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Co-inhibitory and checkpoint molecules suppress T cell function in the tumor microenvironment, thereby rendering T cells dysfunctional. Although immune checkpoint blockade is a successful treatment option for multiple human cancers, severe autoimmune-like adverse effects can limit its application. Here, we show that the gene encoding peptidoglycan recognition protein 1 (PGLYRP1) is highly coexpressed with genes encoding co-inhibitory molecules, indicating that it might be a promising target for cancer immunotherapy. Genetic deletion of Pglyrp1 in mice led to decreased tumor growth and an increased activation/effector phenotype in CD8+ T cells, suggesting an inhibitory function of PGLYRP1 in CD8+ T cells. Surprisingly, genetic deletion of Pglyrp1 protected against the development of experimental autoimmune encephalomyelitis, a model of autoimmune disease in the central nervous system. PGLYRP1-deficient myeloid cells had a defect in antigen presentation and T cell activation, indicating that PGLYRP1 might function as a proinflammatory molecule in myeloid cells during autoimmunity. These results highlight PGLYRP1 as a promising target for immunotherapy that, when targeted, elicits a potent antitumor immune response while protecting against some forms of tissue inflammation and autoimmunity.
Assuntos
Encefalomielite Autoimune Experimental , Neoplasias , Animais , Humanos , Camundongos , Linfócitos T CD8-Positivos/metabolismo , Citocinas/metabolismo , Encefalomielite Autoimune Experimental/genética , Imunoterapia , Inflamação , Doenças Neuroinflamatórias , Microambiente TumoralRESUMO
The expression of co-inhibitory receptors, such as CTLA-4 and PD-1, on effector T cells is a key mechanism for ensuring immune homeostasis. Dysregulated expression of co-inhibitory receptors on CD4+ T cells promotes autoimmunity, whereas sustained overexpression on CD8+ T cells promotes T cell dysfunction or exhaustion, leading to impaired ability to clear chronic viral infections and diseases such as cancer1,2. Here, using RNA and protein expression profiling at single-cell resolution in mouse cells, we identify a module of co-inhibitory receptors that includes not only several known co-inhibitory receptors (PD-1, TIM-3, LAG-3 and TIGIT) but also many new surface receptors. We functionally validated two new co-inhibitory receptors, activated protein C receptor (PROCR) and podoplanin (PDPN). The module of co-inhibitory receptors is co-expressed in both CD4+ and CD8+ T cells and is part of a larger co-inhibitory gene program that is shared by non-responsive T cells in several physiological contexts and is driven by the immunoregulatory cytokine IL-27. Computational analysis identified the transcription factors PRDM1 and c-MAF as cooperative regulators of the co-inhibitory module, and this was validated experimentally. This molecular circuit underlies the co-expression of co-inhibitory receptors in T cells and identifies regulators of T cell function with the potential to control autoimmunity and tumour immunity.
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Linfócitos T CD4-Positivos/citologia , Linfócitos T CD4-Positivos/metabolismo , Linfócitos T CD8-Positivos/citologia , Linfócitos T CD8-Positivos/metabolismo , Redes Reguladoras de Genes/genética , Melanoma/imunologia , Transcrição Gênica , Animais , Linfócitos T CD4-Positivos/imunologia , Linfócitos T CD8-Positivos/imunologia , Feminino , Tolerância Imunológica/genética , Tolerância Imunológica/imunologia , Interleucina-27/imunologia , Linfócitos do Interstício Tumoral/citologia , Linfócitos do Interstício Tumoral/imunologia , Linfócitos do Interstício Tumoral/metabolismo , Masculino , Melanoma/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Fator 1 de Ligação ao Domínio I Regulador Positivo/metabolismo , Proteínas Proto-Oncogênicas c-maf/metabolismo , Receptores de Superfície Celular/genética , Receptores de Superfície Celular/metabolismo , Reprodutibilidade dos TestesRESUMO
