Modeling multiple sclerosis using mobile and wearable sensor data.

Multiple sclerosis (MS) is a neurological disease of the central nervous system that is the leading cause of non-traumatic disability in young adults. Clinical laboratory tests and neuroimaging studies are the standard methods to diagnose and monitor MS. However, due to infrequent clinic visits, it is fundamental to identify remote and frequent approaches for monitoring MS, which enable timely diagnosis, early access to treatment, and slowing down disease progression. In this work, we investigate the most reliable, clinically useful, and available features derived from mobile and wearable devices as well as their ability to distinguish people with MS (PwMS) from healthy controls, recognize MS disability and fatigue levels. To this end, we formalize clinical knowledge and derive behavioral markers to characterize MS. We evaluate our approach on a dataset we collected from 55 PwMS and 24 healthy controls for a total of 489 days conducted in free-living conditions. The dataset contains wearable sensor data - e.g., heart rate - collected using an arm-worn device, smartphone data - e.g., phone locks - collected through a mobile application, patient health records - e.g., MS type - obtained from the hospital, and self-reports - e.g., fatigue level - collected using validated questionnaires administered via the mobile application. Our results demonstrate the feasibility of using features derived from mobile and wearable sensors to monitor MS. Our findings open up opportunities for continuous monitoring of MS in free-living conditions and can be used to evaluate and guide the effectiveness of treatments, manage the disease, and identify participants for clinical trials.

Basic CSF parameters and MRZ reaction help in differentiating MOG antibody-associated autoimmune disease versus multiple sclerosis.

Background: Myelin oligodendrocyte glycoprotein antibody-associated autoimmune disease (MOGAD) is a rare monophasic or relapsing inflammatory demyelinating disease of the central nervous system (CNS) and can mimic multiple sclerosis (MS). The variable availability of live cell-based MOG-antibody assays and difficulties in interpreting low-positive antibody titers can complicate diagnosis. Literature on cerebrospinal fluid (CSF) profiles in MOGAD versus MS, one of the most common differential diagnoses, is scarce. We here analyzed the value of basic CSF parameters to i) distinguish different clinical MOGAD manifestations and ii) differentiate MOGAD from MS. Methods: This is retrospective, single-center analysis of clinical and laboratory data of 30 adult MOGAD patients and 189 adult patients with relapsing-remitting multiple sclerosis. Basic CSF parameters included CSF white cell count (WCC) and differentiation, CSF/serum albumin ratio (QAlb), intrathecal production of immunoglobulins, CSF-restricted oligoclonal bands (OCB) and MRZ reaction, defined as intrathecal production of IgG reactive against at least 2 of the 3 viruses measles (M), rubella (R) and varicella zoster virus (Z). Results: MOGAD patients with myelitis were more likely to have a pleocytosis, a QAlb elevation and a higher WCC than those with optic neuritis, and, after review and combined analysis of our and published cases, they also showed a higher frequency of intrathecal IgM synthesis. Compared to MS, MOGAD patients had significantly more frequently neutrophils in CSF and WCC>30/µl, QAlb>10×10-3, as well as higher mean QAlb values, but significantly less frequently CSF plasma cells and CSF-restricted OCB. A positive MRZ reaction was present in 35.4% of MS patients but absent in all MOGAD patients. Despite these associations, the only CSF parameters with relevant positive likelihood ratios (PLR) indicating MOGAD were QAlb>10×10-3 (PLR 12.60) and absence of CSF-restricted OCB (PLR 14.32), whereas the only relevant negative likelihood ratio (NLR) was absence of positive MRZ reaction (NLR 0.00). Conclusion: Basic CSF parameters vary considerably in different clinical phenotypes of MOGAD, but QAlb>10×10-3 and absence of CSF-restricted OCB are highly useful to differentiate MOGAD from MS. A positive MRZ reaction is confirmed as the strongest CSF rule-out parameter in MOGAD and could be useful to complement the recently proposed diagnostic criteria.

