Multiple Sclerosis and SARS-CoV-2: Has the Interplay Started?

Current knowledge on Multiple Sclerosis (MS) etiopathogenesis encompasses complex interactions between the host's genetic background and several environmental factors that result in dysimmunity against the central nervous system. An old-aged association exists between MS and viral infections, capable of triggering and sustaining neuroinflammation through direct and indirect mechanisms. The novel Coronavirus, SARS-CoV-2, has a remarkable, and still not fully understood, impact on the immune system: the occurrence and severity of both acute COVID-19 and post-infectious chronic illness (long COVID-19) largely depends on the host's response to the infection, that echoes several aspects of MS pathobiology. Furthermore, other MS-associated viruses, such as the Epstein-Barr Virus (EBV) and Human Endogenous Retroviruses (HERVs), may enhance a mechanistic interplay with the novel Coronavirus, with the potential to interfere in MS natural history. Studies on COVID-19 in people with MS have helped clinicians in adjusting therapeutic strategies during the pandemic; similar efforts are being made for SARS-CoV-2 vaccination campaigns. In this Review, we look over 18 months of SARS-CoV-2 pandemic from the perspective of MS: we dissect neuroinflammatory and demyelinating mechanisms associated with COVID-19, summarize pathophysiological crossroads between MS and SARS-CoV-2 infection, and discuss present evidence on COVID-19 and its vaccination in people with MS.

Intestinal Permeability and Circulating CD161+CCR6+CD8+T Cells in Patients With Relapsing-Remitting Multiple Sclerosis Treated With Dimethylfumarate.

Background: The changes of the gut-brain axis have been recently recognized as important components in multiple sclerosis (MS) pathogenesis. Objectives: To evaluate the effects of DMF on intestinal barrier permeability and mucosal immune responses. Methods: We investigated intestinal permeability (IP) and circulating CD161+CCR6+CD8+T cells in 25 patients with MS, who met eligibility criteria for dimethyl-fumarate (DMF) treatment. These data, together with clinical/MRI parameters, were studied at three time-points: baseline (before therapy), after one (T1) and 9 months (T2) of treatment. Results: At baseline 16 patients (64%) showed altered IP, while 14 cases (56%) showed active MRI. During DMF therapy we found the expected decrease of disease activity at MRI compared to T0 (6/25 at T1, p = 0.035 and 3/25 at T2, p < 0.00), and a reduction in the percentage of CD161+CCR6+CD8+ T cells (16/23 at T2; p < 0.001). The effects of DMF on gut barrier alterations was variable, without a clear longitudinal pattern, while we found significant relationships between IP changes and drop of MRI activity (p = 0.04) and circulating CD161+CCr6+CD8+ T cells (p = 0.023). Conclusions: The gut barrier is frequently altered in MS, and the CD161+ CCR6+CD8+ T cell-subset shows dynamics which correlate with disease course and therapy.

MAIT Cells and Microbiota in Multiple Sclerosis and Other Autoimmune Diseases.

The functions of mucosal-associated invariant T (MAIT) cells in homeostatic conditions include the interaction with the microbiota and its products, the protection of body barriers, and the mounting of a tissue-repair response to injuries or infections. Dysfunction of MAIT cells and dysbiosis occur in common chronic diseases of inflammatory, metabolic, and tumor nature. This review is aimed at analyzing the changes of MAIT cells, as well as of the microbiota, in multiple sclerosis and other autoimmune disorders. Common features of dysbiosis in these conditions are the reduced richness of microbial species and the unbalance between pro-inflammatory and immune regulatory components of the gut microbiota. The literature concerning MAIT cells in these disorders is rather complex, and sometimes not consistent. In multiple sclerosis and other autoimmune conditions, several studies have been done, or are in progress, to find correlations between intestinal permeability, dysbiosis, MAIT cell responses, and clinical biomarkers in treated and treatment-naïve patients. The final aims are to explain what activates MAIT cells in diseases not primarily infective, which interactions with the microbiota are potentially pathogenic, and their dynamics related to disease course and disease-modifying treatments.

A Case of Double Standard: Sex Differences in Multiple Sclerosis Risk Factors.