Conformation-sensitive antibodies against myelin oligodendrocyte glycoprotein (MOG) are detectable in patients with optic neuritis, myelitis, opticomyelitis, acute or multiphasic disseminated encephalomyelitis (ADEM/MDEM) and brainstem/cerebral cortical encephalitis, but are rarely detected in patients with prototypic multiple sclerosis. So far, there has been no systematic study on the pathological relationship between demyelinating lesions and cellular/humoral immunity in MOG antibody-associated disease. Furthermore, it is unclear whether the pathomechanisms of MOG antibody-mediated demyelination are similar to the demyelination patterns of multiple sclerosis, neuromyelitis optica spectrum disorders (NMOSD) with AQP4 antibody, or ADEM. In this study, we immunohistochemically analysed biopsied brain tissues from 11 patients with MOG antibody-associated disease and other inflammatory demyelinating diseases. Patient median onset age was 29 years (range 9-64), and the median interval from attack to biopsy was 1 month (range 0.5-96). The clinical diagnoses were ADEM (n = 2), MDEM (n = 1), multiple brain lesions without encephalopathy (n = 3), leukoencephalopathy (n = 3) and cortical encephalitis (n = 2). All these cases had multiple/extensive lesions on MRI and were oligoclonal IgG band-negative. Most demyelinating lesions in 10 of 11 cases showed a perivenous demyelinating pattern previously reported in ADEM (153/167 lesions) and a fusion pattern (11/167 lesions) mainly in the cortico-medullary junctions and white matter, and only three lesions in two cases showed confluent demyelinated plaques. In addition, 60 of 167 demyelinating lesions (mainly in the early phase) showed MOG-dominant myelin loss, but relatively preserved oligodendrocytes, which were distinct from those of AQP4 antibody-positive NMOSD exhibiting myelin-associated glycoprotein-dominant oligodendrogliopathy. In MOG antibody-associated diseases, MOG-laden macrophages were found in the perivascular spaces and demyelinating lesions, and infiltrated cells were abundant surrounding multiple blood vessels in and around the demyelinating lesions, mainly consisting of macrophages (CD68; 1814 ± 1188 cells/mm2), B cells (CD20; 468 ± 817 cells/mm2), and T cells (CD3; 2286 ± 1951 cells/mm2), with CD4-dominance (CD4+ versus CD8+; 1281 ± 1196 cells/mm2 versus 851 ± 762 cells/mm2, P < 0.01). Humoral immunity, evidenced by perivascular deposits of activated complements and immunoglobulins, was occasionally observed in some MOG antibody-associated demyelinating lesions, and the frequency was much lower than that in AQP4 antibody-positive NMOSD. Subpial lesions with perivenous demyelination were observed in both ADEM and cortical encephalitis. Our study suggests that ADEM-like perivenous inflammatory demyelination with MOG-dominant myelin loss is a characteristic finding of MOG antibody-associated disease regardless of whether the diagnostic criteria of ADEM are met. These pathological features are clearly different from those of multiple sclerosis and AQP4 antibody-positive NMOSD, suggesting an independent autoimmune demyelinating disease entity.
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Encéfalo/patologia , Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/imunologia , Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/patologia , Glicoproteína Mielina-Oligodendrócito/imunologia , Adolescente , Adulto , Autoanticorpos/imunologia , Autoantígenos/imunologia , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
BACKGROUND: Fingolimod is an oral drug approved for multiple sclerosis (MS) with an ability to trap central memory T cells in secondary lymphoid tissues; however, its variable effectiveness in individual patients indicates the need to evaluate its effects on other lymphoid cells. OBJECTIVE: To clarify the effects of fingolimod on B-cell populations in patients with MS. METHODS: We analysed blood samples from 9 fingolimod-treated and 19 control patients with MS by flow cytometry, to determine the frequencies and activation states of naive B cells, memory B cells, and plasmablasts. RESULTS: The frequencies of each B-cell population in peripheral blood mononuclear cells (PBMC) were greatly reduced 2 weeks after starting fingolimod treatment. Detailed analysis revealed a significant reduction in activated memory B cells (CD38(int-high)), particularly those expressing Ki-67, a marker of cell proliferation. Also, we noted an increased proportion of activated plasmablasts (CD138(+)) among whole plasmablasts, in the patients treated with fingolimod. CONCLUSIONS: The marked reduction of Ki-67(+) memory B cells may be directly linked with the effectiveness of fingolimod in treating MS. In contrast, the relative resistance of CD138(+) plasmablasts to fingolimod may be of relevance for understanding the differential effectiveness of fingolimod in individual patients.