Correlation of disability with quality of life in patients with multiple sclerosis treated with natalizumab: primary results and post hoc analysis of the TYSabri ImPROvement study (PROTYS).

Background: In patients with multiple sclerosis (MS), relapses and disability progression have been associated with decreased health-related quality of life (HRQoL). Methods: PROTYS, a prospective, multicentre, single-arm, observational study in seven Swiss MS centres, evaluated correlations between change in disability status (measured through the Expanded Disability Status Scale (EDSS)) and HRQoL changes (measured through the global Multiple Sclerosis International Quality of Life (MusiQoL) index questionnaire) in 35 patients with relapsing remitting MS on natalizumab for 1 year. In addition, several other scales were also used, such as: Multiple Sclerosis Intimacy and Sexuality Questionnaire-19, EuroQoL-5 Dimension, and Fatigue Scale of Motor and Cognitive Function. A post hoc analysis further assessed the association between HRQoL changes after 1 year and the MusiQoL subscores and other patient-reported outcome (PRO) measures. Results: At 1 year, patients were categorised into 'EDSS improved' (6/35), 'EDSS stable' (28/35) and 'EDSS worsened' (1/35). Mean disability scores decreased for 'EDSS improved' and 'EDSS stable' but increased for 'EDSS worsened'. Mean MusiQoL index score for 'EDSS improved' increased from 61.2 at baseline to 66.3 at 1 year, while the 'EDSS stable' group increased from 67.9 to 70.8. No meaningful statistical relationship was observed between EDSS group and changes in MusiQoL score. For the post hoc analysis, patients were categorised in 'MusiQoL improved' (n=21) and 'MusiQoL worsened' (n=14) groups. MusiQoL subscores for 'symptoms,' 'psychological well-being' and 'activities of daily living', as well as scores for several related PRO measures, correlated with improvement of the MusiQoL global index. There was no correlation between the changes in MusiQoL global index and EDSS score. Conclusions: Natalizumab treatment for 1 year resulted in either improved or stable EDSS status in most patients, and although no significant relationship was observed between global HRQoL change and EDSS change, several domains of HRQoL seemed to improve with natalizumab treatment. Trial registration number: NCT02386566.

Assessment of oligoclonal bands in cerebrospinal fluid and serum of dogs with meningoencephalitis of unknown origin.

BACKGROUND: Meningoencephalitis of unknown origin (MUO) is an inflammatory disease of the canine central nervous system (CNS) that shares several features with multiple sclerosis (MS) in humans. In approximately 95% of MS patients, ≥ two immunoglobulin G (IgG) oligoclonal bands (OCBs) are detectable exclusively in the cerebrospinal fluid (CSF). HYPOTHESIS/OBJECTIVES: To investigate OCBs in CSF and serum in dogs affected by MUO, intervertebral disc disease (IVDD), idiopathic epilepsy (IE), intracranial neoplasia (IN), steroid-responsive meningitis-arteritis (SRMA), and diseases outside the CNS. We hypothesize that the highest prevalence of CSF-specific OCBs (≥ two OCBs uniquely in the CSF) would be found in dogs affected by MUO. ANIMALS: Client-owned dogs (n = 121) presented to the neurology service due to neurological deficits. METHODS: Prospective study. Measurement of IgG concentration in CSF and serum via a canine IgG ELISA kit. OCB detection via isoelectric focusing (IEF) and immunoblot. RESULTS: Presence of CSF-specific OCBs was significantly higher in dogs with MUO (57%) compared to 22% in IN, 6% in IE, 15% in SRMA, 13% in IVDD, and 0% in the non-CNS group (p < .001). Dogs with MUO were 9.9 times more likely to show CSF-specific OCBs than all other diseases together (95% confidence interval, 3.7-26.4; p < .001). CONCLUSIONS AND CLINICAL IMPORTANCE: MUO showed the highest prevalence of CSF-specific OCBs, indicating an inflammatory B cell response. Future studies are needed to evaluate the prevalence in the specific MUO subtypes and a possible similarity with human MS.

