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1.
IUBMB Life ; 73(6): 843-854, 2021 06.
Artigo em Inglês | MEDLINE | ID: mdl-33960608

RESUMO

The 78 kDa glucose-regulated protein (GRP78) is an endoplasmic reticulum (ER)-resident molecular chaperone. GRP78 is a member of the 70 kDa heat shock family of proteins involved in correcting and clearing misfolded proteins in the ER. In response to cellular stress, GRP78 escapes from the ER and moves to the plasma membrane where it (a) functions as a receptor for many ligands, and (b) behaves as an autoantigen for autoantibodies that contribute to human disease and cancer. Cell surface GRP78 (csGRP78) associates with the major histocompatibility complex class I (MHC-I), and is the port of entry for several viruses, including the predictive binding of the novel SARS-CoV-2. Furthermore, csGRP78 is found in association with partners as diverse as the teratocarcinoma-derived growth factor 1 (Cripto), the melanocortin-4 receptor (MC4R) and the DnaJ-like protein MTJ-1. CsGRP78 also serves as a receptor for a large variety of ligands including activated α2 -macroglobulin (α2 M*), plasminogen kringle 5 (K5), microplasminogen, the voltage-dependent anion channel (VDAC), tissue factor (TF), and the prostate apoptosis response-4 protein (Par-4). In this review, we discuss the mechanisms involved in the translocation of GRP78 from the ER to the cell surface, and the role of secreted GRP78 and its autoantibodies in cancer and neurological disorders.


Assuntos
Doenças Autoimunes do Sistema Nervoso/imunologia , COVID-19/transmissão , Proteínas de Choque Térmico/fisiologia , Proteínas de Neoplasias/fisiologia , Proteínas do Tecido Nervoso/fisiologia , Receptores de Superfície Celular/fisiologia , Receptores Virais/fisiologia , SARS-CoV-2/metabolismo , Glicoproteína da Espícula de Coronavírus/metabolismo , Autoanticorpos/imunologia , Autoantígenos/imunologia , Doenças Autoimunes do Sistema Nervoso/metabolismo , Sobrevivência Celular , Estresse do Retículo Endoplasmático/fisiologia , Exossomos , Proteínas Ligadas por GPI/metabolismo , Proteínas de Choque Térmico/química , Proteínas de Choque Térmico/imunologia , Humanos , Ligantes , Invasividade Neoplásica , Proteínas de Neoplasias/imunologia , Proteínas do Tecido Nervoso/imunologia , Domínios Proteicos , Transporte Proteico , Transdução de Sinais , Microambiente Tumoral , Resposta a Proteínas não Dobradas/fisiologia , Internalização do Vírus
2.
Int J Mol Sci ; 22(7)2021 Mar 30.
Artigo em Inglês | MEDLINE | ID: mdl-33808264

RESUMO

The IL-1 family cytokine IL-33 activates and re-shapes mast cells (MCs), but whether and by what mechanisms it elicits cytokines in MCs from human skin remains poorly understood. The current study found that IL-33 activates CCL1, CCL2, IL-5, IL-8, IL-13, and TNF-α, while IL-1ß, IL-6, IL-31, and VEGFA remain unaffected in cutaneous MCs, highlighting that each MC subset responds to IL-33 with a unique cytokine profile. Mechanistically, IL-33 induced the rapid (1-2 min) and durable (2 h) phosphorylation of p38, whereas the phosphorylation of JNK was weaker and more transient. Moreover, the NF-κB pathway was potently activated, as revealed by IκB degradation, increased nuclear abundance of p50/p65, and vigorous phosphorylation of p65. The activation of NF-κB occurred independently of p38 or JNK. The induced transcription of the cytokines selected for further study (CCL1, CCL2, IL-8, TNF-α) was abolished by interference with NF-κB, while p38/JNK had only some cytokine-selective effects. Surprisingly, at the level of the secreted protein products, p38 was nearly as effective as NF-κB for all entities, suggesting post-transcriptional involvement. IL-33 did not only instruct skin MCs to produce selected cytokines, but it also efficiently co-operated with the allergic and pseudo-allergic/neurogenic activation networks in the production of IL-8, TNF-α, CCL1, and CCL2. Synergism was more pronounced at the protein than at the mRNA level and appeared stronger for MRGPRX2 ligands than for FcεRI. Our results underscore the pro-inflammatory nature of an acute IL-33 stimulus and imply that especially in combination with allergens or MRGPRX2 agonists, IL-33 will efficiently amplify skin inflammation and thereby aggravate inflammatory dermatoses.


