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2.
Nat Commun ; 10(1): 2603, 2019 06 13.
Artigo em Inglês | MEDLINE | ID: mdl-31197149

RESUMO

During thymic negative selection, autoreactive thymocytes carrying T cell receptor (TCR) with overtly strong affinity to self-MHC/self-peptide are removed by Bim-dependent apoptosis, but how Bim is specifically regulated to link TCR activation and apoptosis induction is unclear. Here we identify a murine T cell-specific genomic enhancer EBAB (Bub1-Acoxl-Bim), whose deletion leads to accumulation of thymocytes expressing high affinity TCRs. Consistently, EBAB knockout mice have defective negative selection and fail to delete autoreactive thymocytes in various settings, with this defect accompanied by reduced Bim expression and apoptosis induction. By contrast, EBAB is dispensable for maintaining peripheral T cell homeostasis via Bim-dependent pathways. Our data thus implicate EBAB as an important, developmental stage-specific regulator of Bim expression and apoptosis induction to enforce thymic negative selection and suppress autoimmunity. Our study unravels a part of genomic enhancer codes that underlie complex and context-dependent gene regulation in TCR signaling.


Assuntos
Autoimunidade/genética , Proteína 11 Semelhante a Bcl-2/genética , Elementos Facilitadores Genéticos/imunologia , Receptores de Antígenos de Linfócitos T/metabolismo , Timócitos/fisiologia , Animais , Apoptose/genética , Apoptose/imunologia , Autoimunidade/imunologia , Proteína 11 Semelhante a Bcl-2/metabolismo , Sistemas CRISPR-Cas/genética , Elementos Facilitadores Genéticos/genética , Feminino , Regulação da Expressão Gênica/imunologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Modelos Animais , Receptores de Antígenos de Linfócitos T/imunologia , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Timo/citologia , Timo/imunologia
3.
Nat Immunol ; 20(7): 928-942, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31061532

RESUMO

To define the cell populations that drive joint inflammation in rheumatoid arthritis (RA), we applied single-cell RNA sequencing (scRNA-seq), mass cytometry, bulk RNA sequencing (RNA-seq) and flow cytometry to T cells, B cells, monocytes, and fibroblasts from 51 samples of synovial tissue from patients with RA or osteoarthritis (OA). Utilizing an integrated strategy based on canonical correlation analysis of 5,265 scRNA-seq profiles, we identified 18 unique cell populations. Combining mass cytometry and transcriptomics revealed cell states expanded in RA synovia: THY1(CD90)+HLA-DRAhi sublining fibroblasts, IL1B+ pro-inflammatory monocytes, ITGAX+TBX21+ autoimmune-associated B cells and PDCD1+ peripheral helper T (TPH) cells and follicular helper T (TFH) cells. We defined distinct subsets of CD8+ T cells characterized by GZMK+, GZMB+, and GNLY+ phenotypes. We mapped inflammatory mediators to their source cell populations; for example, we attributed IL6 expression to THY1+HLA-DRAhi fibroblasts and IL1B production to pro-inflammatory monocytes. These populations are potentially key mediators of RA pathogenesis.


Assuntos
Artrite Reumatoide/genética , Artrite Reumatoide/metabolismo , Perfilação da Expressão Gênica , Membrana Sinovial/metabolismo , Transcriptoma , Artrite Reumatoide/patologia , Autoimunidade/genética , Biomarcadores , Biologia Computacional/métodos , Estudos Transversais , Citocinas/metabolismo , Fibroblastos/metabolismo , Citometria de Fluxo , Expressão Gênica , Perfilação da Expressão Gênica/métodos , Sequenciamento de Nucleotídeos em Larga Escala , Antígenos de Histocompatibilidade Classe II/genética , Antígenos de Histocompatibilidade Classe II/imunologia , Humanos , Leucócitos/imunologia , Leucócitos/metabolismo , Monócitos/imunologia , Monócitos/metabolismo , Transdução de Sinais , Análise de Célula Única/métodos , Membrana Sinovial/patologia , Subpopulações de Linfócitos T/imunologia , Subpopulações de Linfócitos T/metabolismo , Fluxo de Trabalho
4.
Nat Rev Dis Primers ; 5(1): 32, 2019 05 09.
Artigo em Inglês | MEDLINE | ID: mdl-31073128

