Central orexin/hypocretin neurones are critical for sustaining consciousness: their firing stimulates wakefulness and their
destruction causes narcolepsy. We explored whether the activity of orexin ...cells is modulated by thyrotropin-releasing hormone
(TRH), an endo-genous stimulant of wakefulness and locomotor activity whose mechanism of action is not fully understood. Living
orexin neurones were identified by targeted expression of green fluorescent protein (GFP) in acute brain slices of transgenic
mice. Using whole-cell patch-clamp recordings, we found that TRH robustly increased the action potential firing rate of these
neurones. TRH-induced excitation persisted under conditions of synaptic isolation, and involved a Na + -dependent depolarization and activation of a mixed cation current in the orexin cell membrane. By double-label immunohistochemistry,
we found close appositions between TRH-immunoreactive nerve terminals and orexin-A-immunoreactive cell bodies. These results
identify a new physiological modulator of orexin cell firing, and suggest that orexin cell excitation may contribute to the
arousal-enhancing actions of TRH.
Non‐technical summary
Normal wakefulness relies on brain cells called orexin/hypocretin neurons. Activity of these cells stimulates awakening while their loss produces the sleep disorder narcolepsy. ...By studying what makes orexin/hypocretin cells more or less active, we can thus gain insights into how the brain switches between different states of consciousness. We describe a new way to turn orexin/hypocretin cells off using a chemical called glycine. We show that glycine shuts down the electrical activity of orexin/hypocretin neurons from the adult brain, but has the opposite effect in the very young brain. Apart from these direct actions on orexin/hypocretin cells, glycine also enhances the ability of other nerve cells to communicate with orexin/hypocretin neurons. These data shed new light on the basic chemical and physical mechanisms regulating orexin/hypocretin neurons, which may also be useful in improving therapeutic strategies for disorders such as insomnia.
Hypothalamic hypocretin/orexin (hcrt/orx) neurons promote arousal and reward seeking, while reduction in their activity has been linked to narcolepsy, obesity and depression. However, the mechanisms influencing the activity of hcrt/orx networks in situ are not fully understood. Here we show that glycine, a neurotransmitter best known for its actions in the brainstem and spinal cord, elicits dose‐dependent postsynaptic Cl− currents in hcrt/orx cells in acute mouse brain slices. This effect was blocked by the glycine receptor (GlyR) antagonist strychnine and mimicked by the GlyR agonist alanine. Postsynaptic GlyRs on hcrt/orx cells remained functional during both early postnatal and adult periods, and gramicidin‐perforated patch‐clamp recordings revealed that they progressively switch from excitatory to inhibitory during the first two postnatal weeks. The pharmacological profile of the glycine response suggested that developed hcrt/orx neurons contain α/β‐heteromeric GlyRs that lack α2‐subunits, whereas α2‐subunits are present in early postnatal hcrt/orx neurons. All postsynaptic currents (PSCs) in developed hcrt/orx cells were blocked by inhibitors of GABA and glutamate receptors, with no evidence of GlyR‐mediated PSCs. However, the frequency but not amplitude of miniature PSCs was reduced by strychnine and increased by glycine in ∼50% of hcrt/orx neurons. Together, these results provide the first evidence for functional GlyRs in identified hcrt/orx circuits and suggest that the activity of developed hcrt/orx cells is regulated by two GlyR pools: inhibitory extrasynaptic GlyRs located on all hcrt/orx cells and excitatory GlyRs located on presynaptic terminals contacting some hcrt/orx cells.
The immunology of multiple sclerosis Attfield, Kathrine E; Jensen, Lise Torp; Kaufmann, Max ...
Nature reviews. Immunology,
12/2022, Letnik:
22, Številka:
12
Journal Article
Recenzirano
Our incomplete understanding of the causes and pathways involved in the onset and progression of multiple sclerosis (MS) limits our ability to effectively treat this complex neurological disease. ...Recent studies explore the role of immune cells at different stages of MS and how they interact with cells of the central nervous system (CNS). The findings presented here begin to question the exclusivity of an antigen-specific cause and highlight how seemingly distinct immune cell types can share common functions that drive disease. Innovative techniques further expose new disease-associated immune cell populations and reinforce how environmental context is critical to their phenotype and subsequent role in disease. Importantly, the differentiation of immune cells into a pathogenic state is potentially reversible through therapeutic manipulation. As such, understanding the mechanisms that provide plasticity to causal cell types is likely key to uncoupling these disease processes and may identify novel therapeutic targets that replace the need for cell ablation.
The MHC class II molecule DQ0602 confers strong susceptibility to narcolepsy but dominant protection against type 1 diabetes. The crystal structure of DQ0602 reveals the molecular features underlying ...these contrasting genetic properties. Structural comparisons to homologous DQ molecules with differential disease associations highlight a previously unrecognized interplay between the volume of the P6 pocket and the specificity of the P9 pocket, which implies that presentation of an expanded peptide repertoire is critical for dominant protection against type 1 diabetes. In narcolepsy, the volume of the P4 pocket appears central to the susceptibility, suggesting that the presentation of a specific peptide population plays a major role.
