IL-37 Represses the Autoimmunity in Myasthenia Gravis via Directly Targeting Follicular Th and B Cells.

IL-37 is a newly identified immune-suppressive factor; however, the function, cellular sources, and mechanism of IL-37 in humoral immunity and Myasthenia gravis (MG) are still unclear. In this study, we found IL-37 were substantially downregulated in the serum and PBMCs of MG patients compared with healthy controls. The lower IL-37 was associated with severer disease (quantitative MG score) and higher follicular Th (Tfh)/Tfh17 and B cell numbers. Flow cytometry analysis revealed that IL-37 was mainly produced by CD4+ T cells without overlapping with Th1, Th17, and Tfh subsets in MG patients. Regulatory IL-37+ T cell rarely expressed Foxp3 and CD25 but produced numerous IL-4. Tfh and B cell expressed high levels of SIGIRR, the receptor of IL-37, in MG patients. Mechanically, IL-37 directly bond to SIGIRR, repressed the proliferation, cytokine production of Tfh and B cells, and the secretion of autoantibody via inhibition of STAT3 signaling in Tfh and B cells.

Human Umbilical Cord Mesenchymal Stem Cells Protect Against SCA3 by Modulating the Level of 70 kD Heat Shock Protein.

Spinocerebellar ataxia 3 (SCA3), which is a progressive neurodegenerative disease, is currently incurable. Emerging studies have reported that human umbilical cord mesenchymal stem cells (HUC-MSCs) transplantation could be a promising therapeutic strategy for cerebellar ataxias. However, few studies have evaluated the effects of HUC-MSCs on SCA3 transgenic mouse. Thus, we investigated the effects of HUC-MSCs on SCA3 mice and the underlying mechanisms in this study. SCA3 transgenic mice received systematic administration of 2 × 106 HUC-MSCs once per week for 12 continuous weeks. Motor coordination was measured blindly by open field tests and footprint tests. Immunohistochemistry and Nissl staining were applied to detect neuropathological alternations. Neurotrophic factors in the cerebellum were assessed by ELISA. We used western blotting to detect the alternations of heat shock protein 70 (HSP70), IGF-1, mutant ataxin-3, and apoptosis-associated proteins. Tunel staining was also used to detect apoptosis of affected cells. The distribution and differentiation of HUC-MSCs were determined by immunofluorescence. Our results exhibited that HUC-MSCs transplantation significantly alleviated motor impairments, corresponding to a reduction of cerebellar atrophy, preservation of neurons, decreased expression of mutant ataxin-3, and increased expression of HSP70. Implanted HUC-MSCs were mainly distributed in the cerebellum and pons with no obvious differentiation, and the expressions of IGF-1, VEGF, and NGF in the cerebellum were significantly elevated. Furthermore, with the use of HSP70 analogy quercetin injection, it demonstrated that HSP70 is involved in mutant ataxin-3 reduction. These results showed that HUC-MSCs implantation is a potential treatment for SCA3, likely through upregulating the IGF-1/HSP70 pathway and subsequently inhibiting mutant ataxin-3 toxicity.

Dyslipidaemia was correlated to the posterior circulation infarction in non-diabetic populations.

BACKGROUND: Diabetes mellitus (DM) was prone to happening in posterior circulation infarction (POCI) and DM also has the impact on the lipids, our study was to investigate the correlation between lipid compositions and POCI. METHODS: Data was collected from the patients with acute ischemic stroke (AIS) hospitalization in Affiliated Drum Tower Hospital of Nanjing University Medical School from October 2008 to May 2012. Lipids and other risk factors in the different populations were investigated in relation to occurrence of POCI based on the infarction location. RESULTS: Six hundred ten patients with AIS were included in this study, which had 428 with anterior circulation infarction (ACI) and 182 with POCI. Elevated Triglyceride (TG) and decreased High density lipoprotein cholesterol (HDL-C) were seen in the POCI of total populations and AIS without DM compared to the ACI, but not in the populations of AIS with DM, so did the elevated TG/HDL-C ratios. Also, the percent of low HDL-C level and high TG level were higher in POCI group than that in ACI group. Furthermore, single factors logistic regression demonstrated that TG, HDL-C and TG/HDL-C ratio were correlated to the POCI whatever in the total populations or AIS without DM, but this kind of trend just maintained in the populations of AIS without DM after adjusting by relative interference factors. CONCLUSION: Dyslipidaemia was prone to happening in POCI compared to ACI in the non-diabetic populations, which was correlated to the pathogenesis of POCI.

