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Reversing the dysfunctional T cell state that arises in cancer and chronic viral infections is the focus of therapeutic interventions; however, current therapies are effective in only some patients and some tumor types. To gain a deeper molecular understanding of the dysfunctional T cell state, we analyzed population and single-cell RNA profiles of CD8(+) tumor-infiltrating lymphocytes (TILs) and used genetic perturbations to identify a distinct gene module for T cell dysfunction that can be uncoupled from T cell activation. This distinct dysfunction module is downstream of intracellular metallothioneins that regulate zinc metabolism and can be identified at single-cell resolution. We further identify Gata-3, a zinc-finger transcription factor in the dysfunctional module, as a regulator of dysfunction, and we use CRISPR-Cas9 genome editing to show that it drives a dysfunctional phenotype in CD8(+) TILs. Our results open novel avenues for targeting dysfunctional T cell states while leaving activation programs intact.
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Linfocitos T CD8-positivos/patología , Activación de Linfocitos/genética , Activación de Linfocitos/inmunología , Linfocitos Infiltrantes de Tumor/inmunología , Linfocitos Infiltrantes de Tumor/patología , Animales , Linfocitos T CD8-positivos/inmunología , Sistemas CRISPR-Cas , Carcinogénesis/genética , Carcinogénesis/inmunología , Femenino , Factor de Transcripción GATA3/metabolismo , Perfilación de la Expresión Génica , Regulación Neoplásica de la Expresión Génica/genética , Humanos , Melanoma/inmunología , Melanoma/fisiopatología , Metalotioneína/deficiencia , Ratones , Ratones Endogámicos BALB C , Ratones Endogámicos C57BLRESUMEN
Intensive immunosuppression has enabled liver transplantation even in recipients with preformed donor-specific antibodies (DSA), an independent risk factor for graft rejection. However, these recipients may also be at high risk of progressive multifocal encephalopathy (PML) due to the comorbid immunosuppressed status. A 58-year-old woman presented with self-limited focal-to-bilateral tonic-clonic seizures 9 months after liver transplantation. She was desensitized using rituximab and plasma exchange before transplantation and was subsequently treated with steroids, tacrolimus, and everolimus after transplantation for her preformed DSA. Neurological examination revealed mild acalculia and agraphia. Cranial MRI showed asymmetric, cortex-sparing white matter lesions that increased over a week in the left frontal, left parietal, and right parieto-occipital lobes. Polymerase chain reaction (PCR) of the cerebrospinal fluid for the JC supported the diagnosis of PML. Immune reconstitution by reducing the immunosuppressant dose stopped lesion expansion, and PCR of the cerebrospinal fluid for the JC virus became negative. Graft rejection occurred 2 months after immune reconstitution, requiring readjustment of immunosuppressants. Forty-eight months after PML onset, the patient lived at home without disabling deficits. Intensive immunosuppression may predispose recipients to PML after liver transplantation with preformed DSA. Early immune reconstitution and careful monitoring of graft rejection may help improve outcomes.
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Virus JC , Leucoencefalopatía Multifocal Progresiva , Trasplante de Hígado , Humanos , Femenino , Persona de Mediana Edad , Trasplante de Hígado/efectos adversos , Donadores Vivos , Virus JC/genética , Inmunosupresores/uso terapéuticoRESUMEN
INTRODUCTION/AIMS: Heterozygous CGG repeat expansions in low-density lipoprotein receptor-related protein 12 (LRP12) have recently been identified as a cause of oculopharyngodistal myopathy (OPDM), and the disease is designated as OPDM type 1 (OPDM1). In contrast to broadening of our knowledge on the genetic background of OPDM, what we know of the clinical phenotype of genetically confirmed OPDM1 remains limited. METHODS: This investigation was a single-center case series study of OPDM consisting of ten patients from seven families. Repeat-primed polymerase chain reaction and Southern blot analyses were performed to confirm the CGG repeat expansions in LRP12. Clinical findings were retrospectively reviewed. RESULTS: Seven patients from five families were identified as having CGG repeat expansions in LRP12. We found a high prevalence of axial muscle involvement, such as neck muscle weakness (6/7) and fatty infiltration in the rectus abdominis muscle, as revealed by computed tomography (5/5). We identified patients with very subtle oculopharyngeal symptoms, mimicking isolated distal myopathy. Muscle specimens were collected from the biceps brachii and tibialis anterior muscles of three patients. Myopathic changes were more severe with more atrophic fibers forming clusters in the tibialis anterior than the biceps brachii muscles of these three patients. No rimmed vacuoles were observed in the biceps brachii muscles in two of the three patients. DISCUSSION: This study shows the expanded clinical spectrum of OPDM1, highlighting the importance of axial muscle evaluation in OPDM1. Considering patients with very subtle oculopharyngeal symptoms, genetic analysis of LRP12 should be considered in patients with isolated distal myopathy.
