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Traumatic spinal cord injury is a devastating insult followed by progressive cord atrophy and neurodegeneration. Dysregulated or non-resolving inflammatory processes can disturb neuronal homeostasis and drive neurodegeneration. Here, we provide an in-depth characterization of innate and adaptive inflammatory responses as well as oxidative tissue injury in human traumatic spinal cord injury lesions compared to non-traumatic control cords. In the lesion core, microglia were rapidly lost while intermediate (co-expressing pro- as well as anti-inflammatory molecules) blood-borne macrophages dominated. In contrast, in the surrounding rim, TMEM119+ microglia numbers were maintained through local proliferation and demonstrated a predominantly pro-inflammatory phenotype. Lymphocyte numbers were low and mainly consisted of CD8+ T cells. Only in a subpopulation of patients, CD138+/IgG+ plasma cells were detected, which could serve as candidate cellular sources for a developing humoral immunity. Oxidative neuronal cell body and axonal injury was visualized by intracellular accumulation of amyloid precursor protein (APP) and oxidized phospholipids (e06) and occurred early within the lesion core and declined over time. In contrast, within the surrounding rim, pronounced APP+/e06+ axon-dendritic injury of neurons was detected, which remained significantly elevated up to months/years, thus providing mechanistic evidence for ongoing neuronal damage long after initial trauma. Dynamic and sustained neurotoxicity after human spinal cord injury might be a substantial contributor to (i) an impaired response to rehabilitation; (ii) overall failure of recovery; or (iii) late loss of recovered function (neuro-worsening/degeneration)., (© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain.)

Multiple sclerosis is characterized by immune mediated neurodegeneration that results in progressive, life-long neurological and cognitive impairments. Yet, the endogenous mechanisms underlying multiple sclerosis pathophysiology are not fully understood. Here, we provide compelling evidence that associates dysregulation of neuregulin-1 beta 1 (Nrg-1β1) with multiple sclerosis pathogenesis and progression. In the experimental autoimmune encephalomyelitis model of multiple sclerosis, we demonstrate that Nrg-1β1 levels are abated within spinal cord lesions and peripherally in the plasma and spleen during presymptomatic, onset and progressive course of the disease. We demonstrate that plasma levels of Nrg-1β1 are also significantly reduced in individuals with early multiple sclerosis and is positively associated with progression to relapsing-remitting multiple sclerosis. The functional impact of Nrg-1β1 downregulation preceded disease onset and progression, and its systemic restoration was sufficient to delay experimental autoimmune encephalomyelitis symptoms and alleviate disease burden. Intriguingly, Nrg-1β1 therapy exhibited a desirable and extended therapeutic time window of efficacy when administered prophylactically, symptomatically, acutely or chronically. Using in vivo and in vitro assessments, we identified that Nrg-1β1 treatment mediates its beneficial effects in EAE by providing a more balanced immune response. Mechanistically, Nrg-1β1 moderated monocyte infiltration at the blood-CNS interface by attenuating chondroitin sulphate proteoglycans and MMP9. Moreover, Nrg-1β1 fostered a regulatory and reparative phenotype in macrophages, T helper type 1 (Th1) cells and microglia in the spinal cord lesions of EAE mice. Taken together, our new findings in multiple sclerosis and experimental autoimmune encephalomyelitis have uncovered a novel regulatory role for Nrg-1β1 early in the disease course and suggest its potential as a specific therapeutic target to ameliorate disease progression and severity., (© The Author(s) (2020). Published by Oxford University Press on behalf of the Guarantors of Brain. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

