Pathogenic role of anti-cN1A autoantibodies in sporadic inclusion body myositis.

BACKGROUND: Sporadic inclusion body myositis (sIBM) is an intractable muscle disease that frequently affects elderly people. Autoantibodies recognising cytosolic 5'-nucleotidase 1A (cN1A) were found in the sera of patients with sIBM. However, the pathogenic role of the autoantibodies remained unknown. This study investigated the pathogenic properties of the autoantibodies using active cN1A peptides immunisation. METHODS: Wild-type C57BL6 mice were injected with three different mouse cN1A peptides corresponding to the previously reported epitope sequences of human cN1A. After confirming the production of autoantibodies to the corresponding cN1A peptides in each group, changes in body weight, exercise capacity by treadmill test and histological changes in mice injected with cN1A peptides or controls were investigated. RESULTS: Autoantibodies against cN1A were detected in serum samples from mice injected with cN1A peptide. Some groups of mice injected with cN1A peptide showed significant weight loss and decreased motor activity. The number of myofibres with internal nuclei increased in all the peptide-injected groups, with surrounding or invading CD8-positive T cells into myofibres, abnormal protein aggregates and overexpression of p62 and LC3. CONCLUSIONS: Active cN1A peptide immunisation partially reproduced the clinical and histological aspects of sIBM in wild-type mice. The murine model demonstrates the pathogenic properties of anti-cN1A autoantibodies to cause sIBM-like histological changes.

Bradykinesia and rigidity modulated by functional connectivity between the primary motor cortex and globus pallidus in Parkinson's disease.

The mechanisms underlying motor fluctuations in patients with Parkinson's disease (PD) are currently unclear. Regional brain stimulation reported the changing of motor symptoms, but the correlation with functional connectivity (FC) in the brain network is not fully understood. Hence, our study aimed to explore the relationship between motor symptom severity and FC using resting-state functional magnetic resonance imaging (rsfMRI) in the "on" and "off" states of PD. In 26 patients with sporadic PD, FC was assessed using rsfMRI, and clinical severity was analyzed using the motor part of the Movement Disorder Society-Unified Parkinson's Disease Rating Scale (MDS-UPDRS Part III) in the on and off states. Correlations between FC values and MDS-UPDRS Part III scores were assessed using Pearson's correlation coefficient. The correlation between FC and motor symptoms differed in the on and off states. FC between the ipsilateral precentral gyrus (PreCG) and globus pallidus (GP) correlated with the total MDS-UPDRS Part III scores and those for bradykinesia/rigidity in the off state. Lateralization analysis indicated that FC between the PreCG and GP correlated with the contralateral total MDS-UPDRS Part III scores and those for bradykinesia/rigidity in the off state. Aberrant FC in cortico-striatal circuits correlated with the severity of motor symptoms in PD. Cortico-striatal hyperconnectivity, particularly in motor pathways involving PreCG and GP, is related to motor impairments in PD. These findings may facilitate our understanding of the mechanisms underlying motor symptoms in PD and aid in developing treatment strategies such as brain stimulation for motor impairment.

Embolic stroke induced by rotational persistent 1st intersegmental artery compression.

A 45-year-old man suffered multiple cerebral infarctions in the vertebrobasilar artery territory, followed by second stroke against conservative treatment. Radiological examinations revealed intra-arterial defect in left persistent 1st intersegmental artery (PFIA) at C1 level, suggesting mural thrombus, and mechanical compression of left PFIA at the level with head rotation to the right clearly revealed by reconstructed 3-dimensional radiological images, but no findings of atlantoaxial instability. One month after the second stroke, posterior fixation was performed. Postoperative course was uneventful without subsequent stroke for 24 months. This unique case demonstrated that PFIA might associate with cerebral stroke as a clinical condition of bow hunter's stroke even in middle age. Reconstructed 3-dimensional radiological images might be useful for clear demonstration of the pathophysiology in this complex clinical entity.

