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1.
Nat Genet ; 51(10): 1486-1493, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31548716

RESUMO

Immune-disease-associated variants are enriched in active chromatin regions of T cells and macrophages. However, whether these variants function in specific cell states is unknown. Here we stimulated T cells and macrophages in the presence of 13 cytokines and profiled active and open chromatin regions. T cell activation induced major chromatin remodeling, while the presence of cytokines fine-tuned the magnitude of changes. We developed a statistical method that accounts for subtle changes in the chromatin landscape to identify SNP enrichment across cell states. Our results point towards the role of immune-disease-associated variants in early rather than late activation of memory CD4+ T cells, with modest differences across cytokines. Furthermore, variants associated with inflammatory bowel disease are enriched in type 1 T helper (TH1) cells, whereas variants associated with Alzheimer's disease are enriched in different macrophage cell states. Our results represent an in-depth analysis of immune-disease-associated variants across a comprehensive panel of activation states of T cells and macrophages.


Assuntos
Cromatina/metabolismo , Citocinas/farmacologia , Estudo de Associação Genômica Ampla , Doenças do Sistema Imunitário/imunologia , Macrófagos/imunologia , Células Th1/imunologia , Cromatina/genética , Humanos , Doenças do Sistema Imunitário/tratamento farmacológico , Doenças do Sistema Imunitário/genética , Ativação Linfocitária , Macrófagos/efeitos dos fármacos , Macrófagos/metabolismo , Células Th1/efeitos dos fármacos , Células Th1/metabolismo
2.
Food Funct ; 10(8): 4792-4801, 2019 Aug 01.
Artigo em Inglês | MEDLINE | ID: mdl-31314026

RESUMO

The immunoregulatory effect of a novel Craterellus cornucopioides polysaccharide (CCP) with a triple-helix structure on immunosuppressive BALB/c mice models was investigated; moreover, the immune response of BALB/c mice models in the preventive and therapeutic treatment groups treated with CCP was explored, and its molecular mechanism was elucidated. It was found that the BALB/c mice models in the preventive groups treated with CCP (120 and 240 mg kg-1 d-1) had better immunoregulatory activity. The spleen and thymus weight indices of the BALB/c mice models were significantly increased, and the histopathological analysis indicated a protective function of CCP against the immunosuppression induced by cyclophosphamide (CTX). Moreover, CCP displayed definite and clear synergistic effects on the T- or B-lymphocyte proliferation induced by ConA or LPS, respectively, promoted the natural killer (NK) cell activity and significantly increased phagocytic activity to activate peritoneal macrophages in immunosuppressive mice. The western blot and quantitative real-time polymerase chain reaction (qRT-PCR) results provided comprehensive evidence that CCP could upregulate the protein expression of the G-protein-coupled cell membrane receptor TLR4 and the production of its downstream protein kinases (TRAF6, TK1, p-IKKα/ß and NF-κB p50); this, in turn, enhanced the production of cytokines (IL-2, IL-6, TNF-α and IFN-α) through both preventive and therapeutic treatments via regulation of the TLR4-NFκB pathway in the peritoneal macrophage of immunosuppressive mice.


Assuntos
Agaricales/química , Doenças do Sistema Imunitário/tratamento farmacológico , Fatores Imunológicos/administração & dosagem , NF-kappa B/imunologia , Polissacarídeos/administração & dosagem , Receptor 4 Toll-Like/imunologia , Animais , Feminino , Humanos , Doenças do Sistema Imunitário/genética , Doenças do Sistema Imunitário/imunologia , Fatores Imunológicos/química , Fatores Imunológicos/isolamento & purificação , Imunossupressão , Interleucina-6 , Células Matadoras Naturais/imunologia , Macrófagos Peritoneais/imunologia , Camundongos , Camundongos Endogâmicos BALB C , NF-kappa B/genética , Polissacarídeos/química , Polissacarídeos/isolamento & purificação , Fator 6 Associado a Receptor de TNF/genética , Fator 6 Associado a Receptor de TNF/imunologia , Receptor 4 Toll-Like/genética , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
4.
Growth Factors ; 37(1-2): 1-11, 2019 04.
Artigo em Inglês | MEDLINE | ID: mdl-31161823

RESUMO

Interleukin (IL)-11 belongs to the IL-6 family of cytokines, discovered over 30 years ago. While early studies focused on the ability of IL-11 to stimulate megakaryocytopoiesis, the importance of this cytokine to inflammatory disease and cancers is only just beginning to be uncovered. This review outlines recent advances in our understanding of IL-11 biology, and highlights the development of novel therapeutics with the potential for clinical targeting of signaling by this cytokine in multiple diseases.