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Subpopulações de Linfócitos B/efeitos dos fármacos , Imunossupressores/uso terapêutico , Esclerose Múltipla/tratamento farmacológico , Propilenoglicóis/uso terapêutico , Esfingosina/análogos & derivados , ADP-Ribosil Ciclase 1/metabolismo , Adulto , Subpopulações de Linfócitos B/imunologia , Subpopulações de Linfócitos B/metabolismo , Biomarcadores/metabolismo , Estudos de Casos e Controles , Proliferação de Células/efeitos dos fármacos , Resistência a Medicamentos , Feminino , Cloridrato de Fingolimode , Citometria de Fluxo , Humanos , Memória Imunológica , Antígeno Ki-67/metabolismo , Ativação Linfocitária/efeitos dos fármacos , Masculino , Glicoproteínas de Membrana/metabolismo , Pessoa de Meia-Idade , Esclerose Múltipla/sangue , Esclerose Múltipla/diagnóstico , Esclerose Múltipla/genética , Esclerose Múltipla/imunologia , Fenótipo , RNA Mensageiro/metabolismo , Receptores de Lisoesfingolipídeo/genética , Receptores de Lisoesfingolipídeo/metabolismo , Esfingosina/uso terapêutico , Receptores de Esfingosina-1-Fosfato , Sindecana-1/metabolismo , Fatores de Tempo , Resultado do TratamentoAssuntos
Anticorpos Monoclonais Humanizados/efeitos adversos , Antineoplásicos Imunológicos/efeitos adversos , Diafragma/fisiopatologia , Miosite/induzido quimicamente , Nervo Frênico/fisiopatologia , Insuficiência Respiratória/fisiopatologia , Neoplasias da Bexiga Urinária/tratamento farmacológico , Idoso , Autoanticorpos/imunologia , Conectina/imunologia , Diafragma/diagnóstico por imagem , Eletromiografia , Humanos , Canal de Potássio Kv1.4/imunologia , Masculino , Miosite/complicações , Miosite/imunologia , Condução Nervosa , Ventilação não Invasiva , Respiração com Pressão Positiva , Insuficiência Respiratória/etiologia , Insuficiência Respiratória/terapia , Ultrassonografia , Capacidade VitalRESUMO
Neuromyelitis optica (NMO) is an inflammatory disease affecting the optic nerve and spinal cord, in which autoantibodies against aquaporin 4 (AQP4) water channel protein probably play a pathogenic role. Here we show that a B-cell subpopulation, exhibiting the CD19(int)CD27(high)CD38(high)CD180(-) phenotype, is selectively increased in the peripheral blood of NMO patients and that anti-AQP4 antibodies (AQP4-Abs) are mainly produced by these cells in the blood of these patients. These B cells showed the morphological as well as the phenotypical characteristics of plasmablasts (PB) and were further expanded during NMO relapse. We also demonstrate that interleukin 6 (IL-6), shown to be increased in NMO, enhanced the survival of PB as well as their AQP4-Ab secretion, whereas the blockade of IL-6 receptor (IL-6R) signaling by anti-IL-6R antibody reduced the survival of PB in vitro. These results indicate that the IL-6-dependent B-cell subpopulation is involved in the pathogenesis of NMO, thereby providing a therapeutic strategy for targeting IL-6R signaling.
