For decades, it was commonly accepted that the brain is secluded from peripheral immune activity and is self-sufficient for its maintenance and repair. This simplistic perception was based on the presence of resident immune cells, the microglia, and barrier systems within the brain, and the assumption that the central nervous system (CNS) lacks lymphatic drainage. This view was revised with the discoveries that higher functions of the CNS, homeostasis and repair are supported by peripheral innate and adaptive immune cells. The findings of bone marrow-derived immune cells in specialized niches, and the renewed observation that a lymphatic drainage system exists within the brain, further contributed to this revised model. In this Review, we describe the immune niches within the brain, the contribution of professional immune cells to brain functions, the bidirectional relationships between the CNS and the immune system and the relevance of immune components to brain aging and neurodegenerative diseases.
BACKGROUND Transthyretin amyloidosis, also called ATTR amyloidosis, is a life-threatening disease characterized by progressive accumulation of misfolded transthyretin (TTR) protein in tissues, predominantly the nerves and heart. NTLA-2001 is an in vivo gene-editing therapeutic agent that is designed to treat ATTR amyloidosis by reducing the concentration of TTR in serum. It is based on the clustered regularly interspaced short palindromic repeats and associated Cas9 endonuclease (CRISPR-Cas9) system and comprises a lipid nanoparticle encapsulating messenger RNA for Cas9 protein and a single guide RNA targeting TTR. METHODS After conducting preclinical in vitro and in vivo studies, we evaluated the safety and pharmacodynamic effects of single escalating doses of NTLA-2001 in six patients with hereditary ATTR amyloidosis with polyneuropathy, three in each of the two initial dose groups (0.1 mg per kilogram and 0.3 mg per kilogram), within an ongoing phase 1 clinical study. RESULTS Preclinical studies showed durable knockout of TTR after a single dose. Serial assessments of safety during the first 28 days after infusion in patients revealed few adverse events, and those that did occur were mild in grade. Dose-dependent pharmacodynamic effects were observed. At day 28, the mean reduction from baseline in serum TTR protein concentration was 52% (range, 47 to 56) in the group that received a dose of 0.1 mg per kilogram and was 87% (range, 80 to 96) in the group that received a dose of 0.3 mg per kilogram. CONCLUSIONS In a small group of patients with hereditary ATTR amyloidosis with polyneuropathy, administration of NTLA-2001 was associated with only mild adverse events and led to decreases in serum TTR protein concentrations through targeted knockout of TTR. (Funded by Intellia Therapeutics and Regeneron Pharmaceuticals; ClinicalTrials.gov number, NCT04601051. opens in new tab.)
A patient presented with recurrent severe pseudotumor cerebri (PTC). Transverse sinus stenting is a very effective treatment option, however stenosis and intracranial hypertension can recur. In our patient, stenting initially resulted in resolution of papilloedema. However, after 5 years, a new stenosis developed which required further stenting. This case highlights the fact that, in patients with PTC who undergo transverse sinus stenting, a small proportion require repeat treatment due to formation of a new stenosis, usually adjacent to the existing stent. Patients with severe disease, such as ours, may be at higher risk of recurrence. Regardless of the severity, all patients who undergo stenting should have regular ocular follow-up.
We report a case of a 72-year-old man who had undergone elective stenting of an asymptomatic high grade stenosis of the proximal left internal carotid artery. The indication was progression of the stenosis over a 3 year period despite receiving maximal medical therapy, and patient preference for stenting over endarterectomy. He became profoundly hypotensive in the immediate post-stent period and required immediate and prolonged vasopressor support over the next week. The etiological hypothesis is baroreceptor hyperactivity related to procedure induced unilateral stretching of the carotid body.
Aims We conducted a cross-sectional survey to estimate the prevalence and clinical manifestation of disulfiram ethanol reaction (DER) and isopropanol toxicity (IT) in patients with alcohol use disorders, on disulfiram. Alcohol-based hand rub contains either ethanol or isopropanol or both. COVID-19 pandemic has led to wide scale usage of sanitizers. Patients with alcohol use disorders, on disulfiram, might experience disulfiram ethanol like reactions with alcohol-based sanitizers. Methods We telephonically contacted 339 patients, prescribed disulfiram between January 2014 and March 2020. The assessment pertained to the last 3 months (i.e. third week of March to third week of June 2020). Result The sample consisted of middle-aged men with a mean 16 years of alcohol dependence. Among the 82 (24%) patients adherent to disulfiram, 42 (12.3%) were using alcohol-based hand rubs. Out of these, a total of eight patients (19%; 95% CI 9–33) had features suggestive of DER; four of whom also had features indicative of IT. Five patients (62.5%) had mild and self-limiting symptoms. Severe systemic reactions were experienced by three (37.5%). Severe reactions were observed with exposure to sanitizers in greater amounts, on moist skin or through inhalation. Conclusion Patients on disulfiram should be advised to use alternate methods of hand hygiene.