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Miopatías Distales , Enfermedades Musculares , Humanos , Estudios Retrospectivos , Enfermedades Musculares/diagnóstico , Enfermedades Musculares/genética , Músculo EsqueléticoRESUMEN
Our objective was to investigate the frequency of KIF5A variants in amyotrophic lateral sclerosis (ALS) and the clinical characteristics of familial ALS (FALS) associated with variants in KIF5A. Whole-exome sequence analysis was performed for a Japanese series of 43 families with FALS and 444 patients with sporadic ALS (SALS), in whom causative variants had not been identified. We compared the frequencies of rare variants (MAF < 0.01) in KIF5A, including missense and loss of function (LoF) variants, between ALS and control subjects (n = 1163). Clinical characteristics of patients with FALS carrying pathogenic variants in KIF5A were also described. LoF variants were identified only in the probands of two families with FALS, both of which were 3' splice-site variants leading to exon skipping and an altered C-terminal domain, located in the mutational hotspot causing FALS, and were considered to be pathogenic for FALS. Rare missense variants in KIF5A were identified in five patients with SALS (1.13%) and 11 control subjects (0.95%, carrier frequency), which were not significantly different. Consequently, the pathogenic LoF variants in KIF5A accounted for 2.1% of all FALS families in this study. These patients suffered from ALS characteristically associated with the predominant involvement of upper motor neuron. In conclusion, we identified two pathogenic splice-site variants in KIF5A in the probands in two Japanese families with FALS, which altered the C-terminal region of KIF5A. Our findings broaden the phenotype spectrum of ALS associated with variants in KIF5A in the Japanese series.
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Esclerosis Amiotrófica Lateral/genética , Predisposición Genética a la Enfermedad/genética , Cinesinas/genética , Mutación/genética , Adulto , Esclerosis Amiotrófica Lateral/diagnóstico , Pueblo Asiatico/genética , Femenino , Estudios de Asociación Genética , Humanos , Japón , Masculino , Persona de Mediana EdadRESUMEN
T cell immunoglobulin-3 (Tim-3) has been identified as a marker of differentiated interferon-γ-producing CD4(+) T helper type 1 and CD8(+) T cytotoxic type 1 cells. The interaction of Tim-3 with its ligand, galectin-9 (Gal-9), induces cell death, and in vivo blockade of this interaction results in exacerbated autoimmunity and abrogation of tolerance in experimental models, establishing Tim-3 as a negative regulatory molecule. Recent studies have uncovered additional mechanisms by which Tim-3 negatively regulates T cell responses, such as promoting the development of CD8(+) T cell exhaustion and inducing expansion of myeloid-derived suppressor cells. In contrast to this inhibitory effect on T cells, Tim-3-Gal-9 interaction promotes macrophage clearance of intracellular pathogens. Here, we focus on the emerging role for Tim-3 in tumor and antimicrobial immunity.
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Infecciones Bacterianas/inmunología , Galectinas/inmunología , Proteínas de la Membrana/inmunología , Neoplasias/inmunología , Células TH1/inmunología , Animales , Antígenos de Neoplasias/inmunología , Apoptosis , Galectinas/metabolismo , Receptor 2 Celular del Virus de la Hepatitis A , Humanos , Tolerancia Inmunológica/genética , Inmunidad Celular , Inmunidad Innata , Terapia de Inmunosupresión , Activación de Macrófagos , Células Mieloides/inmunologíaRESUMEN
Charcot-Marie-Tooth (CMT) disease is a heterogeneous hereditary motor and sensory neuropathy of the peripheral nervous system, with CMT1A in particular being the most common form. We encountered a 76-year-old woman with CMT1A who had a history of pain attacks and hearing loss from a young age, with motor symptoms manifesting late in life. Her pain and hearing loss may have been related to CMT. Our case also raises the possibility that neuropathic pain and hearing loss may precede the classic motor symptoms of CMT1A.
