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1.
Nat Commun ; 11(1): 6385, 2020 12 14.
Artigo em Inglês | MEDLINE | ID: mdl-33318491

RESUMO

The response to the coronavirus disease 2019 (COVID-19) pandemic has been hampered by lack of an effective severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) antiviral therapy. Here we report the use of remdesivir in a patient with COVID-19 and the prototypic genetic antibody deficiency X-linked agammaglobulinaemia (XLA). Despite evidence of complement activation and a robust T cell response, the patient developed persistent SARS-CoV-2 pneumonitis, without progressing to multi-organ involvement. This unusual clinical course is consistent with a contribution of antibodies to both viral clearance and progression to severe disease. In the absence of these confounders, we take an experimental medicine approach to examine the in vivo utility of remdesivir. Over two independent courses of treatment, we observe a temporally correlated clinical and virological response, leading to clinical resolution and viral clearance, with no evidence of acquired drug resistance. We therefore provide evidence for the antiviral efficacy of remdesivir in vivo, and its potential benefit in selected patients.


Assuntos
Monofosfato de Adenosina/análogos & derivados , Alanina/análogos & derivados , Imunidade Humoral/efeitos dos fármacos , /efeitos dos fármacos , Monofosfato de Adenosina/uso terapêutico , Adulto , Alanina/uso terapêutico , Antivirais/uso terapêutico , Febre/prevenção & controle , Humanos , Imunidade Humoral/imunologia , Contagem de Linfócitos , Masculino , /fisiologia , Resultado do Tratamento
2.
Genome Med ; 12(1): 106, 2020 Nov 25.
Artigo em Inglês | MEDLINE | ID: mdl-33239102

RESUMO

BACKGROUND: Genome-wide association studies (GWAS) have identified pervasive sharing of genetic architectures across multiple immune-mediated diseases (IMD). By learning the genetic basis of IMD risk from common diseases, this sharing can be exploited to enable analysis of less frequent IMD where, due to limited sample size, traditional GWAS techniques are challenging. METHODS: Exploiting ideas from Bayesian genetic fine-mapping, we developed a disease-focused shrinkage approach to allow us to distill genetic risk components from GWAS summary statistics for a set of related diseases. We applied this technique to 13 larger GWAS of common IMD, deriving a reduced dimension "basis" that summarised the multidimensional components of genetic risk. We used independent datasets including the UK Biobank to assess the performance of the basis and characterise individual axes. Finally, we projected summary GWAS data for smaller IMD studies, with less than 1000 cases, to assess whether the approach was able to provide additional insights into genetic architecture of less common IMD or IMD subtypes, where cohort collection is challenging. RESULTS: We identified 13 IMD genetic risk components. The projection of independent UK Biobank data demonstrated the IMD specificity and accuracy of the basis even for traits with very limited case-size (e.g. vitiligo, 150 cases). Projection of additional IMD-relevant studies allowed us to add biological interpretation to specific components, e.g. related to raised eosinophil counts in blood and serum concentration of the chemokine CXCL10 (IP-10). On application to 22 rare IMD and IMD subtypes, we were able to not only highlight subtype-discriminating axes (e.g. for juvenile idiopathic arthritis) but also suggest eight novel genetic associations. CONCLUSIONS: Requiring only summary-level data, our unsupervised approach allows the genetic architectures across any range of clinically related traits to be characterised in fewer dimensions. This facilitates the analysis of studies with modest sample size by matching shared axes of both genetic and biological risk across a wider disease domain, and provides an evidence base for possible therapeutic repurposing opportunities.

3.
Sci Rep ; 10(1): 17010, 2020 Oct 07.
Artigo em Inglês | MEDLINE | ID: mdl-33024234

RESUMO

An amendment to this paper has been published and can be accessed via a link at the top of the paper.