27-Hydroxycholesterol regulates human SLC22A12 gene expression through estrogen receptor action.

The excretion and reabsorption of uric acid both to and from urine are tightly regulated by uric acid transporters. Metabolic syndrome conditions, such as obesity, hypercholesterolemia, and insulin resistance, are believed to regulate the expression of uric acid transporters and decrease the excretion of uric acid. However, the mechanisms driving cholesterol impacts on uric acid transporters have been unknown. Here, we show that cholesterol metabolite 27-hydroxycholesterol (27HC) upregulates the uric acid reabsorption transporter URAT1 encoded by SLC22A12 via estrogen receptors (ER). Transcriptional motif analysis showed that the SLC22A12 gene promoter has more estrogen response elements (EREs) than other uric acid reabsorption transporters such as SLC22A11 and SLC22A13, and 27HC-activated SLC22A12 gene promoter via ER through EREs. Furthermore, 27HC increased SLC22A12 gene expression in human kidney organoids. Our results suggest that in hypercholesterolemic conditions, elevated levels of 27HC derived from cholesterol induce URAT1/SLC22A12 expression to increase uric acid reabsorption, and thereby, could increase serum uric acid levels.

Cytotoxic lesions of the corpus callosum after COVID-19 vaccination.

A 23-year-old previously healthy man (Patient 1) and a 33-year-old woman with a past history of depression (Patient 2) developed neurological symptoms approximately 1 week after receipt of the first COVID-19 mRNA vaccination and deteriorated over the next week. Patient 1 reported nausea, headache, a high fever, and retrograde amnesia. Patient 2 reported visual disturbance, headache, dysarthria, a left forearm tremor, dysesthesia of the mouth and distal limbs, and visual agnosia. PCR test results for SARS-CoV-2 were negative. Complete blood cell count, biochemistry, and antibody test and cerebrospinal fluid test findings were unremarkable. Diffusion-weighted and fluid-attenuated inversion recovery MRI of the brain showed a high signal intensity lesion at the midline of the splenium of the corpus callosum compatible with cytotoxic lesions of the corpus callosum (CLOCCs). High-dose intravenous methylprednisolone improved their symptoms and imaging findings. CLOCCs should be considered in patients with neurological manifestation after COVID-19 vaccination.

Prognostic Factor for Subacute Encephalitis with First-Episode Psychosis.

INTRODUCTION: Although symptomatic manifestations in encephalitis vary, they typically include seizures, memory deficit(s), and altered consciousness. Psychosis also occurs as an initial manifestation. In clinical practice, clinicians often encounter the question of whether first-episode psychosis (FEP) originates from encephalitis itself or if encephalitis presenting with FEP develops concurrently. The prognosis of FEP among patients with overall encephalitis, including autoimmune encephalitis, remains uncertain. METHODS: We examined a prognostic factor in patients with encephalitis who had both FEP and CSF pleocytosis. A total of 36 patients who presented with FEP were enrolled. A score of ≥3 and ≤2 on the modified Rankin scale were defined as poor and good outcomes, respectively. A total of 13 independent variables were analyzed by the multivariate logistic regression analysis. RESULTS: Significant variables on univariate logistic regression analysis included female sex (OR 5.571, 95% CI: 1.297-23.934; p = 0.021) and the use of mechanical ventilation during the acute stage (OR 7.286, 95% CI: 1.508-35.211; p = 0.013). On multivariate logistic regression analysis, the use of mechanical ventilation during the acute stage (OR 5.446, 95% CI: 1.044-28.615; p = 0.044) was significantly associated with poor outcomes. CONCLUSIONS: The use of mechanical ventilation is a poor prognostic factor of subacute encephalitis with FEP, and female sex may be a risk factor for unfavorable development of the disease.

Electroencephalographic-Based Functional Connectivity Networks of Visual Hallucinations and Visuospatial Dysfunctions in Parkinson's Disease.

