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1.
Nat Commun ; 11(1): 3730, 2020 07 24.
Artigo em Inglês | MEDLINE | ID: mdl-32709840

RESUMO

Long-term follow up studies from Ebola virus disease (EVD) survivors (EBOV_S) are lacking. Here, we evaluate immune and gene expression profiles in 35 Guinean EBOV_S from the last West African outbreak, a median of 23 months (IQR [18-25]) after discharge from treatment center. Compared with healthy donors, EBOV_S exhibit increases of blood markers of inflammation, intestinal tissue damage, T cell and B cell activation and a depletion of circulating dendritic cells. All survivors have EBOV-specific IgG antibodies and robust and polyfunctional EBOV-specific memory T-cell responses. Deep sequencing of the genes expressed in blood reveals an enrichment in 'inflammation' and 'antiviral' pathways. Integrated analyses identify specific immune markers associated with the persistence of clinical symptoms. This study identifies a set of biological and genetic markers that could be used to define a signature of "chronic Ebola virus disease (CEVD)".


Assuntos
Ebolavirus/imunologia , Doença pelo Vírus Ebola/complicações , Doença pelo Vírus Ebola/imunologia , Doenças do Sistema Imunitário/complicações , Doenças do Sistema Imunitário/imunologia , Adulto , Anticorpos Antivirais/sangue , Anticorpos Antivirais/imunologia , Antivirais/farmacologia , Linfócitos B/imunologia , Citocinas/sangue , Ebolavirus/efeitos dos fármacos , Ebolavirus/genética , Feminino , Marcadores Genéticos , Doença pelo Vírus Ebola/tratamento farmacológico , Doença pelo Vírus Ebola/virologia , Humanos , Doenças do Sistema Imunitário/genética , Imunoglobulina G/sangue , Imunoglobulina G/imunologia , Inflamação/genética , Ativação Linfocitária , Masculino , Sobreviventes , Linfócitos T/imunologia , Transcriptoma , Adulto Jovem
2.
Vet Clin North Am Equine Pract ; 36(2): 273-288, 2020 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-32654783

RESUMO

Host defenses against infection by viruses, bacteria, fungi, and parasites are critical to survival. It has been estimated that upwards of 7% of the coding genes of mammals function in immunity and inflammation. This high level of genomic investment in defense has resulted in an immune system characterized by extraordinary complexity and many levels of redundancy. Because so many genes are involved with immunity, there are many opportunities for mutations to arise that have negative effects. However, redundancy in the mammalian defense system and the adaptive nature of key immune mechanisms buffer the untoward outcomes of many such deleterious mutations.


Assuntos
Doenças dos Cavalos/genética , Doenças dos Cavalos/imunologia , Doenças do Sistema Imunitário/veterinária , Animais , Cavalos , Doenças do Sistema Imunitário/genética , Doenças do Sistema Imunitário/imunologia , Inflamação/genética , Inflamação/imunologia , Inflamação/veterinária
3.
Adv Exp Med Biol ; 1207: 401-403, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32671762

RESUMO

As a result of its multifunction both in innate and adaptive immune systems, autophagy has been demonstrated to take part in the pathogenesis of several immune-related diseases. The study on the pathological mechanism of autophagy in these diseases may provide an experimental and theoretical basis for targeted intervention of autophagy in the prevention and treatment of immune diseases. To date, it has been reported that autophagy can eliminate impaired mitochondrial to inhibit the activation of NLRP3 inflammasome which promotes the progression of atherosclerosis. Moreover, enhanced autophagy can effectively prevent the occurrence of GVHD. It also plays a key role in the development of viral hepatitis. Therefore, autophagy might be a promising regulatory target for the treatment of immune-related diseases.