4.
Nat Immunol ; 21(11): 1408-1420, 2020 11.
Artigo em Inglês | MEDLINE | ID: mdl-32868930

RESUMO

B lymphocyte development and selection are central to adaptive immunity and self-tolerance. These processes require B cell receptor (BCR) signaling and occur in bone marrow, an environment with variable hypoxia, but whether hypoxia-inducible factor (HIF) is involved is unknown. We show that HIF activity is high in human and murine bone marrow pro-B and pre-B cells and decreases at the immature B cell stage. This stage-specific HIF suppression is required for normal B cell development because genetic activation of HIF-1α in murine B cells led to reduced repertoire diversity, decreased BCR editing and developmental arrest of immature B cells, resulting in reduced peripheral B cell numbers. HIF-1α activation lowered surface BCR, CD19 and B cell-activating factor receptor and increased expression of proapoptotic BIM. BIM deletion rescued the developmental block. Administration of a HIF activator in clinical use markedly reduced bone marrow and transitional B cells, which has therapeutic implications. Together, our work demonstrates that dynamic regulation of HIF-1α is essential for normal B cell development.

5.
Cell Rep Med ; 1(6): 100099, 2020 Sep 22.
Artigo em Inglês | MEDLINE | ID: mdl-32905045

RESUMO

Rapid COVID-19 diagnosis in the hospital is essential, although this is complicated by 30%-50% of nose/throat swabs being negative by SARS-CoV-2 nucleic acid amplification testing (NAAT). Furthermore, the D614G spike mutant dominates the pandemic and it is unclear how serological tests designed to detect anti-spike antibodies perform against this variant. We assess the diagnostic accuracy of combined rapid antibody point of care (POC) and nucleic acid assays for suspected COVID-19 disease due to either wild-type or the D614G spike mutant SARS-CoV-2. The overall detection rate for COVID-19 is 79.2% (95% CI 57.8-92.9) by rapid NAAT alone. The combined point of care antibody test and rapid NAAT is not affected by D614G and results in very high sensitivity for COVID-19 diagnosis with very high specificity.

6.
J Proteome Res ; 19(11): 4442-4454, 2020 11 06.
Artigo em Inglês | MEDLINE | ID: mdl-32806897

RESUMO

The metabolic effects of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection on human blood plasma were characterized using multiplatform metabolic phenotyping with nuclear magnetic resonance (NMR) spectroscopy and liquid chromatography-mass spectrometry (LC-MS). Quantitative measurements of lipoprotein subfractions, α-1-acid glycoprotein, glucose, and biogenic amines were made on samples from symptomatic coronavirus disease 19 (COVID-19) patients who had tested positive for the SARS-CoV-2 virus (n = 17) and from age- and gender-matched controls (n = 25). Data were analyzed using an orthogonal-projections to latent structures (OPLS) method and used to construct an exceptionally strong (AUROC = 1) hybrid NMR-MS model that enabled detailed metabolic discrimination between the groups and their biochemical relationships. Key discriminant metabolites included markers of inflammation including elevated α-1-acid glycoprotein and an increased kynurenine/tryptophan ratio. There was also an abnormal lipoprotein, glucose, and amino acid signature consistent with diabetes and coronary artery disease (low total and HDL Apolipoprotein A1, low HDL triglycerides, high LDL and VLDL triglycerides), plus multiple highly significant amino acid markers of liver dysfunction (including the elevated glutamine/glutamate and Fischer's ratios) that present themselves as part of a distinct SARS-CoV-2 infection pattern. A multivariate training-test set model was validated using independent samples from additional SARS-CoV-2 positive patients and controls. The predictive model showed a sensitivity of 100% for SARS-CoV-2 positivity. The breadth of the disturbed pathways indicates a systemic signature of SARS-CoV-2 positivity that includes elements of liver dysfunction, dyslipidemia, diabetes, and coronary heart disease risk that are consistent with recent reports that COVID-19 is a systemic disease affecting multiple organs and systems. Metabolights study reference: MTBLS2014.


Assuntos
Aminoácidos/sangue , Infecções por Coronavirus , Lipoproteínas/sangue , Modelos Biológicos , Insuficiência de Múltiplos Órgãos , Pandemias , Pneumonia Viral , Idoso , Betacoronavirus , Biomarcadores , Glicemia/análise , Infecções por Coronavirus/sangue , Infecções por Coronavirus/complicações , Infecções por Coronavirus/epidemiologia , Infecções por Coronavirus/metabolismo , Feminino , Humanos , Espectroscopia de Ressonância Magnética , Masculino , Espectrometria de Massas , Metaboloma , Pessoa de Meia-Idade , Insuficiência de Múltiplos Órgãos/sangue , Insuficiência de Múltiplos Órgãos/etiologia , Insuficiência de Múltiplos Órgãos/metabolismo , Pneumonia Viral/sangue , Pneumonia Viral/complicações , Pneumonia Viral/epidemiologia , Pneumonia Viral/metabolismo
7.
Cell Rep Med ; 1(5): 100062, 2020 Aug 25.
Artigo em Inglês | MEDLINE | ID: mdl-32838340