RESUMO

Dilated cardiomyopathy (DCM) is a clinical diagnosis characterized by left ventricular or biventricular dilation and impaired contraction that is not explained by abnormal loading conditions (for example, hypertension and valvular heart disease) or coronary artery disease. Mutations in several genes can cause DCM, including genes encoding structural components of the sarcomere and desmosome. Nongenetic forms of DCM can result from different aetiologies, including inflammation of the myocardium due to an infection (mostly viral); exposure to drugs, toxins or allergens; and systemic endocrine or autoimmune diseases. The heterogeneous aetiology and clinical presentation of DCM make a correct and timely diagnosis challenging. Echocardiography and other imaging techniques are required to assess ventricular dysfunction and adverse myocardial remodelling, and immunological and histological analyses of an endomyocardial biopsy sample are indicated when inflammation or infection is suspected. As DCM eventually leads to impaired contractility, standard approaches to prevent or treat heart failure are the first-line treatment for patients with DCM. Cardiac resynchronization therapy and implantable cardioverter-defibrillators may be required to prevent life-threatening arrhythmias. In addition, identifying the probable cause of DCM helps tailor specific therapies to improve prognosis. An improved aetiology-driven personalized approach to clinical care will benefit patients with DCM, as will new diagnostic tools, such as serum biomarkers, that enable early diagnosis and treatment.


Assuntos
Cardiomiopatia Dilatada/diagnóstico , Cardiomiopatia Dilatada/terapia , Autoimunidade/genética , Autoimunidade/fisiologia , Terapia de Ressincronização Cardíaca/métodos , Cardiomiopatia Dilatada/fisiopatologia , Ecocardiografia/métodos , Eletrocardiografia/métodos , Insuficiência Cardíaca/etiologia , Humanos , Inflamação/complicações , Inflamação/fisiopatologia , Imagem por Ressonância Magnética/métodos , Prognóstico , Qualidade de Vida/psicologia , Fatores Sexuais
5.
EBioMedicine ; 42: 76-85, 2019 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-30952617

RESUMO

BACKGROUND: Autoimmune disease prevention requires tools to assess an individual's risk of developing a specific disease. One tool is disease-associated autoantibodies, which accumulate in an asymptomatic preclinical period. However, patients sometimes exhibit autoantibodies associated with a different disease classification. When and how these alternative autoantibodies first appear remain unknown. This cross-sectional study characterizes alternative autoimmunity, and associated genetic and environmental factors, in unaffected first-degree relatives (FDRs) of patients, who exhibit increased future risk for the same disease. METHODS: Samples (n = 1321) from disease-specific autoantibody-positive (aAb+) systemic lupus erythematosus (SLE), rheumatoid arthritis (RA), and type 1 diabetes (T1D) patients; and unaffected aAb+ and autoantibody-negative (aAb-) SLE and RA FDRs were tested for SLE, RA, and T1D aAbs, as well as anti-tissue transglutaminase, anti-cardiolipin and anti-thyroperoxidase. FDR SLE and RA genetic risk scores (GRS) were calculated. FINDINGS: Alternative autoimmunity occurred in SLE patients (56%) and FDRs (57·4%), RA patients (32·6%) and FDRs (34·8%), and T1D patients (43%). Expanded autoimmunity, defined as autoantibodies spanning at least two other diseases, occurred in 18·5% of SLE patients, 16·4% of SLE FDRs, 7·8% of RA patients, 5·3% of RA FDRs, and 10·8% of T1D patients. SLE FDRs were more likely to have alternative (odds ratio [OR] 2·44) and expanded (OR 3·27) autoimmunity than RA FDRs. Alternative and expanded autoimmunity were associated with several environmental exposures. Alternative autoimmunity was associated with a higher RA GRS in RA FDRs (OR 1·41), and a higher SLE GRS in aAb+ RA FDRs (OR 1·87), but not in SLE FDRs. INTERPRETATION: Autoimmunity commonly crosses disease-specific boundaries in systemic (RA, SLE) and organ-specific (T1D) autoimmune diseases. Alternative autoimmunity is more common in SLE FDRs than RA FDRs, and is influenced by genetic and environmental factors. These findings have substantial implications for preclinical disease pathogenesis and autoimmune disease prevention studies. FUND: NIH U01AI101981, R01AR051394, U19AI082714, P30AR053483, P30GM103510, U54GM104938, U01AI101934, R01AI024717, U01AI130830, I01BX001834, & U01HG008666.