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Enfermedad de Charcot-Marie-Tooth , Sordera , Pérdida Auditiva , Neuropatía Hereditaria Motora y Sensorial , Femenino , Humanos , Anciano , Enfermedad de Charcot-Marie-Tooth/complicaciones , Enfermedad de Charcot-Marie-Tooth/diagnóstico , Enfermedad de Charcot-Marie-Tooth/genética , Pérdida Auditiva/etiología , Pérdida Auditiva/genética , Dolor , Proteínas de la Mielina/genéticaRESUMEN
Adrenomyeloneuropathy (AMN)/adrenoleukodystrophy (ALD) is an X-linked genetic disorder caused by pathogenic variants in ABCD1. We treated a 54-year-old man with slowly progressive spastic paraparesis with later development of the cerebral form. A pathogenic splice-site variant of ABCD1 (c.1489-1G>A, p.Val497Alafs*51) and elevated levels of very long-chain fatty acids were found, leading to the diagnosis of AMN. Detailed ABCD1 mRNA expression analyses revealed decreased levels of ABCD1 mRNA accompanied by deletion of the first 31 bp in exon 6. The altered mRNA transcriptional patterns associated with splice site variants are diverse and may provide important insights into ALD pathogenesis.
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Adrenoleucodistrofia , Masculino , Humanos , Persona de Mediana Edad , Adrenoleucodistrofia/genética , Adrenoleucodistrofia/diagnóstico , Adrenoleucodistrofia/metabolismo , Linaje , ARN Mensajero/genética , Miembro 1 de la Subfamilia D de Transportador de Casetes de Unión al ATP/genéticaRESUMEN
We herein report a 78-year-old woman with Gaucher disease (GD) who was initially diagnosed with GD type 1, had been receiving long-term enzyme replacement therapy since 58 years old, and developed neurological manifestations in her 70s. The neurological manifestations included myoclonic seizures and progressive cognitive decline. Although it is rare for GD patients to first develop neurologic manifestations at such an advanced age, physicians engaged in long-term care for GD patients should be alert for this possibility.
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Enfermedad de Gaucher , Anciano , Femenino , Humanos , Terapia de Reemplazo Enzimático , Enfermedad de Gaucher/complicaciones , Enfermedad de Gaucher/diagnóstico , Enfermedad de Gaucher/tratamiento farmacológico , Glucosilceramidasa/uso terapéutico , Cuidados a Largo Plazo , Convulsiones/etiologíaRESUMEN
Post-transplant lymphoproliferative disorders (PTLDs) are lymphoproliferative diseases that occur after solid organ transplantation or hematopoietic stem cell transplantation (HSCT). The development of PTLD is often associated with reactivation of Epstein-Barr virus (EBV). A 26-year-old woman with a history of HSCT and total-body irradiation developed spinal cord hemorrhage from a radiation-induced cavernous hemangioma (RICH) shortly after the development of classical Hodgkin lymphoma PTLD with EBV reactivation. Although little is known about the factors leading to hemorrhagic events from spinal cord RICH, we suspect that EBV reactivation may have been a factor contributing to the hemorrhage in the present case.
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Anti-Lactosylceramide (LacCer) antibodies are associated with neurological inflammation involving both the peripheral and central nervous system (PNS, CNS respectively), however, the documented number of cases is small. Uncertainty remains whether its positivity can identify a unique clinical entity. Here, we describe two anti-LacCer antibody positive cases, both with long histories (> 30 years) of teenage-diagnosed chronic inflammatory demyelinating polyradiculoneuropathy (CIDP). CNS lesions including the medulla oblongata were observed for the first time in adulthood. We suggest that this secondary progression of CNS lesions in juvenile-onset CIDP can be one of the characteristic features of anti-LacCer antibody associated neurological disorder.