Assuntos
Citocinas/imunologia , Interleucina-33/farmacologia , Mastócitos/efeitos dos fármacos , Proteínas do Tecido Nervoso/imunologia , Receptores Acoplados a Proteínas G/imunologia , Receptores de IgE/imunologia , Receptores de Neuropeptídeos/imunologia , Pele/efeitos dos fármacos , Proteínas Quinases p38 Ativadas por Mitógeno/imunologia , Prepúcio do Pênis/citologia , Humanos , Interleucina-33/imunologia , Proteínas Quinases JNK Ativadas por Mitógeno/metabolismo , Masculino , Mastócitos/citologia , Mastócitos/imunologia , Fosforilação , Cultura Primária de Células , Transdução de Sinais/efeitos dos fármacos , Pele/imunologia
3.
Neurology ; 96(20): e2546-e2557, 2021 05 18.
Artigo em Inglês | MEDLINE | ID: mdl-33795390

RESUMO

OBJECTIVE: To determine whether neuronal and neuroaxonal injury, neuroinflammation, and synaptic dysfunction associate with clinical course and outcomes in antibody-mediated encephalitis (AME), we measured biomarkers of these processes in CSF from patients presenting with AME and cognitively normal individuals. METHODS: Biomarkers of neuronal (total tau, VILIP-1) and neuroaxonal damage (neurofilament light chain [NfL]), inflammation (YKL-40), and synaptic function (neurogranin, SNAP-25) were measured in CSF obtained from 45 patients at the time of diagnosis of NMDA receptor (n = 34) or LGI1/CASPR2 (n = 11) AME and 39 age- and sex-similar cognitively normal individuals. The association between biomarkers and modified Rankin Scale (mRS) scores were evaluated in a subset (n = 20) of longitudinally followed patients. RESULTS: Biomarkers of neuroaxonal injury (NfL) and neuroinflammation (YKL-40) were elevated in AME cases at presentation, whereas markers of neuronal injury and synaptic function were stable (total tau) or decreased (VILIP-1, SNAP-25, neurogranin). The log-transformed ratio of YKL-40/SNAP-25 optimally discriminated patients from cognitively normal individuals (area under the receiver operating characteristic curve 0.99; 95% confidence interval 0.97, >0.99). Younger age (ρ = -0.56; p = 0.01), lower VILIP-1 (ρ = -0.60; p < 0.01) and SNAP-25 (ρ = -0.54; p = 0.01), and higher log10(YKL-40/SNAP-25) (ρ = 0.48; p = 0.04) associated with greater disease severity (higher mRS score) in prospectively followed patients. Higher YKL-40 (ρ = 0.60; p = 0.02) and neurogranin (ρ = 0.55; p = 0.03) at presentation were associated with higher mRS scores 12 months following hospital discharge. CONCLUSIONS: CSF biomarkers suggest that neuronal integrity is acutely maintained in AME, despite neuroaxonal compromise. Low levels of biomarkers of synaptic function may reflect antibody-mediated internalization of cell surface receptors and may represent an acute correlate of antibody-mediated synaptic dysfunction, with the potential to inform disease severity and outcomes.


Assuntos
Encefalite Antirreceptor de N-Metil-D-Aspartato/líquido cefalorraquidiano , Proteína 1 Semelhante à Quitinase-3/líquido cefalorraquidiano , Neurocalcina/líquido cefalorraquidiano , Proteínas de Neurofilamentos/líquido cefalorraquidiano , Proteínas tau/líquido cefalorraquidiano , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Autoanticorpos/imunologia , Doenças Autoimunes do Sistema Nervoso/líquido cefalorraquidiano , Doenças Autoimunes do Sistema Nervoso/imunologia , Biomarcadores/líquido cefalorraquidiano , Estudos de Casos e Controles , Criança , Pré-Escolar , Encefalite/líquido cefalorraquidiano , Encefalite/imunologia , Feminino , Humanos , Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Masculino , Proteínas de Membrana/imunologia , Pessoa de Meia-Idade , Proteínas do Tecido Nervoso/imunologia , Neurogranina/líquido cefalorraquidiano , Proteína 25 Associada a Sinaptossoma/líquido cefalorraquidiano , Adulto Jovem
4.
Int Immunopharmacol ; 95: 107556, 2021 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-33756227

RESUMO

The immune and nervous systems possess a highly intricate network of synaptic connections, shared messenger molecules, and exquisite communication ways, allowing intercellular signal transduction. The semaphorins (Semas) were initially identified as axonal guidance molecules in the development of the nervous system but later were found to be implicated also in regulating the immune system, known in this case as the "immune Semas" or "immunoregulatory Semas". Increasingly, these molecules are involved in multiple aspects of both physiological and pathological immune responses and were recently indicated to take part in various immunological disorders, encompassing allergy, cancer, and autoimmunity. Semas transduce signals by connecting to their cognate receptors, namely, plexins and neuropilins. Some of them, like Sema-3F, have been found to function as the inducer of the remyelination process whereas some others, like Sema-3A and Sema-4D, act to inhibit this process, either directly or indirectly. Besides, Sema-4A is crucial to the differentiation of T helper type 1 (Th1) and Th17 cells that are potentially involved in the pathogenesis of multiple sclerosis (MS), an autoimmune disease of the central nervous system. This review aims to reveal the role of immune Semas in the pathogenesis of MS and its animal model, experimental autoimmune encephalomyelitis, focusing on the therapeutic usages of these molecules to treat this neurodegenerative disease.


