the thoracic or mesenteric lymph ducts of dogs. To determine if LPT enhanced the release of leukocytes from the mesenteric lymph nodes (MLN) into lymph, the MLN were fluorescently labeled in situ. Lymph was collected during 4 min pre-LPT, 4 min LPT, and 10 min following cessation of LPT. LPT significantly increased lymph flow and leukocytes in both mesenteric and thoracic duct lymph. LPT had no preferential effect on any specific leukocyte population, since neutrophil, monocyte, CD4+ T cell, CD8+ T cell, IgG+B cell, and IgA+B cell numbers were similarly increased. In addition, LPT significantly increased the mobilization of leukocytes from the MLN into lymph. Lymph flow and leukocyte counts fell following LPT treatment, indicating that the effects of LPT are transient. CONCLUSIONS: LPT mobilizes leukocytes from GALT, and these leukocytes are transported by the lymphatic circulation. This enhanced release of leukocytes from GALT may provide scientific rationale for the clinical use of LPT to improve immune function.

Hodge, L. M., et al. (2007). "Abdominal lymphatic pump treatment increases leukocyte count and flux in thoracic duct lymph." Lymphat Res Biol 5(2): 127-133.
	BACKGROUND: Previous studies suggest that rhythmic compression of the abdomen (abdominal lymphatic pump techniques, LPT) enhances immunity and resistance to infectious disease, but direct evidence of this has not been documented. In this study, the thoracic duct of eight anesthetized mongrel dogs was catheterized, so the immediate effects of LPT on lymph flow and leukocyte output could be measured. METHODS AND RESULTS: Lymph flow was measured by timed collection or ultrasonic flowmeter, and lymph was collected over ice under 1) resting (baseline) conditions, and 2) during application of LPT. The baseline leukocyte count was 4.8 +/- 1.7 x 10(6) cells/ml of lymph, and LPT significantly increased leukocytes to 11.8 +/- 3.6 x 10(6) cells/ml. Flow cytometry and differential cell staining revealed that numbers of macrophages, neutrophils, total lymphocytes, T cells and B cells were similarly increased during LPT. Furthermore, LPT significantly enhanced lymph flow from 1.13 +/- 0.44 ml/min to 4.14 +/- 1.29 ml/min. Leukocyte flux, computed from the product of lymph flow and cell count, was increased by LPT from 8.2 +/- 4.1 x 10(6) to 60 +/- 25 x 10(6) total cells/min. Similar trends were observed in macrophages, neutrophils, total lymphocytes, T cells and B cells during LPT. CONCLUSIONS: LPT significantly increased both thoracic duct lymph flow and leukocyte count, so lymph leukocyte flux was markedly enhanced. Increased mobilization of immune cells is likely and important mechanism responsible for the enhanced immunity and recovery from infection of patients treated with LPT.

Hoover, D. B. (2017). "Cholinergic modulation of the immune system presents new approaches for treating inflammation." Pharmacol Ther 179: 1-16.
	The nervous system and immune system have broad and overlapping distributions in the body, and interactions of these ubiquitous systems are central to the field of neuroimmunology. Over the past two decades, there has been explosive growth in our understanding of neuroanatomical, cellular, and molecular mechanisms that mediate central modulation of immune functions through the autonomic nervous system. A major catalyst for growth in this field was the discovery that vagal nerve stimulation (VNS) caused a prominent attenuation of the systemic inflammatory response evoked by endotoxin in experimental animals. This effect was mediated by acetylcholine (ACh) stimulation of nicotinic receptors on splenic macrophages. Hence, the circuit was dubbed the "cholinergic anti-inflammatory pathway". Subsequent work identified the α7 nicotinic ACh receptor (α7nAChR) as the crucial target for attenuation of pro-inflammatory cytokine release from macrophages and dendritic cells. Further investigation made the important discovery that cholinergic T cells within the spleen and not cholinergic nerve cells were the source of ACh that stimulated α7 receptors on splenic macrophages. Given the important role that inflammation plays in numerous disease processes, cholinergic anti-inflammatory mechanisms are under intensive investigation from a basic science perspective and in translational studies of animal models of diseases such as inflammatory bowel disease and rheumatoid arthritis. This basic work has already fostered several clinical trials examining the efficacy of VNS and cholinergic therapeutics in human inflammatory diseases. This review provides an overview of basic and translational aspects of the cholinergic anti-inflammatory response and relevant pharmacology of drugs acting at the α7nAChR.

