Abstract
Michiaki Takahashi developed the live attenuated varicella vaccine in 1974 . This was the first, and is still the only, herpesvirus vaccine. Early studies showed promise, but the vaccine was ...rigorously tested on immunosuppressed patients because of their high risk of fatal varicella; vaccination proved to be lifesaving. Subsequently, the vaccine was found to be safe and effective in healthy children. Eventually, varicella vaccine became a component of measles mumps rubella vaccine, 2 doses of which are administered in the USA to ~90% of children. The incidence of varicella has dropped dramatically in the USA since vaccine-licensure in 1995. Varicella vaccine is also associated with a decreased incidence of zoster and is protective for susceptible adults. Today, immunocompromised individuals are protected against varicella due to vaccine-induced herd immunity. Latent infection with varicella zoster virus occurs after vaccination; however, the vaccine strain is impaired for its ability to reactivate.
Recent research has highlighted the importance of the two-way interaction between the nervous and immune systems. This interaction is particularly important in the bowel because of the unique ...properties of this organ. The lumen of the gut is lined by a very large but remarkably thin surface that separates the body from the enteric microbiome. Immune defenses against microbial invasion are thus well developed and neuroimmune interactions are important in regulating and integrating these defenses. Important concepts in the phylogeny of neuroimmunity, enteric neuronal and glial regulation of immunity, changes that occur in the enteric nervous system during inflammation, the fundamental role of serotonin (5-HT) in enteric neuroimmune mechanisms, and future perspectives are reviewed.
The enteric nervous system mediates reflexes independently of the brain and spinal cord and transmits signals bidirectionally between the gut and the brain. Hirschsprung disease and chronic ...intestinal pseudo-obstruction (CIPO) and pediatric CIPO are examples of congenital defects that impair gastrointestinal motility. In this issue of the JCI, Thuy-Linh Le et al. analyzed eight patients with defects in tissue that arose from the neural crest. The patients carried homozygous or heterozygous variants in ERBB3 or ERBB2, which encode transmembrane epidermal growth factor receptors that bind neuroregulin 1 (NRG1). Notably, the genetic variants resulted in loss of function with decreased expression or aberrant phosphorylation of the ERBB3/ERBB2 receptors. Experiments using mice revealed that Erbb3 and Erbb2 were expressed in enteric neuronal progenitor cells. This study is an outstanding example of descriptive observation that begs for mechanistic exploration to reveal precisely how the NRG1/ERBB3/ERBB2 pathway influences ENS development.
SUMMARY The primary varicella zoster virus (VZV) infection results in chickenpox (varicella), which is transmitted via the airborne route. VZV is highly infectious, but in the USA the incidence of ...varicella has been reduced by 76–87% as a result of the varicella vaccine. The virus establishes latency in the dorsal root ganglia during varicella and, when reactivated, travels along the sensory nerve axons to cause shingles (herpes zoster HZ). There are over 1 million cases of HZ in the USA each year, with an estimated lifetime attack rate of 30%. The incidence of HZ, which causes significant morbidity, increases with age and reaches approximately 10 cases per 1,000 patient-years by age 80. Cell-mediated immunity (CMI) is known to decline with age as part of immunosenescence, and decreased CMI is associated with reactivation of VZV. This article provides an overview of our emerging understanding of the epidemiology and pathogenesis of varicella and HZ, in addition to exploring the current theories on latency and reactivation. Understanding the risk factors for developing HZ and the complications associated with infection, particularly in older people, is important for prompt diagnosis and management of HZ in primary care, and they are therefore also reviewed.
Historically and quantitatively, the enteric site of serotonin (5-HT) storage has primacy over those of any other organ. 5-HT, by the name of "enteramine", was first discovered in the bowel, and the ...gut produces most of the body's 5-HT. Not only does the bowel secrete 5-HT prodigiously but it also expresses a kaleidoscopic abundance of 5-HT receptors. The larger of two enteric 5-HT stores is mucosal, biosynthetically dependent upon tryptophan hydroxylase1 (TPH1), and located in EC cells. Mechanical stimuli, nutrients, luminal bacteria, and neurotransmitters such as acetylcholine and norepinephrine are all able to stimulate EC cells. Paracrine actions of 5-HT allow the mucosa to signal to neurons to initiate peristaltic and secretory reflexes as well as to inflammatory cells to promote intestinal inflammation. Endocrine effects of 5-HT allow EC cells to influence distant organs, including bone, liver, and endocrine pancreas. The smaller enteric 5-HT store is biosynthetically dependent upon TPH2 and is located within a small subset of myenteric neurons. 5-HT is responsible for slow excitatory neurotransmission manifested primarily in type II/AH neurons. Importantly, neuronal 5-HT also promotes enteric nervous system (ENS) neurogenesis, both pre- and postnatally, through 5-HT
and especially 5-HT
receptors. The early birth of serotonergic neurons allows these cells to function as sculptors of the mature ENS. The inactivation of secreted 5-HT depends on transmembrane transport mediated by a serotonin transporter (SERT; SLC6A4). The importance of SERT in control of 5-HT's function means that pharmacological inhibition of SERT, as well as gain- or loss-of-function mutations in SLC6A4, can exert profound effects on development and function of the ENS. Extra-enteric, TPH1-derived 5-HT from yolk sac and placenta promotes neurogenesis before enteric neurons synthesize 5-HT and contribute to ENS patterning. The impressive multi-functional nature of enteric 5-HT has made the precise identification of individual physiological roles difficult and sometimes controversial.