Assuntos
Autofagia , Doenças do Sistema Imunitário , Humanos , Doenças do Sistema Imunitário/imunologia , Doenças do Sistema Imunitário/patologia , Inflamassomos , Mitocôndrias/patologia , Proteína 3 que Contém Domínio de Pirina da Família NLR
5.
Biochim Biophys Acta Proteins Proteom ; 1868(9): 140458, 2020 09.
Artigo em Inglês | MEDLINE | ID: mdl-32474106

RESUMO

Type 2 Diabetes (T2D) is characterized by alteration in the circulatory levels of key inflammatory proteins, where our body strives to eliminate the perturbing factor through inflammation as a final resort to restore homeostasis. Plasma proteins play a crucial role to orchestrate this immune response. Over the past two decades, rigorous genetic efforts taken to comprehend T2D physiology have been partially successful and have left behind a dearth of knowledge of its causality. Here, we have investigated how the reported genetic variants of T2D are associated with circulatory levels of key plasma proteins. We identified 99 T2D genetic variants that serve as strong pQTL (protein Quantitative Trait Loci) for 72 plasma proteins, of which 4 proteins namely Small nuclear ribonucleoprotein F [SNRPF] (p = 2.99 × 10-14), Platelet endothelial cell adhesion molecule [PECAM1] (p = 1.9 × 10-45), Trypsin-2 [PRSS2] (p = 7.6 × 10-43) and Trypsin-3 [PRSS3] (p = 5.7 × 10-8) were previously not reported for association to T2D. The genes that encode these 72 proteins were observed to be highly expressed in at least one of the four T2D relevant tissues - liver, pancreas, adipose and whole blood. Comparative analysis of interactions of the studied proteins amongst these four tissues revealed distinct molecular connectivity. Assessment of biological function by gene-set enrichment highlighted innate immune system as the lead process enacted by the identified proteins (FDR q = 3.7 × 10-16). To validate the findings, we analyzed Coronary Artery Disease (CAD) and Rheumatoid Arthritis (RA) individually and as expected, we observed innate immune system as a top enriched pathway for RA but not for CAD. Our study illuminates strong regulation of plasma proteome by the established genetic variants of T2D.


Assuntos
Diabetes Mellitus Tipo 2/genética , Diabetes Mellitus Tipo 2/imunologia , Variação Genética , Doenças do Sistema Imunitário/genética , Doenças do Sistema Imunitário/imunologia , Tecido Adiposo/metabolismo , Sangue , Proteínas Sanguíneas/genética , Expressão Gênica , Estudo de Associação Genômica Ampla , Humanos , Fígado/metabolismo , Pâncreas/metabolismo , Molécula-1 de Adesão Celular Endotelial a Plaquetas/genética , Mapas de Interação de Proteínas , Tripsina/genética , Tripsinogênio/genética , Proteínas Centrais de snRNP/genética
6.
Nat Commun ; 11(1): 2781, 2020 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-32493900

RESUMO

Mutations disrupting regulatory T (Treg) cell function can cause IPEX and IPEX-related disorders, but whether established disease can be reversed by correcting these mutations is unclear. Treg-specific deletion of the chromatin remodeling factor Brg1 impairs Treg cell activation and causes fatal autoimmunity in mice. Here, we show with a reversible knockout model that re-expression of Brg1, in conjunction with the severe endogenous proinflammatory environment, can convert defective Treg cells into powerful, super-activated Treg cells (SuperTreg cells) that can resolve advanced autoimmunity,  with  Brg1 re-expression in a minor fraction of Treg cells sufficient for the resolution in some cases. SuperTreg cells have enhanced trafficking and regulatory capabilities, but become deactivated as the inflammation subsides, thus avoiding excessive immune suppression. We propose a simple, robust yet safe gene-editing-based therapy for IPEX and IPEX-related disorders that exploits the defective Treg cells and the inflammatory environment pre-existing in the patients.


