Conventional CSF markers often fail to distinguish immune-mediated neurologic disorders (IMNDs) from non-immune-mediated neurologic disorders (N-IMNDs). We performed multiparametric flow cytometric profiling of CSF T-cell developmental subsets in 37 IMND patients and 10 N-IMND controls to identify IMND-associated T-cell signatures. CSF CD8+ T-cells were detectable in 86% (32/37) of IMND patients versus 0% (0/10) of N-IMND controls (Padj < .001). Among CD8+ T-cell-positive IMND cases, effector memory (CD45RA-CCR7-, median, 65.0%; IQR, 45.5%-73.5%) and terminally differentiated effector memory T-cells (TEMRA, CD45RA+CCR7-, median, 35.0%; IQR, 0%-49.5%) predominated. Hierarchical clustering demonstrated significant separation between IMND and N-IMND driven by CD8+ T-cell subset profiles (R2 = 0.165, P = .001), whereas CD4+ T-cell subsets showed no disease-associated clustering. Paired blood-CSF analysis in 6 treatment-naïve IMND patients revealed compartmentalized enrichment of CD8+ effector memory (blood median 19.2%; IQR, 6.4%-26.9%; CSF median 47.3%; IQR, 42.2%-53.7%; P = .031), confirming CNS-restricted CD8+ T-cell activation. These findings identify CSF CD8+ effector memory profiles as a potential biomarker distinguishing IMNDs from N-IMNDs that may complement conventional biomarkers for CNS autoimmunity.

We present a formalism of a neural network encoding of bonded interactions in molecules. This intramolecular encoding is consistent with models of intermolecular interactions previously designed by this group. Variants of the encoding fed into a corresponding neural network may be used to economically improve representation of torsional degrees of freedom in any force field. We test the accuracy of the reproduction of the ab initio potential energy surface on a set of conformations of two dipeptides - methyl-capped ALA and ASP - in several scenarios. The encoding, either alone or in conjunction with an analytical potential, improves agreement with ab initio energies on par with that of other neural network-based potentials. Using the encoding and neural nets in tandem with an analytical model places the agreements firmly within ‘chemical accuracy’ of ± 0.5 kcal/mol.

Importance:Biomarkers distinguishing nonrelapsing progressive disease biology from relapsing biology in multiple sclerosis (MS) are lacking. Cerebrospinal fluid (CSF) is an accessible fluid that most closely reflects central nervous system biology. Objective:To identify CSF biological measures associated with progressive MS pathobiology. Design, Setting, and Participants:This cohort study assessed data from 2 prospective MS cohorts: a test cohort provided serial CSF, clinical, and imaging assessments in a multicenter study of patients with relapsing MS (RMS) or primary progressive MS (PPMS) who were initiating anti-CD20 treatment (recruitment: 2016-2018; analysis: 2020-2023). A single-site confirmation cohort was used to assess CSF at baseline and long-term (>10 year) clinical follow-up (analysis: 2022-2023). Exposures:Test-cohort participants initiated standard-of-care ocrelizumab treatment. Confirmation-cohort participants were untreated or received standard-of-care disease-modifying MS therapies. Main Outcomes and Measures:Twenty-five CSF markers, including neurofilament light chain, neurofilament heavy chain, and glial fibrillary acid protein (GFAP); 24-week confirmed disability progression (CDP24); and brain magnetic resonance imaging measures reflecting focal injury, tissue loss, and progressive biology (slowly expanding lesions [SELs]). Results:The test cohort (n = 131) included 100 patients with RMS (mean [SD] age, 36.6 [10.4] years; 68 [68%] female and 32 [32%] male; Expanded Disability Status Scale [EDSS] score, 0-5.5), and 31 patients with PPMS (mean [SD] age, 44.9 [7.4] years; 15 [48%] female and 16 [52%] male; EDSS score, 3.0-6.5). The confirmation cohort (n = 68) included 41 patients with RMS and 27 with PPMS enrolled at diagnosis (age, 40 years [range, 20-61 years]; 47 [69%] female and 21 [31%] male). In the test cohort, GFAP was correlated with SEL count (r = 0.33), greater proportion of T2 lesion volume from SELs (r = 0.24), and lower T1-weighted intensity within SELs (r = -0.33) but not with acute inflammatory measures. Neurofilament heavy chain was correlated with SEL count (r = 0.25) and lower T1-weighted intensity within SELs (r = -0.28). Immune markers correlated with measures of acute inflammation and, unlike GFAP, were impacted by anti-CD20. In the confirmation cohort, higher baseline CSF GFAP levels were associated with long-term CDP24 (hazard ratio, 2.1; 95% CI, 1.3-3.4; P = .002). Conclusions and Relevance:In this study, activated glial markers (in particular GFAP) and neurofilament heavy chain were associated specifically with nonrelapsing progressive disease outcomes (independent of acute inflammatory activity). Elevated CSF GFAP was associated with long-term MS disease progression.