RESUMO

There is an urgent need for rapid SARS-CoV-2 testing in hospitals to limit nosocomial spread. We report an evaluation of point of care (POC) nucleic acid amplification testing (NAAT) in 149 participants with parallel combined nasal and throat swabbing for POC versus standard lab RT-PCR testing. Median time to result is 2.6 (IQR 2.3-4.8) versus 26.4 h (IQR 21.4-31.4, p < 0.001), with 32 (21.5%) positive and 117 (78.5%) negative. Cohen's κ correlation between tests is 0.96 (95% CI 0.91-1.00). When comparing nearly 1,000 tests pre- and post-implementation, the median time to definitive bed placement from admission is 23.4 (8.6-41.9) versus 17.1 h (9.0-28.8), p = 0.02. Mean length of stay on COVID-19 "holding" wards is 58.5 versus 29.9 h (p < 0.001). POC testing increases isolation room availability, avoids bed closures, allows discharge to care homes, and expedites access to hospital procedures. POC testing could mitigate the impact of COVID-19 on hospital systems.

8.
Sci Rep ; 10(1): 10570, 2020 06 29.
Artigo em Inglês | MEDLINE | ID: mdl-32601361

RESUMO

The ability to accurately characterize DNA variant proportions using PCR amplification is key to many genetic studies, including studying tumor heterogeneity, 16S microbiome, viral and immune receptor sequencing. We develop a novel generalizable ultrasensitive amplicon barcoding approach that significantly reduces the inflation/deflation of DNA variant proportions due to PCR amplification biases and sequencing errors. This method was applied to immune receptor sequencing, where it significantly improves the quality and estimation of diversity of the resulting library.


Assuntos
Código de Barras de DNA Taxonômico/métodos , Sequenciamento de Nucleotídeos em Larga Escala/métodos , Reação em Cadeia da Polimerase/métodos , Viés , DNA/genética , Primers do DNA/genética , Biblioteca Gênica , Humanos , Técnicas de Amplificação de Ácido Nucleico/métodos , Análise de Sequência de DNA/métodos
9.
Nature ; 583(7814): 96-102, 2020 07.
Artigo em Inglês | MEDLINE | ID: mdl-32581362

RESUMO

Most patients with rare diseases do not receive a molecular diagnosis and the aetiological variants and causative genes for more than half such disorders remain to be discovered1. Here we used whole-genome sequencing (WGS) in a national health system to streamline diagnosis and to discover unknown aetiological variants in the coding and non-coding regions of the genome. We generated WGS data for 13,037 participants, of whom 9,802 had a rare disease, and provided a genetic diagnosis to 1,138 of the 7,065 extensively phenotyped participants. We identified 95 Mendelian associations between genes and rare diseases, of which 11 have been discovered since 2015 and at least 79 are confirmed to be aetiological. By generating WGS data of UK Biobank participants2, we found that rare alleles can explain the presence of some individuals in the tails of a quantitative trait for red blood cells. Finally, we identified four novel non-coding variants that cause disease through the disruption of transcription of ARPC1B, GATA1, LRBA and MPL. Our study demonstrates a synergy by using WGS for diagnosis and aetiological discovery in routine healthcare.


Assuntos
Internacionalidade , Programas Nacionais de Saúde , Doenças Raras/diagnóstico , Doenças Raras/genética , Sequenciamento Completo do Genoma , Complexo 2-3 de Proteínas Relacionadas à Actina/genética , Proteínas Adaptadoras de Transdução de Sinal/genética , Alelos , Bases de Dados Factuais , Eritrócitos/metabolismo , Fator de Transcrição GATA1/genética , Humanos , Fenótipo , Locos de Características Quantitativas , Receptores de Trombopoetina/genética , Medicina Estatal , Reino Unido
10.
Front Immunol ; 11: 466, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32269569