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Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante , Polirradiculoneuropatía , Adolescente , Humanos , Polirradiculoneuropatía Crónica Inflamatoria Desmielinizante/diagnóstico , Inflamación , Sistema Nervioso CentralRESUMEN
Desminopathy is a cardiac and skeletal myopathy caused by disease-causing variants in the desmin (DES) gene and represents a subgroup of myofibrillar myopathies, where cytoplasmic desmin-postive immunoreactivity is the pathological hallmark. We herein report a 28-year-old Japanese man who was initially diagnosed with sporadic hypertrophic cardiomyopathy with atrioventricular block at 9 years old and developed weakness in the soft palate and extremities. The myocardial tissue dissected during implantation of the ventricular-assisted device showed a dilated phase of hypertrophic cardiomyopathy and intracellular accumulation of proteinase K-resistant desmin aggregates. Genetic testing confirmed a de novo mutation of DES, which has already been linked to desminopathy. As the molecular diagnosis of desminopathy is challenging, particularly if patients show predominantly cardiac signs and a routine skeletal muscle biopsy is unavailable, these characteristic pathological findings of endomyocardial proteinase K-resistant desmin aggregates might aid in clinical practice.
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Cardiomiopatías , Cardiomiopatía Hipertrófica , Miopatías Estructurales Congénitas , Masculino , Humanos , Niño , Adulto , Desmina/genética , Desmina/metabolismo , Cardiomiopatías/diagnóstico , Cardiomiopatías/genética , Cardiomiopatías/patología , Endopeptidasa K/genética , Mutación/genéticaRESUMEN
Objective Although aerobic exercise tests on cycle ergometry have long been used for initial assessments of cases of suspected mitochondrial disease, the test parameters in patients with final diagnoses of other diseases via the widely used 15 W for 15 minutes exercise protocol have not been fully characterized. Methods We retrospectively reviewed all patients who underwent the test at our institution. We classified the patients with genetic diagnoses or those who met previously reported clinical criteria as having mitochondrial diseases and those with a final diagnosis of another disease as having other diseases. Results were available from 6 patients with mitochondrial disease and 15 with other diseases. Results During the test, elevated venous peak lactate above the upper normal limit of healthy controls at rest [19.2 mg/dL (2.13 mM)] was observed in 3 patients with mitochondrial diseases (50.0%) and 5 with other diseases (33.3%). In the group of patients with elevated venous peak lactate, a lactate-to-pyruvate ratio of >20 was observed in all 3 patients with mitochondrial disease but in only 1 of the 5 with other diseases. More than a 2-fold increase in venous lactate from baseline was observed in 4 patients with mitochondrial disease (66.7%) and 1 with another disease (6.7%). Conclusion Elevated venous peak lactate levels were observed in patients with final diagnoses of other diseases, even under a low 15-minute workload at 15 W. The lactate-to-pyruvate ratio and increase in lactate level from baseline may add diagnostic value to venous peak lactate levels alone.
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Ácido Láctico , Enfermedades Mitocondriales , Ejercicio Físico , Prueba de Esfuerzo/métodos , Humanos , Enfermedades Mitocondriales/diagnóstico , Piruvatos , Estudios RetrospectivosRESUMEN
Accumulated experience supports the efficacy of allogenic haematopoietic stem cell transplantation in arresting the progression of childhood-onset cerebral form of adrenoleukodystrophy in early stages. For adulthood-onset cerebral form of adrenoleukodystrophy, however, there have been only a few reports on haematopoietic stem cell transplantation and the clinical efficacy and safety of that for adulthood-onset cerebral form of adrenoleukodystrophy remain to be established. To evaluate the clinical efficacy and safety of haematopoietic stem cell transplantation, we conducted haematopoietic stem cell transplantation on 12 patients with adolescent-/adult-onset cerebral form/cerebello-brainstem form of adrenoleukodystrophy in a