Vaccination with Designed Neopeptides Induces Intratumoral, Cross-reactive CD4+ T-cell Responses in Glioblastoma.

PURPOSE: The low mutational load of some cancers is considered one reason for the difficulty to develop effective tumor vaccines. To overcome this problem, we developed a strategy to design neopeptides through single amino acid mutations to enhance their immunogenicity. EXPERIMENTAL DESIGN: Exome and RNA sequencing as well as in silico HLA-binding predictions to autologous HLA molecules were used to identify candidate neopeptides. Subsequently, in silico HLA-anchor placements were used to deduce putative T-cell receptor (TCR) contacts of peptides. Single amino acids of TCR contacting residues were then mutated by amino acid replacements. Overall, 175 peptides were synthesized and sets of 25 each containing both peptides designed to bind to HLA class I and II molecules applied in the vaccination. Upon development of a tumor recurrence, the tumor-infiltrating lymphocytes (TIL) were characterized in detail both at the bulk and clonal level. RESULTS: The immune response of peripheral blood T cells to vaccine peptides, including natural peptides and designed neopeptides, gradually increased with repetitive vaccination, but remained low. In contrast, at the time of tumor recurrence, CD8+ TILs and CD4+ TILs responded to 45% and 100%, respectively, of the vaccine peptides. Furthermore, TIL-derived CD4+ T-cell clones showed strong responses and tumor cell lysis not only against the designed neopeptide but also against the unmutated natural peptides of the tumor. CONCLUSIONS: Turning tumor self-peptides into foreign antigens by introduction of designed mutations is a promising strategy to induce strong intratumoral CD4+ T-cell responses in a cold tumor like glioblastoma.

Cognitive fatigability assessment test (cFAST): Development of a new instrument to assess cognitive fatigability and pilot study on its association to perceived fatigue in multiple sclerosis.

Background: Fatigue is a common symptom of many diseases, including multiple sclerosis. It manifests as a cognitive or physical condition. Fatigue is poorly understood, and effective therapies are missing. Furthermore, there is a lack of methods to measure fatigue objectively. Fatigability, the measurable decline in performance during a task, has been suggested as a complementary method to quantify fatigue. Objective: To develop a new and objective measurement of cognitive fatigability and investigate its association with perceived fatigue. Methods: We introduced the cognitive fatigability assessment test (cFAST), a novel smartphone-based test to quantify cognitive fatigability. Forty-two people with multiple sclerosis (23 fatigued and 19 non-fatigued, defined by the Fatigue Scale for Motor and Cognitive Functions) took part in our validation study. Patients completed cFAST twice. We used t-tests, Monte Carlo sampling, and area under the receiver operating characteristic curves to evaluate our approach using two sets of proposed metrics. Results: When classifying fatigue, our fatigability metric Δresponse time has a mean area under the receiver operating characteristic curve of 0.74 (95% CI 0.64-0.84), making it the best performing metric for this task. Furthermore, Δresponse time shows a statistically significant difference between the fatigued and non-fatigued groups (t = 2.27, P = .03). Particularly, cognitively-fatigued patients decline in performance, while non-fatigued patients do not. Conclusions: We introduce cFAST, a new instrument to quantify cognitive fatigability. Our pilot study provides evidence that cognitive fatigability assessment test produces a quantifiable drop in cognitive performance in a short period. Furthermore, our results indicate that cFAST may have the potential to serve as a surrogate for subjective cognitive fatigue. cFAST is significantly shorter than the existing fatigability assessments and does not require specialized equipment. Thus, it could enable frequent and remote monitoring, which could substantially aid clinicians in better understanding and treating fatigue.

Comparison of Two Different Canine Anti-IgG Antibodies for Assessment of Oligoclonal Bands in Cerebrospinal Fluid and Serum of Dogs via Isoelectric Focusing Followed by an Immunoblot.