Alzheimer’s disease (AD) is the most prevalent cause of dementia1. Although there is no effective treatment for AD, passive immunotherapy with monoclonal antibodies against amyloid beta (Aβ) is a promising therapeutic strategy2,3. Meningeal lymphatic drainage has an important role in the accumulation of Aβ in the brain4, but it is not known whether modulation of meningeal lymphatic function can influence the outcome of immunotherapy in AD. Here we show that ablation of meningeal lymphatic vessels in 5xFAD mice (a mouse model of amyloid deposition that expresses five mutations found in familial AD) worsened the outcome of mice treated with anti-Aβ passive immunotherapy by exacerbating the deposition of Aβ, microgliosis, neurovascular dysfunction, and behavioural deficits. By contrast, therapeutic delivery of vascular endothelial growth factor C improved clearance of Aβ by monoclonal antibodies. Notably, there was a substantial overlap between the gene signature of microglia from 5xFAD mice with impaired meningeal lymphatic function and the transcriptional profile of activated microglia from the brains of individuals with AD. Overall, our data demonstrate that impaired meningeal lymphatic drainage exacerbates the microglial inflammatory response in AD and that enhancement of meningeal lymphatic function combined with immunotherapies could lead to better clinical outcomes.
Both obesity and sarcopenia are frequently associated in ageing, and together may promote the progression of related conditions such as diabetes and frailty. However, little is known about the pathophysiological mechanisms underpinning this association. Here we show that systemic alanine metabolism is linked to glycaemic control. We find that expression of alanine aminotransferases is increased in the liver in mice with obesity and diabetes, as well as in humans with type 2 diabetes. Hepatocyte-selective silencing of both alanine aminotransferase enzymes in mice with obesity and diabetes retards hyperglycaemia and reverses skeletal muscle atrophy through restoration of skeletal muscle protein synthesis. Mechanistically, liver alanine catabolism driven by chronic glucocorticoid and glucagon signalling promotes hyperglycaemia and skeletal muscle wasting. We further provide evidence for amino acid–induced metabolic cross-talk between the liver and skeletal muscle in ex vivo experiments. Taken together, we reveal a metabolic inter-tissue cross-talk that links skeletal muscle atrophy and hyperglycaemia in type 2 diabetes.
γδ T cells link immunity to nutrition Gamma delta (γδ) T cells are immune cells best known for host barrier defenses in epithelial tissues. Sullivan et al. discovered a previously unrecognized role for γδ T cells in sensing nutrient uptake in the small intestine (see the Perspective by Talbot and Littman). The researchers analyzed mice fed a high-carbohydrate versus a high-protein diet and observed remodeling of the small intestinal epithelium in response to dietary carbohydrates. Nutrient availability triggered an epithelial–immune cell circuit that was required for digestion and absorption of carbohydrates. Intestinal γδ T cells regulated the expression of a carbohydrate transcriptional program by limiting interleukin-22 production from type 3 innate lymphoid cells. These findings may also provide insights into how γδ T cells modulate metabolic disease. Structured Abstract INTRODUCTION The gastrointestinal (GI) tract is a multikingdom cellular ecosystem that facilitates the procurement of nutrients from the environment. In constant contact with the external world, the small intestine is at once a gateway for life-threatening pathogens and toxins and the site of absorption for life-sustaining nutrients. Consequently, this tissue is tasked with the challenge of balancing its primary functions of nutrient uptake and host defense in response to a complex and constantly changing environment.This challenge is particularly daunting for omnivores, whose diets change on daily, seasonal, and developmental time scales. The diverse diets of such generalists stand in contrast to those of specialists—animals that consume restricted diets—such as carnivores and herbivores. Whereas these specialists have evolved fixed morphologic adaptations in the organization of the GI tract that facilitate efficient nutrient uptake from their restricted diets, generalists must constantly adapt to the shifting availability of food sources of diverse nutrient composition encountered throughout life. These ongoing changes in diet exist alongside encounters with ingested toxins, enteric pathogens, and commensal microbes. Omnivorous lifestyles therefore require that the GI tracts of such animals dynamically adapt to the changes in availability of different nutrients. We examined the molecular and cellular mechanisms that regulate intestinal adaptation to diverse foods. RATIONALE We investigated how the enzymes and transporters involved in the digestion and absorption of macronutrients are regulated in response to diet. We designed special