Granzyme B + CD8 + T cells with terminal differentiated effector signature determine multiple sclerosis progression.

BACKGROUND: Multiple sclerosis (MS) leads to demyelination and neurodegeneration with autoimmune responses in central nervous system. Patients begin with a relapsing-remitting (RR) course, and more than 80% of them may advance to secondary progressive MS (SPMS), which is characteristic for the gradual decline of neurological functions without demonstrated treating method to prevent. This study aims to investigate the contribution of peripheral CD8 + T cells during the conversion from RRMS to SPMS, as well as reveal potential diagnostic signature in distinguishing SPMS. METHODS: Single-cell RNA sequencing was employed to reveal the heterogeneity of CD8 + T cells between SPMS and RRMS. In addition, flow cytometry was used to further characterized CD8 + T cell dynamic changes in patients. T cell receptor sequencing was performed to detect the clonal expansion of MS. Using Tbx21 siRNA, T-bet was confirmed to manipulate GzmB expression. The correlation between GzmB + CD8 + T cell subsets and clinical characteristics of MS and their potential diagnostic value for SPMS were evaluated by generalized linear regression models and receiver operating characteristic (ROC) curve respectively. RESULTS: Other than diminished naïve CD8 + T cell, elevating of activated CD8 + T cell subsets were observed in SPMS patients. Meanwhile, this aberrant amplified peripheral CD8 + T cells not only exhibited terminal differentiated effector (EMRA) phenotype with GzmB expression, but also possessed distinct trajectory from clonal expansion. In addition, T-bet acted as a key transcriptional factor that elicited GzmB expression in CD8 + TEMRA cells of patients with SPMS. Finally, the expression of GzmB in CD8 + T cells was positively correlated with disability and progression of MS, and could effectively distinguish SPMS from RRMS with a high accuracy. CONCLUSIONS: Our study mapped peripheral immune cells of RRMS and SPMS patients and provided an evidence for the involvement of GzmB + CD8 + TEMRA cells in the progression of MS, which could be used as a diagnostic biomarker for distinguishing SPMS from RRMS.

Brain structural and functional connectivity alterations are associated with fatigue in neuromyelitis optica spectrum disorder.

BACKGROUND: Many patients with neurological disorders experience chronic fatigue, but the neural mechanisms involved are unclear. OBJECTIVE: Here we investigated whether the brain structural and functional connectivity alterations were involved in fatigue related to neuromyelitis optica spectrum disorder (NMOSD). METHODS: This prospective pilot study used structural and resting-state functional brain magnetic resonance imaging to compare total cortical thickness, cortical surface area, deep gray matter volume and functional connectivity (FC) between 33 patients with NMOSD and 20 healthy controls (HCs). Patients were subgrouped as low fatigue (LF) and high fatigue (HF). RESULTS: HF patients scored higher on the Hamilton Anxiety Rating Scale and Hamilton Rating Scale for Depression than LF patients and HCs. The two patient subgroups and HC group did not differ significantly in cortical thickness, cortical surface area and volumes of the bilateral caudate nucleus, bilateral putamen, bilateral amygdala, bilateral hippocampus, bilateral thalamus proper or right nucleus accumbens (p > 0.05). However, after correcting for age, sex, years of education, anxiety and depression, HF patients showed larger left pallidum than HCs (0.1573 ± 0.0214 vs 0.1372 ± 0.0145, p = 0.009). Meanwhile, both LF patients (0.0377 ± 0.0052 vs 0.0417 ± 0.0052, p = 0.009) and HF patients (0.0361 ± 0.0071 vs 0.0417 ± 0.0052, p = 0.013) showed smaller left nucleus accumbens than HCs.. Compared with LF patients, HF patients showed significantly decreased FC between the left pallidum and bilateral cerebellar posterior lobes. CONCLUSIONS: This was the first evidence linking structural and functional alterations in the brain to fatigue in NMOSD, and in the future, long term follow-up was necessary.

Non-immune system comorbidity in neuromyelitis optica spectrum disorders.