Assuntos
Doenças Cardiovasculares/genética , Disostose Craniofacial/genética , Doenças do Sistema Imunitário/genética , Interleucina-11/genética , Neoplasias/genética , Animais , Humanos , Interleucina-11/metabolismo , Mutação
5.
Genes Immun ; 20(5): 415-425, 2019 05.
Artigo em Inglês | MEDLINE | ID: mdl-31000797

RESUMO

Chronic inflammatory diseases such as rheumatoid arthritis, inflammatory bowel disease, spondyloarthritis, and psoriasis cause significant morbidity and are a considerable burden for the patients in terms of pain, impaired function, and diminished quality of life, as well as for society, because of the associated high health-care costs and loss of productivity. Our limited understanding of the pathogenic mechanisms involved in these diseases currently hinders early diagnosis and the development of more specific and effective therapies. The past years have been marked by considerable progress in our insight of the genetic basis of many diseases. In particular, genome-wide association studies (GWAS) performed with thousands of patients have provided detailed information about the genetic variants associated with a large number of chronic inflammatory diseases. These studies have brought to the forefront many genes linked to signaling pathways that were not previously known to be involved in pathogenesis, pointing to new directions in the study of disease mechanisms. GWAS also provided fundamental evidence for a key role of the immune system in the pathogenesis of these diseases, because many of the identified loci map to genes involved in different immune processes. However, the mechanisms by which disease-associated genetic variants act on disease development and the targeted cell populations remain poorly understood. The challenge of the post-GWAS era is to understand how these variants affect pathogenesis, to allow translation of genetic data into better diagnostics and innovative treatment strategies. Here, we review recent results that document the importance of the IL-23/IL-17 pathway for the pathogenesis of several chronic inflammatory diseases and summarize data that demonstrate how therapeutic targeting of this pathway can benefit affected patients.


Assuntos
Predisposição Genética para Doença , Doenças do Sistema Imunitário/genética , Interleucina-17/imunologia , Interleucina-23/imunologia , Animais , Anti-Inflamatórios/uso terapêutico , Anticorpos Monoclonais/uso terapêutico , Humanos , Doenças do Sistema Imunitário/tratamento farmacológico , Doenças do Sistema Imunitário/imunologia , Interleucina-17/genética , Interleucina-23/genética
6.
Crit Rev Eukaryot Gene Expr ; 29(1): 1-15, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31002589

RESUMO

Epigenetics is the variation in organisms that occur by changes in gene expression, and it also occurs in the genetic code. The immune system diseases arise from primarily epigenetic changes of obscure etiology. The current studies demonstrate that a portion of the rearrangements are created by the association of epigenetic alterations. For example, acetylation of histones and methylation of DNA are accounted for. These adjustments in DNA likewise showed the impact in mouse models and immune system illnesses in human. Through this review, it could be reasoned that epigenetic tweaks might be a novel restorative approach against these maladies.


Assuntos
Metilação de DNA , Epigênese Genética , Histonas/metabolismo , Doenças do Sistema Imunitário/genética , Processamento de Proteína Pós-Traducional , Acetilação , Animais , Humanos , Doenças do Sistema Imunitário/metabolismo , Camundongos
9.
J Immunol ; 202(9): 2616-2627, 2019 05 01.
Artigo em Inglês | MEDLINE | ID: mdl-30910863

RESUMO

Appropriate T cell responses are controlled by strict balance between activatory and inhibitory pathways downstream of TCR. Although mice or humans with impaired TCR signaling develop autoimmunity, the precise molecular mechanisms linking reduced TCR signaling to autoimmunity are not fully understood. Engagement of TCR activates Ca2+ signaling mainly through store-operated Ca2+ entry activated by stromal interaction molecule (Stim) 1 and Stim2. Despite defective T cell activation, mice deficient in both Stim1 and Stim2 in T cells (conditional double knockout [cDKO]) developed lymphoproliferative disorders and skin inflammation with a concomitant increase in serum IgG1 and IgE levels. In cDKO mice, follicular helper T (Tfh) cells were dramatically increased in number, and they produced IL-4 spontaneously. These inflammatory symptoms were abolished by the deletion of IL-4 in cDKO mice. Tfh development and inflammatory symptoms in cDKO mice were abrogated by further deletion of NFAT2 in T cells. These findings suggest that Tfh cells spontaneously developed in the absence of Ca2+ signaling and caused unregulated type 2 responses.


