Multiple sclerosis (MS) is the most frequent chronic inflammatory disease of the CNS, and imposes major burdens on young lives. Great progress has been made in understanding and moderating the acute ...inflammatory components of MS, but the pathophysiological mechanisms of the concomitant neurodegeneration--which causes irreversible disability--are still not understood. Chronic inflammatory processes that continuously disturb neuroaxonal homeostasis drive neurodegeneration, so the clinical outcome probably depends on the balance of stressor load (inflammation) and any remaining capacity for neuronal self-protection. Hence, suitable drugs that promote the latter state are sorely needed. With the aim of identifying potential novel therapeutic targets in MS, we review research on the pathological mechanisms of neuroaxonal dysfunction and injury, such as altered ion channel activity, and the endogenous neuroprotective pathways that counteract oxidative stress and mitochondrial dysfunction. We focus on mechanisms inherent to neurons and their axons, which are separable from those acting on inflammatory responses and might, therefore, represent bona fide neuroprotective drug targets with the capability to halt MS progression.
Approximately 200,000 multiple sclerosis (MS) patients worldwide receive B-cell-depleting immunotherapy with rituximab (anti-CD20), which eliminates the ability to generate an antibody response to ...new infections. As severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)–specific antibodies might help viral clearance, these patients could be at risk of severe complications if infected. Here, we report on an MS patient who had received rituximab for ~3 years. The patient was examined 5 days before the onset of coronavirus disease 2019 (COVID-19) symptoms and was admitted to the hospital 2 days after. She recovered 14 days after symptom onset despite having a 0% B lymphocyte count and not developing SARS-CoV-2 immunoglobulin G (IgG) antibodies.
Although there has been much success in identifying genetic variants associated with common diseases using genome-wide association studies (GWAS), it has been difficult to demonstrate which variants ...are causal and what role they have in disease. Moreover, the modest contribution that these variants make to disease risk has raised questions regarding their medical relevance. Here we have investigated a single nucleotide polymorphism (SNP) in the TNFRSF1A gene, that encodes tumour necrosis factor receptor 1 (TNFR1), which was discovered through GWAS to be associated with multiple sclerosis (MS), but not with other autoimmune conditions such as rheumatoid arthritis, psoriasis and Crohn’s disease. By analysing MS GWAS data in conjunction with the 1000 Genomes Project data we provide genetic evidence that strongly implicates this SNP, rs1800693, as the causal variant in the TNFRSF1A region. We further substantiate this through functional studies showing that the MS risk allele directs expression of a novel, soluble form of TNFR1 that can block TNF. Importantly, TNF-blocking drugs can promote onset or exacerbation of MS, but they have proven highly efficacious in the treatment of autoimmune diseases for which there is no association with rs1800693. This indicates that the clinical experience with these drugs parallels the disease association of rs1800693, and that the MS-associated TNFR1 variant mimics the effect of TNF-blocking drugs. Hence, our study demonstrates that clinical practice can be informed by comparing GWAS across common autoimmune diseases and by investigating the functional consequences of the disease-associated genetic variation.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, KISLJ, NUK, PILJ, PNG, SAZU, SIK, UILJ, UKNU, UL, UM, UPUK
MHC class II molecules on the surface of antigen-presenting cells display a range of peptides for recognition by the T-cell receptors of CD4+ T helper cells. Therefore, MHC class II molecules are ...central to effective adaptive immune responses, but conversely, genetic and epidemiological data have implicated these molecules in the pathogenesis of autoimmune diseases. Indeed, the strength of the associations between particular MHC class II alleles and disease render them the main genetic risk factors for autoimmune disorders such as type 1 diabetes. Here, we discuss the insights that the crystal structures of MHC class II molecules provide into the molecular mechanisms by which sequence polymorphisms might contribute to disease susceptibility.
