Type I interferon (IFN) is a common therapy for autoimmune and inflammatory disorders, yet the mechanisms of action are largely unknown. Here we showed that type I IFN inhibited interleukin-1 (IL-1) ...production through two distinct mechanisms. Type I IFN signaling, via the STAT1 transcription factor, repressed the activity of the NLRP1 and NLRP3 inflammasomes, thereby suppressing caspase-1-dependent IL-1β maturation. In addition, type I IFN induced IL-10 in a STAT1-dependent manner; autocrine IL-10 then signaled via STAT3 to reduce the abundance of pro-IL-1α and pro-IL-1β. In vivo, poly(I:C)-induced type I IFN diminished IL-1β production in response to alum and Candida albicans, thus increasing susceptibility to this fungal pathogen. Importantly, monocytes from multiple sclerosis patients undergoing IFN-β treatment produced substantially less IL-1β than monocytes derived from healthy donors. Our findings may thus explain the effectiveness of type I IFN in the treatment of inflammatory diseases but also the observed “weakening” of the immune system after viral infection.
► Type I IFN inhibits NLRP1b and NLRP3 inflammasomes in a STAT1-dependent manner ► Type I IFN decreases the amounts of pro-IL-1α and pro-IL-1β in a STAT3-dependent manner ► Monocytes from MS patients undergoing IFN-β treatment show impaired IL-1β secretion
Blood-brain barrier (BBB) breakdown and immune cell infiltration into the CNS are early hallmarks of multiple sclerosis (MS). The mechanisms leading to BBB dysfunction are incompletely understood and ...generally thought to be a consequence of neuroinflammation. Here, we have challenged this view and asked if intrinsic alterations in the BBB of MS patients contribute to MS pathogenesis. To this end, we made use of human induced pluripotent stem cells derived from healthy controls and MS patients and differentiated them into brain microvascular endothelial cell (BMEC)-like cells as in vitro model of the BBB. MS-derived BMEC-like cells showed impaired junctional integrity, barrier properties and efflux pump activity when compared to healthy controls. Also, MS-derived BMEC-like cells displayed an inflammatory phenotype with increased adhesion molecule expression and immune cell interactions. Activation of Wnt/β-catenin signalling in MS-derived endothelial progenitor cells enhanced barrier characteristics and reduced the inflammatory phenotype. Our study provides evidence for an intrinsic impairment of BBB function in MS patients that can be modelled in vitro. Human iPSC-derived BMEC-like cells are thus suitable to explore the molecular underpinnings of BBB dysfunction in MS and will assist in the identification of potential novel therapeutic targets for BBB stabilization.
Summary Background Natalizumab is used to prevent relapses and progression of disability in patients with multiple sclerosis but has been associated with progressive multifocal leukoencephalopathy ...(PML). We aimed to better understand the associations between JC virus, which causes PML, and natalizumab treatment. Methods We prospectively assessed patients with multiple sclerosis who started treatment with natalizumab. Blood and urine samples were tested for the presence of JC virus DNA with quantitative real-time PCR before treatment and at regular intervals after treatment onset for up to 18 months. At the same timepoints, by use of proliferation and enzyme-linked immunospot assays, the cellular immune responses against JC virus, Epstein-Barr virus, cytomegalovirus, myelin oligodendrocyte glycoprotein, and myelin oligodendrocyte basic protein (MOBP) were assessed. Humoral immune response specific to JC virus was assessed with an enzyme immunoassay. The same experiments were done on blood samples from patients with multiple sclerosis before and 10 months after the start of interferon beta treatment. Findings We assessed 24 patients with multiple sclerosis who received natalizumab and 16 who received interferon beta. In patients treated with natalizumab, JC virus DNA was not detected in the blood at any timepoint. However, JC virus DNA was present in the urine of six patients and in most of these patients the concentrations of JC virus DNA were stable over time. Compared with pretreatment values, the cellular immune response was increased to cytomegalovirus at 6 months, to JC virus at 1, 9, and 12 months, and to Epstein-Barr virus and MOBP at 12 months. Humoral responses remained stable. There were no increases in cellular immune responses specific to the viruses or myelin proteins in the 16 patients treated with interferon beta. Interpretation Natalizumab increases cellular immune responses specific to viruses and myelin proteins in the peripheral blood after 1 year, without evidence of viral reactivation. Funding Swiss National Foundation, Swiss Society for Multiple Sclerosis, and Biogen Dompé.