single-institution-based prospective study. Through careful prospective follow-up of 45 male adrenoleukodystrophy patients, we aimed to enrol patients with adolescent-/adult-onset cerebral form/cerebello-brainstem form of adrenoleukodystrophy at early stages. Indications for haematopoietic stem cell transplantation included cerebral form of adrenoleukodystrophy or cerebello-brainstem form of adrenoleukodystrophy with Loes scores up to 13, the presence of progressively enlarging white matter lesions and/or lesions with gadolinium enhancement on brain MRI. Clinical outcomes of haematopoietic stem cell transplantation were evaluated by the survival rate as well as by serial evaluation of clinical rating scale scores and neurological and MRI findings. Clinical courses of eight patients who did not undergo haematopoietic stem cell transplantation were also evaluated for comparison of the survival rate. All the patients who underwent haematopoietic stem cell transplantation survived to date with a median follow-up period of 28.6 months (4.2-125.3 months) without fatality. Neurological findings attributable to cerebral/cerebellar/brainstem lesions became stable or partially improved in all the patients. Gadolinium-enhanced brain lesions disappeared or became obscure within 3.5 months and the white matter lesions of MRI became stable or small. The median Loes scores before haematopoietic stem cell transplantation and at the last follow-up visit were 6.0 and 5.25, respectively. Of the eight patients who did not undergo haematopoietic stem cell transplantation, six patients died 69.1 months (median period; range 16.0-104.1 months) after the onset of the cerebral/cerebellar/brainstem lesions, confirming that the survival probability was significantly higher in patients with haematopoietic stem cell transplantation compared with that in patients without haematopoietic stem cell transplantation (P = 0.0089). The present study showed that haematopoietic stem cell transplantation was conducted safely and arrested the inflammatory demyelination in all the patients with adolescent-/adult-onset cerebral form/cerebello-brainstem form of adrenoleukodystrophy when haematopoietic stem cell transplantation was conducted in the early stages. Further studies are warranted to optimize the procedures of haematopoietic stem cell transplantation for adolescent-/adult-onset cerebral form/cerebello-brainstem form of adrenoleukodystrophy.
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Hypoglossal nerve palsy (HNP) is a potential cause of dysphagia. A 66-year-old man presented to our hospital with dysphagia and neck pain. One year prior to his first visit, he had been diagnosed with upper cervical tuberculosis and had undergone posterior C1-2 fixation. The physical examination led to the diagnosis of dysphagia with HNP, and he had severe weight loss. Radiographic examination revealed that the O-C kyphosis had been exacerbated and that the deformity was likely the primary cause of HNP. To restore the swallowing function, O-C fusion surgery was performed. Postoperatively, the patient showed immediate improvement of dysphagia with gradual recovery of hypoglossal nerve function. In the last follow-up evaluation, swallowing function was confirmed with no signs of HNP. Our results indicate that HNP could be more prevalent in cases with severe cervical kyphosis, being underdiagnosed due to the more apparent signs of the oropharyngeal narrowing.
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A complete loss of merosin, which is encoded by LAMA2, causes congenital muscular dystrophy with leukoencephalopathy. Partial merosin deficiency can be caused not only by primarily LAMA2 mutations, but also secondarily by dystroglycanopathy. Although it can be molecularly diagnosed based on a genetic analysis, this method is labor-intensive because of its huge genome size. A 26-year-old male patient presented with mild muscular weakness, joint contractures, and epilepsy. Double immunofluorescence staining of a muscle biopsy specimen showed mislocalization of merosin, and a genetic analysis revealed a homozygous c.818G>A (p.Arg273Lys) mutation in LAMA2. Double immunofluorescence staining and whole exome sequencing were useful for the diagnosis of partial merosin deficiency.