Enterprise stents for the treatment of symptomatic non-acute intracranial artery stenosis disease: safety and efficiency evaluation.

BACKGROUND: Enterprise stent was approved for the treatment of wide-necked intracranial aneurysms. However, it has been widely used in the endovascular treatment of intracranial artery stenosis, which is still controversial. The purpose of this study was to evaluate the safety and efficiency of the Enterprise stent in the endovascular treatment of intracranial artery stenosis disease. METHODS: We conducted a retrospective case series of 107 patients with intracranial artery stenosis who received Enterprise stent implantation at Nanjing Drum Tower Hospital from January 2020 to December 2022. The rates of recanalization, perioperative complications, in-stent restenosis at 3-12 months and stroke recurrence were assessed for endovascular treatment. RESULTS: A total of 107 individuals were included in this study, 88 were followed up, and 19 (17.8%) patients were lost to follow-up. The operation success rate was 100%, During the procedure,4（3.7%）patients had vasospasm, and 2(1.9%) patients showed symptomatic bleeding. The overall perioperative complication rate was 5.6%, including 2.8% distal artery embolism, 0.9% in-stent thrombosis, and 1.9% symptomatic bleeding. 88 (82.2%) patients were followed up from 3 to 12 months, of whom 12 (13.6%) had in-stent restenosis, 4 (4.7%) recurrent strokes and 2 died of pulmonary infection caused by COVID-19. Patients were divided into 3 groups according to the cerebral artery, including the middle cerebral artery group, internal carotid artery group, and vertebrobasilar artery group. CONCLUSIONS: In this study, the placement of the Enterprise stent in patients with symptomatic non-acute intracranial stenosis was successful. However, the occurrence of periprocedural and long-term complications after stenting remains of high concern.

Abundant infiltration of B cells and plasma cells in brain biopsy of a male patient with severe anti-NMDA receptor encephalitis: A case report.

RATIONALE: Anti-N-methyl-D-aspartate receptor (NMDAR) is the most common type of autoimmune encephalitis mediated by NMDAR antibodies. The pathological process remains unclear, especially in patients without tumors or infections. Autopsy and biopsy studies have rarely been reported because of the favorable prognosis. Pathological findings generally demonstrate mild-to-moderate inflammation. This case report presents severe anti-NMDAR encephalitis in a 43-year-old man without any identified triggers. The biopsy in this patient showed extensive inflammatory infiltration with evident B cell accumulation, which enriches the pathological study of male anti-NMDAR encephalitis patients without comorbidities. PATIENT CONCERNS: A 43-year-old previously healthy man presented with new-onset seizures with recurrent jerks. The initial autoimmune antibody test with serum and cerebrospinal fluid yielded negative results. After ineffective treatment for viral encephalitis, based on the imaging results indicating the possibility of diffuse glioma, the patient underwent a brain biopsy in the right frontal lobe to rule out malignancy. DIAGNOSIS: The immunohistochemical study showed extensive inflammatory cell infiltration, consistent with the pathological changes in encephalitis. Cerebrospinal fluid and serum samples were then retested and tested positive for IgG antibodies against NMDAR. Therefore, the patient was diagnosed with anti-NMDAR encephalitis. INTERVENTIONS: The patient was administered intravenous immunoglobulin (0.4 g/kg/d for 5 days), intravenous methylprednisolone (1 g/d for 5 days, 500 mg/d for 5 days, subsequently reduced to oral administration), and intravenous cyclophosphamide cycles. OUTCOMES: The patient developed refractory epilepsy 6 weeks later and required mechanical ventilation. Despite brief clinical improvement after extensive immunotherapy, the patient died from bradycardia and circulation. LESSONS: Anti-NMDAR encephalitis cannot be ruled out even if the initial autoantibody test result is negative. For progressive encephalitis of unknown etiology, it is necessary to recheck cerebrospinal fluid for anti-NMDAR antibodies.