Assuntos
Diabetes Mellitus Tipo 1/congênito , Diarreia/imunologia , Doenças Genéticas Ligadas ao Cromossomo X/imunologia , Doenças do Sistema Imunitário/congênito , Linfócitos T Reguladores/imunologia , Alelos , Animais , Citocinas/metabolismo , DNA Helicases/deficiência , Diabetes Mellitus Tipo 1/imunologia , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Proteínas de Fluorescência Verde/metabolismo , Doenças do Sistema Imunitário/imunologia , Ativação Linfocitária/imunologia , Camundongos Endogâmicos C57BL , Camundongos Knockout , Proteínas Nucleares/deficiência , Proteínas Proto-Oncogênicas c-akt/metabolismo , Receptores CXCR3/metabolismo , Fator de Transcrição STAT1/metabolismo , Transdução de Sinais/efeitos dos fármacos , Análise de Sobrevida , Linfócitos T Reguladores/efeitos dos fármacos , Tamoxifeno/farmacologia , Fatores de Transcrição/deficiência
7.
Autoimmun Rev ; 19(6): 102526, 2020 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-32234571

RESUMO

BACKGROUND: Immune dysregulation, polyendocrinopathy, enteropathy, X-linked (IPEX) syndrome is a monogenic disorder characterized by early onset fatal multi-system autoimmunity due to loss-of-function mutations in the gene encoding the forkhead box P3 (FOXP3) transcription factor which is crucial for the development, maturation, and maintenance of CD4+ regulatory T (T-reg) cells. Various autoimmune phenomena such as enteropathy, endocrinopathies, cytopenias, renal disease, and skin manifestations are characteristic findings in patients affected by IPEX syndrome. OBJECTIVES: In this systematic review, we focus on both clinical and demographic characteristics of IPEX patients, highlighting possible genotype-phenotype correlations and address prognostic factors for disease outcome. METHODS: We performed a literature search to systematically investigate the case reports of IPEX which were published before August 7th, 2017. RESULTS: A total of 75 articles (195 patients) were identified. All IPEX patients included had FOXP3 mutations which were most frequently located in the forkhead domain (n = 68, 34.9%) followed by the leucine-zipper domain (n = 30, 15.4%) and repressor domain (n = 36, 18.4%). Clinical manifestations were as follows: enteropathy (n = 191, 97.9%), skin manifestations (n = 121, 62.1%), endocrinopathy (n = 104, 53.3%), hematologic abnormalities (n = 75, 38.5%), infections (n = 78, 40.0%), other immune-related complications (n = 43, 22.1%), and renal involvement (n = 32, 16.4%). Enteropathic presentations (P = 0.017), eczema (P = 0.030), autoimmune hemolytic anemia (P = 0.022) and food allergy (P = 0.009) were associated with better survival, while thrombocytopenia (P = 0.034), septic shock (P = 0.045) and mutations affecting the repressor domain (P = 0.021), intron 7 (P = 0.033) or poly A sequence (P = 0.025) were associated with increased risk of death. Immunosuppressive therapy alone was significantly associated with increased cumulative survival compared to patients who received no treatment (P = 0.041). CONCLUSIONS: We report the most comprehensive summary of demographic and clinical profiles derived from a total of 195 IPEX patients with deleterious mutations in FOXP3. Analysis of our findings provides new insights into genotype/phenotype correlations, and clinical and genetic factors associated with increased risk of death and response to treatment strategies.


Assuntos
Doenças Genéticas Ligadas ao Cromossomo X , Doenças do Sistema Imunitário , Enteropatias , Poliendocrinopatias Autoimunes , Fatores de Transcrição Forkhead/genética , Doenças Genéticas Ligadas ao Cromossomo X/imunologia , Doenças Genéticas Ligadas ao Cromossomo X/patologia , Humanos , Doenças do Sistema Imunitário/imunologia , Doenças do Sistema Imunitário/patologia , Enteropatias/imunologia , Enteropatias/patologia , Mutação , Poliendocrinopatias Autoimunes/imunologia , Poliendocrinopatias Autoimunes/patologia , Síndrome , Linfócitos T Reguladores/imunologia
8.
Am J Chin Med ; 48(3): 535-558, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32345031

