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1.
Ann Neurol ; 93(6): 1069-1081, 2023 06.
Artigo em Inglês | MEDLINE | ID: mdl-36843248

RESUMO

OBJECTIVE: To investigate aquaporin-4 antibody (AQP4-IgG) dynamics and relapse risk in patients with seropositive neuromyelitis optica spectrum disorder treated with immunosuppressants. METHODS: This observational cohort study with prospectively collected data included 400 neuromyelitis optica spectrum disorder patients seropositive for AQP4-IgG and treated with immunosuppressants. Serum AQP4-IgG was detected by fixed cell-based assay every 6 months. RESULTS: After treatment with immunosuppressants, 128 patients became AQP4-IgG seronegative. The median time to become seronegative for 400 patients was 76.4 months (61.4 months, NA). Among those patients with negative change of AQP4-IgG, the mean annualized relapse rate significantly decreased after patients became seronegative (0.20 vs 0.77, p < 0.001), and a positive correlation was observed between time to become seronegative and relapse (OR 1.018, 95% CI 1.001-1.035, p < 0.05). Independent risk factors for AQP4-IgG becoming seronegative were older age at onset, initiation of immunosuppressants at onset, and shorter disease duration before maintenance therapy. Independent risk factors for relapse included younger age (≤46.4 years) at onset, poly-system involvement in the first attack, and unchanged or increased AQP4-IgG titer. The relapse risk was not associated with sex, combination with connective tissue disease, seropositivity for systemic autoimmune antibodies, or incomplete recovery from the first attack. INTERPRETATION: Patients with younger age at onset, poly-system involvement in the first attack, and unchanged or increased titer of AQP4-IgG are most likely to experience relapse under treatment with immunosuppressants. Time to AQP4-IgG becoming seronegative and change of AQP4-IgG titer may become the surrogate efficacy biomarkers in clinical trials. ANN NEUROL 2023;93:1069-1081.


Assuntos
Neuromielite Óptica , Humanos , Pessoa de Meia-Idade , Imunossupressores/uso terapêutico , Aquaporina 4 , Autoanticorpos , Doença Crônica , Biomarcadores , Recidiva , Imunoglobulina G
2.
J Neurol Neurosurg Psychiatry ; 94(8): 605-613, 2023 08.
Artigo em Inglês | MEDLINE | ID: mdl-37225405

RESUMO

To explore the autoimmune response and outcome in the central nervous system (CNS) at the onset of viral infection and correlation between autoantibodies and viruses. METHODS: A retrospective observational study was conducted in 121 patients (2016-2021) with a CNS viral infection confirmed via cerebrospinal fluid (CSF) next-generation sequencing (cohort A). Their clinical information was analysed and CSF samples were screened for autoantibodies against monkey cerebellum by tissue-based assay. In situ hybridisation was used to detect Epstein-Barr virus (EBV) in brain tissue of 8 patients with glial fibrillar acidic protein (GFAP)-IgG and nasopharyngeal carcinoma tissue of 2 patients with GFAP-IgG as control (cohort B). RESULTS: Among cohort A (male:female=79:42; median age: 42 (14-78) years old), 61 (50.4%) participants had detectable autoantibodies in CSF. Compared with other viruses, EBV increased the odds of having GFAP-IgG (OR 18.22, 95% CI 6.54 to 50.77, p<0.001). In cohort B, EBV was found in the brain tissue from two of eight (25.0%) patients with GFAP-IgG. Autoantibody-positive patients had a higher CSF protein level (median: 1126.00 (281.00-5352.00) vs 700.00 (76.70-2899.00), p<0.001), lower CSF chloride level (mean: 119.80±6.24 vs 122.84±5.26, p=0.005), lower ratios of CSF-glucose/serum-glucose (median: 0.50[0.13-0.94] vs 0.60[0.26-1.23], p=0.003), more meningitis (26/61 (42.6%) vs 12/60 (20.0%), p=0.007) and higher follow-up modified Rankin Scale scores (1 (0-6) vs 0 (0-3), p=0.037) compared with antibody-negative patients. A Kaplan-Meier analysis revealed that autoantibody-positive patients experienced significantly worse outcomes (p=0.031). CONCLUSIONS: Autoimmune responses are found at the onset of viral encephalitis. EBV in the CNS increases the risk for autoimmunity to GFAP.


