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1.
Zhonghua Jie He He Hu Xi Za Zhi ; 42(10): 765-770, 2019 Oct 12.
Artigo em Chinês | MEDLINE | ID: mdl-31594111

RESUMO

Objective: To investigate the clinical significance of detection of myositis-specific antibodies (MSAs) and myositis-associated antibodies (MAAs) in patients with connective tissue disease-associated interstitial lung diseases (CTD-ILD). Methods: Serum samples of 120 patients with CTD-ILD admitted to the Department of Respiratory, Affiliated Drum Tower Hospital of Nanjing University Medical College from December 2016 to April 2018 were collected for analysis. The patients included 45 with polymyositis/dermatomyositis (PM/DM), 36 with Sjogren's syndrome (SS) and 39 with undifferentiated connective tissue disease (UCTD). There were 37 males and 83 females with an average age of (56±11) years. Thirty-two patients with non-CTD-ILD, 10 males and 22 females with an average age of (42±17) years, were enrolled as the control group. Euroline Autoimmune Inflammatory Myopathies 16 Ag kit was used for detecting MSAs and MAAs, and the positive rates of serum MSAs and MAAs were calculated. The antibody distribution and clinical characteristics of different groups were analyzed and compared. Results: Eighty-nine of the 120 patients with CTD-ILD were positive for MSA and/or MAA (74.2%), and the detection rates of MSAs and MAAs were 52.5% (63/120) and 61.7% (74/120) respectively. No myositis antibody was detected in the non-CTD-ILD group. The detection rates of MSAs in PM/DM-ILD group, SS-ILD group and UCTD-ILD group were 75.6% (34/45), 33.3%(12/36) and 43.6%(17/39) respectively. The total detection rate of MSAs in PM/DM group was significantly higher than that in SS group and UCTD group (χ(2)=14.53, 8.95, 0.01). The anti-ARS was the most frequent (50/120, 41.7%). The positive rates of MAAs in the three groups were 64.4%(29/45), 77.8%(28/36), 43.6%(17/39) respectively, and anti-Ro-52 accounted for 60%(72/120), and were highly correlated with MSAs such as anti-Jo-1 antibodies. Conclusion: Myositis antibody profiling should be performed in patients with ILD who were negative for conventional autoimmune antibody testing and had no CTD. In patients with SS-ILD and UCTD-ILD, the myositis antibody spectrum could detect the presence of myositis-specific antibodies and myositis-related antibodies in some patients, and its role in clinical diagnosis and treatment needed further observation.


Assuntos
Autoanticorpos/sangue , Autoantígenos/imunologia , Doenças Pulmonares Intersticiais/imunologia , Miosite/imunologia , Polimiosite/imunologia , Adulto , Idoso , China/epidemiologia , Doenças do Tecido Conjuntivo/sangue , Dermatomiosite/sangue , Dermatomiosite/complicações , Dermatomiosite/epidemiologia , Dermatomiosite/imunologia , Feminino , Humanos , Doenças Pulmonares Intersticiais/sangue , Doenças Pulmonares Intersticiais/etiologia , Masculino , Pessoa de Meia-Idade , Miosite/sangue , Miosite/diagnóstico , Miosite/epidemiologia , Polimiosite/complicações , Polimiosite/epidemiologia , Testes Sorológicos
2.
Mol Biol (Mosk) ; 53(5): 849-859, 2019.
Artigo em Russo | MEDLINE | ID: mdl-31661483

RESUMO

T cells play a key role in adaptive immunity reactions, recognizing antigens using variable TCRs. Functional TCR subunit genes are formed by somatic rearrangement, and some of the resulting TCRs recognize autoantigens, the body's own molecules. The autoreactive T cells that carry such TCRs pose a threat of inducing immune reactions against their own organism. In the course of the immune system's development, some autoreactive T lymphocytes are eliminated by apoptosis, some differentiate into immunosuppressive regulatory T cells, which support immunological tolerance to autoantigens, and the rest fall into a non-functional state of anergy. Suppression of effector T cells by regulatory T cells is mediated by immunosuppressive cytokines and costimulatory molecules, depletion of stimulating IL-2, removal of autoreactive peptides together with MHC molecules, and in other ways. Impairment of self-tolerance leads to autoimmune diseases. However, the loss of immunological tolerance can be employed in tumor treatment, allowing immunotherapy and the use of the potential of autoreactive effector T cells. The fact that the efficacious immunotherapy of tumors is often accompanied by adverse autoimmune reactions currently seems to be the inevitable price paid by using this approach.