IV/IT hUC-MSCs Infusion in RRMS and NMO: A 10-Year Follow-Up Study.

Background: Stem cell transplantation is emerging as a potential therapeutic strategy in several autoimmune diseases. However, the safety and feasibility of long-term combined intravenous (IV) and intrathecal (IT) administration of hUC-MSCs in relapse remitting multiple sclerosis (RRMS) and neuromyelitis optica (NMO) is largely unknown. Objectives: In this study, we followed up the long-term safety and feasibility of combined IV and IT human umbilical cord mesenchymal stem cells (hUC-MSCs) transplantation in patients with RRMS and NMO. Methods: Five NMO patients and 5 RRMS patients were treated intravenously (4 times) and intrathecally (3 times) over a 21-day period with low-dose allogeneic umbilical cord blood-derived MSCs. All of the patients were monitored regularly by an investigator in a blinded manner to access the Expanded Disability Status Scale, MRI characteristics, and adverse events every 3 months within 12 months and once every year thereafter for 10 years after transplantation. Results: During the long-term follow-up, our data suggested that combined IV and IT administration of hUC-MSCs transplantation is safe and feasible. None of the intolerant adverse events, such as tumor formation and peripheral organ/tissue disorders, were observed throughout the 10-year follow-up. Conclusions: These data suggest that combined intravenous and intrathecal low-dose hUC-MSCs transplantation is safe and feasible in RRMS and NMO patients in the long term. The conclusion requires confirmation by future clinical trials in a larger cohort.

A comparative study on clinical characterizations between acute myelitis onset of neuromyelitis optica spectrum disease and idiopathic transverse myelitis.

BACKGROUND/AIMS: Both of neuromyelitis optica spectrum disease (NMOSDs) and idiopathic transverse myelitis (ITM) could present as acute transverse myelitis. However, long-term immunological treatment and prognosis are different for high recurrence of NMOSDs. In this study, we summarized clinical differences between acute attack myelitis of NMOSDs and ITM, we further screened serum auto-antibodies to help understand the two distinct clinical entities. METHODS: This is a retrospective study on 48 NMOSD patients and 49 ITM patients in neurological department of Nanjing Drum Tower Hospital from 2013 to 2019. Clinical, CSF and MRI profiles on the acute episode were also compared between NMOSD patients and ITM patients. Serum AQP4 and auto-antibodies were tested. Clinical parameters were further compared between NMOSD patients with and without auto-antibodies. RESULTS: Compared with ITM patients, NMOSD patients manifested with longer vertebral segments (5.42 ± 3.17 segments vs. 2.31 ± 2.36 segments, p < 0.001), higher female/male ratio (13:3 vs. 20:29, p < 0.001), higher IgG index (30.30% vs. 9.09%, p < 0.05). Positive rates of anti-Ro-52 (47.92% vs. 14.29%, p < 0.001), anti-ANAs (50.00% vs.10.20%, p < 0.001) and anti-SSA (35.42% vs. 6.12%, p = 0.001) were significantly higher in the NMOSD patients than the ITM patients. Seropositive Ro-52 and SSA were associated with longer injured spinal cord segments. However, Ro-52 antibody may not be associated with NMOSD relapsing during our follow up. CONCLUSIONS: NMOSD patients manifested with longer vertebral segments, higher female/male ratio, IgG index, anti-ANAs, anti-Ro-52 and anti-SSA seroprevalence than ITM patients. These features may help clinicians better distinguish NMOSD from ITM and provide long-term immunotherapy reasonably.

Human umbilical cord stem cells ameliorate experimental autoimmune encephalomyelitis by regulating immunoinflammation and remyelination.