Assuntos
Diabetes Mellitus Experimental/imunologia , Diabetes Mellitus Tipo 2/imunologia , Doenças do Sistema Imunitário/imunologia , Molécula 1 de Interação Estromal/deficiência , Molécula 2 de Interação Estromal/deficiência , Linfócitos T Auxiliares-Indutores/imunologia , Animais , Sinalização do Cálcio/genética , Sinalização do Cálcio/imunologia , Diabetes Mellitus Experimental/genética , Diabetes Mellitus Experimental/patologia , Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/patologia , Doenças do Sistema Imunitário/genética , Doenças do Sistema Imunitário/patologia , Imunoglobulina E/genética , Imunoglobulina E/imunologia , Imunoglobulina G/genética , Imunoglobulina G/imunologia , Interleucina-4/genética , Interleucina-4/imunologia , Transtornos Linfoproliferativos/genética , Transtornos Linfoproliferativos/imunologia , Transtornos Linfoproliferativos/patologia , Camundongos , Camundongos Knockout , Fatores de Transcrição NFATC/genética , Fatores de Transcrição NFATC/imunologia , Dermatopatias/genética , Dermatopatias/imunologia , Dermatopatias/patologia , Linfócitos T Auxiliares-Indutores/patologia
10.
Dis Markers ; 2019: 5160565, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30733837

RESUMO

TIGIT is an inhibitory immune checkpoint receptor and a putative target for novel immune therapies. Here, we analysed two different types of tissue microarrays of healthy lymphatic and various inflamed tissues, colorectal and lung cancers, as well as >1700 tumour samples from 86 different tumour entities for TIGIT and/or PD-1 by bright field and/or multiplex fluorescence immunohistochemistry. TIGIT was detected in CD8+ cytotoxic T cells, CD4+ T helper cells, FOXP3+ regulatory T cells, and NK cells, but not in CD11c+ dendritic cells, CD68+ macrophages, and CD20+ B lymphocytes. TIGIT expression paralleled that of PD-1. More than 70% of TIGIT+ cells were PD-1+, and more than 90% of the PD-1+ cells were TIGIT+. Expression varied between different tissue compartments. TIGIT expression in tonsil gradually increased from the interfollicular area over the marginal/mantle zone to the germinal centre in all T cell subtypes. In inflammatory diseases, the strongest expression of TIGIT/PD-1 was found in Hashimoto thyroiditis. TIGIT+ lymphocytes were seen in all 86 different tumour entities with considerable high variability of TIGIT positivity within and between different cancer entities. Particularly, high densities of TIGIT+ lymphocytes were, for example, seen in squamous cell cancers of various origins. In summary, the variable expression levels of TIGIT and PD-1 in cell types and tissue compartments illustrate the high complexity of immune microenvironments. The high frequency of TIGIT (and PD-1) expressing lymphocytes in cancers highlights considerable opportunities for cotargeting with checkpoint inhibitors.


Assuntos
Doenças do Sistema Imunitário/genética , Linfonodos/metabolismo , Neoplasias/genética , Receptores Imunológicos/genética , Humanos , Doenças do Sistema Imunitário/metabolismo , Neoplasias/metabolismo , Tonsila Palatina/metabolismo , Receptores Imunológicos/metabolismo
11.
Scand J Immunol ; 89(6): e12759, 2019 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-30793341

