Autoimmune Disease Of Central Nervous System Research Articles

Analysis of effectiveness of Fecal Microbiota Transplantation in Multiple Sclerosis

Multiple Sclerosis is a chronic, autoimmune disorder characterized by demyelination and neuroinflammation affecting 2.3 million people around the world. MS have different types, relapsing and remitting MS being the most prevalent type with unpredicted flare ups with complete or incomplete recovery of the patient. Research suggests the emerging impact of alterations in gut microbiome on various diseases. The dysbiosis of gut flora has been linked to various diseases one of many is central nervous system autoimmune disorders. The study aims to evaluate the potential role and effectiveness of FMT in treating MS. The literature and clinical trials focused on gut microbiota, efficacy, Safety, and mechanisms of FMT were analyzed. The major focus of the study is assessing the impact of FMT on MS symptoms and gut microbiota composition and results of the study were concluded based on outcomes. Primary outcomes noted improvement in MS symptoms both subjectively and objectively including enhanced motor symptoms and improved disability scores like EDSS. Secondary outcomes showed significant improvement in gut microbiota and 55-65% reduction in inflammatory markers like IL 6 and TNF alpha. FMT shows promising outcomes to be considered as a therapeutic intervention in MS by offering symptom relief and halting disease progression.

Early Diagnosis of CNS Virus Infections from Neurological Autoimmune Diseases: A Cross-Sectional Study from China in ER Setting.

It is challenging to differentiate between central nervous system (CNS) virus infections and neurological autoimmune diseases in the emergency department. Considering their different pathogenesis, we assume they differ in neuropsychiatric symptoms and laboratory results. A total of 80 patients were included in this study, 50 with CNS virus infections and 30 with CNS autoimmune diseases, confirmed by a polymerase chain reaction (PCR) of cerebrospinal fluid (CSF). A binary logistic regression model and receiver operating characteristic (ROC) curve were employed to examine the discrimination between the two types of diseases based on neuropsychiatric symptoms and laboratory results. Compared to patients with neurological autoimmune diseases, patients with CNS virus infections had a higher incidence of abnormal behavior (p = 0.026) and abnormal sensation/thought (p = 0.029); higher total (p = 0.005), direct (p = 0.004), and indirect bilirubin (p = 0.004); and increased CSF cell (p = 0.01) and CSF white cell counts (p = 0.01). Patients with disturbance of consciousness and abnormal sensation/thought were 7.79-fold and 5.07-fold more likely to be diagnosed with CNS virus infections (OR = 7.79, p = 0.008; OR = 5.07, p = 0.032). Each unit increase in blood indirect bilirubin concentration and CSF white cell counts increased the risk of developing CNS virus infections by 1.25-fold and 1.01-fold (OR = 1.25, p = 0.016; OR = 1.01, p = 0.011). ROC analysis showed that the area under the curve was 88.0% (p < 0.001). Our study found that patients with CNS viral infections tend to have higher blood indirect bilirubin concentration, CSF leukocyte count, frequency of disorders of consciousness, and abnormal sensation and thought, which may help differentiate them from those with neurological autoimmune diseases.

Classification of optic neuritis in neuromyelitis optica spectrum disorders (NMOSD) on MRI using CNN with transfer learning and manipulation of pre-processing on augmentation