Narcolepsy is a sleep disorder characterized by excessive daytime sleepiness and attacks of muscle atonia triggered by strong emotions (cataplexy). Narcolepsy is caused by hypocretin (orexin) ...deficiency, paralleled by a dramatic loss in hypothalamic hypocretin-producing neurons. It is believed that narcolepsy is an autoimmune disorder, although definitive proof of this, such as the presence of autoantibodies, is still lacking. We engineered a transgenic mouse model to identify peptides enriched within hypocretin-producing neurons that could serve as potential autoimmune targets. Initial analysis indicated that the transcript encoding Tribbles homolog 2 (Trib2), previously identified as an autoantigen in autoimmune uveitis, was enriched in hypocretin neurons in these mice. ELISA analysis showed that sera from narcolepsy patients with cataplexy had higher Trib2-specific antibody titers compared with either normal controls or patients with idiopathic hypersomnia, multiple sclerosis, or other inflammatory neurological disorders. Trib2-specific antibody titers were highest early after narcolepsy onset, sharply decreased within 2-3 years, and then stabilized at levels substantially higher than that of controls for up to 30 years. High Trib2-specific antibody titers correlated with the severity of cataplexy. Serum of a patient showed specific immunoreactivity with over 86% of hypocretin neurons in the mouse hypothalamus. Thus, we have identified reactive autoantibodies in human narcolepsy, providing evidence that narcolepsy is an autoimmune disorder.
Recent studies highlighted the importance of astrocytes in neuroinflammatory diseases, interacting closely with other CNS cells but also with the immune system. However, due to the difficulty in ...obtaining human astrocytes, their role in these pathologies is still poorly characterized. Here, we develop a serum-free protocol to differentiate human induced pluripotent stem cells (hiPSCs) into astrocytes. Gene expression and functional assays show that our protocol consistently yields a highly enriched population of resting mature astrocytes across the 13 hiPSC lines differentiated. Using this model, we first highlight the importance of serum-free media for astrocyte culture to generate resting astrocytes. Second, we assess the astrocytic response to IL-1β, TNF-α, and IL-6, all cytokines important in neuroinflammation, such as multiple sclerosis. Our study reveals very specific profiles of reactive astrocytes depending on the triggering stimulus. This model provides ideal conditions for in-depth and unbiased characterization of astrocyte reactivity in neuroinflammatory conditions.
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•Human iPSCs are differentiated from blood of control and multiple sclerosis subjects•Functional astrocytes are differentiated from hiPSC in serum-free conditions•In-depth characterization of the effect of serum on astrocyte phenotype•Multiple sclerosis cytokines trigger specific activation profiles in astrocytes
Perriot et al. describe a new protocol to differentiate both resting and reactive astrocytes from human induced pluripotent stem cells in serum-free conditions. They show that astrocytes exhibit highly contrasted responses to serum and to cytokines involved in multiple sclerosis, establishing that this model is suitable to study neuroinflammation.
Multiple sclerosis (MS) is a life-long, potentially debilitating disease of the central nervous system (CNS). MS is considered to be an immune-mediated disease, and the presence of autoreactive ...peripheral lymphocytes in CNS compartments is believed to be critical in the process of demyelination and tissue damage in MS. Although MS is not currently a curable disease, several disease-modifying therapies (DMTs) are now available, or are in development. These DMTs are all thought to primarily suppress autoimmune activity within the CNS. Each therapy has its own mechanism of action (MoA) and, as a consequence, each has a different efficacy and safety profile. Neurologists can now select therapies on a more individual, patient-tailored basis, with the aim of maximizing potential for long-term efficacy without interruptions in treatment. The MoA and clinical profile of MS therapies are important considerations when making that choice or when switching therapies due to suboptimal disease response. This article therefore reviews the known and putative immunological MoAs alongside a summary of the clinical profile of therapies approved for relapsing forms of MS, and those in late-stage development, based on published data from pivotal randomized, controlled trials.
To determine the prevalence of cognitive complaints and HIV-associated neurocognitive disorders (HANDs) in a cohort of aviremic HIV-positive patients. To evaluate the relevance of the HIV dementia ...scale to detect HANDs.
Assessment of HANDs with neuropsychological tests.
Two hundred HIV-infected patients with undetectable HIV-1 RNA concentrations in the plasma, no history of major opportunistic infection of the central nervous system in the past 3 years, no current use of intravenous drugs, and no major depression answered a questionnaire designed to elicit cognitive complaints. Cognitive functions of 50 complaining and 50 noncomplaining HIV-positive patients were assessed.