RESUMO

The Th17/Treg axis plays a crucial role in immune-mediated inflammatory diseases (IMID) and might represent an interesting drug target of treatment strategy for these diseases. Accumulating evidence suggests a role for traditional Chinese medicine (TCM) in the modulation of Th17/Treg axis, but a comprehensive overview which summarizes this field hitherto is lacked. This paper performs a systematic literature review of the regulatory effects of TCM on the imbalance of Th17/Treg axis and its potential mechanisms. In addition, the frequency analysis and network pharmacology for the collected TCM herbs from clinical trial data were performed. The studies reported the changes in the ratio of Th17 and/or Treg cells as well as their transcription factor and related cytokines were included. Frequency analysis of composition of the 39 assessed TCM prescriptions showed that Astragalus membranaceus var.mongholicus (5.20%), Glycyrrhiza uralensis (3.67%), Paeonia obovate (3.06%), Salvia digitaloides (3.06%), and Angelica sinensis (2.75%) were the top five herbal components, which were closely associated to the treatment of IMID. Network pharmacology showed that six target proteins (transforming growth factor (TGF)-beta receptor type-1, TGF-beta receptor type-2, retineic-acid-receptor-related orphan nuclear receptor gamma (ROR-gamma), TGFB2, IL-17 and IL-2, respectively) might be involved in the regulatory effects of TCM on Th17/Treg axis. Moreover, there were nine active ingredients (including Oxymatrine, Baicalin, Triptolide, Paeoniflorin, Sinomenine, Celastrol, Emodin, Diosgenin and Chlorogenic acid) originating from TCM reported to have an immunological regulation effect on the Th17/Treg axis. The highlight of this systematic review is to reveal the pharmacological basis of TCM treating IMID and is helpful for supporting future pharmacologic-driven studies. Further research elucidates the immune-modulating mechanisms on Th17/Treg axis by TCM might provide a broader insight for the treatment of IMID.


Assuntos
Medicamentos de Ervas Chinesas/uso terapêutico , Doenças do Sistema Imunitário/tratamento farmacológico , Doenças do Sistema Imunitário/imunologia , Inflamação/tratamento farmacológico , Inflamação/imunologia , Medicina Tradicional Chinesa , Fitoterapia , Linfócitos T Reguladores/imunologia , Células Th17/imunologia , Angelica sinensis , Astrágalo (Planta) , Medicamentos de Ervas Chinesas/química , Glycyrrhiza uralensis , Humanos , Doenças do Sistema Imunitário/metabolismo , Inflamação/metabolismo , Membro 3 do Grupo F da Subfamília 1 de Receptores Nucleares/metabolismo , Paeonia , Receptor do Fator de Crescimento Transformador beta Tipo I/metabolismo , Receptor do Fator de Crescimento Transformador beta Tipo II/metabolismo , Salvia
9.
Nat Rev Immunol ; 20(6): 375-388, 2020 06.
Artigo em Inglês | MEDLINE | ID: mdl-32132681

RESUMO

Immune memory is a defining feature of the acquired immune system, but activation of the innate immune system can also result in enhanced responsiveness to subsequent triggers. This process has been termed 'trained immunity', a de facto innate immune memory. Research in the past decade has pointed to the broad benefits of trained immunity for host defence but has also suggested potentially detrimental outcomes in immune-mediated and chronic inflammatory diseases. Here we define 'trained immunity' as a biological process and discuss the innate stimuli and the epigenetic and metabolic reprogramming events that shape the induction of trained immunity.


Assuntos
Imunidade Adaptativa/imunologia , Epigênese Genética/imunologia , Doenças do Sistema Imunitário/imunologia , Sistema Imunitário/imunologia , Imunidade Inata/imunologia , Memória Imunológica/imunologia , Imunidade Adaptativa/genética , Animais , Humanos , Sistema Imunitário/metabolismo , Doenças do Sistema Imunitário/genética , Tolerância Imunológica/genética , Tolerância Imunológica/imunologia , Imunidade Inata/genética , Memória Imunológica/genética , Inflamação/genética , Inflamação/imunologia
10.
Am J Surg Pathol ; 44(2): 198-205, 2020 02.
Artigo em Inglês | MEDLINE | ID: mdl-31651525