Assuntos
Esclerose Múltipla/imunologia , Semaforinas/imunologia , Animais , Células Dendríticas/imunologia , Humanos , Ativação de Macrófagos , Macrófagos/imunologia , Esclerose Múltipla/terapia , Proteínas do Tecido Nervoso/imunologia , Receptores de Superfície Celular/imunologia
5.
J Neuroimmunol ; 353: 577515, 2021 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-33640718

RESUMO

The spectrum of anti-contactin-associated protein-like 2 (CASPR2) antibody-associated disease is expanding and the involvement of cerebellum was reported in the past few years. We report a 45-year-old male with chronically progressive cerebellar ataxia. CASPR2 antibodies were detected in his serum and cerebellar atrophy was observed on MRI. His symptoms improved prominently with steroids and intravenous immunoglobulins. 23 cases with CASPR2 antibodies and cerebellar ataxia were identified from previous publications. Most of patients showed acute or subacute onset with other typical presentations of anti-CASPR2 antibody-associated disease, such as limbic encephalitis. Immunotherapy was effective in the majority of patients.


Assuntos
Autoanticorpos/imunologia , Doenças Autoimunes/imunologia , Ataxia Cerebelar/imunologia , Proteínas de Membrana/imunologia , Proteínas do Tecido Nervoso/imunologia , Atrofia/imunologia , Atrofia/patologia , Autoantígenos/imunologia , Doenças Autoimunes/tratamento farmacológico , Doenças Autoimunes/patologia , Ataxia Cerebelar/tratamento farmacológico , Ataxia Cerebelar/patologia , Humanos , Fatores Imunológicos/uso terapêutico , Imunoterapia/métodos , Masculino , Pessoa de Meia-Idade
6.
J Neuroimmunol ; 353: 577491, 2021 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-33549944

RESUMO

An autoimmune form of Isaacs' syndrome is commonly associated with VGKC complex antibodies and characterized by continuous muscle activity of extremity muscles. Here, we describe a CASPR2 and LGI1 positive patient with neuromyotonia clinically and electrophysiologically isolated to gastrocnemius muscles only. IVIG course and plasma exchange were ineffective, but symptoms significantly improved after a course of high-dose steroids. This case demonstrates that focal hyperexcitability should raise suspicion for autoimmunity. LGI1 antibody can be positive in patients with only peripheral nerve system involvement and if one treatment fails, other should be tried.


Assuntos
Peptídeos e Proteínas de Sinalização Intracelular/imunologia , Síndrome de Isaacs/diagnóstico , Síndrome de Isaacs/imunologia , Proteínas de Membrana/imunologia , Proteínas do Tecido Nervoso/imunologia , Corticosteroides/uso terapêutico , Adulto , Autoanticorpos/sangue , Autoantígenos/imunologia , Feminino , Humanos , Imunoglobulinas Intravenosas/uso terapêutico , Imunossupressores/uso terapêutico , Síndrome de Isaacs/terapia , Músculo Esquelético , Plasmaferese
7.
BMC Neurol ; 20(1): 355, 2020 Sep 23.
Artigo em Inglês | MEDLINE | ID: mdl-32967629

RESUMO

BACKGROUND: Paraneoplastic cerebellar degeneration (PCD) is a devastating paraneoplastic syndrome that occasionally occurs in patients with Hodgkin lymphoma (HL). Anti-Ma2 is a well-characterized onconeuronal antibody and one of the causes of PCD. There has been only one previous report of anti-Ma2-associated paraneoplastic syndrome as a complication of HL. Here we present a rare case of anti-Ma2-associated PCD in a patient with nodular lymphocyte-predominant HL (NLPHL). CASE PRESENTATION: A 77-year-old man with a 3-month history of gait instability and a 2-month history of oscillopsia was referred to our hospital for further investigation. On examination, his cognition was normal. He had nystagmus in all directions of gaze; specifically, he had horizontal and rotatory nystagmus in the primary position, downbeat nystagmus after right, left, and up gaze, and upbeat nystagmus after down gaze. Although his limb ataxia was mild, his trunk ataxia was so pronounced that he was unable to walk without support. We strongly suspected paraneoplastic syndrome and tested for neuronal autoantibodies. The anti-Ma2 antibody was strongly positive in the blood and cerebrospinal fluid but other antineuronal autoantibodies were negative. Computed tomography showed an enlarged lymph node in the right axilla but no masses. Biopsy confirmed a diagnosis of NLPHL. The NLPHL cells stained with anti-Ma-2 antibody in the cytoplasm, suggesting these abnormal cells contained protein that was cross-reactive with Ma-2. CONCLUSIONS: To the best of our knowledge, this is the first case of anti-Ma2-associated PCD in a patient with NLPHL that was confirmed using immunostaining of the lymph node tissue with anti-Ma2 antibody. Our case confirms an association between anti-Ma2-associated PCD and NLPHL.