Assuntos
Autoantígenos/imunologia , Epitopos/imunologia , Linfócitos T/imunologia , Doenças Autoimunes/imunologia , Humanos , Imunoterapia , Neoplasias/imunologia , Neoplasias/terapia , Receptores de Antígenos de Linfócitos T/imunologia , Tolerância a Antígenos Próprios/imunologia
3.
Isr Med Assoc J ; 21(7): 444-448, 2019 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-31507118

RESUMO

BACKGROUND: Although cross-reactions between Epstein-Barr virus (EBV) and human systemic lupus erythematosus (SLE) autoantigens occur, a complete analysis of the potential EBV peptide cross-reactome has not been performed. OBJECTIVES: To analyze the whole EBV proteome searching for peptides common to SLE-related proteins and endowed with an immunological potential. METHODS: Fifty-one SLE-related proteins were analyzed for hexapeptide sharing with EBV proteome using publicly available databases. RESULTS: An extremely high number of hexapeptides are shared between 34 human SLE autoantigens and EBV proteins. The peptide sharing mostly occurs with complement components C4 and Interleukin-10 (IL-10). CONCLUSIONS: This study thoroughly describes the EBV vs. SLE autoantigens peptide overlap and powerfully supports cross-reactivity as a major mechanism in EBV-associated SLE etiopathogenesis.


Assuntos
Autoantígenos/imunologia , Infecções por Vírus Epstein-Barr/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Peptídeos/imunologia , Proteoma , Complemento C4/imunologia , Reações Cruzadas/imunologia , Bases de Dados Factuais , Herpesvirus Humano 4/imunologia , Humanos , Interleucina-10/imunologia
5.
Cancer Immunol Immunother ; 68(9): 1401-1415, 2019 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-31414180

RESUMO

Although CAR T-cell therapy has demonstrated tremendous clinical efficacy especially in hematological malignancies, severe treatment-associated toxicities still compromise the widespread application of this innovative technology. Therefore, developing novel approaches to abrogate CAR T-cell-mediated side effects is of great relevance. Several promising strategies pursue the selective antibody-based depletion of adoptively transferred T cells via elimination markers. However, given the limited half-life and tissue penetration, dependence on the patients' immune system and on-target/off-side effects of proposed monoclonal antibodies, we sought to exploit αCAR-engineered T cells to efficiently eliminate CAR T cells. For comprehensive and specific recognition, a small peptide epitope (E-tag) was incorporated into the extracellular spacer region of CAR constructs. We provide first proof-of-concept for targeting this epitope by αE-tag CAR T cells, allowing an effective killing of autologous E-tagged CAR T cells both in vitro and in vivo whilst sparing cells lacking the E-tag. In addition to CAR T-cell cytotoxicity, the αE-tag-specific T cells can be empowered with cancer-fighting ability in case of relapse, hence, have versatile utility. Our proposed methodology can most probably be implemented in CAR T-cell therapies regardless of the targeted tumor antigen aiding in improving overall safety and survival control of highly potent gene-modified cells.


Assuntos
Epitopos de Linfócito T/genética , Imunoterapia Adotiva/métodos , Fragmentos de Peptídeos/genética , Neoplasias da Próstata/terapia , Receptores de Antígenos de Linfócitos T/genética , Receptores de Antígenos Quiméricos/genética , Linfócitos T Citotóxicos/imunologia , Animais , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/imunologia , Autoantígenos/imunologia , Citotoxicidade Imunológica , Epitopos de Linfócito T/imunologia , Engenharia Genética , Humanos , Masculino , Camundongos , Recidiva Local de Neoplasia , Células PC-3 , Neoplasias da Próstata/imunologia , Ensaios Antitumorais Modelo de Xenoenxerto
7.
Nature ; 571(7766): 565-569, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31316206