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Aquaporina 4/imunologia , Autoanticorpos/biossíntese , Interleucina-6/metabolismo , Neuromielite Óptica/imunologia , Plasmócitos/imunologia , Transdução de Sinais , ADP-Ribosil Ciclase 1/metabolismo , Adulto , Antígenos CD/metabolismo , Proliferação de Células , Forma Celular , Sobrevivência Celular , Feminino , Regulação da Expressão Gênica , Humanos , Interleucina-6/antagonistas & inibidores , Masculino , Neuromielite Óptica/sangue , Neuromielite Óptica/patologia , Plasmócitos/patologia , Receptores de Citocinas/metabolismo , Membro 7 da Superfamília de Receptores de Fatores de Necrose Tumoral/metabolismoRESUMO
BACKGROUND: Although neurology department ward rounds are among the most important medical education exercises in Japan, they have several issues. Patients may find it unpleasant to undergo repeated neurological tests, especially when in the presence of several students. Only the front row of students can closely observe the examination findings; moreover, students were prohibited from contacting patients altogether during the COVID-19 pandemic. One possible solution is to use commercial videoconferencing systems. However, Japanese patients are reluctant to have their medical information or video footage of them sent outside of the hospital via the internet. OBJECTIVE: The study aimed to confirm the feasibility of conducting remote teaching rounds using an in-house web conferencing system in which the patients' personal data are securely protected. This study also explored whether using remote rounds alongside face-to-face participation would enhance learning. METHODS: We created an on-premises videoconferencing system using an open-source app. To perform video ward rounds, the professor wore a wireless microphone while leading routine in-person rounds and the attending physician carried a tablet device linked to a web conference, allowing students in another room to watch the rounds on a live stream. In total, 112 of 5th-year students who entered their 1-week neurology rotation between 2021 and 2022 were instructed to participate in 1-hour in-person and remote rounds. Students were given questionnaires to evaluate their satisfaction and the educational effects of the remote rounds. RESULTS: The remote ward rounds were conducted easily with no interference with the in-person rounds, nor any complaints from the patients. Each examination technique was explained by another teacher to the students who participated in remote rounds in the conference room. Characteristic neurological findings, such as plantar reflexes (Babinski sign), which are usually seen only by close observers during in-person rounds, could be visualized under magnification by all students. The postexperience survey (82/112, 73% response rate) showed that the mean score of participants' satisfaction was 3.94 (SD 0.83; excellent 5 and poor 1). No participant scoring 1 was noted. The proportion of students who observed 6 representative abnormal neurological findings (Babinski sign, hyperreflexia, cerebellar ataxia, involuntary movement, muscular weakness, and abnormality in sensory examination) increased by 22% (18/82, range 13-24) compared to in-person rounds alone. When self-rating the learning value, 43% (35/82) of the students answered that remote rounds are equally as valuable as in-person rounds, while 32% (26/82) preferred remote rounds. CONCLUSIONS: Live-streaming of neurology ward rounds using a secure in-house web conferencing system provides additional learning experience without concerns regarding leakage of patient information. This initiative could enhance neurology learning before entering a clinical clerkship.
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BACKGROUND AND OBJECTIVES: Interleukin-6 receptor antibodies (IL-6R Abs), including satralizumab, are increasingly used to prevent relapse for neuromyelitis optica spectrum disorder (NMOSD). However, the detailed mechanism of action of this treatment on the lymphocyte phenotype remains unclear. This study focused on B cells in patients with NMOSD, hypothesizing that IL-6R Ab enables B cells to acquire regulatory functions by producing the anti-inflammatory cytokine IL-10. METHODS: Peripheral blood mononuclear cells were stimulated in vitro to induce the expansion of B-cell subsets, double-negative B cells (DNs; CD19+ IgD-, CD27-) and plasmablasts (PBs; CD19+, CD27hi, CD38hi). Whole B cells, DNs, or PBs were isolated after culture with IL-6R Ab, and IL-10 expression was quantified using quantitative PCR and a cytometric bead array. RNA sequencing was performed to identify the marker of regulatory PBs induced by IL-6R Ab. RESULTS: DNs and PBs were observed to expand in patients with NMSOD during the acute attacks. In the in vitro model, IL-6R Ab increased IL-10 expression in B cells. Notably, IL-10 expression increased in PBs but not in DNs. Using RNA sequencing, CD200 was identified as a marker of regulatory PBs among the differentially expressed upregulated genes. CD200+ PBs produced more IL-10 than CD200- PBs. Furthermore, patients with NMOSD who received satralizumab had a higher proportion of CD200+ PBs than patients during the acute attacks. DISCUSSION: Treatment with IL-6 signaling blockade elicited a regulatory phenotype in B cells and PBs. CD200+ PBs may be a marker of treatment responsiveness in the context of NMOSD pathophysiology.