The immune system has crucial roles in the pathogenesis of multiple sclerosis. While the adaptive immune cell subsets, T and B cells, have been the main focus of immunological research in multiple ...sclerosis, it is now important to realize that the innate immune system also has a key involvement in regulating autoimmune responses in the central nervous system. Natural killer cells are innate lymphocytes that play vital roles in a diverse range of infections. There is evidence that they influence a number of autoimmune conditions. Recent studies in multiple sclerosis and its murine model, experimental autoimmune encephalomyelitis, are starting to provide some understanding of the role of natural killer cells in regulating inflammation in the central nervous system. Natural killer cells express a diverse range of polymorphic cell surface receptors, which interact with polymorphic ligands; this interaction controls the function and the activation status of the natural killer cell. In this review, we discuss evidence for the role of natural killer cells in multiple sclerosis and experimental autoimmune encephalomyelitis. We consider how a change in the balance of signals received by the natural killer cell influences its involvement in the ensuing immune response, in relation to multiple sclerosis.
The recent HIV-1 vaccine failures highlight the need to better understand virus-host interactions. One key question is why CD8+ T cell responses to two HIV-Gag regions are uniquely associated with ...delayed disease progression only in patients expressing a few rare HLA class I variants when these regions encode epitopes presented by ∼30 more common HLA variants. By combining epitope processing and computational analyses of the two HIV subtypes responsible for ∼60% of worldwide infections, we identified a hitherto unrecognized adaptation to the antigen-processing machinery through substitutions at subtype-specific motifs. Multiple HLA variants presenting epitopes situated next to a given subtype-specific motif drive selection at this subtype-specific position, and epitope abundances correlate inversely with the HLA frequency distribution in affected populations. This adaptation reflects the sum of intrapatient adaptations, is predictable, facilitates viral subtype diversification, and increases global HIV diversity. Because low epitope abundance is associated with infrequent and weak T cell responses, this most likely results in both population-level immune evasion and inadequate responses in most people vaccinated with natural HIV-1 sequence constructs. Our results suggest that artificial sequence modifications at subtype-specific positions in vitro could refocus and reverse the poor immunogenicity of HIV proteins.
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•HLA class I variants drive selection pressures on Gag to limit epitope production•The strength of the selective pressure is positively correlated to HLA frequencies•HIV adaptation to limit epitope production occurs at subtype-specific HIV motifs•HIV adapts in a predictable way to HLA frequencies in newly infected populations
CD8+ T cell responses against HIV-1 effectively delay disease progression in a minority of patients with relatively rare HLA variants but are ineffective in most. Here, Tenzer et al. identify fundamental HIV-1 adaptation to the conserved human antigen-processing machinery that feeds epitopes to HLA. This adaptation occurs at subtype-specific motifs, facilitates subtype diversification, is predictable, and results in CD8 epitope abundances that correlate inversely with the HLA allele frequencies in affected populations. Thus, HIV vaccine immunogenicity might be increased by unnatural substitutions at subtype-specific motifs.
•Multiple sclerosis (MS) is an autoimmune disorder of the brain and spinal cord.•Immunomodulatory drugs have been used for over two decades to treat relapsing MS.•Their use suggests that ...immunomodulation cannot halt disease progression.•A B-cell-depleting drug has now shown efficacy for treating primary progressive MS.•Better understanding MS immunopathology may improve patient healthcare provision.
Multiple sclerosis (MS) afflicts about 2.5 million people globally and poses a major personal and socioeconomic burden. The recognition of MS as an inflammatory disease, characterized by infiltration of immune cells into the central nervous system, has spurred research into the autoimmune etiology of the condition and has provided the rationale for its treatment through immunomodulation. Experience with immunotherapies in MS to date has suggested a disparity between the observed immune cell infiltration and the progressive loss of neurons. However, recent clinical efforts are providing new insights into progressive MS that once again place the immune system at center stage. This article reviews the main mechanisms of MS immunopathogenesis, and the benefits, risks and challenges of immunomodulatory treatments for the disease.
Effective biomarkers for multiple sclerosis diagnosis, assessment of prognosis, and treatment responses, in particular those measurable in blood, are largely lacking. We have investigated a broad set ...of protein biomarkers in cerebrospinal fluid (CSF) and plasma using a highly sensitive proteomic immunoassay. Cases from two independent cohorts were compared with healthy controls and patients with other neurological diseases. We identified and replicated 10 cerebrospinal fluid proteins including IL-12B, CD5, MIP-1a, and CXCL9 which had a combined diagnostic efficacy similar to immunoglobulin G (IgG) index and neurofilament light chain (area under the curve AUC = 0.95). Two plasma proteins, OSM and HGF, were also associated with multiple sclerosis in comparison to healthy controls. Sensitivity and specificity of combined CSF and plasma markers for multiple sclerosis were 85.7% and 73.5%, respectively. In the discovery cohort, eotaxin-1 (CCL11) was associated with disease duration particularly in patients who had secondary progressive disease (P
CSF < 4 × 10−5, P
plasma < 4 × 10−5), and plasma CCL20 was associated with disease severity (P = 4 × 10−5), although both require further validation. Treatment with natalizumab and fingolimod showed different compartmental changes in protein levels of CSF and peripheral blood, respectively, including many disease-associated markers (e.g., IL12B, CD5) showing potential application for both diagnosing disease and monitoring treatment efficacy. We report a number of multiple sclerosis biomarkers in CSF and plasma for early disease detection and potential indicators for disease activity. Of particular importance is the set of markers discovered in blood, where validated biomarkers are lacking.
Highlights • New therapies are on the horizon for multiple sclerosis disease mechanisms. • Immunotherapies are showing promise as treatments for multiple sclerosis.
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