RESUMO

Parkinson's disease is a neurodegenerative disorder with motor symptoms linked to the loss of dopaminergic neurons in the substantia nigra compacta. Although the mechanisms that trigger the loss of dopaminergic neurons are unclear, mitochondrial dysfunction and inflammation are thought to have key roles1,2. An early-onset form of Parkinson's disease is associated with mutations in the PINK1 kinase and PRKN ubiquitin ligase genes3. PINK1 and Parkin (encoded by PRKN) are involved in the clearance of damaged mitochondria in cultured cells4, but recent evidence obtained using knockout and knockin mouse models have led to contradictory results regarding the contributions of PINK1 and Parkin to mitophagy in vivo5-8. It has previously been shown that PINK1 and Parkin have a key role in adaptive immunity by repressing presentation of mitochondrial antigens9, which suggests that autoimmune mechanisms participate in the aetiology of Parkinson's disease. Here we show that intestinal infection with Gram-negative bacteria in Pink1-/- mice engages mitochondrial antigen presentation and autoimmune mechanisms that elicit the establishment of cytotoxic mitochondria-specific CD8+ T cells in the periphery and in the brain. Notably, these mice show a sharp decrease in the density of dopaminergic axonal varicosities in the striatum and are affected by motor impairment that is reversed after treatment with L-DOPA. These data support the idea that PINK1 is a repressor of the immune system, and provide a pathophysiological model in which intestinal infection acts as a triggering event in Parkinson's disease, which highlights the relevance of the gut-brain axis in the disease10.


Assuntos
Infecções por Enterobacteriaceae/microbiologia , Infecções por Enterobacteriaceae/fisiopatologia , Intestinos/microbiologia , Doença de Parkinson/genética , Doença de Parkinson/microbiologia , Proteínas Quinases/deficiência , Proteínas Quinases/genética , Animais , Apresentação do Antígeno/imunologia , Autoantígenos/imunologia , Axônios/patologia , Linfócitos T CD8-Positivos/imunologia , Linfócitos T CD8-Positivos/patologia , Citrobacter rodentium/imunologia , Citrobacter rodentium/patogenicidade , Modelos Animais de Doenças , Neurônios Dopaminérgicos/imunologia , Neurônios Dopaminérgicos/patologia , Infecções por Enterobacteriaceae/imunologia , Infecções por Enterobacteriaceae/patologia , Feminino , Intestinos/imunologia , Intestinos/patologia , Levodopa/uso terapêutico , Masculino , Camundongos , Mitocôndrias/imunologia , Mitocôndrias/patologia , Neostriado/imunologia , Neostriado/microbiologia , Neostriado/patologia , Neostriado/fisiopatologia , Doença de Parkinson/tratamento farmacológico , Doença de Parkinson/fisiopatologia , Proteínas Quinases/imunologia , Ubiquitina-Proteína Ligases/deficiência , Ubiquitina-Proteína Ligases/genética , Ubiquitina-Proteína Ligases/imunologia
8.
Nat Immunol ; 20(8): 1046-1058, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31209405

RESUMO

The neonatal thymus generates Foxp3+ regulatory T (tTreg) cells that are critical in controlling immune homeostasis and preventing multiorgan autoimmunity. The role of antigen specificity on neonatal tTreg cell selection is unresolved. Here we identify 17 self-peptides recognized by neonatal tTreg cells, and reveal ligand specificity patterns that include self-antigens presented in an age- and inflammation-dependent manner. Fate-mapping studies of neonatal peptidyl arginine deiminase type IV (Padi4)-specific thymocytes reveal disparate fate choices. Neonatal thymocytes expressing T cell receptors that engage IAb-Padi4 with moderate dwell times within a conventional docking orientation are exported as tTreg cells. In contrast, Padi4-specific T cell receptors with short dwell times are expressed on CD4+ T cells, while long dwell times induce negative selection. Temporally, Padi4-specific thymocytes are subject to a developmental stage-specific change in negative selection, which precludes tTreg cell development. Thus, a temporal switch in negative selection and ligand binding kinetics constrains the neonatal tTreg selection window.