Comorbidities may influence the clinical features, prognosis, and treatment outcomes of neuromyelitis optica spectrum disorders (NMOSD). The aim of this study was to determine the status of non-immune system comorbidities in patients with NMOSD and the effect on treatment response and prognosis. We retrospectively collected data from all patients who met the 2015 NMOSD diagnostic criteria from the NMOSD database established by our center. Patients were divided into positive and negative groups based on the presence of non-immune disease comorbidities. Patient data, clinical characteristics, treatment response, prognosis, and mortality were compared between the two groups. A total of 138 patients with NMOSD plus comorbidities were included, and 404 patients without comorbidities were selected as controls. The average age at onset was older (45 years vs 38 years, P < 0.001), the mean body mass index was higher (23.12 vs 22.04, P = 0.042) and more patients experienced relapse after immunotherapy (68.5 % vs 54.5 %, P = 0.020) in the comorbidity group than in the non-comorbidity group. Multifocal central nervous system lesions as an initial symptom was more common in the comorbidity group than in the non-comorbidity group (30.4 % vs 18.32 %, P = 0.003). Further, more patients experienced severe vision attacks (28.3 % vs 15.8 %, P = 0.003) and severe motor attacks (30.4 % vs 11.9 %, P < 0.001) in the comorbidity group than in the non-comorbidity group. In conclusion, patients with NMOSD with comorbidities tended to be older, less responsive to treatment, and at a higher risk of vision loss and paralysis.

Investigation on marital status of patients with neuromyelitis optica spectrum disorders in China.

BACKGROUND: Neuromyelitis optica spectrum disorders (NMOSD) may have a great impact on patients' marriage, and marital status may also affect patients' compliance and prognosis. We investigated the marital status of 494 NMOSD patients in China to explore the mutual influence between them. METHODS: A cross-sectional survey was conducted by the online questionnaires or telephone follow-up. Basic information of all respondents was analyzed from NMOSD-database of West China hospital. All 444 married respondents finished self-assessment of NMOSD's effect on marriage and over 80% of them accepted Marital Cumulative Damage Score (MCDS). RESULTS: The proportion of unmarried male patients is higher than female (23.1% vs. 9.0%), especially in youth stage (44.0% vs. 20.2%). However, the females reported bigger impacts on their marriage among married NMOSD patients (97.5% vs. 70.7%). Compared to married patients, divorced patients costed more in hospital every time (29,857.1 CNY vs. 15,577.2 CNY), received longer education (12.75 years vs. 9.36 years), had longer duration of disease (117.16 vs. 93.62 months), more relapses (5.50 vs. 3.73) and higher EDSS score (3.58 vs. 2.59). EDSS scores are associated with MCDS (R2=0.267, P<0.0001), and divorced patients have higher MCDS (P<0.01). Decreased group activities (84.1%), declined working ability (73.7%) and alienation from friends (72.54%) are the first three factors in MCDS. CONCLUSION: NMOSD exerts cumulative damage for patients' marriage, and the progression of NMOSD is more likely to lead to marital breakdown. Healthy marriage may improve the prognosis of patients by providing the psychological support and improving treatment compliance.

Myocardial Injury in Hospitalized Patients with Myasthenia Gravis.

Objective: To investigate the clinical characteristics and outcome of myocardial injury in patients with myasthenia gravis (MG). Methods: We retrospectively searched medical records to screen hospitalized patients with MG at our hospital. The troponin T (TnT) levels were deemed necessary to be performed based on the patient's clinical symptoms and were used as biomarkers of myocardial injury. The patients' demographic and clinical information were collected. Death was the primary outcome. Results: A total of 336 patients with MG measured TnT levels and were included in the final analysis. The male MG patients with elevated TnT levels had a higher prevalence of infection (56.8% vs. 30.0%, p = 0.001) and myasthenic crisis (37.5% vs. 13.3%, p = 0.001) than those with normal TnT levels. Meanwhile, the female MG patients with elevated TnT levels were older (56.0 (16.6) vs. 49.2 (17.2)) years old, p = 0.007] and had a higher prevalence of infection (65.4% vs. 32.1%, p < 0.001), myasthenic crisis (33.6% vs. 17.9%, p = 0.015), and thymoma (38.5% vs. 16.7%, p = 0.001) than those with normal TnT levels. Older age (coef. = 0.004; p = 0.034), infection (coef. = 0.240; p = 0.001), myasthenic crisis (coef. = 0.312; p < 0.001), thymoma (coef. = 0.228; p = 0.001), and ICI therapy (coef. = 1.220; p < 0.001) were independent risk predictors for increasing log TnT levels. Thirty-seven patients died during hospitalization. High log TnT levels (OR = 8.818; p < 0.001), female sex (OR = 0.346; p = 0.023), thymoma (OR = 5.092; p = 0.002), and infection (OR = 14.597; p < 0.001) were independent risk predictors of death. Conclusions: Our study revealed that the surveillance of myocardial injury biomarkers in MG patients might be beneficial.