Isoelectric focusing followed by immunoblotting is a method routinely used in human medicine to assess the presence of oligoclonal bands (OCBs) in cerebrospinal fluid (CSF) and serum. The detection of OCBs is a valuable diagnostic test, especially important in patients with the suspicion of multiple sclerosis (MS), in which at least two OCBs are found in the CSF not present in paired serum samples in up to 95% of patients. So far, presence of OCBs in CSF and serum of dogs has only been investigated in a small cohort of dogs diagnosed with degenerative myelopathy and healthy dogs. The main objective of the current study was to describe the method used for OCB detection and compare two different canine anti-IgG antibodies: a canine rabbit-anti-IgG antibody (Jackson ImmunoResearch) vs. a canine goat-anti-IgG antibody (Bio-Rad). The method was performed according to the instructions of the commercial kit used. The canine goat-anti-IgG antibody showed a better performance than the canine rabbit-anti-IgG antibody. The availability of the technique of OCB detection in the dog paves the way for further studies, especially in the field of inflammatory diseases of the canine central nervous system, and comparison between specific human and canine diseases.

Continuous monitoring with wearables in multiple sclerosis reveals an association of cardiac autonomic dysfunction with disease severity.

Background: Dysfunction of the autonomic nervous system is common in multiple sclerosis patients, and probably present years before diagnosis, but its role in the disease is poorly understood. Objectives: To study the autonomic nervous system in patients with multiple sclerosis using cardiac autonomic regulation measured with a wearable. Methods: In a two-week study, we present a method to standardize the measurement of heart rate variability using a wearable sensor that allows the investigation of circadian trends. Using this method, we investigate the relationship of cardiac autonomic dysfunction with clinical hallmarks and subjective burden of fatigue and autonomic symptoms. Results: In 55 patients with multiple sclerosis and 24 healthy age- and gender-matched controls, we assessed the cumulative circadian heart-rate variability trend of two weeks. The trend analysis revealed an effect of inflammation (P = 0.0490, SMD = -0.5466) and progressive neurodegeneration (P = 0.0016, SMD = 1.1491) on cardiac autonomic function. No association with subjective symptoms could be found. Conclusions: Trend-based heart rate variability measured with a wearable provides the opportunity for unobtrusive long-term assessment of autonomic functions in patients with multiple sclerosis. It revealed a general dysregulation in patients with multiple sclerosis.

T-Cell Specificity Influences Disease Heterogeneity in Multiple Sclerosis.

BACKGROUND AND OBJECTIVES: Encouraged by the enormous progress that the identification of specific autoantigens added to the understanding of neurologic autoimmune diseases, we undertook here an in-depth study of T-cell specificities in the autoimmune disease multiple sclerosis (MS), for which the spectrum of responsible autoantigens is not fully defined yet. The identification of target antigens in MS is crucial for therapeutic strategies aimed to induce antigen-specific tolerance. In addition, knowledge of relevant T-cell targets can improve our understanding of disease heterogeneity, a hallmark of MS that complicates clinical management. METHODS: The proliferative response and interferon gamma (IFN-γ) release of CSF-infiltrating CD4+ T cells from patients with MS against several autoantigens was used to identify patients with different intrathecal T-cell specificities. Fresh CSF-infiltrating and paired circulating lymphocytes in these patients were characterized in depth by ex vivo immunophenotyping and transcriptome analysis of relevant T-cell subsets. Further examination of these patients included CSF markers of inflammation and neurodegeneration and a detailed characterization with respect to demographic, clinical, and MRI features. RESULTS: By testing CSF-infiltrating CD4+ T cells from 105 patients with MS against seven long-known myelin and five recently described GDP-l-fucose synthase peptides, we identified GDP-l-fucose synthase and myelin oligodendrocyte glycoprotein (35-55) responder patients. Immunophenotyping of CSF and paired blood samples in these patients revealed a significant expansion of an effector memory (CCR7- CD45RA-) CD27- Th1 CD4+ cell subset in GDP-l-fucose synthase responders. Subsequent transcriptome analysis of this subset demonstrated expression of Th1 and cytotoxicity-associated genes. Patients with different intrathecal T-cell specificities also differ regarding inflammation- and neurodegeneration-associated biomarkers, imaging findings, expression of HLA class II alleles, and seasonal distribution of the time of the lumbar puncture. DISCUSSION: Our observations reveal an association between autoantigen reactivity and features of disease heterogeneity that strongly supports an important role of T-cell specificity in MS pathogenesis. These data have the potential to improve patient classification in clinical practice and to guide the development of antigen-specific tolerization strategies.