Assuntos
Autoantígenos/imunologia , Receptores de Antígenos de Linfócitos T alfa-beta/imunologia , Tolerância a Antígenos Próprios/imunologia , Linfócitos T Reguladores/citologia , Animais , Autoimunidade/imunologia , Diferenciação Celular/imunologia , Linhagem Celular , Feminino , Fatores de Transcrição Forkhead/metabolismo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Transgênicos , Linfócitos T Reguladores/imunologia , Timo/citologia
9.
Immunol Med ; 42(1): 22-28, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-31169082

RESUMO

Bullous pemphigoid (BP) is an organ-specific autoantibody-mediated autoimmune blistering skin disorder that tends to affect the elderly. Tense blister formation associated with itchy urticarial erythema is clinically observed in BP, and subepidermal blister formation with eosinophilic infiltration is a histopathological characteristic. BP autoantibodies target two hemidesmosomal components in basal keratinocytes: BP180 and BP230. Anti-BP180 autoantibodies play major roles in blister formation. Although the autoantibody-mediated pathomechanism of blister formation has been extensively studied, little is known about how and why immune tolerance to BP180 may be broken in certain elderly individuals. Recently, BP has been increasingly reported in diabetes mellites (DM) patients receiving dipeptidyl peptidase-IV inhibitors (DPP4is), which are widely used anti-DM drugs. Pharmacovigilance and cohort studies have revealed that DPP4is, especially vildagliptin, teneligliptin, and linagliptin, are a potential risk factor for BP onset. Interestingly, it has been revealed that Japanese DPP4i-BP tends to show a non-inflammatory phenotype, with less erythema than normal BP, and that DPP4i-BP autoantibodies target distinct epitopes on BP180. In addition, human leukocyte antigen-DQB1*03:01 was identified as the major haplotype in Japanese DPP4i-BP. This review summarizes the latest understanding of the pathogenesis of BP, with a special focus on the recently recognized DPP4i-BP.


Assuntos
Autoimunidade , Inibidores da Dipeptidil Peptidase IV/efeitos adversos , Hipoglicemiantes/administração & dosagem , Penfigoide Bolhoso/induzido quimicamente , Penfigoide Bolhoso/imunologia , Grupo com Ancestrais do Continente Asiático , Autoanticorpos , Autoantígenos/imunologia , Epitopos , Cadeias beta de HLA-DQ/genética , Haplótipos , Humanos , Tolerância Imunológica/imunologia , Linagliptina/efeitos adversos , Colágenos não Fibrilares/imunologia , Penfigoide Bolhoso/genética , Pirazóis/efeitos adversos , Fatores de Risco , Tiazolidinas/efeitos adversos , Vildagliptina/efeitos adversos
10.
Mol Immunol ; 112: 188-197, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31176198

RESUMO

Rheumatoid arthritis (RA) is a chronic, systemic, synovitis-based inflammatory disease with unknown etiology. Neutrophils play important roles in the pathogenesis of RA. Apoptosis and NETosis of neutrophils are two major mechanisms of programmed cell death that differ in their morphological characteristics and effects on the immune system. In rheumatoid arthritis, delayed neutrophil apoptosis amplifies the inflammatory response; and massive release of NETs and their components may cause tissue damage and provide self-antigens. Emodin is a natural anthraquinone derivative that occurs in many widely used Chinese medicinal herbs. In this study, we evaluated the effect of emodin on a murine adjuvant-induced arthritis (AA) model of RA in vivo and on neutrophil apoptosis and NETosis in vitro. Our results show that emodin alleviated AA by reducing neutrophil infiltration and proinflammatory cytokine (interleukin-6, interferon-gamma and tumor necrosis factor-α) release. Emodin promoted apoptosis and inhibited autophagy and NETosis in neutrophils. These findings indicate that emodin represents a potential therapeutic agent for RA.