animal diets that differed only in the ratio of protein to carbohydrates and evaluated gene expression changes in the GI tract, as well as systemic metabolism, after feeding these diets to mice. Recent discoveries pertaining to intestinal defenses against parasitic and microbial pathogens have demonstrated that interactions between intestinal epithelial cells and lymphocytes—the largest population of lymphocytes in the body—coordinate tissue responses to enteric infection. Guided by these findings, we hypothesized that the regulation of nutrient-handling machinery may involve coordination between tissue-resident lymphocytes and intestinal epithelial cells. Furthermore, recent work investigating mechanisms of host defense in this tissue led us to hypothesize that cellular remodeling of the intestinal epithelium, which occurs in response to certain infections, may also underlie its adaptation to different nutrients. RESULTS A carbohydrate transcriptional program comprising enzymes and transporters that mediate the digestion and absorption of carbohydrates was induced on demand in small-intestine epithelial cells in response to carbohydrate availability. The induction of this transcriptional program was specifically due to the availability of carbohydrates and reflected functional changes in nutrient handling at the tissue and systemic levels. Mice fed a high-carbohydrate diet exhibited changes in the frequency of specialized enterocyte subsets. This indicated that functional specialization exists within the enterocyte compartment, which constitutes approximately 80% of the intestinal epithelium. This also suggested that the induction of the carbohydrate transcriptional program involved cellular remodeling of the intestinal epithelium. The induction of this program and corresponding epithelial remodeling occurred rapidly, after only 5 days of high-carbohydrate feeding. Unexpectedly, the on-demand induction of this program required γδ T cells, a population of lymphocytes enriched at barrier surfaces whose biology remains poorly understood. Intestinal γδ T cells were altered by diet, with changes observed in their transcriptome, tissue localization, and behavior. The diet-dependent regulation of this program by γδ T cells involved suppression of a negative regulator, interleukin-22 (IL-22). Thus, we defined an epithelial-lymphocyte circuit that regulates the intestinal response to nutrient sensing and facilitates the adaptation to diverse diets. CONCLUSION Our work demonstrates a role for intestinal lymphocytes in regulating the tissue response to dietary nutrients. Together with other studies in the realm of host-pathogen interactions, our results indicate that lymphocyte-epithelial circuits and epithelial remodeling represent general features of how the intestine adapts to environmental change. By linking nutrition and barrier function at both the cellular and molecular levels, these adaptations allow this complex tissue to adjust the balance between nutrient uptake and host defense in response to environmental change.
Situs inversus (SI), a left-right mirror reversal of the visceral organs, can occur with recessive Primary Ciliary Dyskinesia (PCD). However, most people with SI do not have PCD, and the etiology of their condition remains poorly studied. We sequenced the genomes of 15 people with SI, of which six had PCD, as well as 15 controls. Subjects with non-PCD SI in this sample had an elevated rate of left-handedness (five out of nine), which suggested possible developmental mechanisms linking brain and body laterality. The six SI subjects with PCD all had likely recessive mutations in genes already known to cause PCD. Two non-PCD SI cases also had recessive mutations in known PCD genes, suggesting reduced penetrance for PCD in some SI cases. One non-PCD SI case had recessive mutations in PKD1L1, and another in CFAP52 (also known as WDR16). Both of these genes have previously been linked to SI without PCD. However, five of the nine non-PCD SI cases, including three of the left-handers in this dataset, had no obvious monogenic basis for their condition. Environmental influences, or possible random effects in early development, must be considered.
Since its discovery in 1963 by Kare Berg (1), multiple observational studies have implicated lipoprotein (a) [Lp(a)] in cardiovascular risk. Lp(a) consists of a cholesterol-rich lipid particle encircled by a modiﬁed apolipoprotein B and occasionally studded with other apolipoproteins. The Lp(a) particle contains an apolipoprotein B that has undergone covalent linkage to the deﬁning apolipoprotein, apo(a). Unlike low-density lipoprotein(LDL) cholesterol, which follows a roughly Gaussian distribution in the population, Lp(a) levels skew, with most individuals in a lower range and a tail of individuals that display higher Lp(a) concentrations and corresponding elevated cardiovascular risk. Heritability and ethnicity strongly inﬂuence Lp(a)plasma concentrations. In particular, African Americans tend to have higher Lp(a) levels than Caucasians.