We model the auto-ionization of water by determining the free energy of hydration of the major intermediate species of water ions. We represent the smallest ions - the hydroxide ion OH- , the hydronium ion H3O+, and the Zundel ion H5O2+, - by bonded models; and the more extended ionic structures by strong non-bonded interactions (e.g. the Eigen H9O4+ = H3O+ +3(H2O) and the Stoyanov H13O6+ = H5O2+ + 4(H2O)). Our models are faithful to the precise QM energies and their components to within 1% or less. Using the calculated free energies and atomization energies, we compute the pKa of pure water from first principles as a consistency check, and arrive at a value within 1.3 log units of the experimental one. From these calculations we conclude that the hydronium ion, and its hydrated state, the Eigen cation, are the dominant species in the water auto-ionization process.

We incorporate nuclear quantum effects (NQE) in condensed matter simulations by introducing short-range neural network (NN) corrections to the ab initio fitted molecular force field ARROW. Force field NN corrections are fitted to average interaction energies and forces of molecular dimers, which are simulated using the Path Integral Molecular Dynamics (PIMD) technique with restrained centroid positions. The NN-corrected force field allows reproduction of the NQE for computed liquid water and methane properties such as density, radial distribution function (RDF), heat of evaporation (HVAP), and solvation free energy. Accounting for NQE through molecular force field corrections circumvents the need for explicit computationally expensive PIMD simulations in accurate calculations of the properties of chemical and biological systems. The accuracy and locality of pairwise NN NQE corrections indicate that this approach could be applicable to complex heterogeneous systems, such as proteins.

Background and Objectives Neuromyelitis optica spectrum disorder (NMOSD) is a chronic CNS demyelinating autoimmune disorder targeting the astrocyte antigen aquaporin-4 (AQP4), typically presenting with optic neuritis, transverse myelitis, and brain syndromes. Cognitive dysfunction (CD) in NMOSD is under-recognized and poorly understood. The purpose of this study was to evaluate the prevalence and clinical variables associated with CD in NMOSD.Methods This observational retrtive study with longitudinal follow-up describes a clinical cohort seen in the Collaborative International Research in Clinical and Longitudinal Experience Study in NMOSD. Serial Montreal Cognitive Assessments (MoCAs) were performed upon enrollment and at 6-month intervals to evaluate longitudinal cognitive function relative to demographic and disease-related factors. We used 2-tailed t test, analysis of variance, the chi(2) test, linear regression for univariable and adjusted analyses and simultaneous linear regression and mixed-effects model for multivariable analyses.Results Thirty-four percent (75/219) of patients met criteria for CD (MoCA <26); 29% (64/219) showed mild dysfunction (MoCA 20-26/30), and 5% (11/219) showed moderate (MoCA <20/30) dysfunction. Patients with less neurologic disability and lower pain scores had higher MoCA scores (95% CI 0.24-0.65 and 95% CI 0.09-0.42, respectively). Patients with at least high school education scored higher on the MoCA (95% CI 2.2-5). When comparing patients dichotomized for CD, patients never on rituximab scored higher than patients only treated with rituximab (p < 0.029). There was no significant association between annualized relapse rate, age, sex, disease duration, AQP4 serostatus or brain lesions, and CD. CD was more pronounced among Black than White patients (95% CI -2.7 to -0.7). Multivariable analysis of serial MoCA did not indicate change (p = 0.715). Descriptive analysis of serial MoCA showed 30% (45/150) of patients with worsening MoCA performance had impaired language and verbal recall.Discussion To our knowledge, this is the largest study of diverse cohort to investigate CD in patients with NMOSD. Our findings demonstrate 34% of patients with NMOSD experience mild-to-moderate CD, while 30% of patients demonstrated decline on serial testing. The substantial prevalence of CD in this pilot report highlights the need for improved and validated screening tools and comprehensive measures to investigate CD in NMOSD.