Assuntos
Apoptose/imunologia , Artrite Reumatoide/imunologia , Emodina/imunologia , Armadilhas Extracelulares/imunologia , Infiltração de Neutrófilos/imunologia , Neutrófilos/imunologia , Animais , Artrite Experimental/imunologia , Autoantígenos/imunologia , Autofagia/imunologia , Citocinas/imunologia , Modelos Animais de Doenças , Feminino , Interleucina-6/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fator de Necrose Tumoral alfa/imunologia
11.
Scand J Immunol ; 90(4): e12797, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31166602

RESUMO

Distinctive "two signal" paths in immunology, taken by researchers with different academic backgrounds, seem to have both contained facets of the truth. Having been influenced by education at a medical school where Almroth Wright's early contributions were not forgotten, the author's "path less followed" led to views that began to gain recognition late in the twentieth century when the intimate relationship between innate and acquired immunity became more apparent.


Assuntos
Modelos Imunológicos , Agregação de Receptores , Linfócitos T/fisiologia , Timo/imunologia , Imunidade Adaptativa , Animais , Autoantígenos/imunologia , Autoimunidade , Consenso , Quadruplex G , Humanos , Imunidade Inata , Ativação Linfocitária , Tolerância a Antígenos Próprios
12.
Nat Commun ; 10(1): 2150, 2019 05 14.
Artigo em Inglês | MEDLINE | ID: mdl-31089130

RESUMO

Peptide-major histocompatibility complex class II (pMHCII)-based nanomedicines displaying tissue-specific autoantigenic epitopes can blunt specific autoimmune conditions by re-programming cognate antigen-experienced CD4+ T-cells into disease-suppressing T-regulatory type 1 (TR1) cells. Here, we show that single pMHCII-based nanomedicines displaying epitopes from mitochondrial, endoplasmic reticulum or cytoplasmic antigens associated with primary biliary cholangitis (PBC) or autoimmune hepatitis (AIH) can broadly blunt PBC, AIH and Primary Sclerosing Cholangitis in various murine models in an organ- rather than disease-specific manner, without suppressing general or local immunity against infection or metastatic tumors. Therapeutic activity is associated with cognate TR1 cell formation and expansion, TR1 cell recruitment to the liver and draining lymph nodes, local B-regulatory cell formation and profound suppression of the pro-inflammatory capacity of liver and liver-proximal myeloid dendritic cells and Kupffer cells. Thus, autoreactivity against liver-enriched autoantigens in liver autoimmunity is not disease-specific and can be harnessed to treat various liver autoimmune diseases broadly.


Assuntos
Doenças Autoimunes/tratamento farmacológico , Antígenos de Histocompatibilidade Classe II/imunologia , Hepatopatias/tratamento farmacológico , Nanopartículas/administração & dosagem , Peptídeos/administração & dosagem , Idoso , Animais , Autoantígenos/imunologia , Doenças Autoimunes/imunologia , Linhagem Celular , Modelos Animais de Doenças , Epitopos/imunologia , Feminino , Antígenos de Histocompatibilidade Classe II/química , Humanos , Fígado/efeitos dos fármacos , Fígado/imunologia , Hepatopatias/imunologia , Masculino , Camundongos , Pessoa de Meia-Idade , Nanomedicina/métodos , Nanopartículas/química , Peptídeos/química , Peptídeos/imunologia , Linfócitos T Reguladores/efeitos dos fármacos , Linfócitos T Reguladores/imunologia
13.
Nat Commun ; 10(1): 2220, 2019 05 17.
Artigo em Inglês | MEDLINE | ID: mdl-31101805

RESUMO

Both medullary thymic epithelial cells (mTEC) and dendritic cells (DC) present tissue-restricted antigens (TRA) to thymocytes to induce central tolerance, but the relative contributions of these antigen-presenting cell (APC) subsets remain unresolved. Here we developed a two-photon microscopy approach to observe thymocytes interacting with intact APCs presenting TRAs. We find that mTECs and DCs cooperate extensively to induce tolerance, with their relative contributions regulated by the cellular form of the TRA and the class of major histocompatibility complex (MHC) on which antigen is presented. Even when TRA expression is restricted to mTECs, DCs still present self-antigens at least as frequently as mTECs. Notably, the DC subset cDC2 efficiently acquires secreted mTEC-derived TRAs for cross-presentation on MHC-I. By directly imaging interactions between thymocytes and APCs, while monitoring intracellular signaling, this study reveals that distinct DC subsets and AIRE+ mTECs contribute substantially to presentation of diverse self-antigens for establishing central tolerance.