Multiple Sclerosis Therapy Consensus Group (MSTCG): position statement on disease-modifying therapies for multiple sclerosis (white paper).

Multiple sclerosis is a complex, autoimmune-mediated disease of the central nervous system characterized by inflammatory demyelination and axonal/neuronal damage. The approval of various disease-modifying therapies and our increased understanding of disease mechanisms and evolution in recent years have significantly changed the prognosis and course of the disease. This update of the Multiple Sclerosis Therapy Consensus Group treatment recommendation focuses on the most important recommendations for disease-modifying therapies of multiple sclerosis in 2021. Our recommendations are based on current scientific evidence and apply to those medications approved in wide parts of Europe, particularly German-speaking countries (Germany, Austria, and Switzerland).

[Multiple sclerosis treatment consensus group (MSTCG): position paper on disease-modifying treatment of multiple sclerosis 2021 (white paper)]. / Multiple Sklerose Therapie Konsensus Gruppe (MSTKG): Positionspapier zur verlaufsmodifizierenden Therapie der Multiplen Sklerose 2021 (White Paper).

Multiple sclerosis is a complex, autoimmune-mediated disease of the central nervous system characterized by inflammatory demyelination and axonal/neuronal damage. The approval of various disease-modifying therapies and our increased understanding of disease mechanisms and evolution in recent years have significantly changed the prognosis and course of the disease. This update of the Multiple Sclerosis Therapy Consensus Group treatment recommendation focuses on the most important recommendations for disease-modifying therapies of multiple sclerosis in 2021. Our recommendations are based on current scientific evidence and apply to those medications approved in wide parts of Europe, particularly German-speaking countries (Germany, Austria, Switzerland).

Differential Binding of Autoantibodies to MOG Isoforms in Inflammatory Demyelinating Diseases.

OBJECTIVE: To analyze serum immunoglobulin G (IgG) antibodies to major isoforms of myelin oligodendrocyte glycoprotein (MOG-alpha 1-3 and beta 1-3) in patients with inflammatory demyelinating diseases. METHODS: Retrospective case-control study using 378 serum samples from patients with multiple sclerosis (MS), patients with non-MS demyelinating disease, and healthy controls with MOG alpha-1-IgG positive (n = 202) or negative serostatus (n = 176). Samples were analyzed for their reactivity to human, mouse, and rat MOG isoforms with and without mutations in the extracellular MOG Ig domain (MOG-ecIgD), soluble MOG-ecIgD, and myelin from multiple species using live cell-based, tissue immunofluorescence assays and ELISA. RESULTS: The strongest IgG reactivities were directed against the longest MOG isoforms alpha-1 (the currently used standard test for MOG-IgG) and beta-1, whereas the other isoforms were less frequently recognized. Using principal component analysis, we identified 3 different binding patterns associated with non-MS disease: (1) isolated reactivity to MOG-alpha-1/beta-1 (n = 73), (2) binding to MOG-alpha-1/beta-1 and at least one other alpha, but no beta isoform (n = 64), and (3) reactivity to all 6 MOG isoforms (n = 65). The remaining samples were negative (n = 176) for MOG-IgG. These MOG isoform binding patterns were associated with a non-MS demyelinating disease, but there were no differences in clinical phenotypes or disease course. The 3 MOG isoform patterns had distinct immunologic characteristics such as differential binding to soluble MOG-ecIgD, sensitivity to MOG mutations, and binding to human MOG in ELISA. CONCLUSIONS: The novel finding of differential MOG isoform binding patterns could inform future studies on the refinement of MOG-IgG assays and the pathophysiologic role of MOG-IgG.