To create a comprehensive, multidisciplinary biorepository of human tissue from patients with Multiple Sclerosis (MS) and related neuroimmune diseases.

Article Tools CASE REPORTS Article Tools OPTIONS & TOOLS Export Citation Track Citation Add To Favorites Rights & Permissions COMPANION ARTICLES No companion articles ARTICLE CITATION DOI: 10.1200/PO.22.00501 JCO Precision Oncology no. 7 (2023) e2200501. Published online February 1, 2023. PMID: 36724412 Progression of Mycosis Fungoides After Fingolimod Treatment for Multiple Sclerosis and Targeted Next-Generation Sequencing Demonstrating Potential Links Between the Two Diseases Saisindhu Narala , MD, MAS1,2xSaisindhu NaralaSearch for articles by this author; Yonglu Che, MD, PhD2xYonglu CheSearch for articles by this author; Atif Saleem , DO1xAtif SaleemSearch for articles by this author; Christopher B. Lock , MBBS, PhD3xChristopher B. LockSearch for articles by this author; Youn H. Kim , MD2xYoun H. KimSearch for articles by this author; and Kerri E. Rieger , MD, PhD1,2xKerri E. RiegerSearch for articles by this author Show More 1Department of Pathology, Stanford University School of Medicine, Stanford, CA2Department of Dermatology, Stanford University School of Medicine, Stanford, CA3Division of Neuroimmunology, Department of Neurology and Neurological Sciences, Stanford University School of Medicine, Stanford, CA https://doi.org/10.1200/PO.22.00501 First Page Full Text PDF Figures and Tables © 2023 by American Society of Clinical OncologySUPPORTSupported in part by the Haas Family Foundation (Y.H.K.).AUTHOR CONTRIBUTIONSConception and design: Saisindhu Narala, Youn H. Kim, Kerri E. RiegerProvision of study materials or patients: Youn H. KimCollection and assembly of data: Saisindhu Narala, Yonglu Che, Atif Saleem, Christopher B. Lock, Youn H. Kim, Kerri E. RiegerData analysis and interpretation: Saisindhu Narala, Yonglu Che, Youn H. Kim, Kerri E. RiegerManuscript writing: All authorsFinal approval of manuscript: All authorsAccountable for all aspects of the work: All authorsAUTHORS' DISCLOSURES OF POTENTIAL CONFLICTS OF INTERESTThe following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/po/author-center.Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).Christopher B. LockEmployment: NeoTxStock and Other Ownership Interests: NeoTXHonoraria: TG TherapeuticsConsulting or Advisory Role: TG Therapeutics, Diagnose EarlySpeakers' Bureau: Bristol-Myers Squibb/MedarexTravel, Accommodations, Expenses: GenentechYoun H. KimConsulting or Advisory Role: Kyowa Hakko Kirin, Innate Pharma, Corvus Pharmaceuticals, Galderma, Crispr TherapeuticsResearch Funding: Eisai (Inst), Kyowa Hakko Kirin (Inst), Innate Pharma (Inst), Elorac Pharmaceuticals (Inst), Crispr Therapeutics (Inst), Corvus Pharmaceuticals (Inst)Patents, Royalties, Other Intellectual Property: Royalty for Chapters in UpToDateTravel, Accommodations, Expenses: Innate PharmaKerri E. RiegerConsulting or Advisory Role: Kyowa Kirin International, PfizerNo other potential conflicts of interest were reported.