Neuromyelitis optica spectrum disorder (NMOSD), also known as Devic disease, is an autoimmune central nervous system disorder in humans that commonly causes inflammatory demyelination in the optic nerves and spinal cord. Inflammation in the optic nerves is termed optic neuritis (ON). ON is a common clinical presentation; however, it is not necessarily present in all NMOSD patients. ON in NMOSD can be relapsing and result in severe vision loss. To the best of our knowledge, no study utilises deep learning to classify ON changes on MRI among patients with NMOSD. Therefore, this study aims to deploy eight state-of-the-art CNN models (Inception-v3, Inception-ResNet-v2, ResNet-101, Xception, ShuffleNet, DenseNet-201, MobileNet-v2, and EfficientNet-B0) with transfer learning to classify NMOSD patients with and without chronic ON using optic nerve magnetic resonance imaging. This study also investigated the effects of data augmentation before and after dataset splitting on cropped and whole images. Both quantitative and qualitative assessments (with Grad-Cam) were used to evaluate the performances of the CNN models. The Inception-v3 was identified as the best CNN model for classifying ON among NMOSD patients, with accuracy of 99.5%, sensitivity of 98.9%, specificity of 93.0%, precision of 100%, NPV of 99.0%, and F1-score of 99.4%. This study also demonstrated that the application of augmentation after dataset splitting could avoid information leaking into the testing datasets, hence producing more realistic and reliable results.

Central Nervous System Disorders with Auto-Antibodies in People Living with HIV.

People living with HIV (PLWH) may present atypical neurological complications. Recently, autoimmune manifestations of the central nervous system (CNS) have been described. We retrospectively described the features of PLWH presenting with acute neurological symptoms with positive anti-CNS antibodies. We analyzed relevant CSF characteristics. Twelve patients were identified, with demyelinating, inflammatory, or no MRI lesions. We observed CSF inflammatory features. Aspecific CSF anti-CNS antibodies were found in all subjects and a specific antibody (second-level blotting panel) was found in one. The cases presented a slow resolution of symptoms with sequelae. More studies are needed to better describe the spectrum and prognosis of autoimmune CNS diseases in PLWH.

Switching from injectable to other Disease Modifying Therapies may improve sexual dysfunction in people with Multiple Sclerosis

BackgroundMultiple Sclerosis (MS) a central nervous system autoimmune disorder, mainly affecting young adults and more prevalent among women, can lead to sexual dysfunction (SD) among both males and females with MS. Female sexual dysfunction can be defined as dyspareunia, a lack of sexual desire, disorders in the arousal and orgasm phases, and sexual pain disorders. The purpose of this study is to investigate the changes in sexual function among females with MS whose treatment was switched from first-line injectable medications to other agents after a six-month duration. And assess the changes in all three domains of SD.MethodsIn this longitudinal study females diagnosed with MS, aged between 18 and 50 years old, and were candidates for switching their treatment from interferon beta-1a (intra-muscular and subcutaneous), and Glatiramer Acetate (GA), to Fingolimod, Dimethyl Fumarate (DMF), or Natalizumab (NTZ) due to patients’ convenience and tolerability and adverse events were included. “Multiple Sclerosis Intimacy and Sexuality Questionnaire-19” was used to evaluate the SD changes before and six months after the new treatment initiation. Statistical analysis was conducted using SPSS V.24 software. Histograms and the Shapiro-Wilk test were used to assess the normality of the variables; due to the non-normal distribution of quantitative variables (except for age), the Wilcoxon signed-rank test was used to compare the scores, before and six months after the medication change. The level of significance was considered less than 0.05.ResultsOut of 107 female participants (average age: 35.09 ± 5.61), The mean of overall MSISQ-19 scores, before and six months after the medication change were not significant (p-value = 0.091). However, considering the subdomains, the medication changes only affected the tertiary subdomain of MSISQ-19 (p-value = 0.017). Still, the scores of other subdomains did not change significantly (p-value = 0.761 for primary SD and 0.479 for secondary SD). Also, there wasn’t any significant difference between EDSS before and after the medication change (p-value = 0.461).ConclusionsTo our knowledge, this was the first study, assessing the effect of MS medication change on the improvement of SD among patients. According to the results of the presented cross-sectional study, we found that during a six-month period, the tertiary subdomain of MSISQ-19 symptoms improved significantly, while the changes in other SD domains were not significant.