RESUMO

DOCK8 immunodeficiency syndrome (DIDS) is a combined immunodeficiency characterized by recurrent viral infections, severe atopy and early onset malignancy. Immunological abnormalities include lymphopenia, CD8+ T-cell cytoskeleton dysfunction, defective B cell memory and variable serum immunoglobulin levels. Here, we analyse the B cell receptor repertoire (BCR) characteristics and antibody avidity of four DIDS patients, attempt to understand the dysregulated humoral immunity in DIDS patients with a normal antibody titre and suggest a scientific basis for intravenous immunoglobulin (IVIG) replacement therapy for these patients. We analysed BCR characteristics, including somatic hypermutation (SHM) frequency, using deep sequencing of multiplex PCR products derived from BCR heavy chain CDR3 regions from DIDS patients and controls. The antibody avidity of human tetanus and hemophilus influenza B antibodies was determined by ELISA using thiocyanate elution. IVIG replacement treatment and infection conditions were investigated retrospectively. We found skewing of the BCR repertoire and decreased antibody avidity in patients with DIDS. DIDS patients had fewer negatively charged amino acids than healthy controls. The SHM frequency of the IGHV3 gene was lower in patients with DIDS. Patients received regular IVIG therapy, resulting in fewer and less severe infections. We conclude that although IgG levels are normal in most DIDS patients, IVIG replacement therapy is still necessary.


Assuntos
Afinidade de Anticorpos/imunologia , Linfócitos B/imunologia , Fatores de Troca do Nucleotídeo Guanina/deficiência , Doenças do Sistema Imunitário/genética , Doenças do Sistema Imunitário/terapia , Imunoglobulinas Intravenosas/uso terapêutico , Receptores de Antígenos de Linfócitos B/imunologia , Adolescente , Anticorpos Antibacterianos/imunologia , Linfócitos T CD8-Positivos/imunologia , Pré-Escolar , Clostridium tetani/imunologia , Feminino , Fatores de Troca do Nucleotídeo Guanina/genética , Haemophilus influenzae tipo b/imunologia , Humanos , Imunoglobulina A/sangue , Imunoglobulina E/sangue , Imunoglobulina G/sangue , Cadeias Pesadas de Imunoglobulinas/genética , Imunoglobulina M/sangue , Memória Imunológica/imunologia , Masculino , Receptores de Antígenos de Linfócitos B/genética
12.
Cell Mol Immunol ; 16(1): 1-5, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29795339

RESUMO

The metabolic control of immune cell development and function has been shown to be critical for the maintenance of immune homeostasis and is also involved in the pathogenesis of immune disorders. Pathogenic infections or cancers may induce metabolic reprogramming through different pathways to meet the energy and metabolite demands for pathogen propagation or cancer progression. In addition, some deregulated metabolites could trigger or regulate immune responses, thus causing chronic inflammation or immune disorders, such as viral infection, cancer and obesity. Therefore, the methods through which metabolism is regulated and the role of metabolic regulation in inflammation and immunity attract much attention. Epigenetic regulation of inflammation and immunity is an emerging field. Long noncoding RNAs (lncRNAs) have been well documented to play crucial roles in many biological processes through diverse mechanisms, including immune regulation and metabolic alternation. Here, we review the functions and mechanisms of lncRNAs in the metabolic regulation of inflammatory immune disorders, aiming to deepen our understanding of the epigenetic regulation of inflammation and immunity.


Assuntos
Doenças do Sistema Imunitário/genética , Doenças do Sistema Imunitário/metabolismo , Inflamação/genética , Inflamação/metabolismo , RNA Longo não Codificante/genética , Animais , Humanos , Neoplasias/genética , Neoplasias/metabolismo , RNA Longo não Codificante/metabolismo
13.
Nat Rev Genet ; 20(2): 109-127, 2019 02.
Artigo em Inglês | MEDLINE | ID: mdl-30479381

RESUMO

Biomarker discovery and validation are necessary for improving the prediction of clinical outcomes and patient monitoring. Despite considerable interest in biomarker discovery and development, improvements in the range and quality of biomarkers are still needed. The main challenge is how to integrate preclinical data to obtain a reliable biomarker that can be measured with acceptable costs in routine clinical practice. Epigenetic alterations are already being incorporated as valuable candidates in the biomarker field. Furthermore, their reversible nature offers a promising opportunity to ameliorate disease symptoms by using epigenetic-based therapy. Thus, beyond helping to understand disease biology, clinical epigenetics is being incorporated into patient management in oncology, as well as being explored for clinical applicability for other human pathologies such as neurological and infectious diseases and immune system disorders.


