B- and T cell receptor sequencing elucidates characteristics of lymphocyte depletion by ocrelizumab.

Ocrelizumab therapy depletes circulating CD20 lymphocytes. To characterize adaptive immune changes, we analyzed blood B- and T cell receptor repertoires of 35 multiple sclerosis (MS) patients before and alongside ocrelizumab therapy, compared to 11 healthy donors and 14 MS patients alongside natalizumab therapy, as well as cerebrospinal fluid and blood single-cell transcriptomics of 29 donors. Tissue-resident memory cells in cerebrospinal fluid revealed gene expression and initial therapy-resistance.

Cerebrospinal 14-3-3 Protein Levels as a Neuroaxonal Biomarker in Aquaporin-4 Antibody-Positive Neuromyelitis Optica Spectrum Disorder.

Background And Objectives: To investigate whether CSF 14-3-3 protein levels discriminate aquaporin-4 antibody-positive neuromyelitis optica spectrum disorder (AQP4-NMOSD) from myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) and multiple sclerosis (MS) and the association of CSF 14-3-3 protein levels with clinical features in patients with AQP4-NMOSD.

Methods: This was a multicentric retrospective cohort study of patients with AQP4-NMOSD, MOGAD, and MS, with available CSF samples. 14-3-3 protein levels were quantified using ELISA and compared between the 3 conditions.

Complement activation profiles in patients with immune checkpoint inhibitor-associated neuromuscular immune-related adverse events.

Background: Immune-related neuropathy (irNeuropathy) and myositis (irMyositis) are the most common neurologic adverse events (irAE-n) associated with immune checkpoint inhibitors. Although case reports suggest benefits of complement inhibitors, the role of complement activation in irAE-n is understudied.

Methods: In a retrospective multicenter study, we enrolled patients with irNeuropathy or irMyositis, cancer controls (CCs), and healthy controls (HCs).

Prognostic Factors for Multiple Sclerosis Symptoms in Radiologically Isolated Syndrome.

Importance: Understanding the risk factors for symptom development will allow clinicians to stratify people with radiologically isolated syndrome (pwRIS) more effectively and tailor their management strategies accordingly.

Objective: To identify prognostic factors at radiologically isolated syndrome (RIS) diagnosis associated with the development of multiple sclerosis (MS) symptoms.

Design, Setting, And Participants: This cohort study was performed in samples collected between July 2004 and September 2022 and included 33 MS centers.

ATG5 controls CD80 expression in B cells and shapes cognate CD4 T cell responses.

The macroautophagy/autophagy machinery has been implicated in supporting MHC class II but compromising MHC class I restricted antigen presentation by dendritic cells (DCs). Here, we report that loss of the essential autophagy protein ATG5 in B cells reduces internalization and stabilizes co-stimulatory CD80 surface expression. In an adjuvant-free experimental autoimmune encephalomyelitis (EAE) mouse model, co-transfer of MOG-specific induced germinal center B (iGB) cells deficient in ATG5 with MOG-specific CD4 T cells, accelerated disease development.

Suboptimal B-cell depletion is associated with progression independent of relapse activity in multiple sclerosis patients treated with ocrelizumab.

Background: While treatment with ocrelizumab has proven effective in preventing relapse-associated worsening (RAW) in relapsing multiple sclerosis (RMS), a significant number of patients experience progression independent of relapse activity (PIRA).

Objectives: To investigate the association between B-cell depletion status and the risk of disability accumulation in RMS patients receiving ocrelizumab treatment.

Methods: In this monocentric cohort study of 148 RMS patients (2017-2023), we categorized participants into three groups: no evidence of disease activity (NEDA), evidence of disease activity (EDA), and PIRA.

Single-Cell Transcriptomics Identifies a Prominent Role for the MIF-CD74 Axis in Myasthenia Gravis Thymus.

Background And Objectives: Myasthenia gravis (MG) is an autoimmune disease most frequently caused by autoantibodies (auto-Abs) against the acetylcholine receptor (AChR) located at the neuromuscular junction. Thymic follicular hyperplasia is present in most of the patients with early-onset AChR-Ab MG (EOMG), but its cellular and molecular drivers and development remain poorly understood.

Methods: We constructed a single cell-based transcriptional profile of lymphoid cell types in thymi from 11 immunotherapy-naïve patients with EOMG.

EBV-specific T-cell immunity: relevance for multiple sclerosis.

Genetic and environmental factors jointly determine the susceptibility to develop multiple sclerosis (MS). Improvements in the design of epidemiological studies have helped to identify consistent environmental risk associations such as the increased susceptibility for MS following Epstein-Barr virus (EBV) infection, while biological mechanisms that drive the association between EBV and MS remain incompletely understood. An increased and broadened repertoire of antibody and T-cell immune responses to EBV-encoded antigens, especially to the dominant CD4 T-cell EBV nuclear antigen 1 (EBNA1), is consistently observed in patients with MS, indicating that protective EBV-specific immune responses are deregulated in MS and potentially contribute to disease development.