RESUMO

Lymphocytic esophagitis is a well-known manifestation of Crohn disease among children but is not considered to be an immune-mediated mucositis in adults. We hypothesize that adult-onset lymphocyte-predominant esophagitis is also an immune-mediated inflammatory pattern, the nature of which has been masked by other conditions that feature esophageal lymphocytosis and occur in older patients. We performed this study to consolidate diagnostic criteria for lymphocyte-predominant esophagitis and determine its clinical significance. We identified 61 patients with lymphocyte-rich inflammation in the mid or proximal esophagus, none of whom had another explanation for esophageal lymphocytosis. Affected patients were usually older adults and 72% were women. Most (56%) presented with dysphagia and 34% had eosinophilic esophagitis-like changes with rings, exudates, and/or edematous mucosa and linear furrows. Intraepithelial lymphocytosis was accompanied by mucosal injury featuring edema, basal zone hyperplasia, and scattered dyskeratotic cells. Some cases displayed occasional neutrophils or even superficial microabscesses; eosinophils were consistently infrequent. Most (67%) patients had at least 1 systemic immune-mediated disorder, particularly Crohn disease (30%) and connective tissue diseases (23%); only 1 had mucocutaneous lichen planus. We conclude that mild mucosal lymphocytosis (ie, ≥20 lymphocytes/HPF) alone is a frequent and nonspecific finding; criteria for lymphocyte-predominant esophagitis should include evidence of mucosal injury and allow for more than the occasional neutrophil. When this diagnosis is limited to cases that feature lymphocytosis unattributed to acid reflux, motility disorders, or infection, lymphocyte-predominant esophagitis may represent an immune-mediated disorder with characteristic clinical manifestations and a predilection for middle-aged women.


Assuntos
Esofagite/diagnóstico , Linfocitose/diagnóstico , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Bases de Dados Factuais , Diagnóstico Diferencial , Esofagite/imunologia , Esofagite/patologia , Esofagoscopia , Feminino , Humanos , Doenças do Sistema Imunitário/complicações , Doenças do Sistema Imunitário/imunologia , Doenças do Sistema Imunitário/patologia , Linfocitose/imunologia , Linfocitose/patologia , Masculino , Pessoa de Meia-Idade , Adulto Jovem
11.
Eur J Med Chem ; 185: 111842, 2020 Jan 01.
Artigo em Inglês | MEDLINE | ID: mdl-31727470

RESUMO

Aryl Hydrocarbon Receptor (AhR) constitutes a major network hub of genomic and non-genomic signaling pathways, connecting host's immune cells to environmental factors. It shapes innate and adaptive immune processes to environmental stimuli with species-, cell- and tissue-type dependent specificity. Although an ever increasing number of studies has thrust AhR into the limelight as attractive target for the development of next-generation immunotherapies, concerns exist on potential safety issues associated with small molecule modulation of the receptor. Selective AhR modulators (SAhRMs) and rapidly metabolized AhR ligands (RMAhRLs) are two classes of receptor agonists that are emerging as interesting lead compounds to bypass AhR-related toxicity in favor of therapeutic effects. In this article, we discuss SAhRMs and RMAhRLs reported in literature, covering concepts underlying their definitions, specific binding modes, structure-activity relationships and AhR-mediated functions.


Assuntos
Doenças do Sistema Imunitário/terapia , Imunoterapia , Receptores de Hidrocarboneto Arílico/agonistas , Animais , Humanos , Doenças do Sistema Imunitário/imunologia , Ligantes , Estrutura Molecular
13.
Pharmacol Res Perspect ; 7(6): e00535, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31859459