Multiple sclerosis (MS) is an irreversible and demyelinating disease of the central nervous system, in part influenced by chronic inflammation. There is no proven effective therapy to stop the pathological progression of MS, although suppressing the immune system to control the inflammatory response may improve the clinical performance acutely. Here, we found that mesenchymal stem cells from human umbilical cord (hUC-MSCs) could restore behavioral functions and attenuate the histopathological deficits of experimental autoimmune encephalomyelitis mice over the long term (i.e., 50 days) by suppression of perivascular immune cell infiltrations and reduction in both demyelination and axonal injury in the spinal cord. These findings suggest that transplantation of hUC-MSCs may be a potential therapy for MS.

Human umbilical cord mesenchymal stem cell therapy on neuromyelitis optica.

Stem cell transplantation is a promising therapy for neuromyelitis optica (NMO). Among stem cell varieties, human umbilical cord-derived mesenchymal stem cells (hUC-MSCs) possess many advantages, add a differential potential into neural cells, secrete a set of trophic factors and cytokines, regulate immunological function, and have therapeutic potential for neurological diseases. In this study, hUC-MSCs transplantation was used to treat five NMO patients with follow-up for 18 months including evaluation of Expanded Disability Status Scale (EDSS) levels, clinical course, magnetic resonance imaging (MRI) characteristics, adverse events, and so on. Among the five cases, four showed therapeutic improvement after hUC-MSCs treatment. Both symptoms and signs improved and relapse frequencies were reduced. MRI characteristics also showed decreased volume and severity of lesions, while few adverse events occurred. The results suggest that hUC-MSCs transplantation appear safe and might be effective for NMO treatment in the near future. In addition, according to flow cytometry assay (FACS) results, B cells of blood were inhibited while T cells increased after treatment, indicating an immune-related mechanism.

Serum bilirubin after acute ischemic stroke is associated with stroke severity.

Elevated serum bilirubin was prevalent in the acute ischemic stroke (AIS), which was induced in response to oxidative stress and could display the intensity of oxidative stress. As more severe stroke is linked with higher level of oxidative stress, we hypothesized that bilirubin may be associated with the severity of stroke. In this study, bilirubin and other biochemical indexes were measured in 531 enrolled patients with AIS, and NIH Stroke Scale (NIHSS) scores were assessed simultaneous with blood collection. The association between bilirubin and the severity of stroke was performed by Spearman correlation analyze, and the level-risk relationship of bilirubin in different level of NIHSS score was performed through Multinomial logistic regression analysis. We performed multivariable logistic regression to estimate odds ratios (OR) and 95% confidence intervals (CI) of severe stroke dichotomized as NIHSS≥8 with adjustment for other stroke risk factors, the level-risk relationship of severe stroke in different level of bilirubin was also performed through Multinomial logistic regression analysis. We found that NIHSS score was significantly positively correlated with both serum direct bilirubin (Dbil, R=0.229 and P=0.000) and total bilirubin (Tbil, R=0.224 and P=0.000), higher level of serum bilirubin linked to the higher NIHSS score with OR(95% CI) in upper level of NIHSS score group was 1.12(1.01-1.24), 1.23(1.11-1.36), 1.31(1.15-1.51) in Dbil and 1.01(0.99-1.31), 1.05(1.03-1.08), 1.07(1.03-1.11) in Tbil compared to the lowest level group. In unadjusted or adjusted logistic regression analyses, serum Dbil and Tbil still have a significant association with the severe stroke. When both the Dbil and Tbil concentrations were grouped into 4 levels, participants with higher levels of bilirubin showed higher risk with severe stroke compared with the lowest level of bilirubin, with OR(95% CI) 1.881(1.04-3.404) of Dbil in level 3 and 3.702(1.979-6.927) of Tbil, 3.352(1.572-7.147) of total bilirubin in level 4. As a conclusion, serum bilirubins were in significant correlation with severity of AIS, which may be served as useful markers to reflect the degree of illness.