Objective: To investigate immune response against SARS-CoV-2 spike protein in patients treated with anti-complement therapy, Eculizumab. Background: Certain Immunomodulatory therapies used to treat autoimmune conditions attenuate immunoglobulin production following SARS CoV-2 vaccination, and may increase susceptibility to COVID-19 infections and/or COVID-19 severity. Here we studied immune response against SARS-CoV-2 vaccine in patients treated with Eculizumab, a disease modifying treatment used for multiple autoimmune conditions including Neuromyelitis Optica Spectrum Disorders (NMOSD). Design/Methods: We searched the Stanford Research Repository (STARR) database and identified 38 patients treated with eculizumab, who were tested for SARS-CoV-2-IgG and SARS-CoV-2 Interferon Gamma Release Assay (IGRA). 7/38 patients were on eculizumab at the time of vaccination against SARS-CoV-2 and testing for vaccine immunity. Results: Subjects' mean age was 49.28±18.7 years (6 females and 1 male) with average duration of eculizumab at the time of first dose of vaccine of 12.7±11.6 months, and the interval between the second dose of vaccine and testing was 7.09±6.2 months. All patients had a positive antibody response to SARS-CoV-2 spike protein IgG (100%). Only 3 patients who had IGRA tested, of which 2 were positive for IGRA (66.66%). Two out of 7 patients (28.6%) had mild lymphopenia at the time of vaccination. Our results contrast with our previously reported cohort of multiple sclerosis patients on anti-CD20 therapy who had 71% (17/24) positive SARS-CoV-2 IGRA but negative for SARS-CoV-2 IgG. These findings are explained by different mechanisms of action for these two medications. Conclusions: Based on our findings, eculizumab preserves both B and T cell immunity against SARS-CoV-2 vaccine. The clinical correlation is to be determined. Disclosure: Dr. Sattarnezhad has nothing to disclose. Miss Sumera has nothing to disclose. Dr. McDonald has nothing to disclose. An immediate family member of Dr. Nie has received personal compensation for serving as an employee of Collective Acumen . Miss Tomczak has nothing to disclose. Dr. Joseph has nothing to disclose. Dr. Kalle has nothing to disclose. Miss Sarkar has nothing to disclose. The institution of Dr. Kipp has received research support from Biogen. The institution of Dr. Kipp has received research support from Genentech. Dr. Lock has received personal compensation for serving as an employee of InterX Inc. Dr. Lock has received personal compensation for serving as an employee of Diagnose Early . Dr. Lock has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Biogen. Dr. Lock has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Sanofi . Dr. Lock has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for EMD Serono . Dr. Lock has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Alexion Pharmaceuticals. Dr. Lock has received personal compensation in the range of $500-$4,999 for serving on a Scientific Advisory or Data Safety Monitoring board for Bristol Myers Squib. Dr. Lock has received personal compensation in the range of $5,000-$9,999 for serving on a Speakers Bureau for Biogen. Dr. Lock has received personal compensation in the range of $10,000-$49,999 for serving as an Expert Witness for OGLE, WORM & TRAVIS, PLLP. Dr. Dunn has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Alexion. Dr. Dunn has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Janssen. Dr. Dunn has received personal compensation in the range of $500-$4,999 for serving as a Consultant for BMS. Dr. Dunn has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Genzyme. The institution of Dr. Dunn has received personal compensation in the range of $0-$499 for serving on a Scientific Advisory or Data Safety Monitoring board for Progentec Diagnostics. Dr. Han has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Roche. Dr. Han has received personal compensation in the range of $500-$4,999 for serving as a Consultant for Arena Pharmaceuticals.