Assuntos
Interleucina-6 , Neuromielite Óptica , Receptores de Interleucina-6 , Humanos , Neuromielite Óptica/tratamento farmacológico , Neuromielite Óptica/imunologia , Feminino , Adulto , Masculino , Pessoa de Meia-Idade , Interleucina-6/metabolismo , Receptores de Interleucina-6/antagonistas & inibidores , Plasmócitos/efeitos dos fármacos , Plasmócitos/imunologia , Interleucina-10/metabolismo , Transdução de Sinais/efeitos dos fármacosRESUMO
Neuromyelitis optica spectrum disorder (NMOSD) is a rare autoimmune inflammatory disease that can affect multiple generations and cause complications with long-term prednisolone treatment. This study aimed to evaluate the efficacy and safety of mycophenolate mofetil (MMF) in preventing NMOSD relapse while reducing prednisolone dosage. The trial involved nine patients with NMOSD who received MMF along with prednisolone dose reduction. MMF was effective in achieving prednisolone dose reduction without relapse in 77.8% of patients, with a significant decrease in mean annualized relapse rate. All adverse events were mild. The findings suggest that MMF could be a viable treatment option for middle-aged and older patients who require steroid reduction.Clinical trial registration number: jRCT, jRCTs051180080. Registered February 27th, 2019-retrospectively registered, https://jrct.niph.go.jp/en-latest-detail/jRCTs051180080.
Assuntos
Ácido Micofenólico , Neuromielite Óptica , Prednisolona , Adulto , Idoso , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Imunossupressores/efeitos adversos , Imunossupressores/administração & dosagem , Ácido Micofenólico/efeitos adversos , Ácido Micofenólico/administração & dosagem , Neuromielite Óptica/tratamento farmacológico , Prednisolona/administração & dosagem , Prednisolona/efeitos adversos , Estudos Prospectivos , Recidiva , Resultado do TratamentoRESUMO
BACKGROUND: The previous Japanese clinical practice guidelines for multiple sclerosis (MS) and neuromyelitis optica spectrum disorder (NMOSD) were published in 2017. Recently, for the first time in 6 years, the MS and NMOSD guideline development committee revised the Japanese guidelines for MS, NMOSD, and myelin oligodendrocyte glycoprotein antibody-associated disease (MOGAD). METHODS: The committee utilized the Grading of Recommendations Assessment, Development, and Evaluation system based on the "Minds Handbook for Clinical Practice Guideline Development 2020 Ver. 3.0â³ with a focus on clinical questions (CQs). The committee also discussed clinical issues other than CQs, categorizing them as a question-and-answer (Q&A) section, including "issues on which experts' opinions agree to a certain extent" and "issues that are important but not included in the CQ". RESULTS: The committee identified 3, 1, and 1 key CQs related to MS, NMOSD, and MOGAD, respectively, and presented recommendations. A Q&A session regarding disease-modifying therapies and relapse prevention therapies for MS, NMOSD, and MOGAD was conducted. The revised guidelines were published in September 2023. CONCLUSIONS: The Japanese guidelines for clinical practice on MS, NMOSD, and MOGAD were updated. Treatment strategies for MS, NMOSD, and MOGAD are changing, and these updated guidelines may assist with treatment decisions for these diseases in clinical practice.
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We report two male patients who had a sensory seizure, which evolved into a focal impaired awareness tonic seizure, and after that, focal to bilateral tonic-clonic seizure. The first case, a 20-year-old man had been treated with steroids for anti-myelin oligodendrocyte glycoprotein (MOG) antibody-positive optic neuritis. His seizure started with abnormal sensation in the little finger of the left hand, which spread to the left upper and then to the left lower limb. The seizure then evolved into tonic seizures of the upper and lower limbs and he finally lost awareness. The second case, a 19-year-old man experienced floating dizziness while walking, followed by numbness and a pain-like electrical shock in the right upper limb. The right arm somatosensory seizure evolved into a right upper and lower limb tonic seizure, which spread to the bilateral limbs, and finally he lost awareness. Symptoms of both patients improved after the treatment with steroids. Both patients shared a similar high-intensity FLAIR lesion in the posterior midcingulate cortex. Both patients were diagnosed with MOG antibody-positive cerebral cortical encephalitis because of a positive titer of anti-MOG antibody in the serum. Several reports showed involvement of the cingulate gyrus in MOG antibody-positive cerebral cortical encephalitis, but only a few reported seizure semiology in detail. The semiology reported here is consistent with that of cingulate epilepsy or the findings of electrical stimulation of the cingulate cortex, namely, somatosensory (electric shock or heat sensation), motor (tonic posture), and vestibular symptoms (dizziness). Cingulate seizures should be suspected when patients show somatosensory seizures or focal tonic seizures. MOG antibody-positive cerebral cortical encephalitis should be considered as one of the differential diagnoses when the young patient shows the unique symptoms of an acute symptomatic cingulate seizure.