Assuntos
Artrite Reumatoide/etiologia , Autoimunidade/genética , Predisposição Genética para Doença , Lúpus Eritematoso Sistêmico/etiologia , Núcleo Familiar , Adulto , Idoso , Alelos , Artrite Reumatoide/diagnóstico , Autoanticorpos/imunologia , Meio Ambiente , Feminino , Frequência do Gene , Humanos , Lúpus Eritematoso Sistêmico/diagnóstico , Masculino , Pessoa de Meia-Idade , Especificidade de Órgãos/imunologia , Polimorfismo de Nucleotídeo Único , Fatores de Risco
6.
Immunity ; 50(2): 302-316, 2019 02 19.
Artigo em Inglês | MEDLINE | ID: mdl-30784578

RESUMO

Regulatory T (Treg) cells expressing the transcription factor Foxp3 have a critical role in the maintenance of immune homeostasis and prevention of autoimmunity. Recent advances in single cell analyses have revealed a range of Treg cell activation and differentiation states in different human pathologies. Here we review recent progress in the understanding of human Treg cell heterogeneity and function. We discuss these findings within the context of concepts in Treg cell development and function derived from preclinical models and insight from approaches targeting Treg cells in clinical settings. Distinguishing functional Treg cells from other T cells and understanding the context-dependent function(s) of different Treg subsets will be crucial to the development of strategies toward the selective therapeutic manipulation of Treg cells in autoimmunity and cancer.


Assuntos
Autoimunidade/imunologia , Fatores de Transcrição Forkhead/imunologia , Neoplasias/imunologia , Subpopulações de Linfócitos T/imunologia , Linfócitos T Reguladores/imunologia , Animais , Autoimunidade/genética , Diferenciação Celular/genética , Diferenciação Celular/imunologia , Fatores de Transcrição Forkhead/genética , Regulação da Expressão Gênica/imunologia , Heterogeneidade Genética , Humanos , Neoplasias/genética , Subpopulações de Linfócitos T/metabolismo , Linfócitos T Reguladores/metabolismo
7.
Nat Biotechnol ; 37(3): 238-251, 2019 03.
Artigo em Inglês | MEDLINE | ID: mdl-30804535

RESUMO

The main function of the immune system in health is to protect the host from infection by microbes and parasites. Because immune responses to nonself bear the risk of unleashing accidental immunity against self, evolution has endowed the immune system with central and peripheral mechanisms of tolerance, including regulatory T and B cells. Although the past two decades have witnessed the successful clinical translation of a whole host of novel therapies for the treatment of chronic inflammation, the development of antigen-based approaches capable of selectively blunting autoimmune inflammation without impairing normal immunity has remained elusive. Earlier autoantigen-specific approaches employing peptides or whole antigens have evolved into strategies that seek to preferentially deliver these molecules to autoreactive T cells either indirectly, via antigen-presenting cells, or directly, via major histocompatibility complex molecules, in ways intended to promote clonal deletion and/or immunoregulation. The disease specificity, mechanistic underpinnings, developability and translational potential of many of these strategies remain unclear.


Assuntos
Autoimunidade/genética , Linfócitos B Reguladores/imunologia , Inflamação/tratamento farmacológico , Linfócitos T Reguladores/imunologia , Autoantígenos , Autoimunidade/imunologia , Linfócitos B Reguladores/metabolismo , Linfócitos T CD4-Positivos/imunologia , Humanos , Sistema Imunitário , Tolerância Imunológica/genética , Tolerância Imunológica/imunologia , Inflamação/imunologia , Inflamação/patologia , Linfócitos T Reguladores/metabolismo
8.
Immunogenetics ; 71(4): 283-297, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30671674

RESUMO

Systemic lupus erythematosus (SLE) is an autoimmune multi-organ disorder that presents itself in a thousand ways. Its clinical course is extremely unpredictable, which makes diagnosis and treatment a challenge for clinicians. It appears that the clinical course of SLE is determined by genetic material in combination with environmental factors. In this article, we review recent findings on the pathogenesis of SLE from the perspective of genetics, focusing on defects in the clearance of apoptotic bodies and immune complexes, on alterations in the innate immune system response, and on impaired pathways in the adaptive immune system. Furthermore, the major histocompatibility complex (MHC) and non-MHC genes discovered during genome-wide association studies (GWASs) in SLE patients are also evaluated. In addition, the effect of these polymorphisms on the function of their related transcripts and their association with the clinical manifestations of SLE and its pathophysiology are explained. Finally, the association of genetic polymorphisms with clinical responses to common medications used in the treatment of SLE is also discussed.