Assuntos
Tolerância Central/imunologia , Células Dendríticas/imunologia , Timócitos/imunologia , Timo/imunologia , Animais , Apresentação do Antígeno/imunologia , Autoantígenos/imunologia , Autoantígenos/metabolismo , Transplante de Medula Óssea , Separação Celular/métodos , Células Dendríticas/metabolismo , Células Epiteliais/imunologia , Feminino , Citometria de Fluxo/métodos , Microscopia Intravital/métodos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Microscopia de Fluorescência por Excitação Multifotônica/métodos , Linfócitos T Reguladores/imunologia , Timócitos/metabolismo , Timo/citologia , Fatores de Transcrição/imunologia , Fatores de Transcrição/metabolismo , Quimeras de Transplante/imunologia
14.
BMC Neurol ; 19(1): 94, 2019 May 09.
Artigo em Inglês | MEDLINE | ID: mdl-31072329

RESUMO

BACKGROUND: Recurrent optic neuritis (ON) was previously thought to be associated with multiple sclerosis (MS) and neuromyelitis optica spectrum disorders (NMOSD). Meningoencephalitis has recently been suggested to be a clinical finding typical of myelin oligodendrocyte glycoprotein (MOG) encephalomyelitis. We report a Chinese patient with recurrent ON at disease initiation, who had a delayed diagnosis of MOG-IgG syndrome, until recurrent meningoencephalitis appeared and serum MOG-IgG was detected. CASE PRESENTATION: From the age of 7 years, an AQP4-IgG negative female patient had 10 disease recurrences, including 4 episodes of recurrent ON, 4 episodes of fever and meningoencephalitis, and 2 episodes of ON as well as meningoencephalitis. She was initially diagnosed as recurrent ON and treated with glucocorticoids followed by gradual tapering when ON reoccurred. Later, she was diagnosed as central nervous system infection when fever and meningoencephalitis appeared, and antiviral drugs and glucocorticoids were used. However, when she returned to our department for follow-up on July 2017, the results of serum demyelinating autoimmune antibody revealed positive MOG-IgG (titer 1:320 by an in-house, cell-based assay using live cells transfected with full-length human MOG). A diagnosis of MOG-IgG syndrome was established. CONCLUSIONS: Testing for MOG-IgG in atypical MS and NMOSD patients, and patients with meningoencephalitis with a history of relapsing demyelinating symptoms is warranted.


Assuntos
Doenças Autoimunes Desmielinizantes do Sistema Nervoso Central/diagnóstico , Meningoencefalite/imunologia , Glicoproteína Mielina-Oligodendrócito/imunologia , Neurite Óptica/imunologia , Autoanticorpos/sangue , Autoantígenos/imunologia , Criança , Diagnóstico Tardio , Feminino , Humanos , Imunoglobulina G , Recidiva , Síndrome
15.
Cancer Immunol Immunother ; 68(5): 705-707, 2019 May.
Artigo em Inglês | MEDLINE | ID: mdl-30955066

RESUMO

The concept of a dual functional programme of the immune system to destroy malignant cells but also to edit their immunogenic profile, considerably improved our understanding of the process of tumor evolution in the context of a continuum of interactions between tumor cells and immune lymphocytes. Such an endogenous antitumor immunity throughout the period of cancer development established the concept of cancer immunomodulation which is practically based on a process of selection of more clonal tumors which are manageable by the immune system and constitute the equilibrium phase of immunoediting. The duration of this phase is very important, because the immune system keeps the tumor in a dormant state via cell interactions which establish a balanced state of tumor immunosurveillance versus tumor immune evasion. Depending on the quality and quantity of antitumor immune reactivity and the effectiveness of resistance mechanisms employed by the tumor cells to counteract this immune attack, the equilibrium phase may have shorter or longer duration. Notwithstanding its natural course, the equilibrium phase should be considered as a part of tumor evolutionary process guided by genetic as well as epigenetic changes which in turn activate endogenous cellular immunity to certain levels capable of controlling tumor growth rates and maintain tumor dormancy.