Assuntos
Encefalite , Imageamento por Ressonância Magnética , Humanos , Masculino , Autoanticorpos , Tontura , Encefalite/tratamento farmacológico , Glicoproteína Mielina-Oligodendrócito , Oligodendroglia , Convulsões/etiologia , Vertigem , Adulto JovemRESUMO
A 47-year-old woman with dysphagia and ptosis gradually developed dysarthria and muscular weakness. Magnetic resonance imaging, testing for anti-acetylcholine receptor antibodies, edrophonium chloride (EC) test, and electrophysiologic test revealed no abnormalities. A psychogenic reaction was suspected. Four months after disease onset, the patient presented to our hospital. In videofluoroscopic examination of swallowing (VF), there was no aspiration for swallowing of either liquid or soft food. It revealed, however, poor pharyngeal constriction, no epiglottis inversion, repeated swallowing movements, and large amounts of pharyngeal residue. Videofluoroscopic examination of swallowing after an intravenous injection of 10 mg EC showed improvements in all above observations; particularly, it was clear when swallowing soft food. Furthermore, the anti-muscle-specific kinase (MuSK) antibody titer was elevated, and anti-MuSK antibody-positive myasthenia gravis (MuSK-MG) was diagnosed. Thus VF during EC test may be helpful in diagnosing MuSK-MG in patients with dysphagia.
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Autoanticorpos/sangue , Fluoroscopia/métodos , Miastenia Gravis/diagnóstico por imagem , Receptores Proteína Tirosina Quinases/imunologia , Receptores Colinérgicos/imunologia , Gravação de Videoteipe , Diagnóstico Diferencial , Feminino , Humanos , Pessoa de Meia-Idade , Miastenia Gravis/imunologiaRESUMO
Neuromyelitis optica (NMO) is an inflammatory disease that resembles MS in the relapsing clinical course of optic neuritis and myelitis. Two decades of studies have revealed that autoantibodies, reactive to the water channel protein aquaporin 4 (AQP4) are detected in the core group of patients. These autoantibodies play a crucial role in the inflammatory pathology of NMO, involving proinflammatory cytokines, chemokines, and various inflammatory cells such as Th17 cells. Anti-AQP4 antibody-positive NMO differs fundamentally from MS, particularly in the responsiveness to therapies and the neuropathology accompanying destruction of astrocytes. Research into the immunological mechanism has led to the identification of possible targets of therapy, including complement pathway and interleukin-6 (IL-6) receptor signaling. Recent randomized controlled clinical trials have shown the remarkable efficacy of antibodies specific for complement C5, IL-6 receptor, and CD19+ B cells in prevention of NMO spectrum disorder relapses, although no such effects were found in anti-AQP4 antibody-negative patients. These results imply that anti-AQP4 antibody is a biomarker predicting the efficacy of therapies, and indicate the future direction towards "precision medicine."
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Neuromielite Óptica , Aquaporina 4/metabolismo , Aquaporina 4/uso terapêutico , Autoanticorpos , Biomarcadores , Quimiocinas/metabolismo , Complemento C5/metabolismo , Complemento C5/uso terapêutico , Citocinas/metabolismo , Humanos , Interleucina-6/metabolismo , Neuromielite Óptica/etiologia , Neuromielite Óptica/terapia , Receptores de Interleucina-6/metabolismo , Receptores de Interleucina-6/uso terapêuticoRESUMO
Neuromyelitis optica spectrum disorder (NMOSD) is an autoimmune inflammatory disease, occasionally accompanied by malignant tumors. Immunosuppressive therapy is the mainstay treatment for idiopathic NMOSD; no guidelines have been published for paraneoplastic NMOSD because it is rarely reported in the literature. We report a rare case of a 67-year-old man with paraneoplastic NMOSD associated with thymic carcinoid whose cells expressed aquaporin-4 antibody. After surgical resection, the patient's symptoms improved, and serum aquaporin-4 autoantibody turned negative. We believe that radiographic examination for mediastinal tumors in patients with NMOSD is necessary because thymic epithelial tumors could have a role in the pathogenesis of paraneoplastic NMOSD. After mediastinal tumor has been detected, they should be surgically resected to improve neurological symptoms.