Celotno besedilo
Dostopno za:
DOBA, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
Expression of HLA-C varies widely across individuals in an allele-specific manner. This variation in expression can influence efficacy of the immune response, as shown for infectious and autoimmune ...diseases. MicroRNA binding partially influences differential HLA-C expression, but the additional contributing factors have remained undetermined. Here we use functional and structural analyses to demonstrate that HLA-C expression is modulated not just at the RNA level, but also at the protein level. Specifically, we show that variation in exons 2 and 3, which encode the α1/α2 domains, drives differential expression of HLA-C allomorphs at the cell surface by influencing the structure of the peptide-binding cleft and the diversity of peptides bound by the HLA-C molecules. Together with a phylogenetic analysis, these results highlight the diversity and long-term balancing selection of regulatory factors that modulate HLA-C expression.
Multiple sclerosis is a neuroinflammatory disease associated with axonal degeneration. The neuronally expressed, proton-gated acid-sensing ion channel-1 (ASIC1) is permeable to Na+ and Ca2+, and ...excessive accumulation of these ions is associated with axonal degeneration. We tested the hypothesis that ASIC1 contributes to axonal degeneration in inflammatory lesions of the central nervous system (CNS). After induction of experimental autoimmune encephalomyelitis (EAE), Asic1−/− mice showed both a markedly reduced clinical deficit and reduced axonal degeneration compared to wild-type mice. Consistently with acidosis-mediated injury, pH measurements in the spinal cord of EAE mice showed tissue acidosis sufficient to open ASIC1. The acidosis-related protective effect of Asic1 disruption was also observed in nerve explants in vitro. Amiloride, a licensed and clinically safe blocker of ASICs, was equally neuroprotective in nerve explants and in EAE. Although ASICs are also expressed by immune cells, this expression is unlikely to explain the neuroprotective effect of Asic1 inactivation, as CNS inflammation was similar in wild-type and Asic1−/− mice. In addition, adoptive transfer of T cells from wild-type mice did not affect the protection mediated by Asic1 disruption. These results suggest that ASIC1 blockers could provide neuroprotection in multiple sclerosis.
Celotno besedilo
Dostopno za:
DOBA, IJS, IZUM, KILJ, NUK, PILJ, PNG, SAZU, UILJ, UKNU, UL, UM, UPUK
7.
Control of hypothalamic orexin neurons by acid and CO2 Williams, Rhîannan H; Jensen, Lise T; Verkhratsky, Alex ...
Proceedings of the National Academy of Sciences - PNAS,
06/2007, Letnik:
104, Številka:
25
Journal Article
Recenzirano
Odprti dostop
Hypothalamic orexin/hypocretin neurons recently emerged as key orchestrators of brain states and adaptive behaviors. They are critical for normal stimulation of wakefulness and breathing: Orexin loss ...causes narcolepsy and compromises vital ventilatory adaptations. However, it is unclear how orexin neurons generate appropriate adjustments in their activity during changes in physiological circumstances. Extracellular levels of acid and CO 2 are fundamental physicochemical signals controlling wakefulness and breathing, but their effects on the firing of orexin neurons are unknown. Here we show that the spontaneous firing rate of identified orexin neurons is profoundly affected by physiological fluctuations in ambient levels of H + and CO 2 . These responses resemble those of known chemosensory neurons both qualitatively (acidification is excitatory, alkalinization is inhibitory) and quantitatively (≈100% change in firing rate per 0.1 unit change in pH e ). Evoked firing of orexin cells is similarly modified by physiologically relevant changes in pH e : Acidification increases intrinsic excitability, whereas alkalinization depresses it. The effects of pH e involve acid-induced closure of leak-like K + channels in the orexin cell membrane. These results suggest a new mechanism of how orexin/hypocretin networks generate homeostatically appropriate firing patterns. arousal hypocretin hypothalamus pH breathing
Hypothalamic orexin/hypocretin (orx/hcrt) neurons regulate energy balance, wakefulness, and reward; their loss produces narcolepsy and weight gain. Glucose can lower the activity of orx/hcrt cells, ...but whether other dietary macronutrients have similar effects is unclear. We show that orx/hcrt cells are stimulated by nutritionally relevant mixtures of amino acids (AAs), both in brain slice patch-clamp experiments, and in c-Fos expression assays following central or peripheral administration of AAs to mice in vivo. Physiological mixtures of AAs electrically excited orx/hcrt cells through a dual mechanism involving inhibition of KATP channels and activation of system-A amino acid transporters. Nonessential AAs were more potent in activating orx/hcrt cells than essential AAs. Moreover, the presence of physiological concentrations of AAs suppressed the glucose responses of orx/hcrt cells. These results suggest a new mechanism of hypothalamic integration of macronutrient signals and imply that orx/hcrt cells sense macronutrient balance, rather than net energy value, in extracellular fluid.