Visual dysfunction is an important nonmotor symptom of Parkinson's disease (PD). Visual hallucinations (VHs) and visuospatial dysfunctions (VSDs) are common visual dysfunctions in PD; however, the underlying mechanisms remain unclear. Our study aimed to evaluate neuronal synchronization between patients with PD with and without VH or VSD using electroencephalographic (EEG) coherence analysis. Twenty-four patients with sporadic PD were evaluated for the presence of VH and VSD, and were divided into VH-negative and VH-positive groups, and these groups were further subdivided by VSD status. Coherence analysis was performed on EEG data. Whole-brain and regional coherences were calculated and compared between the groups. There was a significant difference in frontal-frontal coherence between the VH+ VSD- and VH+ VSD+ groups (p = 0.026). Our findings suggest that reduced EEG coherence in frontal regions might be involved in VSD in patients with PD. Reduced neuronal synchronization between the frontal lobes may contribute to the disruption of visual processing in PD.

Pathological features of inflammatory myopathy as a manifestation of chronic graft-versus-host disease after allogeneic bone marrow transplantation.

Chronic graft-versus-host disease (cGVHD) is the most important complication resulting in the death of bone marrow transplantation (BMT) survivors. It is also a relatively rare cause of inflammatory myopathy (IM). We report the case of a 46-year-old woman who developed severe cGVHD-related IM after BMT for myelodysplastic syndrome. She presented with severe muscle pain and weakness with cGVHD-related symptoms in other organs. Myopathological analysis showed moderate cell infiltration with remarkable necrotic and regenerative fibers. Sarcoplasm and capillaries expressed C5b9 and myxovirus resistance protein 1. Non-necrotic fibers in perifascicular regions expressed MHC-II. Steroid therapy did not sufficiently control cGVHD-related IM, and the patient was concurrently treated with an immunosuppressant. Our findings show that IM is a key manifestation of cGVHD and that the expression of interferon-inducible proteins in muscle pathology is useful for identifying cGVHD-related IM.

The Impact of Intermittent Hypoxia on Metabolism and Cognition.

Intermittent hypoxia (IH), one of the primary pathologies of sleep apnea syndrome (SAS), exposes cells throughout the body to repeated cycles of hypoxia/normoxia that result in oxidative stress and systemic inflammation. Since SAS is epidemiologically strongly correlated with type 2 diabetes/insulin resistance, obesity, hypertension, and dyslipidemia included in metabolic syndrome, the effects of IH on gene expression in the corresponding cells of each organ have been studied intensively to clarify the molecular mechanism of the association between SAS and metabolic syndrome. Dementia has recently been recognized as a serious health problem due to its increasing incidence, and a large body of evidence has shown its strong correlation with SAS and metabolic disorders. In this narrative review, we first outline the effects of IH on the expression of genes related to metabolism in neuronal cells, pancreatic ß cells, hepatocytes, adipocytes, myocytes, and renal cells (mainly based on the results of our experiments). Next, we discuss the literature regarding the mechanisms by which metabolic disorders and IH develop dementia to understand how IH directly and indirectly leads to the development of dementia.

Inhibition of the ATR kinase enhances 5-FU sensitivity independently of nonhomologous end-joining and homologous recombination repair pathways.

The anticancer agent 5-fluorouracil (5-FU) is cytotoxic and often used to treat various cancers. 5-FU is thought to inhibit the enzyme thymidylate synthase, which plays a role in nucleotide synthesis and has been found to induce single- and double-strand DNA breaks. ATR Ser/Thr kinase (ATR) is a principal kinase in the DNA damage response and is activated in response to UV- and chemotherapeutic drug-induced DNA replication stress, but its role in cellular responses to 5-FU is unclear. In this study, we examined the effect of ATR inhibition on 5-FU sensitivity of mammalian cells. Using immunoblotting, we found that 5-FU treatment dose-dependently induced the phosphorylation of ATR at the autophosphorylation site Thr-1989 and thereby activated its kinase. Administration of 5-FU with a specific ATR inhibitor remarkably decreased cell survival, compared with 5-FU treatment combined with other major DNA repair kinase inhibitors. Of note, the ATR inhibition enhanced induction of DNA double-strand breaks and apoptosis in 5-FU-treated cells. Using gene expression analysis, we found that 5-FU induced the activation of the intra-S cell-cycle checkpoint. Cells lacking BRCA2 were sensitive to 5-FU in the presence of ATR inhibitor. Moreover, ATR inhibition enhanced the efficacy of the 5-FU treatment, independently of the nonhomologous end-joining and homologous recombination repair pathways. These findings suggest that ATR could be a potential therapeutic target in 5-FU-based chemotherapy.