Assuntos
Encefalite , Infecções por Vírus Epstein-Barr , Masculino , Humanos , Feminino , Autoimunidade , Estudos Retrospectivos , Herpesvirus Humano 4 , Autoanticorpos , Imunoglobulina G
3.
Org Biomol Chem ; 16(15): 2634-2638, 2018 04 18.
Artigo em Inglês | MEDLINE | ID: mdl-29611601

RESUMO

A new synthetic approach to dihydrofuran derivatives via the annulation reaction of ß-naphthols and 4-hydroxycoumarins with vinylsulfonium salts has been developed. A variety of dihydrofuran derivatives were prepared in moderate to good yields under mild conditions. The products could be readily transformed to the corresponding furans via the dehydrogenation with DDQ.

4.
CNS Neurosci Ther ; 30(9): e70042, 2024 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-39279053

RESUMO

OBJECTIVE: The objective of this study is to investigate the presence of astrocyte antibodies in patients, excluding aquaporin-4 or glial fibrillary acidic protein (GFAP) antibodies, while evaluating associated biomarkers and pathologies. METHODS: Patient serum and cerebrospinal fluid (CSF) were tested for antibodies using tissue- and cell-based assays. Neurofilament light chain (NFL) and GFAP in the CSF were detected using single-molecule array (SIMOA). RESULTS: 116 patients accepted SIMOA. Fifteen functional neurological disorders patients without antibodies were designated as controls. Thirty-five patients were positive for astrocyte antibodies (Anti-GFAP: 7; Anti-AQP4: 7; unknown antibodies: 21, designed as the double-negative group, DNAP). The most frequent phenotype of DNAP was encephalitis (42.9%), followed by myelitis (23.8%), movement disorders (19.0%), and amyotrophic lateral sclerosis-like (ALS-like) disease (14.2%). The levels of CSF GFAP and NFL in DNAP were higher than in the control (GFAP: 1967.29 [776.60-13214.47] vs 475.38 [16.80-943.60] pg/mL, p < 0.001; NFL: 549.11 [162.08-2462.61] vs 214.18 [81.60-349.60] pg/mL, p = 0.002). GFAP levels decreased in DNAP (n = 5) after immunotherapy (2446.75 [1583.45-6277.33] vs 1380.46 [272.16-2005.80] pg/mL, p = 0.043), while there was no difference in NFL levels (2273.78 [162.08-2462.61] vs 890.42 [645.06-3168.06] pg/mL, p = 0.893). Two brain biopsy patterns were observed: one exhibited prominent tissue proliferation and hypertrophic astrocytes, with local loss of astrocytes, while the other showed severe astrocyte depletion with loss of neurofilaments around the vessels. Eighteen patients received immunotherapy, and improved except one with ALS-like symptoms. We identified anti-vimentin in this patient. DISCUSSION: There are unidentified astrocyte antibodies. The manifestations of double-negativity are heterogeneous; nevertheless, the pathology and biomarkers remain consistent with astrocytopathy. Immunotherapy is effective.


Assuntos
Aquaporina 4 , Astrócitos , Biomarcadores , Proteína Glial Fibrilar Ácida , Imunoglobulina G , Humanos , Proteína Glial Fibrilar Ácida/líquido cefalorraquidiano , Proteína Glial Fibrilar Ácida/imunologia , Feminino , Masculino , Aquaporina 4/imunologia , Pessoa de Meia-Idade , Astrócitos/imunologia , Astrócitos/metabolismo , Astrócitos/patologia , Estudos Retrospectivos , Adulto , Biomarcadores/líquido cefalorraquidiano , Biomarcadores/sangue , Idoso , Imunoglobulina G/líquido cefalorraquidiano , Imunoglobulina G/sangue , Proteínas de Neurofilamentos/líquido cefalorraquidiano , Proteínas de Neurofilamentos/sangue , Autoanticorpos/líquido cefalorraquidiano , Autoanticorpos/sangue , Adulto Jovem , Adolescente
5.
Int J Neurosci ; 121(3): 121-9, 2011 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-21142828