Anti-mitochondrial antibodies, the characteristic markers of primary biliary cirrhosis, have been detected in most patients with this disease. However, the prevalence of these antibodies in inflammatory myopathies and their clinical and histopathological significance has not been determined. Sera from 212 consecutive patients with inflammatory myopathies were screened for anti-mitochondrial antibodies by enzyme-linked immunosorbent assay. The clinical and histopathological features of anti-mitochondrial antibody-positive patients were analysed and statistically compared with those of anti-mitochondrial antibody-negative patients. Twenty-four patients positive for anti-mitochondrial antibodies (seven patients with and 17 patients without primary biliary cirrhosis) were identified (11.3%). Thirteen patients had a clinically chronic disease course of >12 months before their diagnosis at hospitals. Six of these 13 patients (four asymptomatic patients with increased creatine kinase levels and two patients with arrhythmia) had not been aware of muscle weakness, but all 13 patients had muscle atrophy at initial presentation. As complications, eight patients had cardiac involvement including arrhythmias (five patients with supraventricular tachycardia; two with ventricular tachycardia; and one patient with atrioventricular block), six patients had moderately decreased ejection fraction and six patients had decreased vital capacity, two of whom required respiratory support. Regarding muscle histopathological findings, in addition to inflammation, 13 patients had chronic myopathic changes and six had granulomatous lesions. Statistical analysis showed that the clinical features of a chronic disease course, cardiac involvement and muscle atrophy, and the histopathological features of chronic myopathic changes and granulomatous inflammation, were significantly more frequently observed in patients with anti-mitochondrial antibody-positive inflammatory myopathy than in patients who were negative for anti-mitochondrial antibodies. Except for cardiac involvement, which is more frequently observed in patients with primary biliary cirrhosis, no significant differences in clinical or histopathological features were found between patients with or without primary biliary cirrhosis. Our study revealed that inflammatory myopathies associated with anti-mitochondrial antibodies were frequently found in patients with the clinical features of a chronic disease course, muscle atrophy and cardiopulmonary involvement, and the characteristic histopathological feature of granulomatous inflammation. Our study suggests that inflammatory myopathies associated with anti-mitochondrial antibodies form a characteristic subgroup.

A mAb targeting the CD11d subunit of the leukocyte integrin CD11d/CD18 decreases intraspinal inflammation and oxidative damage leading to improved neurological outcomes in rodent models of SCI. CD11d/CD18 is the fourth member of the beta2-integrin family. Current evidence indicates that CD11d/CD18 is regulated differently than other beta2-integrins, suggesting that CD11d(+) leukocytes play a distinct role in inflammation. Although the transcriptional control of CD11d expression has been evaluated, control of the intracellular distribution of CD11d has not been addressed. For this reason and as a result of the potential of CD11d as a therapeutic target for SCI and possibly other CNS injuries, we investigated the intracellular localization and surface expression of CD11d in cultured cells. CD11d and CD18 were fused at their C-termini with YFP and mRFP, respectively. Flow cytometry and confocal microscopy demonstrated that rCD11d-YFP is expressed on the cell surface of leukocyte cell lines expressing CD18. In contrast, in heterologous cell lines, CD11d-YFP is retained intracellularly in the TGN. Coexpression of CD11d-YFP and CD18-mRFP relieves this intracellular restriction and allows the CD11d/CD18 heterodimer to be surface-expressed. Based on domain-swapping experiments with CD25, the extracellular domain of CD11d is required and sufficient for the observed intracellular retention in heterologous cells. Furthermore, the transmembrane and C-terminus are also required for proper heterodimerization with CD18 and localization to the plasma membrane. These findings suggest that multiple CD11d domains play a role in controlling intracellular location and association with CD18.

We evaluated the clinical and laboratory features of the optic-spinal form of multiple sclerosis (OSMS) with no brain lesions on repeated MRI--termed pure OSMS. By reviewing the medical records of 118 Japanese clinically definite multiple sclerosis patients seen between 1988-1999, we found 10 patients (8.5%), nine of whom were women, with only relapsing optic neuritis (ON) and myelitis (MY) clinically and consistently normal brain MRI during follow-ups of >or=5 years. Three patients suffered severe ON and MY, but the other seven had mild disease (six were graded 1 in the Disability Status Scale). Despite frequent relapses, mild pure OSMS was characterized by younger onset and mild spinal symptoms as in 'benign' classical multiple sclerosis (CMS). MRI often revealed multiple cervico-thoracic cord lesions of variable lengths. Oligoclonal IgG bands (OB) were negative in all cases. HLA-DPB1*0501, whose association with OSMS has been reported, was positive only in six patients (including three patients with severe pure OSMS). Four patients with DRB1*1501-DQB1*0602, to which CMS is closely linked, had mild disease. Though pure OSMS was heterogeneous with regard to clinical severity and human leukocyte antigen (HLA) class II alleles, this form of multiple sclerosis was characterized by a definite female preponderance and negative OB that distinguished it from CMS.

A case of fulminant subacute myelooptico-neuropathy that occurred in a native American women following pneumonitis instead of the usual gastrointestinal dysfunction is reported. After the acute stage, which left the patient paraplegic and partially blind, she suffered an exacerbation which resulted in her death 11 months after the onset of illness. Autopsy disclosed symmetric optic and spinal demyelination. Neutralizing antibody titer against subacute, myelo-optico-neuropathy virus was determined on postmortem serum 3 1/2 years after death and found significantly elevated.