Multiple cerebral infarctions associated with lung cancer-induced hypereosinophilia: a case report.

BACKGROUND: Hypereosinophilia (HE) is caused by various conditions, including solid and hematologic tumors. Nonetheless, there exist no reports on cerebral infarctions caused by HE associated with lung cancer metastasis to the bone marrow. CASE PRESENTATION: We report a case of a 67-year-old man with multiple cerebral infarctions associated with HE. His white blood cell and eosinophil counts were 38,900/µL and 13,600/µL, respectively, at 4 weeks before admission. During treatment for HE, he presented with dysarthria and walking difficulties. Magnetic resonance imaging of the brain showed multiple small infarcts in regions such as the bilateral cortex, watershed area, and cerebellum. Chest computed tomography showed small nodes in the lung and enlargement of the left hilar lymph nodes. Bronchoscopic biopsy did not reveal a tumor; however, bone marrow biopsy showed infiltration of tumor cells. We considered a diagnosis of lung cancer metastasizing to the bone marrow, which induced HE and later caused cerebral infarctions. CONCLUSIONS: This case report demonstrates that metastatic cancer in the bone marrow can induce HE, which can consequently cause multiple cerebral infarctions. Clinicians should consider HE as a cause of multiple cerebral infarctions in patients with cancer.

Potential patient screening for late-onset Pompe disease in suspected sleep apnea: a rationale and study design for a Prospective Multicenter Observational Cohort Study in Japan (PSSAP-J Study).

BACKGROUND: Pompe disease is an autosomal recessive disorder caused by deficiency of the acid α-glucosidase (GAA) enzyme. GAA deficiency induces progressive glycogen accumulation which leads to weakness of the respiratory muscle including the diaphragm. Pompe disease is one of the few myopathies, for which an established therapy is available. Thus, earlier detection of potential late-onset Pompe disease (LOPD) and earlier intervention would have a significant clinical impact. PURPOSE: Our hypothesis is that sleep problems including sleep disordered breathing (SDB) and clinical symptoms may indicate an early stage of LOPD since decreased respiratory muscle activity generally first presents during sleep. Thus, the aims of this prospective, multicenter observational cohort study in Japan (PSSAP-J) are to demonstrate a higher prevalence of LOPD in a sleep lab-based population (primary outcome), and to identify predictive factors for LOPD from findings in diagnostic polysomnography (PSG) and clinical symptoms (secondary outcomes). METHODS: The study design is a prospective multicenter observational cohort study. Consecutive patients who present to sleep labs due to suspected SDB for an overnight PSG will be enrolled. All patients will be measured for creatine kinase, GAA activity, and if necessary, genetic analysis of GAA. Furthermore, chest X-ray, pulmonary function test, and arterial blood gas analysis will be collected. Then, prevalence and specific findings of LOPD will be assessed. RESULT: Congenital myopathy shows a shift from slow-deep to rapid-shallow breathing during transition from wakefulness to sleep accompanying a symptom of waking with gasping (actual further results are pending). DISCUSSION: The distribution in respiratory physiology between during wakefulness and sleep specific to LOPD may provide insights into early-stage detection. CLINICAL TRIAL REGISTRATION NUMBER: UMIN000039191, UMIN Clinical Trials Registry ( http://www.umin.ac.jp/ctr ).

Krebs von den Lungen 6 decreased in the serum and muscle of GNE myopathy patients.