Assuntos
Epigênese Genética , Epigenômica , Doenças do Sistema Imunitário , Doenças do Sistema Nervoso , Medicina de Precisão/métodos , Pesquisa Biomédica/métodos , Humanos , Doenças do Sistema Imunitário/genética , Doenças do Sistema Imunitário/metabolismo , Doenças do Sistema Imunitário/terapia , /metabolismo , Doenças do Sistema Nervoso/genética , Doenças do Sistema Nervoso/metabolismo , Doenças do Sistema Nervoso/terapia
14.
Genet Med ; 21(1): 243-251, 2019 01.
Artigo em Inglês | MEDLINE | ID: mdl-29921932

RESUMO

PURPOSE: The etiology of 80% of patients with primary antibody deficiency (PAD), the second most common type of human immune system disorder after human immunodeficiency virus infection, is yet unknown. METHODS: Clinical/immunological phenotyping and exome sequencing of a cohort of 126 PAD patients (55.5% male, 95.2% childhood onset) born to predominantly consanguineous parents (82.5%) with unknown genetic defects were performed. The American College of Medical Genetics and Genomics criteria were used for validation of pathogenicity of the variants. RESULTS: This genetic approach and subsequent immunological investigations identified potential disease-causing variants in 86 patients (68.2%); however, 27 of these patients (31.4%) carried autosomal dominant (24.4%) and X-linked (7%) gene defects. This genetic approach led to the identification of new phenotypes in 19 known genes (38 patients) and the discovery of a new genetic defect (CD70 pathogenic variants in 2 patients). Medical implications of a definite genetic diagnosis were reported in ~50% of the patients. CONCLUSION: Due to misclassification of the conventional approach for targeted sequencing, employing next-generation sequencing as a preliminary step of molecular diagnostic approach to patients with PAD is crucial for management and treatment of the patients and their family members.


Assuntos
Predisposição Genética para Doença , Testes Genéticos , Genômica , Doenças do Sistema Imunitário/genética , Adolescente , Adulto , Idade de Início , Criança , Pré-Escolar , Exoma/genética , Exoma/imunologia , Feminino , Sequenciamento de Nucleotídeos em Larga Escala , Humanos , Doenças do Sistema Imunitário/imunologia , Doenças do Sistema Imunitário/patologia , Masculino , Mutação , Fenótipo , Análise de Sequência de DNA , Sequenciamento Completo do Exoma , Adulto Jovem
16.
Expert Rev Clin Immunol ; 14(12): 1029-1041, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30280610

RESUMO

INTRODUCTION: The transcription factors signal transducer and activator of transcription (STAT) 1 and STAT3 fulfill fundamental functions in nonimmune and immune cells. The description and follow-up of patients with germline mutations that result in either loss-of-function or gain-of-function have contributed to our understanding of the pathophysiology of these regulators. Depending on the type of mutations, clinical symptoms are complex and can include infection susceptibility, immune dysregulation as well as characteristic nonimmune features. Areas covered: In this review, we provide an overview about mechanistic concepts, clinical manifestations, diagnostic process, and traditional as well as innovative treatment options aiming to help the clinical immunologist to better understand and manage these complex and rare diseases. Clinical and research papers were identified and summarized through PubMed Internet searches, and expert opinions are provided. Expert commentary: The last several years have seen an explosion in the clinical descriptions and pathogenesis knowledge of the diseases caused by GOF and LOF mutations in STAT1 and STAT3. However, harmonization of laboratory testing and follow-up in international cohorts is needed to increase our knowledge about the natural history of these disorders as well as the development of curative or supportive targeted therapies.


Assuntos
Alergia e Imunologia/educação , Doenças do Sistema Imunitário/genética , Mutação , Fator de Transcrição STAT1/genética , Fator de Transcrição STAT3/genética , Animais , Educação Médica , Predisposição Genética para Doença , Humanos , Doenças do Sistema Imunitário/tratamento farmacológico , Doenças do Sistema Imunitário/imunologia , Doenças do Sistema Imunitário/metabolismo , Fatores Imunológicos/uso terapêutico , Fenótipo , Prognóstico , Fatores de Risco , Fator de Transcrição STAT1/imunologia , Fator de Transcrição STAT1/metabolismo , Fator de Transcrição STAT3/imunologia , Fator de Transcrição STAT3/metabolismo , Transdução de Sinais
17.
Mol Immunol ; 103: 191-199, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30300798