Assuntos
Antígenos de Neoplasias/imunologia , Doença de Hodgkin/complicações , Proteínas do Tecido Nervoso/imunologia , Degeneração Paraneoplásica Cerebelar/etiologia , Degeneração Paraneoplásica Cerebelar/imunologia , Idoso , Autoanticorpos/sangue , Autoanticorpos/imunologia , Autoantígenos/imunologia , Doença de Hodgkin/imunologia , Humanos , Masculino , Degeneração Paraneoplásica Cerebelar/diagnóstico , Tomografia Computadorizada por Raios X
9.
Nat Immunol ; 21(8): 868-879, 2020 08.
Artigo em Inglês | MEDLINE | ID: mdl-32690950

RESUMO

STING is essential for control of infections and for tumor immunosurveillance, but it can also drive pathological inflammation. STING resides on the endoplasmic reticulum (ER) and traffics following stimulation to the ERGIC/Golgi, where signaling occurs. Although STING ER exit is the rate-limiting step in STING signaling, the mechanism that drives this process is not understood. Here we identify STEEP as a positive regulator of STING signaling. STEEP was associated with STING and promoted trafficking from the ER. This was mediated through stimulation of phosphatidylinositol-3-phosphate (PtdIns(3)P) production and ER membrane curvature formation, thus inducing COPII-mediated ER-to-Golgi trafficking of STING. Depletion of STEEP impaired STING-driven gene expression in response to virus infection in brain tissue and in cells from patients with STING-associated diseases. Interestingly, STING gain-of-function mutants from patients interacted strongly with STEEP, leading to increased ER PtdIns(3)P levels and membrane curvature. Thus, STEEP enables STING signaling by promoting ER exit.


Assuntos
Retículo Endoplasmático/metabolismo , Regulação da Expressão Gênica/fisiologia , Proteínas de Membrana/metabolismo , Proteínas do Tecido Nervoso/metabolismo , Transdução de Sinais/fisiologia , Animais , Retículo Endoplasmático/imunologia , Humanos , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/metabolismo , Proteínas de Membrana/imunologia , Camundongos , Proteínas do Tecido Nervoso/imunologia , Transporte Proteico/fisiologia
11.
BMC Neurol ; 20(1): 208, 2020 May 25.
Artigo em Inglês | MEDLINE | ID: mdl-32450842

RESUMO

BACKGROUND: Cerebellar degeneration as a consequence of a malignancy is a rare condition most commonly related to the presence of anti-Yo, anti-Hu, and anti-Tr/DNER antibodies. In recent years, several reports have indicated Zinc-finger protein 4 (Zic4) antibodies being associated with paraneoplastic cerebellar degeneration (PCD) in patients with small cell lung carcinoma. However, the prevalence and the significance of Zic4-antibodies may be underestimated due to their co-occurrence with more frequent antibodies such as anti-Hu. A literature review of isolated Zic4 mediated paraneoplastic syndromes yielded 14 cases reporting mainly benign clinical courses when treated early. CASE PRESENTATION: We present the case of a 67-year-old woman with progressive Zic4 antibody mediated PCD and rhombencephalitis. Immunomodulatory treatment, including intravenous methylprednisolone, plasmaphereses, and intravenous immunoglobulin (IVIG) was administered. Small cell lung cancer (SCLC) was detected, lobectomy performed and cyclophosphamide started. Despite this considerable therapeutic effort, rhombencephalitis led to defiant dysautonomia. CONCLUSION: Paraneoplastic syndromes related to isolated Zic4 antibodies are rare and typically show a benign clinical course. Here, we present the first case of a rapidly progressive isolated Zic4 associated PCD and rhombencephalitis. Despite considerable therapeutic efforts, the patient passed away on autonomic dysfunction, highlighting the significance of Zic4 associated disease.


Assuntos
Autoanticorpos/imunologia , Encefalite , Proteínas do Tecido Nervoso/imunologia , Degeneração Paraneoplásica Cerebelar , Rombencéfalo , Fatores de Transcrição/imunologia , Idoso , Encefalite/metabolismo , Encefalite/fisiopatologia , Feminino , Humanos , Neoplasias Pulmonares , Disautonomias Primárias , Rombencéfalo/metabolismo , Rombencéfalo/fisiopatologia , Carcinoma de Pequenas Células do Pulmão
12.
Neurology ; 94(22): e2290-e2301, 2020 06 02.
Artigo em Inglês | MEDLINE | ID: mdl-32424051