UDP-N-acetylglucosamine 2-epimerase/N-acetylmannosamine kinase (GNE) is necessary for sialic acid biosynthesis. GNE myopathy is caused by a defect in GNE, and hyposialylation is a key factor in the pathomechanism of GNE myopathy. Although candidates for evaluating hyposialylation have been reported, it is difficult to measure them in routine clinical practice. Sialylation is necessary for synthesis of various glycoproteins, including Krebs von den Lungen-6 (KL-6)/mucin 1 (MUC1). Here we report that KL-6/MUC1 is decreased in GNE myopathy. We observed that KL-6 levels were decreased in the serum of patients with GNE myopathy, and that KL-6 and MUC1-C were also decreased in muscle biopsy specimens from these patients. An immunofluorescent study revealed that KL-6 and MUC1-C were not present in the sarcolemma but were, instead, localized in rimmed vacuoles in specimens from patients with GNE myopathy. KL-6 is already used to detect lung diseases in clinical practice, and this glycoprotein may be a novel candidate for evaluating hyposialylation in GNE myopathy.

Anorexigenic Effects of Intermittent Hypoxia on the Gut-Brain Axis in Sleep Apnea Syndrome.

Sleep apnea syndrome (SAS) is a breathing disorder characterized by recurrent episodes of upper-airway collapse, resulting in intermittent hypoxia (IH) during sleep. Experimental studies with animals and cellular models have indicated that IH leads to attenuation of glucose-induced insulin secretion from pancreatic ß cells and to enhancement of insulin resistance in peripheral tissues and cells, such as the liver (hepatocytes), adipose tissue (adipocytes), and skeletal muscles (myocytes), both of which could lead to obesity. Although obesity is widely recognized as a major factor in SAS, it is controversial whether the development of SAS could contribute directly to obesity, and the effect of IH on the expression of appetite regulatory genes remains elusive. Appetite is regulated appropriately by both the hypothalamus and the gut as a gut-brain axis driven by differential neural and hormonal signals. In this review, we summarized the recent epidemiological findings on the relationship between SAS and feeding behavior and focused on the anorexigenic effects of IH on the gut-brain axis by the IH-induced up-regulation of proopiomelanocortin and cocaine- and amphetamine-regulated transcript in neuronal cells and the IH-induced up-regulation of peptide YY, glucagon-like peptide-1 and neurotensin in enteroendocrine cells and their molecular mechanisms.

Serum adiponectin levels between patients with Parkinson's disease and those with PSP.

INTRODUCTION: Adiponectin receptors are expressed in the hypothalamus, brainstem, and basal ganglia. Experimentally, adiponectin was immunopositive in the phosphorylated α-synuclein-positive Lewy bodies in the brain of individuals with Parkinson's disease (PD), and treatment with recombinant adiponectin suppressed the aggregation of α-synuclein. The close relationship between adiponectin and PD is suggested. METHODS: We assessed whether adiponectin levels may increase in patients with PD and differ in individuals with other neurodegenerative diseases. Blood samples were stored at - 70 °C. Adiponectin levels were measured using a latex turbidimetric immunoassay. RESULTS: Adiponectin levels of patients with PD (p = 0.019) or PD plus multiple systemic atrophy with predominant parkinsonian features (MSA-P) (p = 0.034) increased compared with those of patients with progressive supranuclear palsy (PSP). A multivariate comparison using ANCOVA showed that the adiponectin level was significantly higher in PD plus MSA-P than in patient with PSP, which is independent of age and BMI (adjusted mean difference of 4.388 µg/ml [95% confidence interval 0.602-8.174, p = 0.024]). A significant positive correlation between adiponectin and HDL-C levels was observed in patients with PD on a single linear regression analysis (ß, 0.257; p < 0.001; R2 = 0.271). The results were not significant in patients with MSA-P, PSP, and MSA-P plus PSP. CONCLUSIONS: Adiponectin is likely to play roles in the composition of lipid rafts since the adiponectin level of each patient with alpha-synucleinopathy or PSP differed.