Dietary ellagic acid therapy for CNS autoimmunity: Targeting on Alloprevotella rava and propionate metabolism

BackgroundMediterranean diet rich in polyphenolic compounds holds great promise to prevent and alleviate multiple sclerosis (MS), a central nervous system autoimmune disease associated with gut microbiome dysbiosis. Health-promoting effects of natural polyphenols with low bioavailability could be attributed to gut microbiota reconstruction. However, its underlying mechanism of action remains elusive, resulting in rare therapies have proposed for polyphenol-targeted modulation of gut microbiota for the treatment of MS.ResultsWe found that oral ellagic acid (EA), a natural polyphenol rich in the Mediterranean diet, effectively halted the progression of experimental autoimmune encephalomyelitis (EAE), the animal model of MS, via regulating a microbiota-metabolites-immunity axis. EA remodeled the gut microbiome composition and particularly increased the relative abundances of short-chain fatty acids -producing bacteria like Alloprevotella. Propionate (C3) was most significantly up-regulated by EA, and integrative modeling revealed a strong negative correlation between Alloprevotella or C3 and the pathological symptoms of EAE. Gut microbiota depletion negated the alleviating effects of EA on EAE, whereas oral administration of Alloprevotella rava mimicked the beneficial effects of EA on EAE. Moreover, EA directly promoted Alloprevotella rava (DSM 22548) growth and C3 production in vitro. The cell-free supernatants of Alloprevotella rava co-culture with EA suppressed Th17 differentiation by modulating acetylation in cell models. C3 can alleviate EAE development, and the mechanism may be through inhibiting HDAC activity and up-regulating acetylation thereby reducing inflammatory cytokines secreted by pathogenic Th17 cells.ConclusionsOur study identifies EA as a novel and potentially effective prebiotic for improving MS and other autoimmune diseases via the microbiota-metabolites-immunity axis.7AEBLBqRMMqqUZLLsSi8h5Video

Neuronal nicotinic acetylcholine receptor antibodies in autoimmune central nervous system disorders.

Neuronal nicotinic acetylcholine receptors (nAChRs) are abundant in the central nervous system (CNS), playing critical roles in brain function. Antigenicity of nAChRs has been well demonstrated with antibodies to ganglionic AChR subtypes (i.e., subunit α3 of α3β4-nAChR) and muscle AChR autoantibodies, thus making nAChRs candidate autoantigens in autoimmune CNS disorders. Antibodies to several membrane receptors, like NMDAR, have been identified in autoimmune encephalitis syndromes (AES), but many AES patients have yet to be unidentified for autoantibodies. This study aimed to develop of a cell-based assay (CBA) that selectively detects potentially pathogenic antibodies to subunits of the major nAChR subtypes (α4β2- and α7-nAChRs) and its use for the identification of such antibodies in "orphan" AES cases. The study involved screening of sera derived from 1752 patients from Greece, Turkey and Italy, who requested testing for AES-associated antibodies, and from 1203 "control" patients with other neuropsychiatric diseases, from the same countries or from Germany. A sensitive live-CBA with α4β2-or α7-nAChR-transfected cells was developed to detect antibodies against extracellular domains of nAChR major subunits. Flow cytometry (FACS) was performed to confirm the CBA findings and indirect immunohistochemistry (IHC) to investigate serum autoantibodies' binding to rat brain tissue. Three patients were found to be positive for serum antibodies against nAChR α4 subunit by CBA and the presence of the specific antibodies was quantitatively confirmed by FACS. We detected specific binding of patient-derived serum anti-nAChR α4 subunit antibodies to rat cerebellum and hippocampus tissue. No serum antibodies bound to the α7-nAChR-transfected or control-transfected cells, and no control serum antibodies bound to the transfected cells. All patients positive for serum anti-nAChRs α4 subunit antibodies were negative for other AES-associated antibodies. All three of the anti-nAChR α4 subunit serum antibody-positive patients fall into the AES spectrum, with one having Rasmussen encephalitis, another autoimmune meningoencephalomyelitis and another being diagnosed with possible autoimmune encephalitis. This study lends credence to the hypothesis that the major nAChR subunits are autoimmune targets in some cases of AES and establishes a sensitive live-CBA for the identification of such patients.

