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1.
PLoS One ; 13(12): e0209343, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-30586461

RESUMO

BACKGROUND: The TNFSF13B (TNF superfamily member 13b) gene encodes BAFF, a cytokine with a crucial role in the differentiation and activation of B cells. An insertion-deletion variant (GCTGT→A) of this gene, leading to increased levels of BAFF, has been recently implicated in the genetic predisposition to several autoimmune diseases, including multiple sclerosis, systemic lupus erythematosus, and rheumatoid arthritis. Based on the elevated levels of this cytokine found in patients with giant cell arteritis (GCA) and systemic sclerosis (SSc), we aimed to assess whether this functional variant also represents a novel genetic risk factor for these two disorders. METHODS: A total of 1,728 biopsy-proven GCA patients from 4 European cohorts, 4,584 SSc patients from 3 European cohorts and 5,160 ethnically-matched healthy controls were included in the study. The single nucleotide polymorphism (SNP) rs374039502, which colocalizes with the genetic variant previously implicated in autoimmunity, was genotyped using a custom TaqMan assay. First, association analysis was conducted in each independent cohort using χ2 test in Plink (v1.9). Subsequently, different case/control sets were meta-analyzed by the inverse variance method. RESULTS: No statistically significant differences were found when allele distributions were compared between cases and controls for any of the analyzed cohorts. Similarly, combined analysis of the different sets evidenced a lack of association of the rs374039502 variant with GCA (P = 0.421; OR (95% CI) = 0.92 (0.75-1.13)) and SSc (P = 0.500; OR (95% CI) = 1.05 (0.91-1.22)). The stratified analysis considering the main clinical subphenotypes of these diseases yielded similar negative results. CONCLUSION: Our data suggest that the TNFSF13B functional variant does not contribute to the genetic network underlying GCA and SSc.


Assuntos
Fator Ativador de Células B/genética , Predisposição Genética para Doença , Arterite de Células Gigantes/genética , Escleroderma Sistêmico/genética , Adulto , Idoso , Idoso de 80 Anos ou mais , Biópsia , Estudos de Casos e Controles , Estudos de Coortes , Europa (Continente) , Feminino , Redes Reguladoras de Genes/genética , Técnicas de Genotipagem , Arterite de Células Gigantes/patologia , Humanos , Mutação INDEL , Masculino , Pessoa de Meia-Idade , Polimorfismo de Nucleotídeo Único , Escleroderma Sistêmico/patologia
2.
Cell Mol Biol (Noisy-le-grand) ; 64(5): 46-51, 2018 Apr 30.
Artigo em Inglês | MEDLINE | ID: mdl-29729713

RESUMO

This study explored whether the functional protein tyrosine phosphatase nonreceptor 22 (PTPN22) G788A (R263Q) polymorphism is associated with susceptibility to autoimmune diseases. A meta-analysis was conducted using 23 comparative studies with a total of 16,719 patients and 17,783 controls. The meta-analysis showed an association between the A allele of the PTPN22 G788A polymorphism and decreased risk of autoimmune diseases in all subjects (p < 0.001). Analysis after stratification by ethnicity indicated that the PTPN22 788A allele was significantly associated with autoimmune diseases in Europeans (p < 0.001) but not in Latin Americans. Meta-analysis by autoimmune disease type showed a significant negative association between the PTPN22 788A allele and systemic lupus erythematous (SLE) (p = 001), rheumatoid arthritis (RA) (p = 0.008), ulcerative colitis (UC) (p = 0.016), but not Crohn's disease (CD). A single study for each showed no association between the PTPN22 788A allele and systemic sclerosis, giant cell arteritis, Henoch-schonlein purpura, uveitis, and Grave's disease. This meta-analysis demonstrates that the PTPN22 G788A polymorphism confers protection against SLE, RA, and UC, supporting evidence of association of the PTPN22 gene with a subgroup of autoimmune diseases.


Assuntos
Artrite Reumatoide/genética , Colite Ulcerativa/genética , Resistência à Doença/genética , Lúpus Eritematoso Sistêmico/genética , Polimorfismo de Nucleotídeo Único , Proteína Tirosina Fosfatase não Receptora Tipo 22/genética , Artrite Reumatoide/etnologia , Artrite Reumatoide/imunologia , Artrite Reumatoide/patologia , Estudos de Casos e Controles , Colite Ulcerativa/etnologia , Colite Ulcerativa/imunologia , Colite Ulcerativa/patologia , Doença de Crohn/etnologia , Doença de Crohn/genética , Doença de Crohn/imunologia , Doença de Crohn/patologia , Grupo com Ancestrais do Continente Europeu , Expressão Gênica , Estudos de Associação Genética , Genótipo , Arterite de Células Gigantes/etnologia , Arterite de Células Gigantes/genética , Arterite de Células Gigantes/imunologia , Arterite de Células Gigantes/patologia , Doença de Graves/etnologia , Doença de Graves/genética , Doença de Graves/imunologia , Doença de Graves/patologia , Hispano-Americanos , Humanos , Lúpus Eritematoso Sistêmico/etnologia , Lúpus Eritematoso Sistêmico/imunologia , Lúpus Eritematoso Sistêmico/patologia , Púrpura de Schoenlein-Henoch/etnologia , Púrpura de Schoenlein-Henoch/genética , Púrpura de Schoenlein-Henoch/imunologia , Púrpura de Schoenlein-Henoch/patologia , Escleroderma Sistêmico/etnologia , Escleroderma Sistêmico/genética , Escleroderma Sistêmico/imunologia , Escleroderma Sistêmico/patologia , Uveíte/etnologia , Uveíte/genética , Uveíte/imunologia , Uveíte/patologia
3.
Cardiovasc Pathol ; 33: 55-61, 2018 Mar - Apr.
Artigo em Inglês | MEDLINE | ID: mdl-29414433