Assuntos
Imunidade Celular , Vigilância Imunológica , Imunoterapia/métodos , Neoplasias/imunologia , Linfócitos T/imunologia , Animais , Antígenos de Neoplasias/genética , Antígenos de Neoplasias/imunologia , Autoantígenos/imunologia , Humanos , Tolerância Imunológica , Mutação/genética , Evasão Tumoral
17.
Diabetes ; 68(5): 879-886, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31010879

RESUMO

Type 1 diabetes (T1D) is an autoimmune disease that is caused, in part, by T cell-mediated destruction of insulin-producing ß-cells. High risk for disease, in those with genetic susceptibility, is predicted by the presence of two or more autoantibodies against insulin, the 65-kDa form of glutamic acid decarboxylase (GAD65), insulinoma-associated protein 2 (IA-2), and zinc transporter 8 (ZnT8). Despite this knowledge, we still do not know what leads to the breakdown of tolerance to these autoantigens, and we have an incomplete understanding of T1D etiology and pathophysiology. Several new autoantibodies have recently been discovered using innovative technologies, but neither their potential utility in monitoring disease development and treatment nor their role in the pathophysiology and etiology of T1D has been explored. Moreover, neoantigen generation (through posttranslational modification, the formation of hybrid peptides containing two distinct regions of an antigen or antigens, alternative open reading frame usage, and translation of RNA splicing variants) has been reported, and autoreactive T cells that target these neoantigens have been identified. Collectively, these new studies provide a conceptual framework to understand the breakdown of self-tolerance, if such modifications occur in a tissue- or disease-specific context. A recent workshop sponsored by the National Institute of Diabetes and Digestive and Kidney Diseases brought together investigators who are using new methods and technologies to identify autoantigens and characterize immune responses toward these proteins. Researchers with diverse expertise shared ideas and identified resources to accelerate antigen discovery and the detection of autoimmune responses in T1D. The application of this knowledge will direct strategies for the identification of improved biomarkers for disease progression and treatment response monitoring and, ultimately, will form the foundation for novel antigen-specific therapeutics. This Perspective highlights the key issues that were addressed at the workshop and identifies areas for future investigation.


Assuntos
Autoantígenos/metabolismo , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/metabolismo , Animais , Autoantígenos/imunologia , Biomarcadores/metabolismo , Diabetes Mellitus Tipo 1/patologia , Diabetes Mellitus Tipo 1/fisiopatologia , Humanos
18.
Molecules ; 24(9)2019 Apr 26.
Artigo em Inglês | MEDLINE | ID: mdl-31027344

RESUMO

The objective of this study was to identify novel acetylation (Ac) modifications of the C1-inhibitor (C1-INH) and explain the association of the levels of autoantibodies against acetylated C1-INH peptides with the risk of developing systemic lupus erythematosus (SLE). Ac modifications of the C1-INH were identified and validated through in-gel digestion, nano-liquid chromatography-tandem mass spectrometry, immunoprecipitation, and Western blotting by using serum protein samples obtained from patients with SLE and age-matched healthy controls (HCs). In addition, the levels of serum C1-INH, Ac-protein adducts, and autoantibodies against unmodified and acetylated C1-INH peptides were measured. C1-INH levels in patients with SLE were significantly lower than those in HCs by 1.53-fold (p = 0.0008); however, Ac-protein adduct concentrations in patients with SLE were significantly higher than those in HCs by 1.35-fold (p = 0.0009). Moreover, immunoglobulin M (IgM) anti-C1-INH367-385 Ac and IgA anti-C1-INH367-385 Ac levels in patients with SLE were significantly lower than those in HCs. The low levels of IgM anti-C1-INH367-385 (odds ratio [OR] = 4.725, p < 0.001), IgM anti-C1-INH367-385 Ac (OR = 4.089, p = 0.001), and IgA anti-C1-INH367-385 Ac (OR = 5.566, p < 0.001) indicated increased risks for the development of SLE compared with HCs.