A small proportion of multiple sclerosis (MS) patients develop new disease activity soon after starting anti-CD20 therapy. This activity does not recur with further dosing, possibly reflecting deeper depletion of CD20-expressing cells with repeat infusions. We assessed cellular immune profiles and their association with transient disease activity following anti-CD20 initiation as a window into relapsing disease biology. Peripheral blood mononuclear cells from independent discovery and validation cohorts of MS patients initiating ocrelizumab were assessed for phenotypic and functional profiles using multiparametric flow cytometry. Pretreatment CD20-expressing T cells, especially CD20 dim CD8 + T cells with a highly inflammatory and central nervous system (CNS)-homing phenotype, were significantly inversely correlated with pretreatment MRI gadolinium-lesion counts, and also predictive of early disease activity observed after anti-CD20 initiation. Direct removal of pretreatment proinflammatory CD20 dim CD8 + T cells had a greater contribution to treatment-associated changes in the CD8 + T cell pool than was the case for CD4 + T cells. Early disease activity following anti-CD20 initiation was not associated with reconstituting CD20 dim CD8 + T cells, which were less proinflammatory compared with pretreatment. Similarly, this disease activity did not correlate with early reconstituting B cells, which were predominantly transitional CD19 + CD24 high CD38 high with a more anti-inflammatory profile. We provide insights into the mode-of-action of anti-CD20 and highlight a potential role for CD20 dim CD8 + T cells in MS relapse biology; their strong inverse correlation with both pretreatment and early posttreatment disease activity suggests that CD20-expressing CD8 + T cells leaving the circulation (possibly to the CNS) play a particularly early role in the immune cascades involved in relapse development.

A key goal of molecular modeling is the accurate reproduction of the true quantum mechanical potential energy of arbitrary molecular ensembles with a tractable classical approximation. The challenges are that analytical expressions found in general purpose force fields struggle to faithfully represent the intermolecular quantum potential energy surface at close distances and in strong interaction regimes; that the more accurate neural network approximations do not capture crucial physics concepts, e.g., nonadditive inductive contributions and application of electric fields; and that the ultra-accurate narrowly targeted models have difficulty generalizing to the entire chemical space. We therefore designed a hybrid wide-coverage intermolecular interaction model consisting of an analytically polarizable force field combined with a short-range neural network correction for the total intermolecular interaction energy. Here, we describe the methodology and apply the model to accurately determine the properties of water, the free energy of solvation of neutral and charged molecules, and the binding free energy of ligands to proteins. The correction is subtyped for distinct chemical species to match the underlying force field, to segment and reduce the amount of quantum training data, and to increase accuracy and computational speed. For the systems considered, the hybrid ab initio parametrized Hamiltonian reproduces the two-body dimer quantum mechanics (QM) energies to within 0.03 kcal/mol and the nonadditive many-molecule contributions to within 2%. Simulations of molecular systems using this interaction model run at speeds of several nanoseconds per day.

To elucidate the prevalence and correlates of cognitive impairment in patients with Neuromyelitis Optica Spectrum Disorder (NMOSD).

Multiple sclerosis (MS) is a heterogenous autoimmune disease in which autoreactive lymphocytes attack the myelin sheath of the central nervous system. B lymphocytes in the cerebrospinal fluid (CSF) of patients with MS contribute to inflammation and secrete oligoclonal immunoglobulins(1,2). Epstein-Barr virus (EBV) infection has been epidemiologically linked to MS, but its pathological role remains unclear(3). Here we demonstrate high-affinity molecular mimicry between the EBV transcription factor EBV nuclear antigen 1 (EBNA1) and the central nervous system protein glial cell adhesion molecule (GlialCAM) and provide structural and in vivo functional evidence for its relevance. A cross-reactive CSF-derived antibody was initially identified by single-cell sequencing of the paired-chain B cell repertoire of MS blood and CSF, followed by protein microarray-based testing of recombinantly expressed CSF-derived antibodies against MS-associated viruses. Sequence analysis, affinity measurements and the crystal structure of the EBNA1-peptide epitope in complex with the autoreactive Fab fragment enabled tracking of the development of the naive EBNA1-restricted antibody to a mature EBNA1-GlialCAM cross-reactive antibody. Molecular mimicry is facilitated by a post-translational modification of GlialCAM. EBNA1 immunization exacerbates disease in a mouse model of MS, and anti-EBNA1 and anti-GlialCAM antibodies are prevalent in patients with MS. Our results provide a mechanistic link for the association between MS and EBV and could guide the development of new MS therapies.

To investigate interleukin-6 (IL-6) as a potential prognostic biomarker in steroid-dependent, relapsing MOG antibody disease (MOGAD).