RESUMO

The generation of a potent humoral immune response by B cells relies on the integration of signals induced by the B cell receptor, toll-like receptors and both negative and positive co-receptors. Several reports also suggest that integrin signaling plays an important role in this process. How integrin signaling is regulated in B cells is however still partially understood. Integrin activity and function are controlled by several mechanisms including regulation by molecular adaptors of the paxillin family. In B cells, Leupaxin (Lpxn) is the most expressed member of the family and in vitro studies suggest that it could dampen BCR signaling. Here, we report that Lpxn expression is increased in germinal center B cells compared to naïve B cells. Moreover, Lpxn deficiency leads to decreased B cell differentiation into plasma cells in vitro. However, Lpxn seems dispensable for the generation of a potent B cell immune response in vivo. Altogether our results suggest that Lpxn is dispensable for T-dependent and T-independent B cell immune responses.

11.
Clin Exp Rheumatol ; 38(5): 949-955, 2020.
Artigo em Inglês | MEDLINE | ID: mdl-32167874

RESUMO

OBJECTIVES: The TYK2 gene encodes a tyrosin kinase which is involved in multiple immune functions. A functional variant of this gene has been identified to play a protective role in multiple autoimmune diseases. The goal of this study was to evaluate the involvement of this variant of TYK2 in vasculitides [giant cell arteritis (GCA), ANCA-associated vasculitis (AAV) and IgA vasculitis (IgAV)] and viral infections [hepatitis C virus (HCV) and human immunodeficiency virus type I (HIV-1)]. METHODS: The study sample was composed of 13,745 European individuals. The genotyping was performed by Immunochip and TaqMan 5' allele discrimination assays and the allele frequencies were compared using PLINK. RESULTS: Although the results obtained did not reach the genome-wide level of significance, p-values at nominal significance were observed, suggesting that the TYK2 variant provides protection against two vasculitides: GCA (p=5.94E-3; OR (95%CI) = 0.56 (0.37-0.85) and AAV (p=6.79E-3; OR (95%CI) = 0.65 (0.47-0.89). However, this variant was not found to be associated with IgAV. No evidence was gained that the TYK2 variant confers susceptibility to HCV and HIV-1 infection. CONCLUSIONS: This is the first study to propose the association between the TYK2 and both GCA and AAV. Our findings also suggest that TYK2 does not play a relevant role in IgAV or in susceptibility to HCV and HVI-1.


Assuntos
Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos , Arterite de Células Gigantes , Infecções , Alelos , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/genética , Frequência do Gene , Predisposição Genética para Doença , Arterite de Células Gigantes/genética , Humanos , Polimorfismo de Nucleotídeo Único , TYK2 Quinase
12.
Immunology ; 159(4): 393-403, 2020 04.
Artigo em Inglês | MEDLINE | ID: mdl-31880316

RESUMO

Signalling lymphocyte activation molecule family member 9 (SLAMF9) is an orphan receptor of the CD2/SLAM family of leucocyte surface proteins. Examination of SLAMF9 expression and function indicates that SLAMF9 promotes inflammation by specialized subsets of antigen-presenting cells. Within healthy liver and circulating mouse peripheral blood mononuclear cells, SLAMF9 is expressed on CD11b+ , Ly6C- , CD11clow , F4/80low , MHC-II+ , CX3 CR1+ mononuclear phagocytes as well as plasmacytoid dendritic cells. In addition, SLAMF9 can be found on peritoneal B1 cells and small (F4/80low ), but not large (F4/80high ), peritoneal macrophages. Upon systemic challenge with Salmonella enterica Typhimurium, Slamf9-/- mice were impaired in their ability to clear the infection from the liver. In humans, SLAMF9 is up-regulated upon differentiation of monocytes into macrophages, and lipopolysaccharide stimulation of PMA-differentiated, SLAMF9 knockdown THP-1 cells showed an essential role of SLAMF9 in production of granulocyte-macrophage colony-stimulating factor, tumour necrosis factor-α, and interleukin-1ß. Taken together, these data implicate SLAMF9 in the initiation of inflammation and clearance of bacterial infection.