Hu, D., et al. (2019). "Immunofluorescence characterization of innervation and nerve-immune cell interactions in mouse lymph nodes." Eur J Histochem 63(4).
	The peripheral nervous system communicates specifically with the immune system via local interactions. These interactions include the "hardwiring" of sympathetic/parasympathetic (efferent) and sensory nerves (afferent) to primary (e.g., thymus and bone marrow) and secondary (e.g., lymph node, spleen, and gut-associated lymphoid tissue) lymphoid tissue/organs. To gain a better understanding of this bidirectional interaction/crosstalk between the two systems, we have investigated the distribution of nerve fibres and PNS-immune cell associations in situ in the mouse lymph node by using immunofluorescent staining and confocal microscopy/ three-dimensional reconstruction. Our results demonstrate i) the presence of extensive nerve fibres in all compartments (including B cell follicles) in the mouse lymph node; ii) close contacts/associations of nerve fibres with blood vessels (including high endothelial venules) and lymphatic vessels/sinuses; iii) close contacts/associations of nerve fibres with various subsets of dendritic cells (e.g., B220+CD11c+, CD4+CD11c+, CD8a+CD11c+, and Mac1+CD11c+), Mac1+ macrophages, and B/T lymphocytes. Our novel findings concerning the innervation and nerve-immune cell interactions inside the mouse lymph node should greatly facilitate our understanding of the effects that the peripheral nervous system has on cellular- and humoral-mediated immune responses or vice versa in health and disease.

Huston, J. M., et al. (2006). "Splenectomy inactivates the cholinergic antiinflammatory pathway during lethal endotoxemia and polymicrobial sepsis." J Exp Med 203(7): 1623-1628.
	The innate immune system protects against infection and tissue injury through the specialized organs of the reticuloendothelial system, including the lungs, liver, and spleen. The central nervous system regulates innate immune responses via the vagus nerve, a mechanism termed the cholinergic antiinflammatory pathway. Vagus nerve stimulation inhibits proinflammatory cytokine production by signaling through the alpha7 nicotinic acetylcholine receptor subunit. Previously, the functional relationship between the cholinergic antiinflammatory pathway and the reticuloendothelial system was unknown. Here we show that vagus nerve stimulation fails to inhibit tumor necrosis factor (TNF) production in splenectomized animals during lethal endotoxemia. Selective lesioning of the common celiac nerve abolishes TNF suppression by vagus nerve stimulation, suggesting that the cholinergic pathway is functionally hard wired to the spleen via this branch of the vagus nerve. Administration of nicotine, an alpha7 agonist that mimics vagus nerve stimulation, increases proinflammatory cytokine production and lethality from polymicrobial sepsis in splenectomized mice, indicating that the spleen is critical to the protective response of the cholinergic pathway. These results reveal a specific, physiological connection between the nervous and innate immune systems that may be exploited through either electrical vagus nerve stimulation or administration of alpha7 agonists to inhibit proinflammatory cytokine production during infection and tissue injury.

Ikomi, F., et al. (2012). "Recent advance in lymph dynamic analysis in lymphatics and lymph nodes." Ann Vasc Dis 5(3): 258-268.
	Lymphatics are a unidirectional transport system that carries fluid from the interstitial space and back into the blood stream. Initial lymphatics take up not only fluid but also high-molecular-weight substances, such as plasma proteins and hyaluronan; immune cells, such as lymphocytes, macrophages, and dendritic cells; and colloidal particles, such as carbon particles, bacteria, and tattoo dye. Interstitially injected colloidal particles are known to accumulate in the regional lymph nodes. This phenomenon is applied to find sentinel lymph nodes in cancer patients. Lymph flow rate and composition are influenced by interstitial fluid, lymphatic pump activity, and intra-lymphatic pressure. Lymph composition is changed during its flow downstream. In this review, the main focus is on the mechanisms of lymph formation at the initial lymphatics and lymph transport through the collecting lymphatics and lymph nodes. (*English Translation of J Jpn Coll Angiol, 2008, 48: 113-123.).