Antigen-Specific Immune Tolerance in Multiple Sclerosis-Promising Approaches and How to Bring Them to Patients.

Antigen-specific tolerance induction aims at treating multiple sclerosis (MS) at the root of its pathogenesis and has the prospect of personalization. Several promising tolerization approaches using different technologies and modes of action have already advanced to clinical testing. The prerequisites for successful tolerance induction include the knowledge of target antigens, core pathomechanisms, and how to pursue a clinical development path that is distinct from conventional drug development. Key aspects including patient selection, outcome measures, demonstrating the mechanisms of action as well as the positioning in the rapidly growing spectrum of MS treatments have to be considered to bring this therapy to patients.

Altered CSF Albumin Quotient Links Peripheral Inflammation and Brain Damage in MS.

OBJECTIVE: CNS damage can increase the susceptibility of the blood-brain barrier (BBB) to changes induced by systemic inflammation. The aim of this study is to better understand BBB permeability in patients with MS and to examine whether compromised BBB integrity in some of these patients is associated with CNS damage and systemic inflammation. METHODS: Routine CSF measurements of 121 patients with MS were analyzed including number and type of infiltrating cells, total protein, lactate, and oligoclonal bands, as well as intrathecal production of immunoglobulins and CSF/serum quotients for albumin, immunoglobulins, and glucose. In addition, in a subcohort of these patients, we performed ex vivo immunophenotyping of CSF-infiltrating and paired circulating lymphocytes using a panel of 13 monoclonal antibodies, we quantified intrathecal neurofilament light chain (NF-L) and chitinase 3-like 1 (CHI3L1), and we performed intrathecal lipidomic analysis. RESULTS: Patients with MS with abnormal high levels of albumin in the CSF showed a distinct CSF cell infiltrate and markers of CNS damage such as increased intrathecal levels of NF-L and CHI3L1 as well as a distinct CSF lipidomic profile. In addition, these patients showed higher numbers of circulating proinflammatory Th1 and Th1* cells compatible with systemic inflammation. Of interest, the abnormally high levels of albumin in the CSF of those patients were preserved over time. CONCLUSIONS: Our results support the hypothesis that CNS damage may increase BBB vulnerability to systemic inflammation in a subset of patients and thus contribute to disease heterogeneity.

Anti-IgLON5 Disease: A New Bulbar-Onset Motor Neuron Mimic Syndrome.

OBJECTIVE: To expand the spectrum of anti-IgLON5 disease by adding 5 novel anti-IgLON5-seropositive cases with bulbar motor neuron disease-like phenotype. METHODS: We characterized the clinical course, brain MRI and laboratory findings, and therapy response in these 5 patients. RESULTS: Patients were severely affected by bulbar impairment and its respiratory consequences. Sleep-related breathing disorders and parasomnias were common. All patients showed clinical or electrophysiologic signs of motor neuron disease without fulfilling the diagnostic criteria for amyotrophic lateral sclerosis. One patient regained autonomy in swallowing and eating, possibly related to immunotherapy. CONCLUSION: IgLON5 disease is an important differential diagnosis to evaluate in patients with bulbar motor neuron disease-like phenotype and sleep disorders. There is need for a deeper understanding of the underlying pathobiology to determine whether IgLON5 disease is an immunotherapy-responsive condition.

Benralizumab in eosinophilic granulomatosis with polyangiitis complicated by Staphylococcus aureus sepsis.