Assuntos
Predisposição Genética para Doença/genética , Estudo de Associação Genômica Ampla/métodos , Lúpus Eritematoso Sistêmico/genética , Polimorfismo Genético/genética , Imunidade Adaptativa/genética , Autoimunidade/genética , Humanos , Imunidade Inata/genética , Lúpus Eritematoso Sistêmico/terapia , Complexo Principal de Histocompatibilidade/genética
9.
Pediatr Diabetes ; 20(3): 263-270, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-30628751

RESUMO

OBJECTIVE: The capacity to precisely predict progression to type 1 diabetes (T1D) in young children over a short time span is an unmet need. We sought to develop a risk algorithm to predict progression in children with high-risk human leukocyte antigen (HLA) genes followed in The Environmental Determinants of Diabetes in the Young (TEDDY) study. METHODS: Logistic regression and 4-fold cross-validation examined 38 candidate predictors of risk from clinical, immunologic, metabolic, and genetic data. TEDDY subjects with at least one persistent, confirmed autoantibody at age 3 were analyzed with progression to T1D by age 6 serving as the primary endpoint. The logistic regression prediction model was compared to two non-statistical predictors, multiple autoantibody status, and presence of insulinoma-associated-2 autoantibodies (IA-2A). RESULTS: A total of 363 subjects had at least one autoantibody at age 3. Twenty-one percent of subjects developed T1D by age 6. Logistic regression modeling identified 5 significant predictors - IA-2A status, hemoglobin A1c, body mass index Z-score, single-nucleotide polymorphism rs12708716_G, and a combination marker of autoantibody number plus fasting insulin level. The logistic model yielded a receiver operating characteristic area under the curve (AUC) of 0.80, higher than the two other predictors; however, the differences in AUC, sensitivity, and specificity were small across models. CONCLUSIONS: This study highlights the application of precision medicine techniques to predict progression to diabetes over a 3-year window in TEDDY subjects. This multifaceted model provides preliminary improvement in prediction over simpler prediction tools. Additional tools are needed to maximize the predictive value of these approaches.


Assuntos
Autoanticorpos/sangue , Diabetes Mellitus Tipo 1/diagnóstico , Ilhotas Pancreáticas/imunologia , Fatores Etários , Autoanticorpos/análise , Autoimunidade/genética , Criança , Pré-Escolar , Estudos de Coortes , Diabetes Mellitus Tipo 1/sangue , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/patologia , Progressão da Doença , Feminino , Predisposição Genética para Doença , Antígenos HLA-DQ/genética , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Prognóstico
10.
Diabetes ; 68(4): 847-857, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30655385

RESUMO

The risk for autoimmunity and subsequently type 1 diabetes is 10-fold higher in children with a first-degree family history of type 1 diabetes (FDR children) than in children in the general population (GP children). We analyzed children with high-risk HLA genotypes (n = 4,573) in the longitudinal TEDDY birth cohort to determine how much of the divergent risk is attributable to genetic enrichment in affected families. Enrichment for susceptible genotypes of multiple type 1 diabetes-associated genes and a novel risk gene, BTNL2, was identified in FDR children compared with GP children. After correction for genetic enrichment, the risks in the FDR and GP children converged but were not identical for multiple islet autoantibodies (hazard ratio [HR] 2.26 [95% CI 1.6-3.02]) and for diabetes (HR 2.92 [95% CI 2.05-4.16]). Convergence varied depending upon the degree of genetic susceptibility. Risks were similar in the highest genetic susceptibility group for multiple islet autoantibodies (14.3% vs .12.7%) and diabetes (4.8% vs. 4.1%) and were up to 5.8-fold divergent for children in the lowest genetic susceptibility group, decreasing incrementally in GP children but not in FDR children. These findings suggest that additional factors enriched within affected families preferentially increase the risk of autoimmunity and type 1 diabetes in lower genetic susceptibility strata.


Assuntos
Autoimunidade/fisiologia , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/imunologia , Autoanticorpos/imunologia , Autoimunidade/genética , Predisposição Genética para Doença/genética , Genótipo , Antígenos HLA-DQ/genética , Antígenos HLA-DQ/imunologia , Humanos , Ilhotas Pancreáticas/metabolismo , Modelos de Riscos Proporcionais , Fatores de Risco
11.
Int J Rheum Dis ; 22(3): 386-391, 2019 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-30548416

RESUMO

Co-occurrence of autoimmune diseases (ADs) within an individual is postulated to be a frequent phenomenon in rheumatic diseases. Similar clinical signs and symptoms, pathophysiological mechanisms, genetic factors within autoimmune diseases and aggregation of diverse ADs within families sustain the theory of shared pathogenesis of several ADs (autoimmune tautology). Polyautoimmunity (PA) is defined as the presence of more than one autoimmune disease in a single patient. When three or more autoimmune diseases coexist, this condition is called multiple autoimmune syndrome (MAS). This analysis summarizes an estimated prevalence of PA in the most common rheumatic diseases, the presumable risk factors for PA and influence of concomitant diseases on the course of disease.