Multiple sclerosis is a complex, multifactorial, dysimmune disease prevalent in women. Its etiopathogenesis is extremely intricate, since each risk factor behaves as a variable that is interconnected with others. In order to understand these interactions, sex must be considered as a determining element, either in a protective or pathological sense, and not as one of many variables. In particular, sex seems to highly influence immune response at chromosomal, epigenetic, and hormonal levels. Environmental and genetic risk factors cannot be considered without sex, since sex-based immunological differences deeply affect disease onset, course, and prognosis. Understanding the mechanisms underlying sex-based differences is necessary in order to develop a more effective and personalized therapeutic approach.

Operationalization of a frailty index in patients with multiple sclerosis: A cross-sectional investigation.

BACKGROUND: Frailty is an age-related status of increased vulnerability to stressors caused by the accumulation of multiple health deficits. This construct may allow to capture the clinical complexity of patients with multiple sclerosis (MS). OBJECTIVE: To investigate the relationship between frailty and the clinical manifestations of MS. METHODS: Patients with MS were consecutively enrolled at five tertiary dedicated services. Disability and fatigue were assessed. The phenotypes of MS were also identified. Frailty was measured using a frailty index (FI), computed by cumulatively considering 42 age-related multidimensional health deficits. RESULTS: Overall, 745 MS patients (mean age = 48.2 years, standard deviation = 11.7 years; women 68%) were considered. The median FI value was 0.12 (interquartile range = 0.05-0.19) and the 99th percentile was 0.40. FI scores were associated with MS disease duration, disability, fatigue, as well as with the number of previous disease-modifying treatments and current symptomatic therapies. A logistic regression analysis model showed that FI score was independently associated with the secondary progressive phenotype. CONCLUSION: Frailty is significantly associated with major characteristics of MS. The findings of the present cross-sectional investigation should be explored in future longitudinal studies.

Autoimmune Encephalitis and CSF Anti-GluR3 Antibodies in an MS Patient after Alemtuzumab Treatment.

A 45-year-old Italian woman, affected by relapsing-remitting multiple sclerosis (RR-MS) starting from 2011, started treatment with alemtuzumab in July 2016. Nine months after the second infusion, she had an immune thrombocytopenic purpura (ITP) with complete recovery after steroid treatment. Three months after the ITP, the patient presented with transient aphasia, cognitive deficits, and focal epilepsy. Serial brain magnetic resonance imaging showed a pattern compatible with encephalitis. Autoantibodies to glutamate receptor 3 peptide A and B were detected in cerebrospinal fluid and serum, in the absence of any other diagnostic cues. After three courses of intravenous immunoglobulin (0.4 mg/kg/day for 5 days, 1 month apart), followed by boosters (0.4 mg/kg/day) every 4-6 weeks, her neurological status improved and is currently comparable with that preceding the encephalitis. Autoimmune complications of the central nervous system during alemtuzumab therapy are relatively rare: only one previous case of autoimmune encephalitis following alemtuzumab treatment has been reported to date.

The Contribution of Gut Barrier Changes to Multiple Sclerosis Pathophysiology.

The gut barrier consists of several components, including the mucus layer, made of mucins and anti-bacterial molecule, the epithelial cells, connected by tight junction proteins, and a mixed population of cells involved in the interplay with microbes, such as M cells, elongations of "antigen presenting cells" dwelling the lamina propria, intraepithelial lymphocytes and Paneth cells secreting anti-bacterial peptides. Recently, the influence of intestinal permeability (IP) changes on organs far from gut has been investigated, and IP changes in multiple sclerosis (MS) have been described. A related topic is the microbiota dysfunction that underpins the development of neuroinflammation in animal models and human diseases, including MS. It becomes now of interest to better understand the mechanisms through which IP changes contribute to pathophysiology of neuroinflammation. The following aspects seem of relevance: studies on other biomarkers of IP alterations; the relationship with known risk factors for MS development, such as vitamin D deficiency; the link between blood brain barrier and gut barrier breakdown; the effects of IP increase on microbial translocation and microglial activation; the parallel patterns of IP and neuroimmune changes in MS and neuropsychiatric disorders, that afflict a sizable proportion of patients with MS. We will also discuss the therapeutic implications of IP changes, considering the impact of MS-modifying therapies on gut barrier, as well as potential approaches to enhance or protect IP homeostasis.