Patients had undetectable HIV-1 RNA concentrations for a median time of 48 months (range 3.2-136.6). The prevalence of cognitive complaints was 27%. The prevalence of HANDs was 84% among patients with cognitive complaints (asymptomatic neurocognitive impairment 24%, mild neurocognitive disorders 52%, and HIV-associated dementia 8%) and 64% among noncomplainers (asymptomatic neurocognitive impairment 60%, mild neurocognitive disorders 4%, and HIV-associated dementia 0%; P < 0.001). A score of 14 points or less on the HIV dementia scale yielded a positive predictive value of HANDs of 92% in complainers and 82% in noncomplainers.
The prevalence of HANDs is high even in long-standing aviremic HIV-positive patients. However, HANDs without functional repercussion in daily life (asymptomatic neurocognitive impairment) is the most frequent subtype observed. In this population, the HIV dementia scale with a cutoff of 14 points or less seems to provide a useful tool to screen for the presence of HANDs.
OBJECTIVE:Inflammation-related epilepsy is increasingly recognized; however, studies on status epilepticus (SE) are very infrequent. We therefore aimed to determine the frequency of inflammatory ...etiologies in adult SE, and to assess related demographic features and outcomes.
METHODS:This was a retrospective analysis of a prospective registry of adult patients with SE treated in our center, from January 2008 to June 2014, excluding postanoxic causes. We classified SE episodes into 3 etiologic categoriesinfectious, autoimmune, and noninflammatory. Demographic and clinical variables were analyzed regarding their relationship to etiologies and functional outcome.
RESULTS:Among the 570 SE consecutive episodes, 33 (6%) were inflammatory (2.5% autoimmune; 3.3% infectious), without any change in frequency over the study period. Inflammatory SE episodes involved younger patients (mean age 53 vs 61 years, p = 0.015) and were more often refractory to initial antiepileptic treatment (58% vs 38%, odds ratio = 2.19, 95% confidence interval = 1.07–4.47, p = 0.041), despite similar clinical outcome. Subgroup analysis showed that, compared with infectious SE episodes, autoimmune SE involved younger adults (mean age 44 vs 60 years, p = 0.017) and was associated with lower morbidity (return to baseline conditions in 71% vs 32%, odds ratio = 5.41, 95% confidence interval = 1.19–24.52, p = 0.043) without any difference in mortality.
CONCLUSIONS:Despite increasing awareness, inflammatory SE etiologies were relatively rare; their occurrence in younger individuals and higher refractoriness to treatment did not have any effect on outcome. Autoimmune SE episodes also occurred in younger patients, but tended to have better outcomes in survivors than infectious SE.
The aim of this study was to examine neurocognitive course over time among people with well treated HIV.
The Neurocognitive Assessment in the Metabolic and Aging Cohort (NAMACO) study is an ongoing, ...prospective, longitudinal, multicenter and multilingual study within the Swiss HIV Cohort Study (SHCS). Participants undergo neuropsychological assessment at baseline and two-yearly follow-up.
Seven SHCS centres.
Patients aged at least 45 years enrolled in the SHCS with fluency in the local language (French, German or Italian) and agreeing to participate in the NAMACO study: 981 participants at baseline, 720 at 2-year follow-up of whom 644 had complete data sets.
Standardized neuropsychological assessment at baseline and 2-year follow-up.
Neurocognitive performance using Frascati criteria and mean z-scores.
Four participants (of 644, 0.6%) had plasma HIV-1 RNA more than 50 copies/ml; median CD4+ cell count was 660 cells/μl. According to Frascati criteria, 204 participants (31.7%) had neurocognitive impairment (NCI) at baseline. NCI severity in these participants changed little over 2 years and comprehensive models based on Frascati criteria were not feasible. Examining mean z-scores, however, we observed neurocognitive stability or improvement over two years in five of seven neurocognitive domains assessed. Age at least 65 years (P = 0.02) and cognitive complaints (P = 0.004) were associated with neurocognitive decline, while black race (P = 0.01) and dolutegravir treatment (P = 0.002) were associated with improvement.
Frascati criteria were less sensitive in measuring NCI change and therefore unsuitable for following neurocognitive course in our cohort of people with well treated HIV. Examining neurocognitive course by mean z-score change, we observed stability or improvement.
Pattern of cognitive deficits in severe COVID-19 Beaud, Valérie; Crottaz-Herbette, Sonia; Dunet, Vincent ...
Journal of neurology, neurosurgery and psychiatry,
05/2021, Letnik:
92, Številka:
5
Journal Article
PDF
