Significance: Multiple sclerosis (MS) can transition from a relapsing-remitting form (RRMS) into a chronic progressive form (secondary progressive MS, SPMS). SPMS pathogenesis remains poorly understood with diagnosis based entirely on retrospective clinical monitoring. We show that T helper cells expressing the transcription factor Eomes (Eomes ⁺ Th cells) were significantly increased in peripheral blood from SPMS patients versus healthy subjects or RRMS and other progressive MS patients. Moreover, Eomes ⁺ Th cells expressing granzyme B were found infiltrating brain tissues in SPMS autopsy samples, providing support for a pathogenic role. Analysis of clinical status on follow-up indicated the value of measuring Eomes ⁺ Th cells for SPMS diagnosis and prognostic monitoring. This study may contribute to future development of biomarker-assisted “precision medicine” for MS.

Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a debilitating condition characterized by fatigue and post-exertional malaise, accompanied by various signs of neurological and autonomic dysfunction. ME/CFS is often triggered by an infectious episode and associated with an aberrant immune system. Here we report that ME/CFS is a disorder characterized by skewed B cell receptor gene usage. By applying a next-generation sequencing to determine the clone-based IGHV/IGHD/IGHJ repertoires, we revealed a biased usage of several IGHV genes in peripheral blood B cells from ME/CFS patients. Results of receiver operating characteristic (ROC) analysis further indicated a possibility of distinguishing patients from healthy controls, based on the skewed B cell repertoire. Meanwhile, B cell clones using IGHV3-30 and IGHV3-30-3 genes were more frequent in patients with an obvious infection-related episode at onset, and correlated to expression levels of interferon response genes in plasmablasts. Collectively, these results imply that B cell responses in ME/CFS are directed against an infectious agents or priming antigens induced before disease onset.

Neuromyelitis optica (NMO) is an autoimmune astrocytopathy mediated by anti-AQP4 antibody-producing B cells. Recently, a B-cell subset highly expressing CD11c and T-bet, originally identified as age-associated B cells, has been shown to be involved in the pathogenesis of various autoimmune diseases. The objective of this study was to determine the relationship between the frequency of CD11c^high B cells per CD19⁺ B cells in the peripheral blood of patients with NMO and the clinical profiles including the brain volume. In this observational study, 45 patients with anti-AQP4 antibody-positive NMO in remission and 30 healthy control subjects (HCs) were enrolled. Freshly isolated peripheral blood mononuclear cells were analyzed for immune cell phenotypes. The frequency of CD11c^high B cells per CD19⁺ B cells was assessed by flow cytometry and was evaluated in association with the clinical profiles of patients. Brain MRI data from 26 patients were included in the study for the analysis on the correlation between CD11c^high B-cell frequency and brain atrophy. We found that the frequency of CD11c^high B cells in CD19⁺ B cells was significantly increased in patients with NMO compared with HCs. The expansion of CD11c^high B cells significantly correlated with EDSS, past relapse numbers, and disease duration. In addition, a higher frequency of CD11c^high B cells negatively correlated with total brain, white matter, and gray matter volumes and positively correlated with T2/FLAIR high lesion volumes. When the past clinical relapse episodes of patients with or without the expansion of CD11c^high B cells were compared, relapses in the brain occurred more frequently in patients with CD11c^high B-cell expansion. CD11c^high B cells had distinct features including expression of chemokine receptors associated with migration into peripheral inflammatory tissues and antigen presentation. CD11c^high B-cell frequency was positively correlated with T peripheral helper-1 (Tph-1) cell frequency. Even during the relapse-free period, CD11c^high B cells could expand in the long disease context, possibly through the interaction with Tph-1 cells. The increased frequency of CD11c^high B cells associated with brain atrophy and disease severity, indicating that this cell population could be involved in chronic neuroinflammation in NMO.

Pathogenic T helper cells (Th cells) that respond to self‐antigen cannot be easily distinguished from beneficial Th cells. These cells can generate systemic autoimmune disease in response to widely expressed self‐antigens. In this study, we have identified neuropilin‐1 (NRP1) as a cell surface marker of self‐reactive Th cells. NRP1⁺ Th cells, absent in non‐regulatory T cell subsets in normal mice, appeared in models of systemic autoimmune disease and strongly correlated with disease symptoms. NRP1⁺ Th cells were greatly reduced in Nr4a2 cKO mice, which have reduced self‐reactive responses but showed normal responses against exogenous antigens. Transfer of NRP1⁺ Th cells was sufficient to initiate or accelerate systemic autoimmune disease, and targeting NRP1‐expressing Th cells therapeutically ameliorated SLE‐like autoimmune symptoms in BXSB‐Yaa mice. Peripheral NRP1⁺ Th cells were significantly increased in human SLE patients. Our data suggest that self‐reactive Th cells can be phenotypically distinguished within the Th cell pool. These findings offer a novel approach to identify self‐reactive Th cells and target them to treat systemic autoimmune disease.

Early cognitive impairment (CI) detection is crucial in multiple sclerosis (MS). However, it can progress silently regardless of relapse activity and reach an advanced stage. We aimed to determine whether the corpus callosum area (CCA) is a sensitive and feasible marker for CI in MS compared to other neuroimaging markers. We assessed cognitive function in 77 MS patients using the Symbol Digit Modalities Test, Paced Auditory Serial Additions Task, Wechsler Adult Intelligence Scale-IV, and Wechsler Memory Scale-Revised. The neuroimaging markers included manually measured CCA, two diffusion tensor imaging markers, and nine volumetric measurements. Apart from volumes of the hippocampus and cerebellum, ten markers showed a significant correlation with all neuropsychological tests and significant differences between the groups. The normalized CCA demonstrated a moderate-to-strong correlation with all neuropsychological tests and successfully differentiated between the CI and cognitively normal groups with 80% sensitivity and 83% specificity. The marker had a large area under the curve and a high Youden index (0.82 and 0.63, respectively) and comparability with established cognitive markers. Therefore, the normalized CCA may serve as a reliable marker for CI in MS and can be easily implemented in clinical practice, providing a supportive diagnostic tool for CI in MS.