► Brain orexin/hypocretin cells are stimulated by dietary amino acids (AAs) ► AA sensing involves K-ATP channels and system-A transporters ► Nonessential AAs stimulate orexin/hypocretin cells more than essential AAs ► AA presence prevents glucose from blocking orexin/hypocretin cells
Although there is growing evidence for a role of excess intracellular cations, particularly calcium ions, in neuronal and glial cell injury in multiple sclerosis, as well as in non-inflammatory ...neurological conditions, the molecular mechanisms involved are not fully determined. We previously showed that the acid-sensing ion channel 1 which, when activated under the acidotic tissue conditions found in inflammatory lesions opens to allow influx of sodium and calcium ions, contributes to axonal injury in experimental autoimmune encephalomyelitis, an animal model of multiple sclerosis. However, the extent and cellular distribution of acid-sensing ion channel 1 expression in neurons and glia in inflammatory lesions is unknown and, crucially, acid-sensing ion channel 1 expression has not been determined in multiple sclerosis lesions. Here we studied acute and chronic experimental autoimmune encephalomyelitis and multiple sclerosis spinal cord and optic nerve tissues to describe in detail the distribution of acid-sensing ion channel 1 and its relationship with neuronal and glial damage. We also tested the effects of amiloride treatment on tissue damage in the mouse models. We found that acid-sensing ion channel 1 was upregulated in axons and oligodendrocytes within lesions from mice with acute experimental autoimmune encephalomyelitis and from patients with active multiple sclerosis. The expression of acid-sensing ion channel 1 was associated with axonal damage as indicated by co-localization with the axonal injury marker beta amyloid precursor protein. Moreover, blocking acid-sensing ion channel 1 with amiloride protected both myelin and neurons from damage in the acute model, and when given either at disease onset or, more clinically relevant, at first relapse, ameliorated disability in mice with chronic-relapsing experimental autoimmune encephalomyelitis. Together these findings suggest that blockade of acid-sensing ion channel 1 has the potential to provide both neuro- and myelo-protective benefits in multiple sclerosis.
JAK inhibitors impact multiple cytokine pathways simultaneously, enabling high efficacy in treating complex diseases such as cancers and immune-mediated disorders. However, their broad reach also ...poses safety concerns, which have fuelled a demand for increasingly selective JAK inhibitors. Deucravacitinib, a first-in-class allosteric TYK2 inhibitor, represents a remarkable advancement in the field. Rather than competing at kinase domain catalytic sites as classical JAK1-3 inhibitors, deucravacitinib targets the regulatory pseudokinase domain of TYK2. It strikingly mirrors the functional effect of an evolutionary conserved naturally occurring TYK2 variant, P1104A, known to protect against multiple autoimmune diseases yet provide sufficient TYK2-mediated cytokine signalling required to prevent immune deficiency. The unprecedentedly high functional selectivity and efficacy-safety profile of deucravacitinib, initially demonstrated in psoriasis, combined with genetic support, and promising outcomes in early SLE clinical trials make this inhibitor ripe for exploration in other autoimmune diseases for which better, safe, and efficacious treatments are urgently needed.
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