RESUMO

OBJECTIVE: To delineate autoimmune disease in association with contactin-associated protein 2 (CASPR2) antibodies in childhood, we reviewed the clinical phenotype of children with CASPR2 antibodies. METHODS: Retrospective assessment of patients recruited through laboratories specialized in autoimmune CNS disease. RESULTS: Ten children with serum CASPR2 antibodies were identified (age at manifestation 18 months to 17 years). Eight children with CASPR2 antibody titers from ≥1:160 to 1:5,120 had complex autoimmune diseases with an age-dependent clinical phenotype. Two children with structural epilepsy due to CNS malformations harbored nonspecific low-titer CASPR2 antibodies (serum titers 1:80). The clinical symptoms of the 8 children with high-titer CASPR2 antibodies were general weakness (8/8), sleep dysregulation (8/8), dysautonomia (8/8) encephalopathy (7/8), neuropathic pain (7/8), neuromyotonia (3/8), and flaccid paresis (3/8). Adolescents (3/8) showed pain, neuromyotonia, and encephalopathy, whereas younger children (5/8) displayed severe hypertension, encephalopathy, and hormonal dysfunction mimicking a systemic disease. No tumors were identified. Motor symptoms remitted with immunotherapy. Mild behavioral changes persisted in 1 child, and autism spectrum disorder was diagnosed during follow-up in a young boy. CONCLUSION: High-titer CASPR2 antibodies are associated with Morvan syndrome in children as young as 2 years. However, CASPR2 autoimmunity mimics systemic disease and hypertensive encephalopathy in children younger than 7 years. The outcome following immunotherapy was mostly favorable; long-term behavioral impairment may occur in younger children.


Assuntos
Autoanticorpos/sangue , Autoimunidade/fisiologia , Encefalopatias/sangue , Hipertensão/sangue , Proteínas de Membrana/sangue , Proteínas do Tecido Nervoso/sangue , Siringomielia/sangue , Adolescente , Autoanticorpos/imunologia , Encefalopatias/imunologia , Encefalopatias/terapia , Criança , Pré-Escolar , Feminino , Humanos , Hipertensão/imunologia , Hipertensão/terapia , Imunoterapia/métodos , Lactente , Masculino , Proteínas de Membrana/imunologia , Proteínas do Tecido Nervoso/imunologia , Estudos Retrospectivos , Siringomielia/imunologia , Siringomielia/terapia
13.
Proc Natl Acad Sci U S A ; 117(23): 12826-12835, 2020 06 09.
Artigo em Inglês | MEDLINE | ID: mdl-32461371

RESUMO

Complete cancer regression occurs in a subset of patients following adoptive T cell therapy (ACT) of ex vivo expanded tumor-infiltrating lymphocytes (TILs). However, the low success rate presents a great challenge to broader clinical application. To provide insight into TIL-based immunotherapy, we studied a successful case of ACT where regression was observed against tumors carrying the hotspot mutation G12D in the KRAS oncogene. Four T cell receptors (TCRs) made up the TIL infusion and recognized two KRAS-G12D neoantigens, a nonamer and a decamer, all restricted by human leukocyte antigen (HLA) C*08:02. Three of them (TCR9a, 9b, and 9c) were nonamer-specific, while one was decamer-specific (TCR10). We show that only mutant G12D but not the wild-type peptides stabilized HLA-C*08:02 due to the formation of a critical anchor salt bridge to HLA-C. Therapeutic TCRs exhibited high affinities, ranging from nanomolar to low micromolar. Intriguingly, TCR binding affinities to HLA-C inversely correlated with their persistence in vivo, suggesting the importance of antigenic affinity in the function of therapeutic T cells. Crystal structures of TCR-HLA-C complexes revealed that TCR9a to 9c recognized G12D nonamer with multiple conserved contacts through shared CDR2ß and CDR3α. This allowed CDR3ß variation to confer different affinities via a variable HLA-C contact, generating an oligoclonal response. TCR10 recognized an induced and distinct G12D decamer conformation. Thus, this successful case of ACT included oligoclonal TCRs of high affinity recognizing distinct conformations of neoantigens. Our study revealed the potential of a structural approach to inform clinical efforts in targeting KRAS-G12D tumors by immunotherapy and has general implications for T cell-based immunotherapies.


Assuntos
Antígenos de Neoplasias/imunologia , Imunoterapia Adotiva/métodos , Proteínas Proto-Oncogênicas p21(ras)/genética , Receptores de Antígenos de Linfócitos T/imunologia , Linfócitos T/imunologia , Apresentação do Antígeno , Antígenos de Neoplasias/química , Sítios de Ligação , Antígenos HLA-C/química , Antígenos HLA-C/imunologia , Humanos , Células Jurkat , Mutação de Sentido Incorreto , Proteínas do Tecido Nervoso/química , Proteínas do Tecido Nervoso/imunologia , Ligação Proteica , Proteínas Proto-Oncogênicas p21(ras)/química , Proteínas Proto-Oncogênicas p21(ras)/imunologia , Receptores de Antígenos de Linfócitos T/química
14.
J Neuroimmunol ; 343: 577231, 2020 06 15.
Artigo em Inglês | MEDLINE | ID: mdl-32302793

RESUMO

Autoimmune limbic encephalitis is part of CASPR 2 antibody-associated disease. A man with this rare disorder and a very high antibody titre had a unique history of laboratory exposure to the antigen. Together with earlier observations this case calls for caution in laboratory handling of nerve tissue.