Risk for later rapid eye movement sleep behavior disorder in Parkinson's disease: a 6-year prospective study.

Background: Rapid eye movement (REM) sleep behavior disorder (RBD) is recognized worldwide as an early indicator of Parkinson's disease, and it occurs in the later stages of the disease. It is known that idiopathic RBD occurs more frequently in males than in females, but a reliable marker for predicting the development of this disorder after the onset of the motor disability symptoms of Parkinson's disease is yet to be identified. Our objective was to determine whether male sex is a reliable indicator of later development of RBD by studying patients for 6 years.Methods: We registered 89 patients with Parkinson's disease into our study from initially screened 100 consecutive patients by diary questionnaires for 4 weeks. A same sole interviewer interviewed once every 1 to 3 months for 6 years. The final follow-up of 49 patients was included in data analysis.Results: Men exhibited a higher prevalence (57%) among patients with positive rapid eye movement sleep behavior disorder. Male sex and enacting behavior during sleep was significantly different between patients with and without rapid eye movement sleep behavior disorder after 6 years. Multivariate logistic regression analysis revealed that male sex [odds ratio (OR) = 5.301, p = .014, 95% confidence interval (CI) = 1.396-20.13] and enacting behavior during sleep (OR = 0.138, p = .032, 95% CI = 0.023-0.843) were related to RBD after 6 years.Conclusion: Patients with Parkinson's disease exhibit rapid eye movement sleep behavior disorder after the onset of motor symptoms.

Levodopa-responsive retrocollis on the background of choreic dyskinesia.

Purpose/aim: Retrocollis can substantially disturb the daily living of individuals with Parkinson's disease (PD). Clinician often encounter the difficulty in managing the retrocollis. Materials and Methods: We describe a patient with PD who presented with choreic dyskinesia and levodopa-responsive retrocollis. Results: The patient had dyskinesia and the off periods, and received levodopa (700 mg, 14 times/day). The patient received levodopa-carbidopa intestinal gel (LCIG) treatment. After several months, the patient complained of difficulty in swallowing and speech due to severe retrocollis. Thirty minutes following a fast levodopa infusion of LCIG, the retrocollis improved. As a result, a frontal view was obtained, and her talking abilities showed improvement. Conclusions: Severe retrocollis can be superimposed on choreic dyskinesia, and it was likely to increase during the off periods. Duodenal levodopa infusion may reduce the severity of retrocollis.

Low Serum Eicosapentaenoic Acid Levels in Cryptogenic Stroke with Active Cancer.

BACKGROUND AND PURPOSE: The increased prevalence of cancer has led to it being considered an important factor in the cause of cryptogenic stroke. In recent years, polyunsaturated fatty acids, particularly omega-3 polyunsaturated fatty acids, have been shown to prevent cancer development and progression. This study aimed to clarify the characteristics of serum polyunsaturated fatty acids in cryptogenic stroke with active cancer. METHODS: The serum levels polyunsaturated fatty acid fractions (eicosapentaenoic acid, EPA; docosahexaenoic acid, DHA; dihomo-gamma-linolenic acid, DHLA; and arachidonic acid, AA) in cases of cryptogenic stroke, sampled within 5 days after admission, were measured. Active cancer was defined as a new diagnosis, treatment, progression or recurrence within 6 months before admission, or metastatic cancer. Multivariate logistic regression analyses were performed to explore the relationship between serum polyunsaturated fatty acids and cryptogenic stroke with active cancer. RESULTS: Among 123 cases classified as cryptogenic stroke, 27 had active cancer. The serum EPA levels (1.26 ± 0.72 versus 1.89 ± 1.27 umol/l; P = 0.02) were significantly lower in cryptogenic stroke with active cancer, whereas the serum DHA, DHLA and AA levels did not significantly differ. Multivariate logistic analysis revealed that the serum EPA levels were associated with cryptogenic stroke with active cancer independently of age and serum D-dimer levels (odds ratio, 0.974; 95% confidence interval, 0.949-0.999; P = 0.04). CONCLUSIONS: In our study, low serum EPA levels were associated with cryptogenic stroke with active cancer. This suggests that low serum EPA levels may have some involvement in the pathogenesis of cryptogenic stroke with active cancer.