RESUMO

Monoclonal antibodies (mAbs) have emerged as a major class of therapeutic agents on the market. To date, approximately 80 mAbs have been granted marketing approval. In 2018, 12 new mAbs were approved by the FDA, representing 20% of the total number of approved drugs. The majority of mAb therapeutics are for oncological and immunological/infectious diseases, but these are expanding into other disease areas. Over 100 monoclonal antibodies are in development, and their unique features ensure that these will remain a part of the therapeutic pipeline. Thus, the therapeutic value and the elucidation of their pharmacological properties supporting clinical development of these large molecules are unquestioned. However, their utilization as pharmacological tools in academic laboratories has lagged behind their small molecule counterparts. Early therapeutic mAbs targeted soluble cytokines, but now that mAbs also target membrane-bound receptors and have increased circulating half-life, their pharmacology is more complex. The principles of pharmacology have enabled the development of high affinity, potent and selective small molecule therapeutics with reduced off-target effects and drug-drug interactions. This review will discuss how the same basic principles can be applied to mAbs, with some important differences. Monoclonal antibodies have several benefits, such as fewer off-target adverse effects, fewer drug-drug interactions, higher specificity, and potentially increased efficacy through targeted therapy. Modifications to decrease the immunogenicity and increase the efficacy are described, with examples of optimizing their pharmacokinetic properties and enabling oral bioavailability. Increased awareness of these advances may help to increase their use in exploratory research and further understand and characterize their pharmacological properties.


Assuntos
Anticorpos Monoclonais/farmacologia , Doenças do Sistema Imunitário/tratamento farmacológico , Infecções/tratamento farmacológico , Neoplasias/tratamento farmacológico , Animais , Anticorpos Monoclonais/química , Anticorpos Monoclonais/uso terapêutico , Disponibilidade Biológica , Modelos Animais de Doenças , Avaliação Pré-Clínica de Medicamentos , Humanos , Doenças do Sistema Imunitário/imunologia , Infecções/imunologia , Terapia de Alvo Molecular/métodos , Neoplasias/imunologia , Relação Estrutura-Atividade , Distribuição Tecidual , Resultado do Tratamento
14.
Nat Immunol ; 20(12): 1594-1602, 2019 12.
Artigo em Inglês | MEDLINE | ID: mdl-31745337

RESUMO

IL-17 is a highly versatile pro-inflammatory cytokine crucial for a variety of processes, including host defense, tissue repair, the pathogenesis of inflammatory disease and the progression of cancer. In contrast to its profound impact in vivo, IL-17 exhibits surprisingly moderate activity in cell-culture models, which presents a major knowledge gap about the molecular mechanisms of IL-17 signaling. Emerging studies are revealing a new dimension of complexity in the IL-17 pathway that may help explain its potent and diverse in vivo functions. Discoveries of new mRNA stabilizers and receptor-directed mRNA metabolism have provided insights into the means by which IL-17 cooperates functionally with other stimuli in driving inflammation, whether beneficial or destructive. The integration of IL-17 with growth-receptor signaling in specific cell types offers new understanding of the mitogenic effect of IL-17 on tissue repair and cancer. This Review summarizes new developments in IL-17 signaling and their pathophysiological implications.


Assuntos
Doenças do Sistema Imunitário/imunologia , Inflamação/imunologia , Interleucina-17/metabolismo , Neoplasias/imunologia , Receptores de Interleucina-7/metabolismo , Animais , Células Cultivadas , Humanos , Transdução de Sinais
15.
Biomed Res Int ; 2019: 2072635, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-31781596

RESUMO

Objectives: To explore the differences of immune disorders in peripheral blood between patients with early-onset Parkinson's disease (EOPD) and late-onset Parkinson's disease (LOPD). Methods: We retrospectively reviewed medical records of Parkinson's disease (PD) patients and healthy controls between June 2002 and July 2017. At last, we included 117 PD patients who were divided into EOPD and LOPD according to whether onset age of PD was after 50 and 99 controls divided into E-Control (match for EOPD) and L-Control (match for LOPD) according to whether their age was after 53 which was onset age plus median of disease duration. We compared the ratios of cells between multiple groups and performed the multinominal logistic regression analysis to explore the relationship between ratios and subtypes of PD. We also carried out the receiver operating characteristic (ROC) curve analysis to estimate the diagnostic value of the variable. Results: Lymphocyte-red blood cell ratio (LRR) was lower in LOPD compared with that in EOPD or L-Control. LRR was also negatively associated with LOPD (OR: 0.623; 95% CI: 0.397-0.980; P=0.040). The ROC curve analysis showed the optimal cutoff value of 4.53 (×10-4) of LRR for discrimination of LOPD versus L-Control (sensitivity: 0.596, specificity: 0.764). The area under curve (AUC) was 0.721. As for LOPD versus EOPD, the optimal threshold of LRR was 4.10 (×10-4) (sensitivity: 0.516, specificity: 0.745). AUC was 0.641. Conclusions: Peripheral immune disorders might play an important part in the pathological progression of LOPD. Also, LRR has potential diagnostic value.