De-escalating and discontinuing disease-modifying therapies in multiple sclerosis.

The development of disease-modifying therapies (DMTs) for the treatment of multiple sclerosis (MS) has been highly successful in recent decades. It is now widely accepted that early initiation of DMTs after disease onset is associated with a better long-term prognosis. However, the question of when and how to de-escalate or discontinue DMTs remains open and critical.

Increased EBNA1-specific antibody response in primary-progressive multiple sclerosis.

Background And Objectives: The impact of viral infections on disease susceptibility and progression has predominantly been studied in patients with relapse-onset MS (RMS). Here, we determined immune responses to ubiquitous viruses in patients with primary progressive MS (PPMS).

Methods: Antibody responses to Epstein-Barr virus (EBV), specifically to the latent EBV nuclear antigen 1 and the lytic viral capsid antigen VCA, human herpesvirus 6 (HHV-6), human cytomegalovirus (HCMV), and measles virus were determined in a cohort of 68 PPMS patients with a mean follow-up of 8 years and compared with 66 healthy controls matched for sex and age.

Complement Activation Profiles Predict Clinical Outcomes in Myelin Oligodendrocyte Glycoprotein Antibody-Associated Disease.

Background And Objectives: The role of the complement system in myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD) is not completely understood, and studies exploring its potential utility for diagnosis and prognosis are lacking. We aimed to investigate the value of complement factors (CFs) as diagnostic and prognostic biomarkers in patients with MOGAD.

Methods: Multicentric retrospective cohort study including patients with MOGAD, multiple sclerosis (MS) and aquaporin-4 seropositive neuromyelitis optica spectrum disorder (AQP4-NMOSD) with available paired serum and CSF samples.

Ravulizumab and Efgartigimod in Myasthenia Gravis: A Real-World Study.

Background And Objectives: Biologics that target pathogenic antibodies (Abs) and their effector functions such as the complement inhibitor ravulizumab and the neonatal Fc receptor agonist efgartigimod have recently been approved for the treatment of acetylcholine receptor (AChR)-Ab-positive myasthenia gravis (MG), but comparative studies are lacking.

Methods: In a prospective, exploratory real-world study, we assessed clinical efficacy, safety, and biological effects of ravulizumab and efgartigimod treatment initiation. Myasthenia Gravis-Activities of Daily Living and Quantitative Myasthenia Gravis scores were used as clinical endpoints.

Cytomegalovirus immune responses are associated with lower serum NfL and disability accumulation risk at multiple sclerosis onset.

Background: Infection by cytomegalovirus (HCMV) and Epstein-Barr virus (EBV) play a prognostic role in multiple sclerosis (MS).

Objectives: To explore whether humoral immune responses to HCMV and EBV at disease onset were associated with changes in serum and cerebrospinal fluid (CSF) levels of inflammatory and neurodegeneration biomarkers.

Methods: Ninety-eight MS patients with a median follow-up of 20 years were included in the study.

Association of Complement Factors With Disability Progression in Primary Progressive Multiple Sclerosis.

Background And Objectives: The complement system is known to play a role in multiple sclerosis (MS) pathogenesis. However, its contribution to disease progression remains elusive. The study investigated the role of the complement system in disability progression of patients with primary progressive MS (PPMS).

Fatigue and associated factors in myasthenia gravis: a nationwide registry study.

Fatigue is commonly associated with myasthenia gravis (MG), but factors contributing to fatigue development in MG are incompletely understood. This nationwide cross-sectional registry study included 1464 patients diagnosed with autoimmune MG, recruited between February 2019 and April 2023. Frequency and severity of fatigue was assessed at study inclusion using the patient-reported Chalder Fatigue Questionnaire (CFQ).

Functional Signature of LRP4 Antibodies in Myasthenia Gravis.

Background And Objectives: Antibodies (Abs) specific for the low-density lipoprotein receptor-related protein 4 (LRP4) occur in up to 5% of patients with myasthenia gravis (MG). The objective of this study was to profile LRP4-Ab effector actions.

Methods: We evaluated the efficacy of LRP4-specific compared with AChR-specific IgG to induce Ab-dependent cellular phagocytosis (ADCP), Ab-dependent cellular cytotoxicity (ADCC), and Ab-dependent complement deposition (ADCD).

Single-cell profiling reveals preferential reduction of memory B cell subsets in cladribine patients that correlates with treatment response.

Background: Cladribine is a highly effective immunotherapy that is applied in two short-term courses over 2 years and reduces relapse rate and disease progression in patients with relapsing multiple sclerosis (MS). Despite the short treatment period, cladribine has a long-lasting effect on disease activity even after recovery of lymphocyte counts, suggesting a yet undefined long-term immune modulating effect.

Objectives: Our aim was to provide a more profound understanding of the detailed effects of cladribine, also with regard to the patients' therapy response.