Assuntos
Células Dendríticas/imunologia , Interações Hospedeiro-Patógeno/imunologia , Fígado/imunologia , Infecções por Salmonella/imunologia , Salmonella typhimurium/imunologia , Família de Moléculas de Sinalização da Ativação Linfocitária/imunologia , Animais , Linfócitos B/imunologia , Linfócitos B/microbiologia , Diferenciação Celular , Células Dendríticas/efeitos dos fármacos , Células Dendríticas/microbiologia , Regulação da Expressão Gênica , Fator Estimulador de Colônias de Granulócitos e Macrófagos/genética , Fator Estimulador de Colônias de Granulócitos e Macrófagos/imunologia , Interações Hospedeiro-Patógeno/genética , Humanos , Interleucina-1beta/genética , Interleucina-1beta/imunologia , Lipopolissacarídeos/farmacologia , Fígado/microbiologia , Macrófagos/efeitos dos fármacos , Macrófagos/imunologia , Macrófagos/microbiologia , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Monócitos/efeitos dos fármacos , Monócitos/imunologia , Monócitos/microbiologia , Infecções por Salmonella/genética , Infecções por Salmonella/microbiologia , Salmonella typhimurium/patogenicidade , Transdução de Sinais , Família de Moléculas de Sinalização da Ativação Linfocitária/deficiência , Família de Moléculas de Sinalização da Ativação Linfocitária/genética , Células THP-1 , Fator de Necrose Tumoral alfa/genética , Fator de Necrose Tumoral alfa/imunologia
13.
Nat Commun ; 10(1): 5120, 2019 11 12.
Artigo em Inglês | MEDLINE | ID: mdl-31719529

RESUMO

Eosinophilic granulomatosis with polyangiitis (EGPA) is a rare inflammatory disease of unknown cause. 30% of patients have anti-neutrophil cytoplasmic antibodies (ANCA) specific for myeloperoxidase (MPO). Here, we describe a genome-wide association study in 676 EGPA cases and 6809 controls, that identifies 4 EGPA-associated loci through conventional case-control analysis, and 4 additional associations through a conditional false discovery rate approach. Many variants are also associated with asthma and six are associated with eosinophil count in the general population. Through Mendelian randomisation, we show that a primary tendency to eosinophilia contributes to EGPA susceptibility. Stratification by ANCA reveals that EGPA comprises two genetically and clinically distinct syndromes. MPO+ ANCA EGPA is an eosinophilic autoimmune disease sharing certain clinical features and an HLA-DQ association with MPO+ ANCA-associated vasculitis, while ANCA-negative EGPA may instead have a mucosal/barrier dysfunction origin. Four candidate genes are targets of therapies in development, supporting their exploration in EGPA.


Assuntos
Anticorpos Anticitoplasma de Neutrófilos/metabolismo , Loci Gênicos , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Granulomatose com Poliangiite/genética , Granulomatose com Poliangiite/imunologia , Eosinófilos/patologia , Estudos de Associação Genética , Humanos , Análise da Randomização Mendeliana
14.
J Exp Med ; 216(9): 1986-1998, 2019 09 02.
Artigo em Inglês | MEDLINE | ID: mdl-31235509

RESUMO

IL-6 excess is central to the pathogenesis of multiple inflammatory conditions and is targeted in clinical practice by immunotherapy that blocks the IL-6 receptor encoded by IL6R We describe two patients with homozygous mutations in IL6R who presented with recurrent infections, abnormal acute-phase responses, elevated IgE, eczema, and eosinophilia. This study identifies a novel primary immunodeficiency, clarifying the contribution of IL-6 to the phenotype of patients with mutations in IL6ST, STAT3, and ZNF341, genes encoding different components of the IL-6 signaling pathway, and alerts us to the potential toxicity of drugs targeting the IL-6R.


Assuntos
Síndromes de Imunodeficiência/patologia , Inflamação/patologia , Receptores de Interleucina-6/deficiência , Adolescente , Adulto , Criança , Pré-Escolar , Feminino , Células HEK293 , Humanos , Recém-Nascido , Masculino , Receptores de Interleucina-6/metabolismo
15.
J Exp Med ; 216(6): 1311-1327, 2019 06 03.
Artigo em Inglês | MEDLINE | ID: mdl-31040185