Jung, W. C., et al. (2017). "It takes nerve to fight back: The significance of neural innervation of the bone marrow and spleen for immune function." Semin Cell Dev Biol 61: 60-70.
	Inflammation is a natural part of wound healing but it can also cause secondary (bystander) damage and/or negatively interfere with endogenous repair mechanisms if non-resolving. Regulation of inflammation is traditionally looked at from the perspective of danger signals, cytokines and chemokines, and their respective receptors. A neuronal contribution to the regulation of inflammation is, however, increasingly appreciated, and this has important implications for the bodily response under conditions where the nervous system itself may be damaged. In this review article, we provide an up-to-date overview of the current literature on neural innervation of primary and secondary lymphoid organs, focusing in particular on the bone marrow and spleen, its significance in relation to immune function and, lastly, also briefly discussing how a major neurotraumatic event like spinal cord injury (SCI) may impact on this.

Lo Re, S., et al. (2010). "IL-17A-producing gammadelta T and Th17 lymphocytes mediate lung inflammation but not fibrosis in experimental silicosis." J Immunol 184(11): 6367-6377.
	IL-17-producing T lymphocytes play a crucial role in inflammation, but their possible implication in fibrosis remains to be explored. In this study, we examined the involvement of these cells in a mouse model of lung inflammation and fibrosis induced by silica particles. Upregulation of IL-17A was associated with the development of experimental silicosis, but this response was markedly reduced in athymic, gammadelta T cell-deficient or CD4(+) T cell-depleted mice. In addition, gammadelta T lymphocytes and CD4(+) T cells, but not macrophages, neutrophils, NK cells or CD8 T cells, purified from the lungs of silicotic mice markedly expressed IL-17A. Depletion of alveolar macrophages or neutralization of IL-23 reduced upregulation of IL-17A in the lung of silicotic mice. IL-17R-deficient animals (IL-17R(-/-)) or IL-17A Ab neutralization, but not IL-22(-/-) mice, developed reduced neutrophil influx and injury during the early lung response to silica. However, chronic inflammation, fibrosis, and TGF-beta expression induced by silica were not attenuated in the absence of IL-17R or -22 or after IL-17A Ab blockade. In conclusion, a rapid lung recruitment of IL-17A-producing T cells, mediated by macrophage-derived IL-23, is associated with experimental silicosis in mice. Although the acute alveolitis induced by silica is IL-17A dependent, this cytokine appears dispensable for the development of the late inflammatory and fibrotic lung responses to silica.

Magrone, T. and E. Jirillo (2019). "Development and Organization of the Secondary and Tertiary Lymphoid Organs: Influence of Microbial and Food Antigens." Endocr Metab Immune Disord Drug Targets 19(2): 128-135.
	BACKGROUND: Secondary lymphoid organs (SLO) are distributed in many districts of the body and, especially, lymph nodes, spleen and gut-associated lymphoid tissue are the main cellular sites. On the other hand, tertiary lymphoid organs (TLO) are formed in response to inflammatory, infectious, autoimmune and neoplastic events. Developmental Studies: In the present review, emphasis will be placed on the developmental differences of SLO and TLO between small intestine and colon and on the role played by various chemokines and cell receptors. Undoubtedly, microbiota is indispensable for the formation of SLO and its absence leads to their poor formation, thus indicating its strict interaction with immune and non immune host cells. Furthermore, food antigens (for example, tryptophan derivatives, flavonoids and byphenils) bind the aryl hydrocarbon receptor on innate lymphoid cells (ILCs), thus promoting the development of postnatal lymphoid tissues. Also retinoic acid, a metabolite of vitamin A, contributes to SLO development during embryogenesis. Vitamin A deficiency seems to account for reduction of ILCs and scarce formation of solitary lymphoid tissue. Translational Studies: The role of lymphoid organs with special reference to intestinal TLO in the course of experimental and human disease will also be discussed. Future Perspectives: Finally, a new methodology, the so-called "gut-in-a dish", which has facilitated the in vitro interaction study between microbe and intestinal immune cells, will be described.