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Epilepsia/genética , Laminina/genética , Distrofias Musculares/genética , Receptores de Laminina/deficiencia , Receptores de Laminina/genética , Adulto , Pueblo Asiatico , Epilepsia/fisiopatología , Pruebas Genéticas , Homocigoto , Humanos , Masculino , Distrofias Musculares/fisiopatología , MutaciónRESUMEN
Invariant NKT (iNKT) cells are a unique subset of lymphocytes that recognize glycolipid antigens presented by a monomorphic glycoprotein CD1d. Numerous works have shown that iNKT cells may serve as regulatory cells in autoimmune diseases including multiple sclerosis (MS). However, recent studies have revealed that the presence of iNKT cells accelerates some inflammatory conditions, implying that their protective role against autoimmunity is not predetermined. Here we review recent information concerning the mechanism of how iNKT cells intervene or promote autoimmune inflammation. Although iNKT cells are thought to be specific for a limited set of glycolipids, they may cross-react to self and non-self ligands. Regarding the response to non-self, it is now known that iNKT cells produce enormous amounts of proinflammatory cytokines during the course of infectious diseases, which is triggered by TCR ligation by microbial lipids, cytokines produced from APCs or both. Whereas the strongly activated iNKT cells play a beneficial role in combating environmental pathogens, they could play a deleterious role in autoimmunity by producing disease-promoting cytokines. However, iNKT cells in the steady state would retain an ability to produce anti-inflammatory cytokines, which is needed for terminating the ongoing inflammation. Though an initial trigger for their regulatory responses remains elusive, our recent work indicates that iNKT cells may start regulating inflammation after sensing the presence of IL-2 in addition to recognizing a ubiquitous endogenous ligand. Understanding of how iNKT cells regulate autoimmunity should lead to a more sophisticated strategy for controlling autoimmune diseases.
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Enfermedades Autoinmunes/inmunología , Células Asesinas Naturales/inmunología , Animales , Células Presentadoras de Antígenos/fisiología , Autoinmunidad , Citocinas/biosíntesis , Galactosilceramidas/metabolismo , Globósidos/metabolismo , Humanos , Células Asesinas Naturales/metabolismo , Células TH1/inmunología , Células Th2/inmunología , Trihexosilceramidas/metabolismoRESUMEN
OBJECTIVE: To assess the temporal relationship between excitability changes of the motor cortex and periodic synchronous discharges (PSDs) of electroencephalograms (EEGs) in Creutzfeld-Jakob disease (CJD) patients. METHODS: In four patients with classical type CJD we gave transcranial magnetic stimulation (TMS) randomly in time while simultaneously recording their EEGs and electromyograms (EMGs). The intensity of TMS was fixed to evoke 0.3-0.5 mV EMG in the abductor pollicis brevis muscle (APB) during periods in which there were no PSDs. We assessed the relation between the timing of TMS and EMG response sizes when PSD appeared in EEGs. The time interval between TMS and the onset of preceding PSD was plotted against the amplitude of acquired motor evoked potentials (MEPs). RESULTS: The amplitude of MEP was at a minimum when the TMS pulse was given just after the beginning of PSD and was maximal when given just before the onset of the next PSD. As a result, the size of MEP amplitude periodically changed and was phase-locked to the PSD, though its cycle slightly preceded that of PSD. CONCLUSIONS: Our study has demonstrated that excitability changes in motor cortex are closely related to the occurrence of PSD. SIGNIFICANCE: It has been revealed for the first time that motor cortical excitability is related to PSD cycle.
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Síndrome de Creutzfeldt-Jakob/fisiopatología , Electroencefalografía , Potenciales Evocados Motores/fisiología , Corteza Motora/fisiología , Anciano , Estimulación Eléctrica , Electromiografía , Femenino , Humanos , Magnetismo , Masculino , Persona de Mediana EdadRESUMEN
Coinhibitory receptors are critical for the maintenance of immune homeostasis. Upregulation of these receptors on effector T cells terminates T cell responses, while their expression on Tregs promotes their suppressor function. Understanding the function of coinhibitory receptors in effector T cells and Tregs is crucial, as therapies that target coinhibitory receptors are currently at the forefront of treatment strategies for cancer and other chronic diseases. T cell Ig and ITIM domain (TIGIT) is a recently identified coinhibitory receptor that is found on the surface of a variety of lymphoid cells, and its role in immune regulation is just beginning to be elucidated. We examined TIGIT-mediated immune regulation in different murine cancer models and determined that TIGIT marks the most dysfunctional subset of CD8+ T cells in tumor tissue as well as tumor-tissue Tregs with a highly active and suppressive phenotype. We demonstrated that TIGIT signaling in Tregs directs their phenotype and that TIGIT primarily suppresses antitumor immunity via Tregs and not CD8+ T cells. Moreover, TIGIT+ Tregs upregulated expression of the coinhibitory receptor TIM-3 in tumor tissue, and TIM-3 and TIGIT synergized to suppress antitumor immune responses. Our findings provide mechanistic insight into how TIGIT regulates immune responses in chronic disease settings.