Assuntos
Doenças Autoimunes/etiologia , Doenças Autoimunes/imunologia , Encefalite Límbica/etiologia , Encefalite Límbica/imunologia , Pessoal de Laboratório Médico , Proteínas de Membrana/imunologia , Proteínas do Tecido Nervoso/imunologia , Exposição Ocupacional/efeitos adversos , Idoso , Autoanticorpos/imunologia , Autoantígenos/imunologia , Humanos , Masculino
15.
Rev. esp. med. nucl. imagen mol. (Ed. impr.) ; 39(2): 92-95, mar.-abr. 2020. ilus, tab
Artigo em Espanhol | IBECS | ID: ibc-196349

RESUMO

Un inicio temprano de la inmunoterapia es fundamental para mejorar el pronóstico de los pacientes con encefalitis aguda de origen autoinmune (EAI). Se ha propuesto un nuevo abordaje clínico para el diagnóstico temprano basado en aspectos clínicos y pruebas complementarias, pero estas pueden tener una sensibilidad limitada principalmente en las primeras semanas. Mientras que las formas más comunes de EAI (anti-LGI-1 y anti-NMDAR), muestran frecuentemente patrones de PET con 18Flúor-fluordeoxiglucosa (PET-FDG) consistentes, las anti-Caspr2 son menos frecuentes y los patrones de PET-FDG no están establecidos. En nuestra experiencia la PET-FDG en la EAI anti-Caspr2 presenta un hipermetabolismo temporal medial y un déficit difuso cortical, incluso con pruebas complementarias negativas. No obstante, es necesaria la estandarización del análisis de las imágenes PET mediante métodos basados en vóxeles con comparación con bases de datos de normalidad para definir con claridad las áreas de metabolismo alterado que pueden pasar desapercibidas al análisis visual


Early immunotherapy is of paramount importance for a positive outcome in patients suffering acute encephalitis of autoimmune origin (AIE). A new approach for early diagnosis based on clinical presentation and complementary tests has been proposed, but not all these tests show positive findings in the first weeks. While common forms of AIE (anti-LGI-1 and anti-NMDAR antibodies) exhibit consistent 18Fluor-fluorodeoxiglucose (FDG-PET) patterns in many cases, the anti-Caspr2 form of AIE is infrequent and FDG-PET patterns have not been well characterized. In our experience, FDG-PET in anti-Caspr2 limbic encephalitis shows medial temporal hypermetabolism and diffuse cortical hypometabolism, even in the absence of findings in these tests. However, it is necessary to standardize PET image analysis by means of visual and voxel-based methods compared to normal databases to define the areas of pathological metabolism that may go unnoticed when using visual analysis exclusively


Assuntos
Humanos , Masculino , Idoso , Fluordesoxiglucose F18 , Encefalite Límbica/diagnóstico por imagem , Encefalite Límbica/imunologia , Proteínas de Membrana/imunologia , Proteínas do Tecido Nervoso/imunologia , Tomografia Computadorizada por Raios X/métodos , Compostos Radiofarmacêuticos , Anticorpos/sangue , Anticorpos/líquido cefalorraquidiano , Fluordesoxiglucose F18/metabolismo , Encefalite Límbica/metabolismo , Espectroscopia de Ressonância Magnética , Transtornos da Memória/etiologia , Testes Neuropsicológicos , Tomografia por Emissão de Pósitrons , Tomografia Computadorizada por Raios X/normas , Compostos Radiofarmacêuticos/metabolismo
16.
J Immunol ; 204(7): 1724-1735, 2020 04 01.
Artigo em Inglês | MEDLINE | ID: mdl-32086386

RESUMO

IL-23 and IL-12, two structurally related heterodimeric cytokines sharing a common subunit, divergently promote Th cell development and expansion. Both cytokines have been implicated in the pathogenesis of thyroid-associated ophthalmopathy (TAO), an autoimmune component of Graves disease. In TAO, CD34+ fibrocytes, putatively derived from bone marrow, can be identified in the orbit. There they masquerade as CD34+ orbital fibroblasts (OF) (CD34+ OF) and cohabitate with CD34- OF in a mixed fibroblast population (GD-OF). Slit2, a neural axon repellent, is expressed and released by CD34- OF and dampens the inflammatory phenotype of fibrocytes and CD34+ OF. In this study we report that thyrotropin (TSH) and the pathogenic, GD-specific monoclonal autoantibody, M22, robustly induce IL-23 in human fibrocytes; however, IL-12 expression is essentially undetectable in these cells under basal conditions or following TSH-stimulation. In contrast, IL-12 is considerably more inducible in GD-OF, cells failing to express IL-23. This divergent expression and induction of cytokines appears to result from cell type-specific regulation of both gene transcription and mRNA stabilities. It appears that the JNK pathway activity divergently attenuates IL-23p19 expression while enhancing that of IL-12p35. The shift from IL-23p19 expression in fibrocytes to that of IL-12p35 in their derivative CD34+ OF results from the actions of Slit2. Thus, Slit2 might represent a molecular determinant of balance between IL-23 and IL-12 expression, potentially governing immune responses in TAO.