Martelli, D., et al. (2014). "The cholinergic anti-inflammatory pathway: a critical review." Auton Neurosci 182: 65-69.
	From a critical review of the evidence on the cholinergic anti-inflammatory pathway and its mode of action, the following conclusions were reached. (1) Both local and systemic inflammation may be suppressed by electrical stimulation of the peripheral cut end of either vagus. (2) The spleen mediates most of the systemic inflammatory response (measured by TNF-alpha production) to systemic endotoxin and is also the site where that response is suppressed by vagal stimulation. (3) The anti-inflammatory effect of vagal stimulation depends on the presence of noradrenaline-containing nerve terminals in the spleen. (4) There is no disynaptic connection from the vagus to the spleen via the splenic sympathetic nerve: vagal stimulation does not drive action potentials in the splenic nerve. (5) Acetylcholine-synthesizing T lymphocytes provide an essential non-neural link in the anti-inflammatory pathway from vagus to spleen. (6) Alpha-7 subunit-containing nicotinic receptors are essential for the vagal anti-inflammatory action: their critical location is uncertain, but is suggested here to be on splenic sympathetic nerve terminals. (7) The vagal anti-inflammatory pathway can be activated electrically or pharmacologically, but it is not the efferent arm of the inflammatory reflex response to endotoxemia.

Martelli, D., et al. (2014). "Reflex control of inflammation by sympathetic nerves, not the vagus." J Physiol 592(7): 1677-1686.
	We investigated a neural reflex that controls the strength of inflammatory responses to immune challenge - the inflammatory reflex. In anaesthetized rats challenged with intravenous lipopolysaccharide (LPS, 60 mug kg(-1)), we found strong increases in plasma levels of the key inflammatory mediator tumour necrosis factor alpha (TNFalpha) 90 min later. Those levels were unaffected by previous bilateral cervical vagotomy, but were enhanced approximately 5-fold if the greater splanchnic sympathetic nerves had been cut. Sham surgery had no effect, and plasma corticosterone levels were unaffected by nerve sections, so could not explain this result. Electrophysiological recordings demonstrated that efferent neural activity in the splanchnic nerve and its splenic branch was strongly increased by LPS treatment. Splenic nerve activity was dependent on inputs from the splanchnic nerves: vagotomy had no effect on the activity in either nerve. Together, these data demonstrate that immune challenge with this dose of LPS activates a neural reflex that is powerful enough to cause an 80% suppression of the acute systemic inflammatory response. The efferent arm of this reflex is in the splanchnic sympathetic nerves, not the vagi as previously proposed. As with other physiological responses to immune challenge, the afferent pathway is presumptively humoral: the present data show that vagal afferents play no measurable part. Because inflammation sits at the gateway to immune responses, this reflex could play an important role in immune function as well as inflammatory diseases.

Matsubara, S., et al. (2019). "Tertiary lymphoid organs in the inflammatory myopathy associated with PD-1 inhibitors." J Immunother Cancer 7(1): 256.
	BACKGROUND: Programmed cell death 1 inhibitors have revolutionized therapy for cancer by their outstanding effectiveness. However, they may cause adverse effects, among which inflammatory myopathy is one of the most disabling. To elucidate its mechanism, we analysed muscle biopsies and compared them with other inflammatory myopathies. METHODS: Muscle biopsies from three patients with inflammatory myopathy after treatment with PD-1 inhibitors for cancer were subjected to immunohistochemical and ultrastructural analyses to localize CD8+ cytotoxic cells and markers of lymphoid follicles. For comparison, two cases of polymyositis and one of juvenile dermatomyositis were examined. RESULTS: Nearly identical pathological features were observed in the three cases. In the island-like foci of inflammation, muscle fibers were undergoing degeneration. CD8+ cytotoxic T cells, macrophages, CD4+ cells, and B cells were observed in the foci. CD8+ cells were seen outside and inside the basal lamina of non-necrotic muscle fibers. Lymphoid follicle-like structures with CD21+ follicular dendritic cells were present. The blood vessels in the foci showed features consistent with the high endothelial venules, on which their markers, PNAd and CCL21, were expressed. In polymyositis, blood vessels stained only faintly for PNAd and CCL21, while in juvenile dermatomyositis, in which tertiary lymphoid follicle-like structure was reported in the past, they stained positively. CONCLUSIONS: In inflammatory myopathy associated with PD-1 inhibitors, CD8+ cells appear to predominantly destruct muscle fibers. The presence of lymphoid follicle-like structures and expression of PNAd and CCL21 on the endothelial cells suggest the tertiary lymphoid organs are formed, and involved in the leakage of lymphocytes. Thus, in the three cases examined, formation of the tertiary lymphoid organs is likely to play an important role in genesis of the PD-1 myopathy.