Assuntos
Doenças do Sistema Imunitário/sangue , Doenças do Sistema Imunitário/imunologia , Doença de Parkinson/sangue , Doença de Parkinson/imunologia , Adulto , Idade de Início , Idoso , Estudos de Casos e Controles , Progressão da Doença , Contagem de Eritrócitos , Eritrócitos/imunologia , Eritrócitos/patologia , Feminino , Humanos , Doenças do Sistema Imunitário/fisiopatologia , Modelos Logísticos , Contagem de Linfócitos , Linfócitos/imunologia , Linfócitos/patologia , Masculino , Registros Médicos , Pessoa de Meia-Idade , Doença de Parkinson/fisiopatologia , Curva ROC
16.
Medicine (Baltimore) ; 98(41): e17348, 2019 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-31593084

RESUMO

Immune checkpoint inhibitors (ICIs) like cytotoxic T-lymphocyte-associated protein 4 (anti-CTLA4) and programmed death cell protein 1 (anti-PD1) have revolutionized cancer treatment. As ICI use becomes widespread, more immune-related adverse events (irAE's) are being reported. Our aim was to investigate the frequency and nature of new irAE's as well as report the frequency of flare-ups of pre-existing autoimmune conditions occurring after ICI therapy.We performed a retrospective chart review of all patients treated for cancer with anti-PD1 or anti-CTLA4 or combination therapy at our tertiary care center from January 2014 to April 2016. Demographic data, cancer type and stage, irAE's (new immune disorders and disease flares of pre-existing autoimmune disorders on ICI therapy), and drug treatment information were extracted.We identified 220 patients treated with ICI therapy during the study period out of which 27% (60/220) developed irAE's. 11% in anti-CTLA4 group and 16% among anti-PD1 treated patients developed irAE's. IrAE's resulted in discontinuation of cancer therapy in 28% of those who developed irAE's. 21.4% had a flare of their autoimmune disease but only 1 required discontinuation of immunotherapy.IrAE's are an important emerging clinical disease entity for specialists to be aware of. Our study shows that ICI's can be safely used in patients with pre-existing autoimmune conditions with close monitoring. However, there is still a large unmet need to have a better understanding of how to systematically evaluate and manage patients with irAE's as well as for identifying the predictors of irAE's.


Assuntos
Antineoplásicos Imunológicos/efeitos adversos , Doenças do Sistema Imunitário/induzido quimicamente , Imunoterapia/efeitos adversos , Melanoma/tratamento farmacológico , Neoplasias/tratamento farmacológico , Adulto , Idoso , Idoso de 80 Anos ou mais , Doenças Autoimunes/induzido quimicamente , Doenças Autoimunes/imunologia , Antígeno CTLA-4/antagonistas & inibidores , Feminino , Humanos , Doenças do Sistema Imunitário/imunologia , Masculino , Melanoma/imunologia , Pessoa de Meia-Idade , Neoplasias/imunologia , Receptor de Morte Celular Programada 1/antagonistas & inibidores , Estudos Retrospectivos
17.
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
18.
Nature ; 574(7776): 122-126, 2019 10.
Artigo em Inglês | MEDLINE | ID: mdl-31554970

