SARS-CoV-2 Spike protein induces TLR4-mediated long-term cognitive dysfunction recapitulating post-COVID-19 syndrome in mice.

Cognitive dysfunction is often reported in patients with post-coronavirus disease 2019 (COVID-19) syndrome, but its underlying mechanisms are not completely understood. Evidence suggests that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) Spike protein or its fragments are released from cells during infection, reaching different tissues, including the CNS, irrespective of the presence of the viral RNA. Here, we demonstrate that brain infusion of Spike protein in mice has a late impact on cognitive function, recapitulating post-COVID-19 syndrome. We also show that neuroinflammation and hippocampal microgliosis mediate Spike-induced memory dysfunction via complement-dependent engulfment of synapses. Genetic or pharmacological blockage of Toll-like receptor 4 (TLR4) signaling protects animals against synapse elimination and memory dysfunction induced by Spike brain infusion. Accordingly, in a cohort of 86 patients who recovered from mild COVID-19, the genotype GG TLR4-2604G>A (rs10759931) is associated with poor cognitive outcome. These results identify TLR4 as a key target to investigate the long-term cognitive dysfunction after COVID-19 infection in humans and rodents.

Practical Evidence-Based Recommendations for Patients with Multiple Sclerosis Who Want to Have Children.

Multiple sclerosis (MS) management presently aims to reach a state of no (or minimal) evidence of disease activity. The development and commercialization of new drugs has led to a renewed interest in family planning, since patients with MS may face a future with reduced (or no) disease-related neurological disability. The advice of neurologists is often sought by patients who want to have children and need to know more about disease control at conception and during pregnancy and the puerperium. When MS is well controlled, the simple withdrawal of drugs for patients who intend to conceive is not an option. On the other hand, not all treatments presently recommended for MS are considered safe during conception, pregnancy and/or breastfeeding. The objective of the present study was to summarize the practical and evidence-based recommendations for family planning when our patients (women and men) have MS.Funding TEVA Pharmaceutical Brazil.

Fatigue favors in vitro Th1 and Th17-like cell expansion and reduces corticoid sensitivity in MS patients.

Fatigue is a common "ghost" symptom in patients with multiple sclerosis (MS), an autoimmune disease mediated by T cells that target myelin antigens of the central nervous system. As fatigue has been associated with inflammatory states, its occurrence may negatively impact MS progression. The aim of this study was to evaluate the impact of fatigue on the cytokine profile of patients with relapsing-remitting (RR) MS. For our study, blood were collected from MS patients in clinical remission phase with (n=15) and without (n=15) fatigue. Cytokines were detected by ELISA in the plasma and supernatant collected from anti-CD3/anti-CD28-activated T cells or LPS-stimulated monocytes. In some wells, different doses of hydrocortisone (HC) were added at the beginning of the culture. Here, peripheral levels of IL-6 and TNF-α, as well as in vitro production of cytokines related to Th17 (IL-6, IL-17, IL-22, and GM-CSF) or Th1 (IFN-γ) phenotypes, were elevated in fatigued patients and their levels were associated with fatigue severity. The same phenomenon was observed between the production of IL-6, TNF-α, IL-1ß, and IL-23 by monocytes and fatigue. Moreover, HC was less efficient in inhibiting in vitro inflammatory cytokine production in patients with fatigue, mainly those produced by both CD8+ T cells and monocytes. Our data, although preliminary, suggests that the occurrence of fatigue, by favoring the in vitro production of Th1/Th17-related cytokines and corticoid resistance, may negatively impact the course of MS.

Endogenous interleukin-6 amplifies interleukin-17 production and corticoid-resistance in peripheral T cells from patients with multiple sclerosis.

Interleukin-6 (IL-6) has been implicated in the induction of pathogenic IL-17-producing T cells in autoimmune diseases, and studies evaluating the role of this cytokine in T-cell function in patients with multiple sclerosis (MS) are lacking. Our objective was to evaluate the role of IL-6 receptor (IL-6R) signalling on in vitro functional status of T cells from patients with relapsing-remitting MS during clinical remission. Our results demonstrated that, even during the remission phase, activated T cells from patients produce higher levels of IL-17, and this cytokine was positively correlated with disease severity, as determined by Expanded Disability Status Scale score. In the MS group, the blockade of IL-6R signalling by anti-IL-6R monoclonal antibody reduced IL-17 production and elevated IL-10 release by activated CD4(+) T cells, but it did not alter the production of these cytokines by activated CD8(+) T cells. Blockade of IL-6R signalling also reduced the ability of monocytes to up-regulate T helper type 17 phenotype in patients with MS. Finally, both cell proliferation and IL-17 release by CD4(+) and, mainly, CD8(+) T cells from patients with MS were less sensitive to hydrocortisone inhibition than control group. Interestingly, IL-6R signalling blockade restored the ability of hydrocortisone to inhibit both T-cell proliferation and IL-17 production. Collectively, these results suggest that IL-6 might be involved in MS pathogenesis by enhancing IL-17 production and reducing corticoid inhibitory effects on activated T cells.