RESUMO

The difficulty of studying small tissue samples and rare cell populations have been some of the main limitations in performing efficient translational studies of immune mediated diseases. Many of these conditions are grouped under the name of a single disease whilst there are strong suggestions that disease heterogeneity leads to variable disease progression as well as therapeutic responses. The recent development of single cell techniques, such as single cell RNA sequencing, gene expression profiling, or multiparametric cytometry, is likely to be a turning point. Single cell approaches provide researchers the opportunity to finally dissect disease pathology at a level that will allow mechanistic classifications and precision therapeutic strategies. In this review, we will give an overview of the current and developing repertoire of single cell techniques, the benefits and limitations of each, and provide an example of how single cell techniques can be utilized to understand complex immune mediated diseases and their translation from mouse to human.


Assuntos
Perfilação da Expressão Gênica/métodos , Doenças do Sistema Imunitário/genética , Análise de Sequência de RNA/métodos , Análise de Célula Única/métodos , Animais , Epigenômica/métodos , Humanos , Doenças do Sistema Imunitário/patologia , Espectrometria de Massas/métodos , Proteoma/genética , Proteoma/metabolismo , Proteômica/métodos
18.
Clin Immunol ; 197: 219-223, 2018 12.
Artigo em Inglês | MEDLINE | ID: mdl-30368009

RESUMO

Early onset multisystem autoimmunity is commonly the defining feature of IPEX. Recurrent sinopulmonary infections and CVID-like phenotype were not previously recognized as a presentation in IPEX. Herein, we describe three extended family members with IPEX. In addition to autoimmunity, all three had a CVID-like presentation consisting of recurrent sinopulmonary infections, hypogammaglobulinemia and B-cell class switching defect. In vitro studies have shown that the B cell class switching defect is not B cell intrinsic. Additionally, a marked increase in circulating T follicular helper (cTFH) cells with high IFN-γ and IL-17 secretion on stimulation was noted in our patients. The dysregulated cTFH cells could contribute to a decreased B cell class switching. However, the exact mechanism of how expanded and dysregulated cTFH lead to B cell class switching defect and hypogammaglobulinemia in our patients is not clear. Our study could extend the clinical spectrum of IPEX to include a CVID-like presentation.


Assuntos
Agamaglobulinemia/imunologia , Autoimunidade/imunologia , Linfócitos B/imunologia , Diabetes Mellitus Tipo 1/congênito , Diarreia/imunologia , Doenças Genéticas Ligadas ao Cromossomo X/imunologia , Doenças do Sistema Imunitário/congênito , Linfócitos T Auxiliares-Indutores/imunologia , Adulto , Agamaglobulinemia/terapia , Anemia Hemolítica Autoimune/imunologia , Diabetes Mellitus Tipo 1/genética , Diabetes Mellitus Tipo 1/imunologia , Diabetes Mellitus Tipo 1/terapia , Diarreia/genética , Diarreia/terapia , Eczema/imunologia , Família , Feminino , Fatores de Transcrição Forkhead/genética , Doenças Genéticas Ligadas ao Cromossomo X/genética , Doenças Genéticas Ligadas ao Cromossomo X/terapia , Heterozigoto , Humanos , Doenças do Sistema Imunitário/genética , Doenças do Sistema Imunitário/imunologia , Doenças do Sistema Imunitário/terapia , Switching de Imunoglobulina/imunologia , Imunoglobulinas Intravenosas/uso terapêutico , Fatores Imunológicos/uso terapêutico , Enteropatias/imunologia , Masculino , Pessoa de Meia-Idade , Linhagem , Pneumonia/imunologia , Recidiva , Sinusite/imunologia , Adulto Jovem
19.
Cytokine ; 111: 112-118, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30138899