RESUMO

B cells are important in the pathogenesis of many, and perhaps all, immune-mediated diseases. Each B cell expresses a single B cell receptor (BCR)1, and the diverse range of BCRs expressed by the total B cell population of an individual is termed the 'BCR repertoire'. Our understanding of the BCR repertoire in the context of immune-mediated diseases is incomplete, and defining this could provide new insights into pathogenesis and therapy. Here, we compared the BCR repertoire in systemic lupus erythematosus, anti-neutrophil cytoplasmic antibody (ANCA)-associated vasculitis, Crohn's disease, Behçet's disease, eosinophilic granulomatosis with polyangiitis, and immunoglobulin A (IgA) vasculitis by analysing BCR clonality, use of immunoglobulin heavy-chain variable region (IGHV) genes and-in particular-isotype use. An increase in clonality in systemic lupus erythematosus and Crohn's disease that was dominated by the IgA isotype, together with skewed use of the IGHV genes in these and other diseases, suggested a microbial contribution to pathogenesis. Different immunosuppressive treatments had specific and distinct effects on the repertoire; B cells that persisted after treatment with rituximab were predominately isotype-switched and clonally expanded, whereas the inverse was true for B cells that persisted after treatment with mycophenolate mofetil. Our comparative analysis of the BCR repertoire in immune-mediated disease reveals a complex B cell architecture, providing a platform for understanding pathological mechanisms and designing treatment strategies.


Assuntos
Doenças do Sistema Imunitário/imunologia , Isotipos de Imunoglobulinas/análise , Isotipos de Imunoglobulinas/imunologia , Receptores de Antígenos de Linfócitos B/análise , Receptores de Antígenos de Linfócitos B/imunologia , Adulto , Idoso , Células Clonais/citologia , Células Clonais/imunologia , Humanos , Imunoglobulina A/análise , Imunoglobulina A/imunologia , Switching de Imunoglobulina/imunologia , Imunoglobulina G/análise , Imunoglobulina G/imunologia , Pessoa de Meia-Idade , Adulto Jovem
19.
Ned Tijdschr Geneeskd ; 1632019 08 19.
Artigo em Holandês | MEDLINE | ID: mdl-31433146

RESUMO

The next step in the treatment of immune diseases: jakinibs, inhibitors of the intracellular Janus kinase The intracellular Janus kinase (JAK) and the signal transduction and activator of transcription (STAT) proteins are involved in the whole spectrum of immune-mediated diseases. Currently, agents are developed that influence the JAK-STAT mechanism. JAK inhibitors (jakinibs) have only recently made their way into clinical practice. These agents exhibit both similarities and differences in terms of effectiveness and safety. In the coming years, results from basic and clinical research will improve our knowledge of these agents. For patients who suffer from immune-mediated diseases, their introduction appears to be a breakthrough that will offer new treatment options. One advantage over biologicals is that jakinibs can be taken orally. As with all new innovative medicines, with jakinibs one cannot escape a discussion over costs as well. The balance between the added value of jakinibs compared to biologicals, and the actual purchase prices for each of these treatment modalities, will influence the eventual positioning of jakinibs.


Assuntos
Doenças do Sistema Imunitário/imunologia , Inibidores de Janus Quinases/metabolismo , Janus Quinases/imunologia , Transdução de Sinais/imunologia , Animais , Humanos , Janus Quinase 2/imunologia
20.
Immunol Lett ; 215: 48-59, 2019 11.
Artigo em Inglês | MEDLINE | ID: mdl-31442542

RESUMO

Regulatory B cells (Bregs) are immune-modulating cells that affect the immune system by producing cytokines or cellular interactions. These cells have immunomodulatory effects on the immune system by cytokine production. The abnormalities in Bregs could be involved in various disorders such as autoimmunity, chronic infectious disease, malignancies, allergies, and primary immunodeficiencies are immune-related scenarios. Ongoing investigation could disclose the biology and the exact phenotype of these cells and also the assigned mechanisms of action of each subset, as a result, potential therapeutic strategies for treating immune-related anomalies. In this review, we collect the findings of human and mouse Bregs and the therapeutic efforts to change the pathogenicity of these cells in diverse disease.


Assuntos
Linfócitos B Reguladores/imunologia , Doenças do Sistema Imunitário/imunologia , Neoplasias/imunologia , Animais , Linfócitos B Reguladores/patologia , Humanos , Doenças do Sistema Imunitário/patologia , Camundongos , Neoplasias/patologia
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