RESUMO

The course of myasthenia gravis (MG) may get complicated by the development of other autoimmune diseases. Estimates of the frequency of autoimmune diseases will help inform patients and physicians, direct health policy discussion, provide etiologic clues, and optimize the management of MG. However, the frequency of autoimmune diseases in people with MG is still uncertain. A systematic search for English language studies was conducted by MEDLINE and EMBASE from 1960 through 2010. Incidence studies and case series of all MG subtypes with information about autoimmune diseases were included; 25 studies met the inclusion criteria. Although there was considerable heterogeneity, the pooled estimate of the coexisting autoimmune diseases in MG was 13% (95% confidence interval, 12%-14%). Autoimmune thyroid disease seems to occur more frequently than other autoimmune conditions in MG patients. Heterogeneity in study estimates could be explained by ascertainment bias and case mix. Furthermore, autoimmune diseases occurred significantly more often in females and anti-acetylcholine receptor seropositive MG patients. Patients with MG have an increased frequency of coexisting autoimmune diseases. Autoimmune diseases seem to occur more often in female and seropositive MG patients. Further research is needed to expand our understanding of these associations.


Assuntos
Doenças Autoimunes/epidemiologia , Miastenia Gravis/epidemiologia , Viés , Comorbidade , Suscetibilidade a Doenças , Feminino , Humanos , Incidência , Masculino , Miastenia Gravis/imunologia , Razão de Chances , Projetos de Pesquisa , Fatores Sexuais , Tireoidite Autoimune/epidemiologia
6.
Chin Med J (Engl) ; 130(8): 964-971, 2017 Apr 20.
Artigo em Inglês | MEDLINE | ID: mdl-28397727

RESUMO

BACKGROUND: Th9 cells are a newly discovered CD4+ T helper cell subtype, characterized by high interleukin (IL)-9 secretion. Growing evidences suggest that Th9 cells are involved in the pathogenic mechanism of multiple sclerosis (MS). Mast cells are multifunctional innate immune cells, which are perhaps best known for their role as dominant effector cells in allergies and asthma. Several lines of evidence point to an important role for mast cells in MS and its animal models. Simultaneously, there is dynamic "cross-talk" between Th9 and mast cells. The aim of the present study was to examine the IL-9-mast cell axis in experimental autoimmune encephalomyelitis (EAE) and determine its interaction after neutralizing anti-IL-9 antibody treatment. METHODS: Female C57BL/6 mice were randomly divided into three groups (n = 5 in each group): mice with myelin oligodendrocyte glycoprotein (MOG)-induced EAE (EAE group), EAE mice treated with anti-IL-9 antibody (anti-IL-9 Abs group), and EAE mice treated with IgG isotype control (IgG group). EAE clinical score was evaluated. Mast cells from central nervous system (CNS) were detected by flow cytometry. The production of chemokine recruiting mast cells in the CNS was explored by reverse transcription-polymerase chain reaction (RT-PCR). In mice with MOG-induced EAE, the expression of IL-9 receptor (IL-9R) complexes in CNS and spleen mast cells was also explored by RT-PCR, and then was repeating validated by immunocytochemistry. In vitro, spleen cells from EAE mice were cultured with anti-IL-9 antibody, and quantity of mast cells was counted by flow cytometry after co-culture. RESULTS: Compared with IgG group, IL-9 blockade delayed clinical disease onset and ameliorated EAE severity (t = -2.217, P = 0.031), accompany with mast cells infiltration decreases (day 5: t = -8.005, P < 0.001; day 15: t = -11.857, P < 0.001; day 20: t = -5.243, P = 0.001) in anti-IL-9 Abs group. The messenger RNA expressions of C-C motif chemokine ligand 5 (t = -5.932, P = 0.003) and vascular cell adhesion molecule-1 (t = -4.029, P = 0.004) were significantly decreased after IL-9 neutralization in anti-IL-9 Abs group, compared with IgG group. In MOG-induced EAE, the IL-9R complexes were expressed in CNS and spleen mast cells. In vitro, splenocytes cultured with anti-IL-9 antibody showed significantly lower levels of mast cells in a dose-dependent manner, compared with splenocytes cultured with anti-mouse IgG (5 µg/ml: t = -0.894, P = 0.397; 10 µg/ml: t = -3.348, P = 0.019; 20 µg/ml: t = -7.639, P < 0.001). CONCLUSIONS: This study revealed that IL-9 neutralization reduced mast cell infiltration in CNS and ameliorated EAE, which might be relate to the interaction between IL-9 and mast cells.