Assuntos
Proteína Inibidora do Complemento C1/imunologia , Imunoglobulina A/imunologia , Imunoglobulina M/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Peptídeos/imunologia , Acetilação , Sequência de Aminoácidos , Autoanticorpos/imunologia , Autoantígenos/imunologia , Proteína Inibidora do Complemento C1/química , Proteína Inibidora do Complemento C1/metabolismo , Feminino , Humanos , Lúpus Eritematoso Sistêmico/sangue , Peso Molecular , Peptídeos/química , Ligação Proteica/imunologia , Curva ROC , Taiwan
19.
Clin Chim Acta ; 495: 77-81, 2019 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-30928572

RESUMO

OBJECTIVE: To produce 60-kDa recombinant Sjoren's syndrome antigen A (SSA-60) by gene engineering and establish and evaluate the performance of a magnetic microparticle chemiluminescence quantitative method for detecting anti-SSA-60 antibody in sera. METHODS: Recombinant antigen was prepared by gene recombination technology and purified by high affinity Ni2+ resin. The immunogenicity of the recombinant antigen was verified in immunized BALB/c female mice, and the immune reactivity of our recombinant antigen was assessed using the enzyme-linked immunosorbent assay (ELISA) method. With this recombinant antigen, a specific magnetic microparticles chemiluminescence assay (MMC assay) was developed and performed using various parameters. RESULTS: The inner-group difference among high, medium and low density sera mixtures was 7.65%, 2.24%, and 2.47%, respectively, and the inter-group precision rate was 8.25%, 6.26%, and 4.87%, respectively, using the MMC assay. The low detection limit was 1.36 relative unit per milliliter (Ru/mL), and the quantitative limit was 4.48 Ru/mL. The linear range of this method was 2-400 Ru/mL, which is wider than that of ELISA. The standard error (SE) of the differences was 31.3 between the two methods. Good correlation (y = 1.04x - 7.86, R2 = 0.979, P < 0.05) and high agreement (Kappa = 0.95) were noted between the two methods. CONCLUSIONS: These data show that the MMC assay provides high sensitivity and specificity and a wider linear range in anti-SSA-60 aab detection and fairly good agreement and correlation between the MMC assay and ELISA. The MMC assay has potential in rapid, high-throughput, quantitative and automated autoimmune antibody testing.


Assuntos
Autoanticorpos/sangue , Autoantígenos/imunologia , Medições Luminescentes/métodos , Imãs/química , Microesferas , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Autoanticorpos/imunologia , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Adulto Jovem
20.
Exp Mol Pathol ; 107: 165-170, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30817909

RESUMO

The major epitopes recognized by autoantibodies in anti-glomerular basement membrane (GBM) disease are found in the α3-subunit non-collagenous domain of type IV collagen [α3(IV)NC1], which is present in the glomerular and alveolar basement membranes. These epitopes are structurally cryptic, owing to the hexamer formation of the non-collagenous domain of α3, α4, and α5 subunits and are expressed by the dissociation of the hexamer. Anti-GBM disease usually manifests as a single attack (SA), and we rarely see patients who repeatedly relapse. We recently treated a patient with anti-GBM disease who exhibited repeated relapse (RR). Here, we conducted immunohistochemistry of formalin-fixed paraffin-embedded normal kidney sections and immunoblotting using recombinant human α3(IV)NC1 to compare the epitopes recognized by anti-GBM antibodies in the RR patient and SA patients. Although a clear staining of GBM especially in the connecting basement membrane of Bowman's capsule was observed when IgGs of SA patients were used as primary antibodies, such staining was not obtained when IgG of the RR patient was employed. In immunoblotting of α3(IV)NC1 using the IgG of the RR patient as a primary antibody, an 18-kDa band was detected besides the 56.8-kDa band corresponding to the whole-size α3(IV)NC1. Whereas the 56.8-kDa band disappeared after digestion of the recombinant α3(IV)NC1 by protease, the 18-kDa band remained. Furthermore, the 18-kDa band was not detected by a commercially available anti-α3(IV)NC1 monoclonal antibody. These findings suggest that the IgG of the RR patient recognizes the epitope distinct from that recognized by the anti-α3(IV)NC1 monoclonal antibody.


Assuntos
Doença Antimembrana Basal Glomerular/imunologia , Autoanticorpos/imunologia , Autoantígenos/imunologia , Epitopos de Linfócito B/imunologia , Membrana Basal Glomerular/imunologia , Feminino , Humanos , Recidiva , Adulto Jovem
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