Eosinophilic Granulomatosis with Polyangiitis (EGPA) is an ANCA-associated small-vessels vasculitis characterized by hypereosinophilia and eosinophilic asthma. EGPA with life-threatening organ involvement, particularly cardiac and central nervous system (CNS), is a medical emergency requiring immediate immunosuppression. We describe a 58-year-old patient with a history of chronic rhinosinusitis and eosinophilic asthma, who presented with fever, hypereosinophilia and systemic inflammation. Diagnostic workup identified a cardiac mass, CNS vasculitis, CNS embolization and Staphylococcus aureus in blood cultures. Due to rapid normalization of blood cultures, the intracardiac mass was not considered as primarily infective. Active EGPA with cardiac and CNS involvement complicated by a secondary S. aureus sepsis was diagnosed. In order to not negatively impact antibacterial immunity in active EGPA, antibiotic therapy was combined with Benralizumab, which was well tolerated and EGPA resolved rapidly. Benralizumab could serve as a therapeutic option for eosinophil-mediated pathologies in severely ill patients where immunosuppressives are initially contraindicated.

Mechanistic and Biomarker Studies to Demonstrate Immune Tolerance in Multiple Sclerosis.

The induction of specific immunological tolerance represents an important therapeutic goal for multiple sclerosis and other autoimmune diseases. Sound knowledge of the target antigens, the underlying pathomechanisms of the disease and the presumed mechanisms of action of the respective tolerance-inducing approach are essential for successful translation. Furthermore, suitable tools and assays to evaluate the induction of immune tolerance are key aspects for the development of such treatments. However, investigation of the mechanisms of action underlying tolerance induction poses several challenges. The optimization of sensitive, robust methods which allow the assessment of low frequency autoreactive T cells and the long-term reduction or change of their responses, the detection of regulatory cell populations and their immune mediators, as well as the validation of specific biomarkers indicating reduction of inflammation and damage, are needed to develop tolerance-inducing approaches successfully to patients. This short review focuses on how to demonstrate mechanistic proof-of-concept in antigen-specific tolerance-inducing therapies in MS.

Large and Small Cerebral Vessel Involvement in Severe COVID-19: Detailed Clinical Workup of a Case Series.

BACKGROUND AND PURPOSE: Case series indicating cerebrovascular disorders in coronavirus disease 2019 (COVID-19) have been published. Comprehensive workups, including clinical characteristics, laboratory, electroencephalography, neuroimaging, and cerebrospinal fluid findings, are needed to understand the mechanisms. METHODS: We evaluated 32 consecutive critically ill patients with COVID-19 treated at a tertiary care center from March 9 to April 3, 2020, for concomitant severe central nervous system involvement. Patients identified underwent computed tomography, magnetic resonance imaging, electroencephalography, cerebrospinal fluid analysis, and autopsy in case of death. RESULTS: Of 32 critically ill patients with COVID-19, 8 (25%) had severe central nervous system involvement. Two presented with lacunar ischemic stroke in the early phase and 6 with prolonged impaired consciousness after termination of analgosedation. In all but one with delayed wake-up, neuroimaging or autopsy showed multiple cerebral microbleeds, in 3 with additional subarachnoid hemorrhage and in 2 with additional small ischemic lesions. In 3 patients, intracranial vessel wall sequence magnetic resonance imaging was performed for the first time to our knowledge. All showed contrast enhancement of vessel walls in large cerebral arteries, suggesting vascular wall pathologies with an inflammatory component. Reverse transcription-polymerase chain reactions for SARS-CoV-2 in cerebrospinal fluid were all negative. No intrathecal SARS-CoV-2-specific IgG synthesis was detectable. CONCLUSIONS: Different mechanisms of cerebrovascular disorders might be involved in COVID-19. Acute ischemic stroke might occur early. In a later phase, microinfarctions and vessel wall contrast enhancement occur, indicating small and large cerebral vessels involvement. Central nervous system disorders associated with COVID-19 may lead to long-term disabilities. Mechanisms should be urgently investigated to develop neuroprotective strategies.

HLA-DR15 Molecules Jointly Shape an Autoreactive T Cell Repertoire in Multiple Sclerosis.