Characterizing immune-mediated neuronal microtubule destabilization and axonal transport defects in a mouse model of optic neuritis

Abstract Multiple sclerosis (MS) is a central nervous system autoimmune disease that often presents with inflammation of the optic nerve, optic neuritis (ON). The mechanisms of neuronal damage in MS and ON are unknown. In vitro studies modeling MS neurodegeneration demonstrated that cytolytic lymphocytes drive microtubule destabilization in human induced pluripotent stem cell-derived spinal motor neurons. Microtubules are essential for axonal transport, a key function for neuron health. We hypothesize that immune-mediated neuronal microtubule destabilization drives development of ON through disruption of axonal transport. MOG35-55 T cell receptor transgenic mice were used as a model of ON. The non-invasive ophthalmologic technique optical coherence tomography (OCT) allows for confirmation of symptomatic ON. Using OCT, increasing severity of progressive ON was observed over 5 months. To examine transport efficiency, cholera toxin subunit B (CTB), an axonal transport tracer, was injected into the eyes of mice with ON. Optic nerves were collected and stained for β3-tubulin, a marker of microtubules, and imaged by immunofluorescence. Preliminary data found decreased β3-tubulin staining and markedly reduced CTB transport in the presence of immune cell infiltration in mice with ON. These data confirm that OCT can be used to monitor ON progression and provide evidence that immune-mediated neuronal microtubule destabilization causes axonal transport deficits that underly ON development.

Specimen type validation and establishment of normal cytokine reference intervals in cerebrospinal fluid

Cerebrospinal fluid (CSF) is a critical body fluid to examine in attempts to discover potential biomarkers for neuroinflammatory and other disorders of the central nervous system (CNS). Serum and/or plasma cytokine levels have been associated with a variety of inflammatory conditions, and some have been shown to be actionable therapeutic targets. Less is known, however, about cytokine levels in CSF. Serum and plasma cytokine testing is widely available in clinical and research laboratories, but cytokine testing in CSF is extremely limited and if performed, accompanied by a disclaimer that it is an unvalidated specimen type. In this study, we validate CSF as a suitable specimen type and determine normal reference intervals for multiple cytokines as well as a soluble cytokine receptor. CSF was validated as a specimen type for testing using a laboratory developed multiplexed cytokine assay previously validated to measure 13 cytokines/markers in serum and plasma. Performance parameters including specimen dilution, specimen interference, linearity and precision were examined. Reference intervals were established using 197 normal and control CSF specimens by non-parametric quantile-based methods. CSF cytokine analysis demonstrated within and between run precision of <10% and < 20% CV, respectively and linearity of ±15% for all analytes throughout the analytical measurement range of the assay. Reference intervals for the 13 cytokines/markers were established from 197 normal and control CSF specimens (78 Male; mean 44.8 y ± 21.7 SD, 119 Female; mean 42.8 y ± 20.3 SD). Cytokine concentrations in CSF from normal donors and controls were less than the lower limit of quantitation of our assay for 6 of the 13 measured cytokines/markers. The chemokine IL8 demonstrated the highest concentration of all analytes measured. CSF demonstrated acceptable performance as a specimen type in our multiplexed cytokine assay. By validating CSF as a specimen type and establishing normal reference intervals for cytokine concentrations in CSF, their potential as biomarkers for infectious, autoimmune and other inflammatory CNS disorders can be more appropriately investigated.

Paediatric antibody prevalence in seizure score to predict autoimmune aetiology in seizure disorders.