RESUMO

The immuno-inflammatory origin of schizophrenia in a subset of patients is viewed as a key element of an overarching etiological construct. Despite substantial research, the immune components exerting major effect are yet to be fully clarified. Disrupted T cell networks have consistently been linked to the pathogenesis of schizophrenia. Amongst the Th cell subsets, the Th17 cells have emerged as a paradigmatic lineage with significant functional implications in a vast number of immune mediated diseases including brain disorders such as schizophrenia. The present study was aimed at examining the functional role of the Th17 pathway in schizophrenia. To address this, genotyping of IL17A (rs2275913; G197A) Single Nucleotide Polymorphism was carried out by the PCR-RFLP method in 221 schizophrenia patients and 223 healthy control subjects. Gene expression of two transcription factors STAT3 and RORC was quantified in a subset of drug naïve schizophrenia patients (n = 56) and healthy controls (n = 52) by TaqMan assay. The plasma levels of fifteen cytokines belonging to Th17 pathway were estimated in a subset of drug naïve schizophrenia patients (n = 61) and healthy controls (n = 50) by using Bio-Plex Pro Human Th17 cytokine assays. The AA genotype was associated with higher total score of bizarre behaviour and apathy in female schizophrenia patients. A high gene expression level of RORC was observed in drug naïve schizophrenia patients. In addition, significantly elevated plasma levels of IL-6 and IL-22, and reduced levels of IL-1ß and IL-17F were noted in schizophrenia patients. Taken together, these findings indicate a dysregulated Th17 pathway in schizophrenia patients.


Assuntos
Doenças do Sistema Imunitário , Interleucina-6 , Interleucinas , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares , Polimorfismo de Nucleotídeo Único , Células Th17 , Adolescente , Adulto , Feminino , Genótipo , Humanos , Doenças do Sistema Imunitário/sangue , Doenças do Sistema Imunitário/genética , Doenças do Sistema Imunitário/imunologia , Doenças do Sistema Imunitário/patologia , Interleucina-6/sangue , Interleucina-6/genética , Interleucina-6/imunologia , Interleucinas/sangue , Interleucinas/genética , Interleucinas/imunologia , Masculino , Pessoa de Meia-Idade , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/sangue , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/genética , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/imunologia , Esquizofrenia/sangue , Esquizofrenia/genética , Esquizofrenia/imunologia , Esquizofrenia/patologia , Fatores Sexuais , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Células Th17/imunologia , Células Th17/metabolismo , Células Th17/fisiologia
20.
J Immunol ; 201(5): 1442-1451, 2018 09 01.
Artigo em Inglês | MEDLINE | ID: mdl-30012848

RESUMO

Phenotypic differences among substrains of laboratory mice due to spontaneous mutations or pre-existing genetic variation confound the interpretation of targeted mutagenesis experiments and contribute to challenges with reproducibility across institutions. Notably, C57BL/6 Hsd mice and gene-targeted mice that have been backcrossed to this substrain have been reported to harbor a duplication in exons 28 and 29 of Dock2 In this study, we demonstrate the presence of this Dock2 variant in the widely used Nod2-/- mice. Nucleotide-binding oligomerization domain-containing protein 2 (NOD2) is a cytosolic innate immune receptor associated with inflammatory bowel disease susceptibility. Consistent with a role of NOD2 in an immunological disorder, Nod2-/- mice bred at our institution displayed multiple B cell defects including deficiencies in recirculating B cells, marginal zone B cells, and B1a cells in vivo, as well as defects in class switch recombination in vitro. However, we found that these effects are due to the Dock2 variant and are independent of Nod2 deletion. Despite originating from the same gene-targeted founder mice, Nod2-/- mice from another source did not harbor the Dock2 variant or B cell defects. Finally, we show that Dock2-/- mice display the same B cell defects as mice harboring the Dock2 variant, confirming that the variant is a loss-of-function mutation and is sufficient to explain the alterations to the B cell compartment observed in Nod2-/- mice. Our findings highlight the effects of confounding mutations from widely used inbred strains on gene-targeted mice and reveal new functions of DOCK2 in B cells.


Assuntos
Linfócitos B/imunologia , Proteínas Ativadoras de GTPase , Doenças do Sistema Imunitário , Mutação , Proteína Adaptadora de Sinalização NOD2/deficiência , Animais , Linfócitos B/patologia , Proteínas Ativadoras de GTPase/genética , Proteínas Ativadoras de GTPase/imunologia , Doenças do Sistema Imunitário/genética , Doenças do Sistema Imunitário/imunologia , Doenças do Sistema Imunitário/patologia , Camundongos , Camundongos Knockout , Proteína Adaptadora de Sinalização NOD2/imunologia
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