The HLA-DR15 haplotype is the strongest genetic risk factor for multiple sclerosis (MS), but our understanding of how it contributes to MS is limited. Because autoreactive CD4+ T cells and B cells as antigen-presenting cells are involved in MS pathogenesis, we characterized the immunopeptidomes of the two HLA-DR15 allomorphs DR2a and DR2b of human primary B cells and monocytes, thymus, and MS brain tissue. Self-peptides from HLA-DR molecules, particularly from DR2a and DR2b themselves, are abundant on B cells and thymic antigen-presenting cells. Furthermore, we identified autoreactive CD4+ T cell clones that can cross-react with HLA-DR-derived self-peptides (HLA-DR-SPs), peptides from MS-associated foreign agents (Epstein-Barr virus and Akkermansia muciniphila), and autoantigens presented by DR2a and DR2b. Thus, both HLA-DR15 allomorphs jointly shape an autoreactive T cell repertoire by serving as antigen-presenting structures and epitope sources and by presenting the same foreign peptides and autoantigens to autoreactive CD4+ T cells in MS.

Comparative Analysis of T-Cell Responses to Aquaporin-4 and Myelin Oligodendrocyte Glycoprotein in Inflammatory Demyelinating Central Nervous System Diseases.

Autoantibodies against aquaporin-4 (AQP4-Ab) and myelin oligodendrocyte glycoprotein (MOG-Ab) are associated with rare central nervous system inflammatory demyelinating diseases like neuromyelitis optica spectrum disorders (NMOSD). Previous studies have shown that not only antibodies, but also autoreactive T-cell responses against AQP4 are present in NMOSD. However, no study has yet analyzed the presence of MOG reactive T-cells in patients with MOG antibodies. Therefore, we compared AQP4 and MOG specific peripheral T-cell response in individuals with AQP4-Ab (n = 8), MOG-Ab (n = 10), multiple sclerosis (MS, n = 8), and healthy controls (HC, n = 14). Peripheral blood mononuclear cell cultures were stimulated with eight AQP4 and nine MOG peptides selected from previous studies and a tetanus toxoid peptide mix as a positive control. Antigen-specific T-cell responses were assessed using the carboxyfluorescein diacetate succinimidyl ester proliferation assay and the detection of granulocyte macrophage colony-stimulating factor (GM-CSF), interferon (IFN)-ɤ and interleukin (IL)-4, IL-6, and IL-17A in cell culture supernatants. Additionally, human leukocyte antigen (HLA)-DQ and HLA-DR genotyping of all participants was performed. We classified a T-cell response as positive if proliferation (measured by a cell division index ≥3) was confirmed by the secretion of at least one cytokine. Reactivity against AQP4 peptides was observed in many groups, but the T-cell response against AQP4 p156-170 was present only in patients with AQP4-Ab (4/8, 50%) and absent in patients with MOG-Ab, MS and HC (corrected p = 0.02). This AQP4 p156-170 peptide specific T-cell response was significantly increased in participants with AQP4-Ab compared to those without [Odds ratio (OR) = 59.00, 95% confidence interval-CI 2.70-1,290.86]. Moreover, T-cell responses against at least one AQP4 peptide were also more frequent in participants with AQP4-Ab (OR = 11.45, 95% CI 1.24-106.05). We did not observe any significant differences for the other AQP4 peptides or any MOG peptide. AQP4-Ab were associated with HLA DQB1*02 (OR = 5.71, 95% CI 1.09-30.07), DRB1*01 (OR = 9.33, 95% CI 1.50-58.02) and DRB1*03 (OR = 6.75, 95% CI = 1.19-38.41). Furthermore, HLA DRB1*01 was also associated with the presence of AQP4 p156-170 reactive T-cells (OR = 31.67, 95% CI 1.30-772.98). To summarize, our findings suggest a role of AQP4-specific, but not MOG-specific T-cells, in NMOSD.