RESUMO

Interleukin-2, which conveys essential signals for immunity, operates through a heterotrimeric receptor. Here we identify human interleukin-2 receptor (IL-2R) ß chain (IL2RB) gene defects as a cause of life-threatening immune dysregulation. We report three homozygous mutations in the IL2RB gene of eight individuals from four consanguineous families that cause disease by distinct mechanisms. Nearly all patients presented with autoantibodies, hypergammaglobulinemia, bowel inflammation, dermatological abnormalities, lymphadenopathy, and cytomegalovirus disease. Patient T lymphocytes lacked surface expression of IL-2Rß and were unable to respond to IL-2 stimulation. By contrast, natural killer cells retained partial IL-2Rß expression and function. IL-2Rß loss of function was recapitulated in a recombinant system in which IL2RB mutations caused reduced surface expression and IL-2 binding. Stem cell transplant ameliorated clinical symptoms in one patient; forced expression of wild-type IL-2Rß also increased the IL-2 responsiveness of patient T lymphocytes in vitro. Insights from these patients can inform the development of IL-2-based therapeutics for immunological diseases and cancer.


Assuntos
Tolerância Imunológica/genética , Imunidade/genética , Subunidade beta de Receptor de Interleucina-2/genética , Mutação/genética , Alelos , Autoimunidade/genética , Genótipo , Células HEK293 , Humanos , Síndromes de Imunodeficiência/genética , Células Matadoras Naturais/metabolismo , Lentivirus/metabolismo , Mutação de Sentido Incorreto/genética , Fenótipo , Fosforilação , Fator de Transcrição STAT3/metabolismo , Fator de Transcrição STAT5/metabolismo , Transdução de Sinais , Linfócitos T/metabolismo
16.
Nat Commun ; 10(1): 1970, 2019 04 29.
Artigo em Inglês | MEDLINE | ID: mdl-31036800

RESUMO

Several tolerance checkpoints exist throughout B cell development to control autoreactive B cells and prevent the generation of pathogenic autoantibodies. FcγRIIb is an Fc receptor that inhibits B cell activation and, if defective, is associated with autoimmune disease, yet its impact on specific B cell tolerance checkpoints is unknown. Here we show that reduced expression of FcγRIIb enhances the deletion and anergy of autoreactive immature B cells, but in contrast promotes autoreactive B cell expansion in the germinal center and serum autoantibody production, even in response to exogenous, non-self antigens. Our data thus show that FcγRIIb has opposing effects on pre-immune and post-immune tolerance checkpoints, and suggest that B cell tolerance requires the control of bystander germinal center B cells with low or no affinity for the immunizing antigen.


Assuntos
Linfócitos B/imunologia , Diferenciação Celular/fisiologia , Proliferação de Células/fisiologia , Tolerância Imunológica/imunologia , Receptores de IgG/metabolismo , Algoritmos , Animais , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Centro Germinativo , Humanos , Leucócitos Mononucleares/imunologia , Leucócitos Mononucleares/metabolismo , Masculino , Camundongos , Receptores de IgG/genética , Software
17.
Science ; 364(6442)2019 05 24.
Artigo em Inglês | MEDLINE | ID: mdl-31123110

RESUMO

Approximately 2.4% of the human mitochondrial DNA (mtDNA) genome exhibits common homoplasmic genetic variation. We analyzed 12,975 whole-genome sequences to show that 45.1% of individuals from 1526 mother-offspring pairs harbor a mixed population of mtDNA (heteroplasmy), but the propensity for maternal transmission differs across the mitochondrial genome. Over one generation, we observed selection both for and against variants in specific genomic regions; known variants were more likely to be transmitted than previously unknown variants. However, new heteroplasmies were more likely to match the nuclear genetic ancestry as opposed to the ancestry of the mitochondrial genome on which the mutations occurred, validating our findings in 40,325 individuals. Thus, human mtDNA at the population level is shaped by selective forces within the female germ line under nuclear genetic control, which ensures consistency between the two independent genetic lineages.


Assuntos
DNA Mitocondrial/genética , Genoma Mitocondrial , Herança Materna , Óvulo/crescimento & desenvolvimento , Seleção Genética , Feminino , Variação Genética , Humanos
18.
Arterioscler Thromb Vasc Biol ; 39(7): 1379-1389, 2019 07.
Artigo em Inglês | MEDLINE | ID: mdl-31092015