Mignini, F., et al. (2014). "Neuro-immune modulation of the thymus microenvironment (review)." Int J Mol Med 33(6): 1392-1400.
	The thymus is the primary site for T-cell lympho-poiesis. Its function includes the maturation and selection of antigen specific T cells and selective release of these cells to the periphery. These highly complex processes require precise parenchymal organization and compartmentation where a plethora of signalling pathways occur, performing strict control on the maturation and selection processes of T lymphocytes. In this review, the main morphological characteristics of the thymus microenvironment, with particular emphasis on nerve fibers and neuropeptides were assessed, as both are responsible for neuro-immunemodulation functions. Among several neurotransmitters that affect thymus function, we highlight the dopaminergic system as only recently has its importance on thymus function and lymphocyte physiology come to light.

Murray, K., et al. (2019). "Functional circuitry of neuro-immune communication in the mesenteric lymph node and spleen." Brain Behav Immun 82: 214-223.
	The peripheral nervous system is an active participant in immune responses capable of blocking aberrant activation of a variety of immune cells. As one of these neuro-immune circuits, the cholinergic anti-inflammatory pathway has been well established to reduce the severity of several immunopathologies. While the activation of this pathway by vagal nerve stimulation requires sympathetic innervation of the spleen, the neuro-immune circuitry remains highly controversial. Neuro-immune pathways in other lymphoid tissues such as mesenteric lymph nodes (MLN) that are critical to the surveillance of the small intestine and proximal colon have not been assessed. Using conditionally expressed Channelrhodopsin, selective stimulation of sympathetic post-ganglionic neurons in the superior mesenteric ganglion (SMG) prevented macrophage activation and LPS-induced TNFalpha production in the spleen and MLN, but not in the inguinal LN. Site selective stimulation of the SMG induced the release of norepinephrine, resulting in beta2AR dependent acetylcholine release in the MLN and spleen. VNS-evoked release of norepinephrine and acetylcholine in the MLN and spleen was significantly reduced using selective optogenetic blockade applied at the SMG. Additionally, this optogenetic blockade restored LPS-induced TNFalpha production, despite VNS. These studies identify the superior mesenteric ganglion as a critical node in a neuro-immune circuit that can inhibit immune function in the MLN and the spleen.

Niijima, A. (1995). "An electrophysiological study on the vagal innervation of the thymus in the rat." Brain Res Bull 38(4): 319-323.
	Vagal innervation of the thymus was studied by means of electrophysiological technique in the rat. Under urethane anesthesia, evoked action potentials originated from cervical vagus by electrical stimulations were recorded from the central cut end of the thymic branch of the vagus nerve after averaging for 32 times. It was observed that the conduction velocities are distributed in the range of 0.56-6.84 m/s, and the majority of vagal fibers in the thymic branch of the vagus nerve belong to a nonmyelinated C-fiber group. Further, it was confirmed that the right and left lobes of the thymus are innervated by cervical vagi bilaterally. The results suggest that the thymic branch of the vagus nerve plays a role in modulation of thymic function.

Ottman, N., et al. (2012). "The function of our microbiota: who is out there and what do they do?" Front Cell Infect Microbiol 2: 104.
	Current meta-omics developments provide a portal into the functional potential and activity of the intestinal microbiota. The comparative and functional meta-omics approaches have made it possible to get a molecular snap shot of microbial function at a certain time and place. To this end, metagenomics is a DNA-based approach, metatranscriptomics studies the total transcribed RNA, metaproteomics focuses on protein levels and metabolomics describes metabolic profiles. Notably, the metagenomic toolbox is rapidly expanding and has been instrumental in the generation of draft genome sequences of over 1000 human associated microorganisms as well as an astonishing 3.3 million unique microbial genes derived from the intestinal tract of over 100 European adults. Remarkably, it appeared that there are at least 3 clusters of co-occurring microbial species, termed enterotypes, that characterize the intestinal microbiota throughout various continents. The human intestinal microbial metagenome further revealed unique functions carried out in the intestinal environment and provided the basis for newly discovered mechanisms for signaling, vitamin production and glycan, amino-acid and xenobiotic metabolism. The activity and composition of the microbiota is affected by genetic background, age, diet, and health status of the host. In its turn the microbiota composition and activity influence host metabolism and disease development. Exemplified by the differences in microbiota composition and activity between breast- as compared to formula-fed babies, healthy and malnourished infants, elderly and centenarians as compared to youngsters, humans that are either lean or obese and healthy or suffering of inflammatory bowel diseases (IBD). In this review we will focus on our current understanding of the functionality of the human intestinal microbiota based on all available metagenome, metatranscriptome, and metaproteome results.