Assuntos
Doenças Autoimunes/imunologia , Autoimunidade , Doenças Reumáticas/imunologia , Animais , Doenças Autoimunes/diagnóstico , Doenças Autoimunes/epidemiologia , Doenças Autoimunes/genética , Autoimunidade/genética , Predisposição Genética para Doença , Humanos , Multimorbidade , Fenótipo , Prevalência , Prognóstico , Doenças Reumáticas/diagnóstico , Doenças Reumáticas/epidemiologia , Doenças Reumáticas/genética , Medição de Risco , Fatores de Risco , Síndrome
12.
J Clin Immunol ; 39(1): 37-44, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30543054

RESUMO

PURPOSE: Human signal transducer and activator of transcription 1 (STAT1) gain-of-function (GOF) mutations present with a broad range of manifestations ranging from chronic mucocutaneous candidiasis and autoimmunity to combined immunodeficiency (CID). So far, there is very limited experience with hematopoietic stem cell transplantation (HSCT) as a therapeutic modality in this disorder. Here, we describe two patients with heterozygous STAT1 GOF mutations mimicking CID who were treated with HSCT. METHODS: Data on the HSC sources, conditioning regimen, graft-versus-host disease (GvHD) and antimicrobial prophylaxis, and the post-transplant course including engraftment, GvHD, transplant-related complications, infections, chimerism, and survival were evaluated. Pre- and post-transplant immunological studies included enumeration of circulating interferon gamma (IFN-γ)- and interleukin 17 (IL-17)-expressing CD4+ T cells and analysis of IFN-ß-induced STAT1 phosphorylation in patient 1 (P1)'s T cells. RESULTS: P1 was transplanted with cord blood from an HLA-identical sibling, and P2 with bone marrow from a fully matched unrelated donor using a reduced toxicity conditioning regimen. While P1 completely recovered from her disease, P2 suffered from systemic CMV disease and secondary graft failure and died due to severe pulmonary involvement and hemorrhage. The dysregulated IFN-γ production, suppressed IL-17 response, and enhanced STAT1 phosphorylation previously found in the CD4+ T cells of P1 were normalized following transplantation. CONCLUSION: HSCT could be an alternative and curative therapeutic option for selected STAT1 GOF mutant patients with progressive life-threatening disease unresponsive to conventional therapy. Morbidity and mortality-causing complications included secondary graft failure, infections, and bleeding.


Assuntos
Mutação com Ganho de Função/genética , Doença Enxerto-Hospedeiro/genética , Fator de Transcrição STAT1/genética , Autoimunidade/genética , Linfócitos T CD4-Positivos/metabolismo , Pré-Escolar , Feminino , Transplante de Células-Tronco Hematopoéticas/métodos , Heterozigoto , Humanos , Masculino , Condicionamento Pré-Transplante/métodos
13.
Immunol Rev ; 287(1): 50-61, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30565243

RESUMO

The human adaptive immune system recognizes almost all the pathogens that we encounter and all the tumor antigens that may arise during our lifetime. Primary immunodeficiencies affecting lymphocyte development or function therefore lead to severe infections and tumor susceptibility. Furthermore, the fact that autoimmunity is a frequent feature of primary immunodeficiencies reveals a third function of the adaptive immune system: its self-regulation. Indeed, the generation of a broad repertoire of antigen receptors (via a unique strategy of random somatic rearrangements of gene segments in T cell and B cell receptor loci) inevitably creates receptors with specificity for self-antigens and thus leads to the presence of autoreactive lymphocytes. There are many different mechanisms for controlling the emergence or action of autoreactive lymphocytes, including clonal deletion in the primary lymphoid organs, receptor editing, anergy, suppression of effector lymphocytes by regulatory lymphocytes, and programmed cell death. Here, we review the genetic defects affecting lymphocyte apoptosis and that are associated with lymphoproliferation and autoimmunity, together with the role of somatic mutations and their potential involvement in more common autoimmune diseases.


Assuntos
Apoptose/genética , Autoimunidade/genética , Linfócitos B/imunologia , Leucemia/genética , Linfócitos T/imunologia , Receptor fas/genética , Proteínas ras/genética , Animais , Autoantígenos/imunologia , Humanos , Mutação/genética , Receptores de Antígenos/genética
14.
Immunol Cell Biol ; 97(1): 17-28, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-30052286