Intermittent Hypoxia Up-Regulates Gene Expressions of Peptide YY (PYY), Glucagon-like Peptide-1 (GLP-1), and Neurotensin (NTS) in Enteroendocrine Cells.

The patients with sleep apnea syndrome are exposed to intermittent hypoxia (IH) during sleep. We previously demonstrated the IH-induced up-regulation of the mRNA levels of anorexigenic peptides proopiomelanocortin (POMC), and cocaine- and amphetamine-regulated transcript (CART) in human neuronal cells. Appetite is regulated not only by the central nervous system but also by the peptides from gastrointestinal tract. Here, we investigated the effects of IH on the gene expression(s) of appetite-inhibiting gut hormones. Human enteroendocrine Caco-2 and mouse STC-1 cells were exposed to IH [64 cycles of 5 min hypoxia (1% O2) and 10 min normoxia (21% O2)] or normoxia for 24 h. Real-time RT-PCR revealed that IH significantly increased the mRNA levels of peptide YY (PYY), glucagon-like peptide-1 (GLP-1), and neurotensin (NTS) in Caco-2 and STC-1 cells. ELISA showed that the concentrations of PYY, GLP-1, and NTS in the culture medium were significantly increased by IH. The mRNA levels of PYY, GLP-1, and NTS were significantly up-regulated even in normoxia by Trichostatin A (TSA) and were significantly decreased even in IH by 5-azacytidine (5AZC), suggesting that IH increases PYY, GLP-1, and NTS mRNAs via alterations in the chromatin structure in enteroendocrine cells. IH might have an anorexigenic influence on the enteric nervous system.

Pathomechanisms of anti-cytosolic 5'-nucleotidase 1A autoantibodies in sporadic inclusion body myositis.

OBJECTIVE: Sporadic inclusion body myositis (sIBM), an intractable progressive muscle disease, frequently occurs in older persons. sIBM pathogenesis may involve protein degradation dysfunction and immune abnormalities. Autoantibodies recognizing cytosolic 5'-nucleotidase 1A (cN1A) were found in plasma and serum from sIBM patients. However, whether anti-cN1A autoantibodies play a pathogenic role in sIBM is controversial. This study investigated the pathogenic properties of anti-cN1A autoantibodies in sIBM pathogenesis. METHODS: We developed a cell-based assay to detect anti-cN1A autoantibodies, which we found in serum from patients with neuromuscular diseases including sIBM. We also investigated the clinicopathological differences between sIBM patients with and without the autoantibodies. We used passive in vitro and in vivo immunization models to evaluate the pathogenic role of the autoantibodies. RESULTS: Of 67 patients with sIBM, 24 (35.8%) possessed anti-cN1A autoantibodies as determined via our cell-based assay. In the anti-cN1A-positive group, the percentage of patients with hepatitis C virus antibodies was significantly lower and the mean area of type 2 myofibers was significantly smaller compared with the autoantibody-negative group. In the in vitro passive immunization model, p62/SQSTM1 significantly increased in anti-cN1A-positive sIBM immunoglobulin G (IgG)-supplemented cells. In the in vivo passive immunization model, anti-cN1A-positive sIBM IgG-injected mice demonstrated p62/SQSTM1-positive sarcoplasmic aggregates in myofibers, associated with macrophage infiltration. INTERPRETATION: Our cell-based assay is useful for anti-cN1A autoantibodies detection. Patients with anti-cN1A autoantibodies demonstrated unique clinicopathological features. In vitro and in vivo passive immunization model results suggest that anti-cN1A autoantibodies may affect protein degradation in myofibers. Ann Neurol 2017;81:512-525.