Robey, R. C., et al. (2010). "The T-Cell Immune Response against Kaposi&#39;s Sarcoma-Associated Herpesvirus." Advances in Virology 2010: 340356.
	Kaposi's sarcoma-associated herpesvirus (KSHV) is the aetiological agent of Kaposi's sarcoma (KS), the most frequently arising malignancy in individuals with untreated HIV/AIDS. There are several lines of evidence to indicate that Kaposi's sarcoma oncogenesis is associated with loss of T-cell-mediated control of KSHV-infected cells. KSHV can establish life-long asymptomatic infection in immune-competent individuals. However, when T-cell immune control declines, for example, through AIDS or treatment with immunosuppressive drugs, both the prevalence of KSHV infection and the incidence of KS in KSHV carriers dramatically increase. Moreover, a dramatic and spontaneous improvement in KS is frequently seen when immunity is restored, for example, through antiretroviral therapy or the cessation of iatrogenic drugs. In this paper we describe the current state of knowledge on the T-cell immune responses against KSHV.

Roggero, E., et al. (2011). "The role of the sympathetic nervous system in the thymus in health and disease." Neuroimmunomodulation 18(5): 339-349.
	The existence of a network of immunoneuroendocrine interactions that results in the reciprocal modulation of the classical functions of each system is well established at present. Most of the evidence derives from studies on secondary lymphoid organs, such as the spleen and lymph nodes. In this article, several aspects relevant to understand the role of the sympathetic nervous system in the establishment of these interactions in the thymus are discussed. At present, the sympathetic innervation of the thymus, the expression of adrenergic receptors in thymic cells, particularly of beta-adrenergic receptors, and the effect of sympathetic neurotransmitters, although mainly derived from in vitro or pharmacological studies, seem to be relatively well studied. However, other aspects, such as the relevance that immune-sympathetic interactions at the thymic level may have for certain diseases, specially autoimmune or other diseases that primarily involve the activation of the immune system, as well as how the integration of sympathetic and hormonal signals at local levels may affect thymic functions, certainly deserve further investigation.

Schafer, E. A. and B. Moore (1896). "On the Contractility and Innervation of the Spleen." J Physiol 20(1): 1-50.
	
Schander, A., et al. (2013). "Lymphatic pump treatment repeatedly enhances the lymphatic and immune systems." Lymphat Res Biol 11(4): 219-226.
	BACKGROUND: Osteopathic practitioners utilize manual therapies called lymphatic pump techniques (LPT) to treat edema and infectious diseases. While previous studies examined the effect of a single LPT treatment on the lymphatic system, the effect of repeated applications of LPT on lymphatic output and immunity has not been investigated. Therefore, the purpose of this study was to measure the effects of repeated LPT on lymphatic flow, lymph leukocyte numbers, and inflammatory mediator concentrations in thoracic duct lymph (TDL). METHODS AND RESULTS: The thoracic ducts of five mongrel dogs were cannulated, and lymph samples were collected during pre-LPT, 4 min of LPT, and 2 hours post-LPT. A second LPT (LPT-2) was applied after a 2 hour rest period. TDL flow was measured, and TDL were analyzed for the concentration of leukocytes and inflammatory mediators. Both LPT treatments significantly increased TDL flow, leukocyte count, total leukocyte flux, and the flux of interleukin-8 (IL-8), keratinocyte-derived chemoattractant (KC), nitrite (NO2(-)), and superoxide dismutase (SOD). The concentration of IL-6 increased in lymph over time in all experimental groups; therefore, it was not LPT dependent. CONCLUSION: Clinically, it can be inferred that LPT at a rate of 1 pump per sec for a total of 4 min can be applied every 2 h, thus providing scientific rationale for the use of LPT to repeatedly enhance the lymphatic and immune system.