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Tumor Carcinoide , Neuromielite Óptica , Masculino , Humanos , Idoso , Neuromielite Óptica/complicações , Neuromielite Óptica/diagnóstico por imagem , Neuromielite Óptica/cirurgia , Resultado do Tratamento , Aquaporina 4 , Autoanticorpos , Tumor Carcinoide/complicações , Tumor Carcinoide/diagnóstico por imagem , Tumor Carcinoide/cirurgiaRESUMO
BACKGROUND AND OBJECTIVES: Multiple sclerosis (MS) is an inflammatory demyelinating disease of the CNS. CD8+ T cells are prominently found at inflammatory sites. Recent advances in understanding checkpoint molecules, including programmed cell death 1 (PD-1), expressed on CD8+ T cells, highlight the immune regulatory roles of this T-cell subset; however, the role of CD8+ T cells in MS is unclear. Thus, we aimed to reveal the characteristics of PD-1-expressed (PD-1+) CD8+ T cells in MS. METHODS: We performed a cohort, case-control study for phenotyping analysis of PD-1+CD8+ T cells in disease remission and flare states using CSF and peripheral blood samples of 45 patients with MS or clinically isolated syndrome and 12 healthy subjects. We further analyzed the transcriptome of sorted PD-1+CD8+ T cells obtained from interferon (IFN)-ß-treated patients and validated their regulatory machinery using in vitro cell culture assays with lentiviral gene transfer. RESULTS: In the disease remission state, PD-1+CD8+ T cells were decreased in the peripheral blood of patients with MS and resolved in patients treated with IFN-ß treatment who showed immune regulatory cytokine interleukin (IL)-10 expression. In the disease flare state, we found that PD-1+CD8+ T cells were enriched in the CSF, which predicted a good response to subsequent IV steroid therapy. Transcriptome analysis of sorted PD-1+CD8+ T cells revealed the transcription factor c-Maf as a potential major regulator of the gene module, including multiple coinhibitory molecules. Furthermore, c-Maf expressed in CD8+ T cells induced PD-1 expression and production of IL-10 as well as suppressed alloactivated CD4+ T-cell survival. DISCUSSION: This study uncovered a favorable role of PD-1+CD8+ T cells against MS and demonstrated that c-Maf-driven IL-10 is an immune regulatory machinery.
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Linfócitos T CD8-Positivos , Esclerose Múltipla , Proteínas Proto-Oncogênicas c-maf , Apoptose , Linfócitos T CD8-Positivos/metabolismo , Estudos de Casos e Controles , Humanos , Interleucina-10/metabolismo , Receptor de Morte Celular Programada 1/metabolismo , Proteínas Proto-Oncogênicas c-maf/metabolismoRESUMO
Background and Objectives: We describe 2 long-surviving siblings with a mild phenotype of Joubert syndrome (JBTS) harboring a novel compound heterozygous missense variant in the CPLANE1 gene. Methods: Targeted sequencing data of 2 middle-aged siblings (sister and brother) with JBTS were analyzed. Results: The patients were older than 60 years and presented with an inborn facial anomaly and ataxia, accompanied by a molar tooth sign on brain MRI. The male patient showed mild intellectual disability, abnormal eye movements, and progressive gait disturbance. Targeted sequencing revealed a compound heterozygous missense variant of CPLANE1 p.Arg1193Cys_Gln1223Pro; c.3577C>T_3668A>C. Multiple in silico assays predicted that the missense sites were pathogenic. Discussion: The phenotype-genotype correlation of CPLANE1 remains controversial, although many cases have been previously reported in children and young adults. Our study revealed a novel pathogenic variant of CPLANE1 in patients, confirming the role of this gene in JBTS, thus providing an opportunity for neurologists to recognize JBTS as a differential diagnosis for chronic progressive ataxia in an aging society.