Dopamine favors expansion of glucocorticoid-resistant IL-17-producing T cells in multiple sclerosis.

Dopamine (DA) is a neurotransmitter produced mainly in the central nervous system (CNS) that has immunomodulatory actions on T cells. As the multiple sclerosis (MS) has long been regarded as an autoimmune disease of CNS mediated by T cells, the objective of this study was to evaluate the impact of DA on in vitro functional status of T cells from relapsing-remitting (RR)-MS patients. Peripheral T-cells from RR-MS patients were activated by mitogens and cell proliferation and cytokine production were assayed by [(3)H]-thymidine uptake and ELISA, respectively. Our results demonstrated that DA enhanced in vitro T cell proliferation and Th17-related cytokines in MS-derived cell cultures. In addition, this catecholamine reduced Treg-related cytokines (IL-10 and TGF-ß) release by activated CD4(+) T cells. These DA-induced effects on T cells were mainly dependent on IL-6 production by both polyclonally-activated CD4(+) T cells and LPS-stimulated monocytes. Furthermore, the production of IL-17 and IL-6 by MS-derived T cells was directly related with neurological disability (EDSS score), and the release of these cytokines was less sensitive to glucocorticoid inhibition in MS patients than in control group, mainly after DA addition. In conclusion, our data suggest that DA amplifies glucocorticoid-resistant Th17 phenotype in MS patients, and this phenomenon could be, at least in part, due to its ability to induce IL-6 production by monocytes and CD4(+) T cells.

Supplementation and therapeutic use of vitamin D in patients with multiple sclerosis: consensus of the Scientific Department of Neuroimmunology of the Brazilian Academy of Neurology.

Multiple sclerosis (MS) is an inflammatory, autoimmune, demyelinating, and degenerative central nervous system disease. Even though the etiology of MS has not yet been fully elucidated, there is evidence that genetic and environmental factors interact to cause the disease. Among the main environmental factors studied, those more likely associated with MS include certain viruses, smoking, and hypovitaminosis D. This review aimed to determine whether there is evidence to recommend the use of vitamin D as monotherapy or as adjunct therapy in patients with MS. We searched PUBMED, EMBASE, COCHRANNE, and LILACS databases for studies published until September 9 th , 2013, using the keywords "multiple sclerosis", "vitamin D", and "clinical trial". There is no scientific evidence up to the production of this consensus for the use of vitamin D as monotherapy for MS in clinical practice.

Supplementation and therapeutic use of vitamin D in patients with multiple sclerosis: Consensus of the Scientific Department of Neuroimmunology of the Brazilian Academy of Neurology / Suplementacao e uso terapeutico de vitamina D nos pacientes com esclerose multipla: Consenso do Departamento Cientifico de Neuroimunologia da Academia Brasileira de Neurologia

Multiple sclerosis (MS) is an inflammatory, autoimmune, demyelinating, and degenerative central nervous system disease. Even though the etiology of MS has not yet been fully elucidated, there is evidence that genetic and environmental factors interact to cause the disease. Among the main environmental factors studied, those more likely associated with MS include certain viruses, smoking, and hypovitaminosis D. This review aimed to determine whether there is evidence to recommend the use of vitamin D as monotherapy or as adjunct therapy in patients with MS. We searched PUBMED, EMBASE, COCHRANNE, and LILACS databases for studies published until September 9 th , 2013, using the keywords “multiple sclerosis”, “vitamin D”, and “clinical trial”. There is no scientific evidence up to the production of this consensus for the use of vitamin D as monotherapy for MS in clinical practice.

A esclerose múltipla (EM) é uma doença inflamatória, autoimune, desmielinizante e degenerativa do sistema nervoso central. Estudos epidemiológicos têm identificado associações de hipovitaminose D com doenças autoimunes. O principal objetivo desta revisão é responder se há evidências que indiquem o uso terapêutico de vitamina D em monoterapia para pacientes com EM. Por meio dos sites PUBMED, EMBASE, LILACS e Scielo foram realizadas buscas usando os descritores “vitamin D”, e “multiple sclerosis” até 12/09/2013. Estudos clínicos randomizados, controlados e duplo-cegos foram selecionados para avaliar a resposta terapêutica da vitamina D na EM. Não foram encontradas evidências científicas que justifiquem o uso da vitamina D em monoterapia no tratamento da EM, na prática clínica.