RESUMO

Inflammasomes are protein complexes activated by infection and cellular stress that promote caspase-1 activation and subsequent inflammatory cytokine processing and cell death. It has been anticipated that inflammasome activity contributes to autoimmunity. However, we previously showed that macrophages from autoimmune New Zealand Black (NZB) mice lack NLRP3 inflammasome function, and their absent in melanoma 2 (AIM2) inflammasome responses are compromised by high expression of the AIM2 antagonist protein p202. Here we found that the point mutation leading to lack of NLRP3 expression occurred early in the NZB strain establishment, as it is shared with the related obese strain New Zealand Obese, but not with the unrelated New Zealand White (NZW) strain. The first cross progeny of NZB and NZW mice develop more severe lupus nephritis than the NZB strain. We have compared AIM2 and NLRP3 inflammasome function in macrophages from NZB, NZW, and NZB/W F1 mice. The NZW parental strain showed strong inflammasome function, whereas the NZB/W F1 have haploinsufficient expression of NLRP3 and show reduced NLRP3 and AIM2 inflammasome responses, particularly at low stimulus strength. It remains to be established whether the low inflammasome function could contribute to loss of tolerance and the onset of autoimmunity in NZB and NZB/W F1. However, with amplifying inflammatory stimuli through the course of disease, the NLRP3 response in the NZB/W F1 may be sufficient to contribute to kidney damage at later stages of disease.


Assuntos
Autoimunidade , Proteínas de Ligação a DNA/deficiência , Inflamassomos , Macrófagos , Proteína 3 que Contém Domínio de Pirina da Família NLR/deficiência , Animais , Autoimunidade/genética , Proteínas de Ligação a DNA/imunologia , Feminino , Inflamassomos/genética , Nefrite Lúpica/genética , Nefrite Lúpica/imunologia , Nefrite Lúpica/patologia , Macrófagos/imunologia , Macrófagos/metabolismo , Camundongos , Camundongos Endogâmicos NZB , Proteína 3 que Contém Domínio de Pirina da Família NLR/genética , Proteína 3 que Contém Domínio de Pirina da Família NLR/imunologia , Mutação Puntual
15.
Diabetes Care ; 42(2): 192-199, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30061316

RESUMO

OBJECTIVE: There are variable reports of risk of concordance for progression to islet autoantibodies and type 1 diabetes in identical twins after one twin is diagnosed. We examined development of positive autoantibodies and type 1 diabetes and the effects of genetic factors and common environment on autoantibody positivity in identical twins, nonidentical twins, and full siblings. RESEARCH DESIGN AND METHODS: Subjects from the TrialNet Pathway to Prevention Study (N = 48,026) were screened from 2004 to 2015 for islet autoantibodies (GAD antibody [GADA], insulinoma-associated antigen 2 [IA-2A], and autoantibodies against insulin [IAA]). Of these subjects, 17,226 (157 identical twins, 283 nonidentical twins, and 16,786 full siblings) were followed for autoantibody positivity or type 1 diabetes for a median of 2.1 years. RESULTS: At screening, identical twins were more likely to have positive GADA, IA-2A, and IAA than nonidentical twins or full siblings (all P < 0.0001). Younger age, male sex, and genetic factors were significant factors for expression of IA-2A, IAA, one or more positive autoantibodies, and two or more positive autoantibodies (all P ≤ 0.03). Initially autoantibody-positive identical twins had a 69% risk of diabetes by 3 years compared with 1.5% for initially autoantibody-negative identical twins. In nonidentical twins, type 1 diabetes risk by 3 years was 72% for initially multiple autoantibody-positive, 13% for single autoantibody-positive, and 0% for initially autoantibody-negative nonidentical twins. Full siblings had a 3-year type 1 diabetes risk of 47% for multiple autoantibody-positive, 12% for single autoantibody-positive, and 0.5% for initially autoantibody-negative subjects. CONCLUSIONS: Risk of type 1 diabetes at 3 years is high for initially multiple and single autoantibody-positive identical twins and multiple autoantibody-positive nonidentical twins. Genetic predisposition, age, and male sex are significant risk factors for development of positive autoantibodies in twins.


Assuntos
Autoimunidade/fisiologia , Diabetes Mellitus Tipo 1 , Ilhotas Pancreáticas/imunologia , Gêmeos Dizigóticos , Gêmeos Monozigóticos , Adolescente , Adulto , Autoanticorpos/análise , Autoanticorpos/sangue , Autoimunidade/genética , Criança , Pré-Escolar , Diabetes Mellitus Tipo 1/diagnóstico , Diabetes Mellitus Tipo 1/epidemiologia , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/prevenção & controle , Progressão da Doença , Doenças em Gêmeos/diagnóstico , Doenças em Gêmeos/epidemiologia , Doenças em Gêmeos/genética , Doenças em Gêmeos/imunologia , Meio Ambiente , Feminino , Predisposição Genética para Doença , Glutamato Descarboxilase/imunologia , Humanos , Insulina/metabolismo , Masculino , Programas de Rastreamento/métodos , Fatores de Risco , Estudos Soroepidemiológicos , Irmãos , Gêmeos/genética , Gêmeos Dizigóticos/genética , Gêmeos Dizigóticos/estatística & dados numéricos , Gêmeos Monozigóticos/genética , Gêmeos Monozigóticos/estatística & dados numéricos , Adulto Jovem
16.
Plant Cell Physiol ; 60(4): 778-787, 2019 Apr 01.
Artigo em Inglês | MEDLINE | ID: mdl-30590768