Assuntos
Anticorpos/uso terapêutico , Encefalomielite Autoimune Experimental/tratamento farmacológico , Encefalomielite Autoimune Experimental/metabolismo , Interleucina-9/antagonistas & inibidores , Interleucina-9/metabolismo , Mastócitos/metabolismo , Animais , Sistema Nervoso Central/metabolismo , Feminino , Imuno-Histoquímica , Interleucina-9/imunologia , Camundongos , Camundongos Endogâmicos C57BL , RNA Mensageiro/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa
7.
J Neurol Sci ; 366: 3-7, 2016 Jul 15.
Artigo em Inglês | MEDLINE | ID: mdl-27288767

RESUMO

BACKGROUND: Neuromyelitis optica spectrum disorders (NMOSD) are complicated neuroautoimmune disorders which can coexist with other organ-specific autoimmune disorders. The most frequently specific organ is the thyroid. The aim of this study is to evaluate the thyroid function of NMOSD patients and detect the difference between anti-thyroid antibodies (ATAbs) seropositive and seronegative NMOSD patients. METHODS: 88 patients diagnosed with NMOSD were enrolled and their thyroid functions were evaluated. They were divided into two groups by ATAbs abnormalities. In addition, demographic characteristics, clinical symptoms and MRI scan results of brain and spinal cord were assessed. RESULTS: Anti-thyroid peroxidase antibodies (TPOAbs) and anti-thyroglobulin antibodies (TGAbs) seropositivities were detected more frequently in patients with NMOSDs when compared with healthy controls (37.5% vs 14.9%, P=0.01, Diff22.6%, 95CI[9.0%, 34.9%]; 31.8% vs 16.2%, P=0.022, Diff15.6%, 95CI[2.27%, 27.9%]). In NMOSD patients, the Expanded disability status scale score (EDSS) score was significantly higher in ATAbs seropositive group than that in ATAbs seronegative group (median 6.5 vs 3.75, P=0.012). However, there is no significant difference for demographic characteristics and other clinical symptoms. Moreover, NMOSD patients with ATAbs abnormalities had more brain and cervical cord lesions when compared with ATAbs negative NMOSD patients (83.8% vs 61.4%, P=0.029, Diff22.4%, 95CI[0.9%, 40.9%]; 93.9% vs 59.6%, P=0.001, Diff34.3%, 95CI[13.6%, 50.4%]). CONCLUSIONS: NMOSD patients have a higher frequency of ATAbs abnormalities. ATAbs may be associated with disability status, brain abnormalities and cervical cord lesions.


Assuntos
Autoanticorpos/sangue , Autoantígenos/imunologia , Iodeto Peroxidase/imunologia , Proteínas de Ligação ao Ferro/imunologia , Neuromielite Óptica/imunologia , Neuromielite Óptica/fisiopatologia , Glândula Tireoide/fisiopatologia , Adulto , Biomarcadores/sangue , Encéfalo/diagnóstico por imagem , Avaliação da Deficiência , Feminino , Humanos , Imageamento por Ressonância Magnética , Masculino , Neuromielite Óptica/diagnóstico por imagem , Neuromielite Óptica/tratamento farmacológico , Estudos Retrospectivos , Medula Espinal/diagnóstico por imagem , Testes de Função Tireóidea , Glândula Tireoide/imunologia
9.
J Clin Neurol ; 8(3): 161-9, 2012 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-23091524

RESUMO

BACKGROUND AND PURPOSE: Myasthenia gravis (MG) is usually comorbid with thymoma. More accurate estimates of the incidence thymoma in MG will help inform patients and their physicians, facilitate health policy discussions, provide etiologic clues, and optimize the management of MG. METHODS: We conducted a systematic review search of relevant English-language studies published between 1960 and 2012 using MEDLINE and Embase. We identified additional studies by reviewing the bibliographies of the retrieved articles and hand searched the main neurology journals. Only incidence studies and case series of unselected MG patients in which information about thymoma were included. RESULTS: Out of 2206 potentially relevant studies, 49 met the inclusion criteria. Although there was a considerable degree of heterogeneity, the pooled estimate of the incidence of thymoma in MG was 21% (95% confidence interval, 20-22%). The pooled incidence was significantly higher for surgery-based studies than for population- and hospital-based studies. A large proportion of the reported thymomas were noninvasive. Furthermore, thymoma appears to occur significantly more frequently among male MG patients and those older than 40 years at the onset of MG. CONCLUSIONS: Thymoma is common in MG patients, but appears to be found more often in male MG patients and those older than 40 years at the onset of MG. Further research is needed to expand our understanding of these association conditions.

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