To modify the antibody prevalence in epilepsy (APE) score of children with suspected autoimmune central nervous system disease with seizures. We retrospectively analysed the cerebrospinal fluid of 157 children (aged 0-18 years) with suspected autoimmune central nervous system disease for antineuronal antibodies in our laboratory from 2016 to 2023. Participants were randomly divided into the development cohort (n = 79, 35 females; median 7 years, SD 4 years 7 months, range 4-11 years) and validation cohort (n = 78, 28 females; median 7 years, SD 4 years 5 months, range 4-12 years). A paediatric antibody prevalence in seizure (PAPS) score was created for one cohort and evaluated in the other. Seven variables were selected through univariate and multivariate analysis to create a PAPS score. One hundred and fifty-seven children who fulfilled the inclusion criteria were enrolled; 49 tested positive for antineuronal antibodies. The sensitivity and specificity of an APE score of 4 and greater were 92% and 22.2% respectively; the sensitivity and specificity of a PAPS score of 2.5 and greater were 83.3% and 77.8% respectively. The area under the curve was 0.832 (95% confidence interval = 0.743-0.921), which was significantly better than that for the APE score (p < 0.001). The APE score had high sensitivity but low specificity in children. The PAPS score may be useful for determining the need for antineuronal antibody testing.

Neuropathology of Inflammatory and Autoimmune-Mediated Diseases

Herein, the author summarize the basic findings on the neuropathology of inflammatory and autoimmune central nervous system (CNS) diseases. Current knowledge on infectious, demyelinating, and autoimmune diseases have also been reported. Further, I emphasize the importance of considering the neuropathology of meningitis, encephalitis, and abscesses as infectious diseases; multiple sclerosis and neuromyelitis optica as demyelinating diseases; and vasculitis, paraneoplastic neurological syndrome, and collagen diseases as autoimmune diseases.

Granulocytes in cerebrospinal fluid of adults suspected of a central nervous system infection: a prospective study of diagnostic accuracy.

Cerebrospinal fluid (CSF) granulocytes are associated with bacterial meningitis, but information on its diagnostic value is limited and primarily based on retrospective studies. Therefore, we assessed the diagnostic accuracy of CSF granulocytes. We analyzed CSF granulocytes (index test) from all consecutive patients in two prospective cohort studies in the Netherlands. Both studies included patients ≥ 16years, suspected of a central nervous system (CNS) infection, who underwent a diagnostic lumbar puncture. All episodes with elevated CSF leukocytes (≥ 5 cells per mm3) were selected and categorized by clinical diagnosis (reference standard). Of 1261 episodes, 625 (50%) had elevated CSF leukocytes and 541 (87%) were included. 117 of 541 (22%) were diagnosed with bacterial meningitis, 144 (27%) with viral meningoencephalitis, 49 (9%) with other CNS infections, 76 (14%) with CNS autoimmune disorders, 93 (17%) with other neurological diseases and 62 (11%) with systemic diseases. The area under the curve to discriminate bacterial meningitis from other diagnoses was 0.97 (95% confidence interval [CI] 0.95-0.98) for CSF granulocyte count and 0.93 (95% CI 0.91-0.96) for CSF granulocyte percentage. CSF granulocyte predominance occurred in all diagnostic categories. A cutoff at 50% CSF granulocytes gave a sensitivity of 94% (95% CI 90-98), specificity of 80% (95% CI 76-84), negative predictive value of 98% (95% CI 97-99) and positive predictive value of 57% (95% CI 52-62). CSF granulocytes have a high diagnostic accuracy for bacterial meningitis in patients suspected of a CNS infection. CSF granulocyte predominance occurred in all diagnostic categories, limiting its value in clinical practice.

Administration methods and dosage of poly(lactic acid)-glycol intervention to myelin oligodendrocyte glycoprotein-induced experimental autoimmune encephalitis mice