Assuntos
Fibroblastos/metabolismo , Peptídeos e Proteínas de Sinalização Intercelular/imunologia , Interleucina-12/metabolismo , Interleucina-23/metabolismo , Proteínas do Tecido Nervoso/imunologia , Tireotropina/metabolismo , Antígenos CD34/metabolismo , Células Cultivadas , Citocinas/metabolismo , Doença de Graves/metabolismo , Oftalmopatia de Graves/metabolismo , Humanos , Órbita/metabolismo , Estabilidade de RNA/fisiologia , Receptores da Tireotropina/metabolismo , Transdução de Sinais/fisiologia
17.
Artigo em Inglês | MEDLINE | ID: mdl-32069133

RESUMO

CD271 is a common receptor for all neurotrophins that is localized to neurons, endothelial cells, and the basal layer of the epithelium in normal tissue. Recently, we and others reported that CD271 plays essential roles in the development of squamous cell carcinoma, especially in tumor-initiating cells. Since little is known about how CD271 regulates cancer cell initiation and proliferation, antibodies that recognize different domains of CD271 are needed to enable investigation. Therefore, this study aimed to develop an antihuman CD271 antibody by immunizing mice with a CD271 antigen produced by a baculovirus. The antibody was named hCD271mAb#13, and it recognized cysteine-rich domain 1 with a higher affinity than the commercially available antibody ME20.4. We determined that hCD271mAb#13 is suitable for flow cytometry, Western blotting, immunocytochemistry, and immunohistochemistry of formalin-fixed paraffin-embedded tissue. Use of hCD271mAb#13 for CD271 labeling could enable detailed analyses of cancer cell regulation and other biological processes.


Assuntos
Adapaleno/imunologia , Anticorpos Monoclonais/análise , Anticorpos Monoclonais/imunologia , Cisteína/química , Cisteína/imunologia , Proteínas do Tecido Nervoso/imunologia , Receptores de Fator de Crescimento Neural/imunologia , Animais , Carcinoma de Células Escamosas , Imuno-Histoquímica , Camundongos , Células-Tronco Neoplásicas , Domínios Proteicos/imunologia , RNA Interferente Pequeno
18.
Phytomedicine ; 68: 153149, 2020 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-32032836

RESUMO

BACKGROUND: Mast cells (MCs) are crucial effectors in allergic disorders by secreting inflammatory mediators. The Mas-related G-protein-coupled receptor X2 (Mrgprx2) was shown to have a key role in IgE-independent allergic reactions. Therefore, potential drug candidates that directly target Mrgprx2 could be used to treat pseudo-allergic diseases. Shikonin, an active ingredient derived from Lithospermum erythrorhizon Sieb. et Zucc has been used for its anti-inflammatory properties since ancient China. PURPOSE: To investigate the inhibitory effects of Shikonin on IgE-independent allergy both in vitro and in vivo, as well as the mechanism underlying its effects. METHODS/STUDY DESIGNS: The anti-anaphylactoid activity of Shikonin was evaluated in PCA and systemic anaphylaxis models, Calcium imaging was used to assess intracellular Ca2+ mobilization. The release of cytokines and chemokines was measured using enzyme immunoassay kits. Western blot analysis was conducted to investigate the molecules of PLCγ-PKC-IP3 signaling pathway. The analytical method of surface plasmon resonance was employed to study the interaction between Shikonin and potential target protein Mrgprx2. RESULTS: Shikonin can suppress compound 48/80 (C48/80)-induced PCA, active systemic anaphylaxis, and MCs degranulation in mice in a dose-dependent manner. In addition, Shikonin reduced C48/80-induced calcium flux and suppressed LAD2 cell degranulation via PLCγ-PKC-IP3 signaling pathway. Moreover, Shikonin was found to inhibit C48/80-induced Mrgprx2 expression in HEK cells, displaying specific interactions with the Mrgprx2 protein. CONCLUSION: Shikonin could be a potential antagonist of Mrgprx2, thereby inhibiting pseudo-allergic reactions through Ca2+ mobilization.