RESUMO

Objective- Investigate the impact of modulating B cell FcγRIIb (Fcγ receptor IIb) expression on atherosclerosis. Approach and Results- Western diet-induced atherosclerosis was assessed in Ldlr-/- or Apoe-/- mice with B cell-specific overexpression of FcγRIIb or with an FcγRIIb promoter mutation that alters FcγRIIb expression in germinal center (GC) B cells. In males, overexpression of FcγRIIb on B cells severely reduced activated, class switched B cell responses, as indicated by reductions in GC B cells, plasma cells, and serum IgG but not IgM antibodies. Male mice overexpressing FcγRIIb developed less atherosclerosis, suggesting a pathogenic role for GC B cell IgG responses. In support of this hypothesis, male mice with a promoter polymorphism-driven reduction in FcγRIIb on GC B cells but not plasma cells have a converse phenotype of enhanced GC responses and IgG2c antibodies and enhanced atherosclerosis. IgG2c significantly enhanced TNF (tumor necrosis factor) secretion by CD11b+ CD11c+ cells expressing the high-affinity receptor FcγRIV. In females, overexpression of FcγRIIb on B cells not only reduced GC B cell responses but also substantially reduced B-1 cells and IgM antibodies, which translated into acceleration of atherosclerosis. Promoter-driven reduction in FcγRIIb did not alter GC B cell responses in females and, therefore, had no impact on atherosclerosis. Conclusions- B cell FcγRIIb differentially alters proatherogenic adaptive GC B cell and atheroprotective innate B-1 responses in male and female mice fed a western diet. Our results highlight the importance of a better understanding and ability to selectively target B cell responses in future immunotherapeutic approaches against human cardiovascular disease. Visual Overview- An online visual overview is available for this article.


Assuntos
Aterosclerose/imunologia , Linfócitos B/imunologia , Centro Germinativo/imunologia , Receptores de IgG/fisiologia , Animais , Apolipoproteínas E/fisiologia , Feminino , Imunidade Inata , Imunoglobulina M/biossíntese , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Fator de Necrose Tumoral alfa/biossíntese
19.
Gut ; 68(8): 1386-1395, 2019 08.
Artigo em Inglês | MEDLINE | ID: mdl-31030191

RESUMO

OBJECTIVE: We have previously described a prognostic transcriptional signature in CD8 T cells that separates patients with IBD into two phenotypically distinct subgroups, termed IBD1 and IBD2. Here we sought to develop a blood-based test that could identify these subgroups without cell separation, and thus be suitable for clinical use in Crohn's disease (CD) and ulcerative colitis (UC). DESIGN: Patients with active IBD were recruited before treatment. Transcriptomic analyses were performed on purified CD8 T cells and/or whole blood. Phenotype data were collected prospectively. IBD1/IBD2 patient subgroups were identified by consensus clustering of CD8 T cell transcriptomes. In a training cohort, machine learning was used to identify groups of genes ('classifiers') whose differential expression in whole blood recreated the IBD1/IBD2 subgroups. Genes from the best classifiers were quantitative (q)PCR optimised, and further machine learning was used to identify the optimal qPCR classifier, which was locked down for further testing. Independent validation was sought in separate cohorts of patients with CD (n=66) and UC (n=57). RESULTS: In both validation cohorts, a 17-gene qPCR-based classifier stratified patients into two distinct subgroups. Irrespective of the underlying diagnosis, IBDhi patients (analogous to the poor prognosis IBD1 subgroup) experienced significantly more aggressive disease than IBDlo patients (analogous to IBD2), with earlier need for treatment escalation (hazard ratio=2.65 (CD), 3.12 (UC)) and more escalations over time (for multiple escalations within 18 months: sensitivity=72.7% (CD), 100% (UC); negative predictive value=90.9% (CD), 100% (UC)). CONCLUSION: This is the first validated prognostic biomarker that can predict prognosis in newly diagnosed patients with IBD and represents a step towards personalised therapy.


Assuntos
Linfócitos T CD8-Positivos/metabolismo , Colite Ulcerativa , Doença de Crohn , Adulto , Biomarcadores/sangue , Colite Ulcerativa/sangue , Colite Ulcerativa/diagnóstico , Doença de Crohn/sangue , Doença de Crohn/diagnóstico , Diagnóstico Diferencial , Feminino , Expressão Gênica , Perfilação da Expressão Gênica/métodos , Humanos , Aprendizado de Máquina , Masculino , Pessoa de Meia-Idade , Fenótipo , Valor Preditivo dos Testes , Prognóstico , Reprodutibilidade dos Testes , Sensibilidade e Especificidade , Índice de Gravidade de Doença
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