BackgroundMyelin oligodendrocyte glycoprotein-associated disorders (MOGAD) is an autoimmune central nervous system disease. Antigen-specific immune tolerance using nanoparticles such as Polylactic-co-glycolic acid (PLGA) have recently been used as a new therapeutic tolerization approach for CNS autoimmune diseases. We examined whether MOG1-125 conjugated with PLGA could induce MOG-specific immune tolerance in an experimental autoimmune encephalitis (EAE) mouse model. EAE was induced in sixty C57BL/6 J wild-type mice using MOG1-125 peptide with complete Freund’s Adjuvant. The mice were divided into 12 groups (n = 5 each) to test the ability of MOG1-125 conjugated PLGA intervention to mitigate the severity or improve the outcomes from EAE with and without rapamycin compared to antigen alone or PLGA alone. EAE score and serum MOG-IgG titers were compared among the interventions.Kindly check and confirm the processed Affiliation “4” is appropriate.I confirmed the Aff 4.Affiliation: Corresponding author information have been changed to present affiliation. Kindly check and confirm.I checked and confirmed the Corresponding author's information.ResultsMice with EAE that were injected intraperitoneally with MOG1-125 conjugated PLGA + rapamycin complex showed dose-dependent mitigation of EAE score. Intraperitoneal and intravenous administration resulted in similar clinical outcomes, whereas 80% of mice treated with subcutaneous injection had a recurrence of clinical score worsening after approximately 1 week. Although there was no significant difference in EAE scores between unconjugated-PLGA and MOG-conjugated PLGA, serum MOG-IgG tended to decrease in the MOG-conjugated PLGA group compared to controls.ConclusionIntraperitoneal administration of PLGA resulted in dose-dependent and longer-lasting immune tolerance than subcutaneous administration. The induction of immune tolerance using PLGA may represent a future therapeutic option for patients with MOGAD.

Successful use of tacrolimus for treatment-refractory neuroblastoma-associated opsoclonus-myoclonus-ataxia syndrome: A case series.

Opsoclonus-myoclonus-ataxia syndrome (OMAS) is an autoimmune central nervous system disorder, primarily manifesting as a paraneoplastic sequalae to neuroblastoma, and characterized by motor disorders and behavioral disturbances. OMAS is typified by aberrant B-cell and T-cell activation. Current treatment involves immunosuppression using corticosteroids, intravenous immunoglobulin, and rituximab. However, these approaches often lead to treatment-related toxicities and symptomatic recurrences with chronic neurocognitive impairment. We treated three children with refractory neuroblastoma-associated OMAS with tacrolimus, a T-cell-targeting calcineurin inhibitor, effectively controlling symptoms within a month and enabling the discontinuation of immunosuppression with minimal side effects. Tacrolimus shows promise as a therapeutic option for refractory OMAS.

New insights into neuropathology and pathogenesis of autoimmune glial fibrillary acidic protein meningoencephalomyelitis.

Anti-glial fibrillary acidic protein (GFAP) meningoencephalomyelitis (autoimmune GFAP astrocytopathy) is a new autoimmune central nervous system (CNS) disease diagnosable by the presence of anti-GFAP autoantibodies in the cerebrospinal fluid and presents as meningoencephalomyelitis in the majority of patients. Only few neuropathological reports are available and little is known about the pathogenic mechanisms. We performed a histopathological study of two autopsies and nine CNS biopsies of patients with anti-GFAP autoantibodies and found predominantly a lymphocytic and in one autopsy case a granulomatous inflammatory phenotype. Inflammatory infiltrates were composed of B and T cells, including tissue-resident memory T cells. Although obvious astrocytic damage was absent in the GFAP-staining, we found cytotoxic T cell-mediated reactions reflected by the presence of CD8+/perforin+/granzyme A/B+ cells, polarized towards astrocytes. MHC-class-I was upregulated in reactive astrocytes of all biopsies and two autopsies but not in healthy controls. Importantly, we observed a prominent immunoreactivity of astrocytes with the complement factor C4d. Finally, we provided insight into an early phase of GFAP autoimmunity in an autopsy of a pug dog encephalitis that was characterized by marked meningoencephalitis with selective astrocytic damage with loss of GFAP and AQP4 in the lesions.Our histopathological findings indicate that a cytotoxic T cell-mediated immune reaction is present in GFAP autoimmunity. Complement C4d deposition on astrocytes could either represent the cause or consequence of astrocytic reactivity. Selective astrocytic damage is prominent in the early phase of GFAP autoimmunity in a canine autopsy case, but mild or absent in subacute and chronic stages in human disease, probably due to the high regeneration potential of astrocytes. The lymphocytic and granulomatous phenotypes might reflect different stages of lesion development or patient-specific modifications of the immune response. Future studies will be necessary to investigate possible implications of pathological subtypes for clinical disease course and therapeutic strategies.

Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS): contemporary advances and current controversies.

Chronic lymphocytic inflammation with pontine perivascular enhancement responsive to steroids (CLIPPERS) is an inflammatory syndrome with characteristic clinical, radiological, and pathological features, and can be effectively treated with corticosteroid-based immunotherapies. The exact pathogenesis of CLIPPERS remains unclear, and specific diagnostic biomarkers are not available. According to the 2017 diagnostic criteria, probable CLIPPERS should be considered in middle-aged patients with subacute onset of pontocerebellar symptoms and typical punctuate and curvilinear gadolinium enhancement lesions ("salt-and-pepper" appearance) located in the hindbrain (especially pons) on magnetic resonance imaging. In addition, CLIPPERS-mimics, such as central nervous system (CNS) lymphoma, and several antibody-associated autoimmune CNS diseases (e.g., myelin oligodendrocyte glycoprotein antibody-associated disease, autoimmune glial fibrillary acidic protein astrocytopathy, and anti-N-methyl-D-aspartatereceptor encephalitis), should be extensively excluded. The prerequisite for definite CLIPPERS is the perivascular T-cell-predominant inflammatory infiltration observed on pathological analysis. A biopsy is strongly suggested when clinical/radiological red flags are present. Most patients with CLIPPERS respond well to corticosteroids and have a good prognosis. Long-term low-dose corticosteroid maintenance therapy or corticosteroids coupled with immunosuppressants are recommended to prevent the recurrence of the syndrome. The potential progression of CLIPPERS to lymphoma has been suggested in some cases; therefore, at least 2-year clinical and radiological follow-up is essential. Here, we critically review the recent developments and provided an update on the clinical characteristics, diagnostic criteria, differential diagnoses, and therapeutic management of CLIPPERS. We also discuss the current controversies in this context that can be resolved in future research studies.

A Mild Phenotype of Overlapping Syndrome With Myelin-Oligodendrocyte Glycoprotein and Glial Fibrillary Acidic Protein Immunoglobulin G: Mimicking Viral Meningitis in a Patient.

Glial fibrillary acidic protein (GFAP) astrocytopathy, an autoimmune central nervous system disorder characterized by the development of immunoglobulin G reactive with GFAP, has received growing attention in recent years. It is documented that GFAP-immunoglobulin G and other autoantibodies can be both detected in some patients. However, the coexistence of anti-myelin-oligodendrocyte glycoprotein (MOG) and GFAP antibodies is rarely reported. A 45-year-old man presented with headache, fever, backache, dysuria, tremble of hands, numbness of lower limbs, without diplopia, decreased vision, or other manifestations of optic neuritis. He was initially diagnosed with viral meningitis. After antiviral therapy, his headache, fever, and dysuria were improved, but the tremble of his upper limbs and numbness of his lower limbs still existed. A lumbar puncture was further performed and found both anti-GFAP and anti-MOG antibodies in the cerebrospinal fluid. No evidence of other immune disorders or infectious diseases was revealed. Meanwhile, a magnetic resonance scan showed enhancement of spinal pia mater in cervical, thoracic, and lumbar segments. He was then treated with immunoglobulin (intravenous immunoglobulin) therapy (25 g for 5 d), and steroid pulse therapy (methylprednisolone, 1 g for 5 d), followed by a gradual tapering of oral prednisolone. We reported a case of overlapping anti-GFAP and anti-MOG antibody-associated syndrome. This case enriches our understanding of the clinical manifestations of overlapping syndrome and expands the spectrum of this disorder.