RESUMO

Mitogen-activated protein kinase (MAPK) pathways have a pivotal role in innate immunity signaling in plants. In Arabidopsis, the MAPK pathway that consists of MEKK1, MKK1/MKK2 and MPK4 is involved in pattern-triggered immunity signaling upstream of defense gene expression. This pathway is partly guarded by SUMM2, a nucleotide-binding domain leucine-rich repeat (NLR) protein, which is activated by disruption of the MAPK pathway. To identify other components required for the guard mechanism, here we developed a new mutant screening system utilizing a dwarf autoimmune line that overexpressed the N-terminal regulatory domain of MEKK1. Mutants with suppression of the dwarf, autoimmune phenotypes were identified, and one locus responsible for the phenotype was designated as suppressor of MEKK1N overexpression-induced dwarf 1 (SMN1). MutMap analysis revealed that SMN1 encodes the Toll/Interleukin-1 receptor (TIR)-class NLR protein RPS6, a previously identified resistant protein against bacterial pathogen Pseudomonas syringae pv. tomato expressing the HopA1 effector. Importantly, mutations in SMN1/RPS6 also partially suppressed the dwarf, autoimmune phenotypes of mekk1 and mpk4 plants. Our results suggest that the two structurally distinct NLR proteins, SMN1/RPS6 and SUMM2, monitor integrity of the MEKK1-MKK1/MKK2-MPK4 pathway.


Assuntos
Autoimunidade/fisiologia , Proteínas Quinases Ativadas por Mitógeno/metabolismo , Proteínas Serina-Treonina Quinases/metabolismo , Arabidopsis/genética , Arabidopsis/metabolismo , Arabidopsis/microbiologia , Proteínas de Arabidopsis/genética , Proteínas de Arabidopsis/metabolismo , Autoimunidade/genética , Proteínas Quinases Ativadas por Mitógeno/genética , Proteínas NLR/genética , Proteínas NLR/metabolismo , Imunidade Vegetal/genética , Imunidade Vegetal/fisiologia , Proteínas Serina-Treonina Quinases/genética , Pseudomonas syringae/patogenicidade , Transdução de Sinais
17.
RNA Biol ; 16(4): 504-517, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-30109815

RESUMO

Adaptive immunity of prokaryotes is mediated by CRISPR-Cas systems that employ a large variety of Cas protein effectors to identify and destroy foreign genetic material. The different targeting mechanisms of Cas proteins rely on the proper protection of the host genome sequence while allowing for efficient detection of target sequences, termed protospacers. A short DNA sequence, the protospacer-adjacent motif (PAM), is frequently used to mark proper target sites. Cas proteins have evolved a multitude of PAM-interacting domains, which enables them to cope with viral anti-CRISPR measures that alter the sequence or accessibility of PAM elements. In this review, we summarize known PAM recognition strategies for all CRISPR-Cas types. Available structures of target bound Cas protein effector complexes highlight the diversity of mechanisms and domain architectures that are employed to guarantee target specificity.


Assuntos
Sistemas CRISPR-Cas/genética , Motivos de Nucleotídeos/genética , Adaptação Fisiológica/genética , Autoimunidade/genética , Sequência de Bases , Modelos Moleculares , Ribonucleases/metabolismo
18.
Int Endod J ; 52(1): 5-12, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-29904933