Within the gastrointestinal stem cell niche, nerves help to regulate both normal and neoplastic stem cell dynamics. Here, we reveal the mechanisms underlying the cancer-nerve partnership. We find ...that Dclk1+ tuft cells and nerves are the main sources of acetylcholine (ACh) within the gastric mucosa. Cholinergic stimulation of the gastric epithelium induced nerve growth factor (NGF) expression, and in turn NGF overexpression within gastric epithelium expanded enteric nerves and promoted carcinogenesis. Ablation of Dclk1+ cells or blockade of NGF/Trk signaling inhibited epithelial proliferation and tumorigenesis in an ACh muscarinic receptor-3 (M3R)-dependent manner, in part through suppression of yes-associated protein (YAP) function. This feedforward ACh-NGF axis activates the gastric cancer niche and offers a compelling target for tumor treatment and prevention.
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•NGF expression is induced in gastric cancer by ACh from nerves and tuft cells•NGF promotes innervation and proliferation in gastric epithelium•Blockade of NGF or ablation of cholinergic tuft cells inhibits tumor development•Cholinergic signaling activates YAP signaling that is essential for Wnt activation
Hayakawa et al. use a series of mouse models to show that acetylcholine from Dclk1+ tuft cells and nerves induces NGF in gastric epithelial cells, which promotes neuron expansion and tumorigenesis. YAP is activated through the cholinergic signaling, and inhibition of this pathway can block NGF-driven tumors.
In the enteric nervous system (ENS), glia outnumber neurons by 4‐fold and form an extensive network throughout the gastrointestinal tract. Growing evidence for the essential role of enteric glia in ...bowel function makes it imperative to understand better their molecular marker expression and how they relate to glia in the rest of the nervous system. We analyzed expression of markers of astrocytes and oligodendrocytes in the ENS and found, unexpectedly, that proteolipid protein 1 (PLP1) is specifically expressed by glia in adult mouse intestine. PLP1 and S100β are the markers most widely expressed by enteric glia, while glial fibrillary acidic protein expression is more restricted. Marker expression in addition to cellular location and morphology distinguishes a specific subpopulation of intramuscular enteric glia, suggesting that a combinatorial code of molecular markers can be used to identify distinct subtypes. To assess the similarity between enteric and extraenteric glia, we performed RNA sequencing analysis on PLP1‐expressing cells in the mouse intestine and compared their gene expression pattern to that of other types of glia. This analysis shows that enteric glia are transcriptionally unique and distinct from other cell types in the nervous system. Enteric glia express many genes characteristic of the myelinating glia, Schwann cells and oligodendrocytes, although there is no evidence of myelination in the murine ENS. GLIA 2015;63:2040–2057
Main points
Proteolipid protein 1 (PLP1) is expressed by enteric glia throughout the intestine.
Transcriptional profiling of PLP1+ enteric glia reveals that they are most similar to myelinating glia, not astrocytes.
When the glial fibrillary acidic protein (GFAP) promoter is used to express cellular toxins that eliminate glia in mice, intestinal epithelial permeability and proliferation increase; this led to the ...concept that glia are required for maintenance of the gastrointestinal epithelium. Many enteric glia, however, particularly in the mucosa, do not express GFAP. In contrast, virtually all enteric glia express proteolipid protein 1 (PLP1). We investigated whether elimination of PLP1-expressing cells compromises epithelial maintenance or gastrointestinal motility.
We generated mice that express tamoxifen-inducible Cre recombinase under control of the Plp1 promoter and carry the diptheria toxin subunit A (DTA) transgene in the Rosa26 locus (Plp1CreER;Rosa26DTA mice). In these mice, PLP1-expressing glia are selectively eliminated without affecting neighboring cells. We measured epithelial barrier function and gastrointestinal motility in these mice and littermate controls, and analyzed epithelial cell proliferation and ultrastructure from their intestinal tissues. To compare our findings with those from previous studies, we also eliminated glia with ganciclovir in GfapHSV-TK mice.
Expression of DTA in PLP1-expressing cells selectively eliminated enteric glia from the small and large intestines, but caused no defects in epithelial proliferation, barrier integrity, or ultrastructure. In contrast, administration of ganciclovir to GfapHSV-TK mice eliminated fewer glia but caused considerable non-glial toxicity and epithelial cell death. Elimination of PLP1-expressing cells did not reduce survival of neurons in the intestine, but altered gastrointestinal motility in female, but not male, mice.
Using the Plp1 promoter to selectively eliminate glia in mice, we found that enteric glia are not required for maintenance of the intestinal epithelium, but are required for regulation of intestinal motility in females. Previous observations supporting the concept that maintenance of the intestinal epithelium requires enteric glia can be attributed to non-glial toxicity in GfapHSV-TK mice and epithelial-cell expression of GFAP. Contrary to widespread notions, enteric glia are therefore not required for epithelial homeostasis. However, they regulate intestinal motility in a sex-dependent manner.
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