Molecular Mimicry between SARS-CoV-2 Proteins and Human Self-Antigens Related with Autoimmune Central Nervous System (CNS) Disorders.

SARS-CoV-2 can trigger autoimmune central nervous system (CNS) diseases in genetically susceptible individuals, a mechanism poorly understood. Molecular mimicry (MM) has been identified in other viral diseases as potential triggers of autoimmune CNS events. This study investigated if MM is the process through which SARS-CoV-2 induces the breakdown of immune tolerance. The frequency of autoimmune CNS disorders was evaluated in a prospective cohort with patients admitted to the COVID-19 Intense Care Unity (ICU) in Rio de Janeiro. Then, an in silico analysis was performed to identify the conserved regions that share a high identity between SARS-CoV-2 antigens and human proteins. The sequences with significant identity and antigenic properties were then assessed for their binding capacity to HLA subtypes. Of the 112 patients included, 3 were classified as having an autoimmune disorder. A total of eleven combinations had significant linear and three-dimensional overlap. NMDAR1, MOG, and MPO were the self-antigens with more significant combinations, followed by GAD65. All sequences presented at least one epitope with strong or intermediate binding capacity to the HLA subtypes selected. This study underscores the possibility that CNS autoimmune attacks observed in COVID-19 patients, including those in our population, could be driven by MM in genetically predisposed individuals.

Intestinal epithelial dopamine receptor signaling drives sex-specific disease exacerbation in a mouse model of multiple sclerosis

Although the gut microbiota can influence central nervous system (CNS) autoimmune diseases, the contribution of the intestinal epithelium to CNS autoimmunity is less clear. Here, we showed that intestinal epithelial dopamine D2 receptors (IEC DRD2) promoted sex-specific disease progression in an animal model of multiple sclerosis. Female mice lacking Drd2 selectively in intestinal epithelial cells showed a blunted inflammatory response in the CNS and reduced disease progression. In contrast, overexpression or activation of IEC DRD2 by phenylethylamine administration exacerbated disease severity. This was accompanied by altered lysozyme expression and gut microbiota composition, including reduced abundance of Lactobacillus species. Furthermore, treatment with N2-acetyl-L-lysine, a metabolite derived from Lactobacillus, suppressed microglial activation and neurodegeneration. Taken together, our study indicates that IEC DRD2 hyperactivity impacts gut microbial abundances and increases susceptibility to CNS autoimmune diseases in a female-biased manner, opening up future avenues for sex-specific interventions of CNS autoimmune diseases.

Autotaxin in encephalitogenic CD4 T cells as a therapeutic target for multiple sclerosis.

Multiple sclerosis (MS) is an immune-mediated inflammatory disease of the CNS. A defining characteristic of MS is the ability of autoreactive T lymphocytes to cross the blood-brain barrier and mediate inflammation within the CNS. Previous work from our lab found the gene Enpp2 to be highly upregulated in murine encephalitogenic T cells. Enpp2 encodes for the protein autotaxin, a secreted glycoprotein that catalyzes the production of lysophosphatidic acid and promotes transendothelial migration of T cells from the bloodstream into the lymphatic system. The present study sought to characterize autotaxin expression in T cells during CNS autoimmune disease and determine its potential therapeutic value. Myelin-activated CD4 T cells upregulated expression of autotaxin in vitro, and ex vivo analysis of CNS-infiltrating CD4 T cells showed significantly higher autotaxin expression compared with cells from healthy mice. In addition, inhibiting autotaxin in myelin-specific T cells reduced their encephalitogenicity in adoptive transfer studies and decreased in vitro cell motility. Importantly, using two mouse models of MS, treatment with an autotaxin inhibitor ameliorated EAE severity, decreased the number of CNS infiltrating T and B cells, and suppressed relapses, suggesting autotaxin may be a promising therapeutic target in the treatment of MS.