RESUMO

AIM: To investigate the DNA methylation profiles of immune response-related genes in apical periodontitis (AP) lesions. METHODOLOGY: The methylation profiles on the cytosine-phosphate-guanine (CpG) regions of 22 gene promoters involved in inflammation and autoimmunity were assessed in 60 human AP lesions and 24 healthy periodontal ligaments (controls) using a pathway-specific real-time polymerase chain reaction array (EpiTect® Methyl Signature PCR Array Human Inflammatory Response). Differentially methylated genes were subsequently assessed for their mRNA expression. Data analyses (One-way anova, Tukey's multiple comparisons tests and Mann-Whitney tests) were performed using GraphPad Prism 6 software. P values ≤ 0.05 were considered statistically significant. RESULTS: Significant DNA hypermethylation was observed for CXCL3 and FADD gene promoters in AP lesions when compared to control tissues (P < 0.001) and among other genes (P < 0.05). In contrast, IL12B and IL4R were associated with significant hypomethylation in comparison to other genes (P < 0.05). IL12B, IL4R, CXCL3 and FADD had differential mRNA expression in AP lesions and controls (P < 0.001). CONCLUSIONS: Differential methylation profiles of immune response-related genes, such as FADD, CXCL3, IL12B and IL4R, may have an influence on individual AP susceptibility and patient treatment outcomes, through their potential contributions to altered expression of disease-relevant genes. Methylation and/or genetic variations in additional genes may also contribute to the dynamics of AP development and should be considered in future studies.


Assuntos
Metilação de DNA , Periodontite Periapical/genética , Periodontite Periapical/imunologia , Periodontite Periapical/metabolismo , Transcriptoma , Adolescente , Adulto , Idoso , Autoimunidade/genética , Brasil , Quimiocinas/genética , Quimiocinas CXC/genética , Citocinas/genética , Proteína de Domínio de Morte Associada a Fas/genética , Regulação da Expressão Gênica , Humanos , Inflamação , Subunidade p40 da Interleucina-12/genética , Subunidade alfa de Receptor de Interleucina-4/genética , Pessoa de Meia-Idade , Ligamento Periodontal , Regiões Promotoras Genéticas , RNA Mensageiro/biossíntese , Reação em Cadeia da Polimerase em Tempo Real , Receptores de Citocinas/genética , Adulto Jovem
19.
Int J Mol Sci ; 19(12)2018 Dec 07.
Artigo em Inglês | MEDLINE | ID: mdl-30544541

RESUMO

The TGFß superfamily is composed of more than 33 growth and differentiation factors, including TGFß1, ß2, ß3, BMPs, GDFs, nodal-related proteins, and activins. These members usually exert pleiotropic actions on several tissues and control multiple cellular processes, such as cell growth, cell survival, cell migration, cell fate specification, and differentiation, both during embryonic development and postnatal life. Although the effects of these factors on immune responses were elucidated long ago, most studies have been focused on the actions of TGFßs on T cells, as major regulators of adaptive immunity. In this review, we discuss new findings about the involvement of TGFß superfamily members in the control of B cell development and function. Moreover, the potential contribution of TGFß signaling to control B cell-mediated autoimmune diseases and its utility in the design of new therapies are also discussed.


Assuntos
Autoimunidade/fisiologia , Linfócitos B/metabolismo , Fator de Crescimento Transformador beta/metabolismo , Animais , Autoimunidade/genética , Diferenciação Celular/fisiologia , Sobrevivência Celular/fisiologia , Humanos , Transdução de Sinais/fisiologia
20.
Nat Commun ; 9(1): 5344, 2018 12 17.
Artigo em Inglês | MEDLINE | ID: mdl-30559442

RESUMO

Foxp3-expressing CD4+ regulatory T (Treg) cells need to differentiate into effector Treg (eTreg) cells to maintain immune homeostasis. T-cell receptor (TCR)-dependent induction of the transcription factor IRF4 is essential for eTreg differentiation, but how IRF4 activity is regulated in Treg cells is still unclear. Here we show that the AP-1 transcription factor, JunB, is expressed in eTreg cells and promotes an IRF4-dependent transcription program. Mice lacking JunB in Treg cells develop multi-organ autoimmunity, concomitant with aberrant activation of T helper cells. JunB promotes expression of Treg effector molecules, such as ICOS and CTLA4, in BATF-dependent and BATF-independent manners, and is also required for homeostasis and suppressive functions of eTreg. Mechanistically, JunB facilitates the accumulation of IRF4 at a subset of IRF4 target sites, including those located near Icos and Ctla4. Thus, JunB is a critical regulator of IRF4-dependent Treg effector programs, highlighting important functions for AP-1 in Treg-mediated immune homeostasis.


Assuntos
Fatores Reguladores de Interferon/metabolismo , Ativação Linfocitária/imunologia , Linfócitos T Reguladores/citologia , Linfócitos T Reguladores/imunologia , Fatores de Transcrição/metabolismo , Animais , Autoimunidade/genética , Autoimunidade/imunologia , Antígeno CTLA-4/biossíntese , Diferenciação Celular/imunologia , Proteína Coestimuladora de Linfócitos T Induzíveis/biossíntese , Ativação Linfocitária/genética , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Linfócitos T Auxiliares-Indutores/imunologia , Fatores de Transcrição/genética
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