Simon, A. K., et al. (2015). "Evolution of the immune system in humans from infancy to old age." Proc Biol Sci 282(1821): 20143085.
	This article reviews the development of the immune response through neonatal, infant and adult life, including pregnancy, ending with the decline in old age. A picture emerges of a child born with an immature, innate and adaptive immune system, which matures and acquires memory as he or she grows. It then goes into decline in old age. These changes are considered alongside the risks of different types of infection, autoimmune disease and malignancy.

Sloan, E. K., et al. (2008). "Social temperament and lymph node innervation." Brain Behav Immun 22(5): 717-726.
	Socially inhibited individuals show increased vulnerability to viral infections, and this has been linked to increased activity of the sympathetic nervous system (SNS). To determine whether structural alterations in SNS innervation of lymphoid tissue might contribute to these effects, we assayed the density of catecholaminergic nerve fibers in 13 lymph nodes from seven healthy adult rhesus macaques that showed stable individual differences in propensity to socially affiliate (Sociability). Tissues from Low Sociable animals showed a 2.8-fold greater density of catecholaminergic innervation relative to tissues from High Sociable animals, and this was associated with a 2.3-fold greater expression of nerve growth factor (NGF) mRNA, suggesting a molecular mechanism for observed differences. Low Sociable animals also showed alterations in lymph node expression of the immunoregulatory cytokine genes IFNG and IL4, and lower secondary IgG responses to tetanus vaccination. These findings are consistent with the hypothesis that structural differences in lymphoid tissue innervation might potentially contribute to relationships between social temperament and immunobiology.

Yamashita, T., et al. (1984). "Autonomic nervous system in human palatine tonsil." Acta Otolaryngol Suppl 416: 63-71.
	The autonomic nervous system in the human palatine tonsil was studied systematically as follows: 1) Using the radio binding assay method, the presence of beta-adrenergic receptors and muscarinic-cholinergic receptors was demonstrated in the tonsil. 2) Using high performance liquid chromatography, the quantity of catecholamines in the tonsillar tissue was determined for the first time. 3) The distributions of sympathetic and parasympathetic nerves in the tonsillar tissue were demonstrated by fluorescence- or enzyme-histochemistry. 4) Cases of habitual tonsillitis were compared with cases of simple tonsillitis concerning the quantities of beta-adrenergic receptors and catecholamines. As a result, the difference in quantity of beta-adrenergic receptors between the two was insignificant, but the quantity of catecholamine was greater in the former.

Zahran, A. M., et al. (2019). "Circulating microparticle subpopulation in metabolic syndrome: relation to oxidative stress and coagulation markers." Diabetes Metab Syndr Obes 12: 485-493.
	Background: Circulating microparticles (MPs) contribute to the pathogenesis of atherothrombotic disorders and are raised in cardiovascular diseases. Herein, we aimed to investigate the effect of moderate metabolic abnormalities in an early stage of metabolic syndrome (MetS) on the level of MP subpopulations and to study relationships between MP subpopulations and both oxidative stress and coagulation markers. Methods: Flow cytometry used to evaluate circulating MPs subpopulations in 40 patients with an early stage MetS and 30 healthy controls. ELISA was used to quantify plasminogen activator inhibitor type 1/tissue plasminogen activator (PAI-1/TPA) while plasma glutathione peroxidase (GPx) activity was measured spectrophotometrically. Results: Total MPs were significantly elevated in MetS (P<0.001). Glutathione peroxidase and PAI1/TPA activity was significantly increased in subjects with MetS (P<0.001). Waist circumference, diastolic blood pressure, and total cholesterol positively influenced levels of total MPs, platelet-derived microparticles, and endothelium-derived microparticles. Fasting blood glucose, cholesterol, triglycerides, and low-density lipoprotein positively influenced the coagulation factors (TPA, PAI1). However, high-density lipoprotein negatively influenced platelet-derived MPs and factors associated with fibrinolysis (TPA, PAI1). Conclusion: Elevated circulating MPs are associated with MetS abnormalities, oxidative stress and coagulation factors and may act as early predictor of metabolic syndrome with risk of cardiovascular disease.