Assuntos
Anafilaxia/tratamento farmacológico , Hipersensibilidade/tratamento farmacológico , Naftoquinonas/farmacologia , Proteínas do Tecido Nervoso/imunologia , Receptores Acoplados a Proteínas G/imunologia , Receptores de Neuropeptídeos/imunologia , Anafilaxia/induzido quimicamente , Animais , Cálcio/metabolismo , Degranulação Celular/efeitos dos fármacos , Linhagem Celular , Quimiocinas/metabolismo , Citocinas/metabolismo , Humanos , Hipersensibilidade/imunologia , Masculino , Mastócitos/efeitos dos fármacos , Mastócitos/metabolismo , Camundongos Endogâmicos C57BL , Naftoquinonas/química , Proteínas do Tecido Nervoso/antagonistas & inibidores , Proteínas do Tecido Nervoso/química , Proteínas do Tecido Nervoso/metabolismo , Fosfolipase C gama/metabolismo , Receptores Acoplados a Proteínas G/antagonistas & inibidores , Receptores Acoplados a Proteínas G/química , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Neuropeptídeos/antagonistas & inibidores , Receptores de Neuropeptídeos/química , Receptores de Neuropeptídeos/metabolismo , Secretagogos/toxicidade , p-Metoxi-N-metilfenetilamina/toxicidade
19.
Immunity ; 52(2): 404-416.e5, 2020 02 18.
Artigo em Inglês | MEDLINE | ID: mdl-32049054

RESUMO

Mast cells are rare tissue-resident cells of importance to human allergies. To understand the structural basis of principle mast cell functions, we analyzed the proteome of primary human and mouse mast cells by quantitative mass spectrometry. We identified a mast-cell-specific proteome signature, indicative of a unique lineage, only distantly related to other immune cell types, including innate immune cells. Proteome comparison between human and mouse suggested evolutionary conservation of core mast cell functions. In addition to specific proteases and proteins associated with degranulation and proteoglycan biosynthesis, mast cells expressed proteins potentially involved in interactions with neurons and neurotransmitter metabolism, including cell adhesion molecules, ion channels, and G protein coupled receptors. Toward targeted cell ablation in severe allergic diseases, we used MRGPRX2 for mast cell depletion in human skin biopsies. These proteome analyses suggest a unique role of mast cells in the immune system, probably intertwined with the nervous system.


Assuntos
Mastócitos/citologia , Mastócitos/imunologia , Animais , Biomarcadores/metabolismo , Degranulação Celular , Linhagem da Célula , Células Cultivadas , Tecido Conjuntivo/imunologia , Humanos , Imunoterapia , Mastócitos/metabolismo , Proteínas de Membrana/imunologia , Proteínas de Membrana/metabolismo , Camundongos , Camundongos Endogâmicos C57BL , Proteínas do Tecido Nervoso/imunologia , Proteínas do Tecido Nervoso/metabolismo , Neuroimunomodulação , Proteoglicanas/biossíntese , Proteoma , Receptores Acoplados a Proteínas G/imunologia , Receptores Acoplados a Proteínas G/metabolismo , Receptores de Neuropeptídeos/imunologia , Receptores de Neuropeptídeos/metabolismo , Pele/imunologia
20.
J Neuroimmunol ; 341: 577192, 2020 04 15.
Artigo em Inglês | MEDLINE | ID: mdl-32087460

RESUMO

Stiff person spectrum disorders (SPSD) are a broad group of immune-mediated disorders. Clinical presentations include classical stiff person syndrome (SPS), focal SPS, and progressive encephalomyelitis with rigidity and myoclonus (PERM). The most frequently associated antibodies are anti-GAD65, anti-GlyR, anti-amphiphysin, and anti-DPPX. Immunotherapy is the primary treatment modality. We present an illustrative case series of three patients: anti-GlyR antibody-mediated PERM presenting as rapidly progressive dementia; anti-amphiphysin antibody-mediated SPS; and SPS presentation with anti-Zic4 antibodies, spasmodic laryngeal stridor and fluctuating eyelid ptosis. Clinical characteristics, CSF findings, neurophysiological features, adequate immunological assays and a high suspicion index are essential for prompt diagnosis and management.


Assuntos
Diversidade de Anticorpos , Autoanticorpos/imunologia , Rigidez Muscular Espasmódica/imunologia , Idoso , Idoso de 80 Anos ou mais , Especificidade de Anticorpos , Autoantígenos/imunologia , Transtornos Cognitivos/etiologia , Transtornos Cognitivos/imunologia , Diarreia/etiologia , Diplopia/etiologia , Evolução Fatal , Transtornos Neurológicos da Marcha/etiologia , Humanos , Imunossupressores/uso terapêutico , Imunoterapia , Masculino , Pessoa de Meia-Idade , Rigidez Muscular/etiologia , Mioclonia/etiologia , Proteínas do Tecido Nervoso/imunologia , Neuroimagem , Fenótipo , Receptores de Glicina/imunologia , Convulsões/etiologia , Rigidez Muscular Espasmódica/complicações , Rigidez Muscular Espasmódica/diagnóstico por imagem , Rigidez Muscular Espasmódica/terapia , Fatores de Transcrição/imunologia , Tremor/etiologia
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