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BACKGROUND: In the current consensus criteria, onset after age 75 is considered as non-supporting for diagnosis of multiples system atrophy (MSA); however, some MSA patients present after age 75. Clinical and pathological characteristics of such later onset MSA (LO-MSA) compared to usual onset MSA (UO-MSA) remain poorly understood. METHODS: The clinical cohort included patients from Kobe University Hospital and Amagasaki General Medical Center Hospital, while the autopsy cohort was from the brain bank at Mayo Clinic Florida. We identified 83 patients in the clinical cohort and 193 patients in the autopsy cohort. We divided MSA into two groups according to age at onset: UO-MSA (≤ 75) and LO-MSA (> 75). We compared clinical features and outcomes between the two groups in the clinical cohort and compared the findings to the autopsy cohort. RESULTS: LO-MSA accounted for 8% in the clinical cohort and 5% in the autopsy cohort. The median time from onset to death or to life-saving tracheostomy was significantly shorter in LO-MSA than in UO-MSA in both cohorts (4.8 vs 7.9 years in the clinical cohort and 3.9 vs 7.5 years in the autopsy cohort; P = 0.043 and P < 0.0001, respectively). The median time from diagnosis to death was less than 3 years in LO-MSA in the clinical cohort. CONCLUSIONS: Some MSA patients have late age of onset and short survival, limiting time for clinical decision making. MSA should be considered in the differential diagnosis of elderly patients with autonomic symptoms and extrapyramidal and/or cerebellar syndromes.
Assuntos
Atrofia de Múltiplos Sistemas , Idoso , Autopsia , Encéfalo/patologia , Estudos de Coortes , Diagnóstico Diferencial , Humanos , Atrofia de Múltiplos Sistemas/diagnósticoRESUMO
Autoimmune epilepsy (AE) is an inflammatory disease of the central nervous system with symptoms that have seizures that are refractory to antiepileptic drugs. Since the diagnosis of AE tends to rely on a limited number of anti-neuronal antibody tests, a more comprehensive analysis of the immune background could achieve better diagnostic accuracy. This study aimed to compare the characteristics of anti-neuronal antibody-positive autoimmune epilepsy (AE/Ab(+)) and antibody-negative suspected autoimmune epilepsy (AE/Ab(-)) groups. A total of 23 patients who met the diagnostic criteria for autoimmune encephalitis with seizures and 11 healthy controls (HC) were enrolled. All patients were comprehensively analyzed for anti-neuronal antibodies; 13 patients were identified in the AE/Ab(+) group and 10 in the AE/Ab(-) group. Differences in clinical characteristics, including laboratory and imaging findings, were evaluated between the groups. In addition, the immunophenotype of peripheral blood mononuclear cells (PBMCs) and CSF mononuclear cells, particularly B cells and circulating Tfh (cTfh) subsets, and multiplex assays of serum and CSF were analyzed using flow cytometry. Patients with AE/Ab(+) did not show any differences in clinical parameters compared to patients with AE/Ab(-). However, the frequency of plasmablasts within PBMCs and CSF in patients with AE/Ab(+) was higher than that in patients with AE/Ab(-) and HC, and the frequency of cTfh17 cells and inducible T-cell co-stimulator (ICOS) expressing cTfh17 cells within cTfh subsets was higher than that in patients with AE/Ab(-). Furthermore, the frequency of ICOShighcTfh17 cells was positively correlated with that of the unswitched memory B cells. We also found that IL-12, IL-23, IL-6, IL-17A, and IFN-γ levels were elevated in the serum and IL-17A and IL-6 levels were elevated in the CSF of patients with AE/Ab(+). Our findings indicate that patients with AE/Ab(+) showed increased differentiation of B cells and cTfh subsets associated with antibody production. The elevated frequency of plasmablasts and ICOS expressing cTfh17 shift in PBMCs may be indicative of the presence of antibodies in patients with AE.
Assuntos
Epilepsia , Linfócitos T Auxiliares-Indutores , Humanos , Interleucina-17 , Leucócitos Mononucleares , Interleucina-6 , ConvulsõesRESUMO
A 62-year-old man showed abnormal behavior. Brain magnetic resonance imaging revealed multifocal lesions on T2-weighted images. Initial screening revealed that he was seropositive for antibodies against glutamate decarboxylase, which usually indicates treatment resistance to autoimmune encephalitis (AE). Intensive immunosuppressive therapies, however, improved the neurological symptoms. In line with this, we also detected seropositivity for antibodies against leucine-rich glioma-inactivated 1 and gamma-aminobutyric acid A receptor (GABAAR). Brain imaging and treatment responsiveness suggested that antibodies against GABAAR were the main cause of symptoms. Furthermore, the patient showed the presence of triple anti-neural antibodies in the absence of malignancy and had a favorable clinical course.