RESUMO

Giant cell arteritis (GCA) is the most common vasculitis in adults affecting large and medium-sized arteries. IL-6 and T cell accumulation within the arterial wall contribute to the pathogenesis of GCA, and blockade of IL-6 activity is efficacious in its treatment. We examined the relationship between levels of IL-6 expression and immunological processes that control the expansion of T cells in GCA-positive temporal artery biopsies. CD4 T cells accumulated in clusters within the media and deep intima of all GCA lesions. There was a significant positive correlation between the expression of IL-6 mRNA and increased frequency of proliferating CD4 T cells. The expansion of T cells can be inhibited by T regs but IL-6 expression was not correlated with differences in T reg accumulation. Increased IL-6 levels were also significantly correlated with lower frequencies of CD4 T cells undergoing apoptotic cell death. In conclusion, IL-6 may contribute to the accumulation of CD4 T cells in GCA by supporting their proliferation and survival within the arterial wall through mechanisms that are independent of effects on local T reg expansion.


Assuntos
Linfócitos T CD4-Positivos/química , Proliferação de Células , Arterite de Células Gigantes/genética , Arterite de Células Gigantes/patologia , Interleucina-6/genética , Ativação Linfocitária , Artérias Temporais/química , Artérias Temporais/patologia , Idoso , Idoso de 80 Anos ou mais , Apoptose , Linfócitos T CD4-Positivos/imunologia , Sobrevivência Celular , Feminino , Arterite de Células Gigantes/imunologia , Humanos , Masculino , RNA Mensageiro/genética , Linfócitos T Reguladores/química , Linfócitos T Reguladores/imunologia , Artérias Temporais/imunologia
4.
Rheumatology (Oxford) ; 57(1): 64-72, 2018 01 01.
Artigo em Inglês | MEDLINE | ID: mdl-28968695

RESUMO

Objectives: GCA is characterized by arterial remodelling driven by inflammation. IL-22 is an attractive cytokine which acts at the crosstalk between immune and stromal cells. We hypothesized that IL-22 might be induced in GCA and might be involved in disease pathogenesis. Methods: Patients subjected to temporal artery biopsies (TABs) naïve from therapy were enrolled: 27 biopsy-proven GCA, 8 biopsy-negative GCA, 21 biopsy-negative non-GCA patients. Expression of IL-22 was determined in TABs by immunohystochemistry, in plasma by ELISA, in peripheral blood mononuclear cells by real-time PCR and flow cytometry. Effects of IL-22 on viability and gene expression of primary cultures obtained from TABs were also evaluated. Results: Inflamed TABs from GCA patients showed a higher expression of IL-22 and IL-22 specific receptor subunit (IL-22R1) than non-inflamed TABs. IL-22 was expressed in infiltrating immune cells and spindle shaped cells, IL-22R1 was expressed in endothelial cells. Patients with biopsy-proven GCA showed increased levels of IL-22 in plasma than patients with biopsy-negative GCA, without GCA and healthy subjects. Peripheral blood mononuclear cells from GCA patients expressed higher IL-22 transcript than healthy subjects. After stimulation in vitro with phorbol 12-myristate 13-acetate and ionomycin, the frequencies of Th22 and IL-22+ CD4+ lymphocytes were similar between patients with and without GCA. Treatment with IL-22 of primary cultures obtained from TABs increased cell viability under stress conditions and expression of B-cell activating factor. Conclusion: IL-22 is increased in patients with GCA and affects viability and gene expression of arterial cells, supporting a potential role in disease pathogenesis.


Assuntos
Arterite de Células Gigantes/metabolismo , Interleucinas/metabolismo , Artérias Temporais/metabolismo , Idoso , Idoso de 80 Anos ou mais , Linfócitos T CD4-Positivos , Ionóforos de Cálcio/farmacologia , Carcinógenos/farmacologia , Estudos de Casos e Controles , Ensaio de Imunoadsorção Enzimática , Feminino , Citometria de Fluxo , Arterite de Células Gigantes/genética , Humanos , Imuno-Histoquímica , Técnicas In Vitro , Interleucinas/sangue , Interleucinas/genética , Ionomicina/farmacologia , Leucócitos Mononucleares/efeitos dos fármacos , Leucócitos Mononucleares/metabolismo , Masculino , RNA Mensageiro/metabolismo , Reação em Cadeia da Polimerase em Tempo Real , Acetato de Tetradecanoilforbol/farmacologia
5.
Curr Opin Rheumatol ; 30(1): 4-15, 2018 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-28957963

RESUMO

PURPOSE OF REVIEW: The purpose of this review is to discuss recent observations of epigenetic changes related to the complex pathogenesis of systemic vasculitides and their contribution to the field. RECENT FINDINGS: There have been new observations of epigenetic changes in vasculitis and their potential role in disease pathogenesis in antineutrophil cytoplasmic antibody-associated vasculitis, giant-cell arteritis, Kawasaki disease, Behçet's disease, and IgA vasculitis. Some of this recent work has focused on the efficacy of using DNA methylation and miRNA expression as clinical biomarkers for disease activity and how DNA methylation and histone modifications interact to regulate disease-related gene expression. SUMMARY: DNA methylation, histone modification, and miRNA expression changes are all fruitful ground for biomarker discovery and therapeutic targets in vasculitis. Current knowledge has provided targeted and suggested effects, but in many cases, has relied upon small cohorts, cosmopolitan cell populations, and limited knowledge of functional interactions. Expanding our knowledge of how these epigenetic mechanisms interact in a disease-specific and cell-specific manner will help to better understand the pathogenesis of systemic vasculitis.


Assuntos
Metilação de DNA/genética , Epigênese Genética/genética , Código das Histonas/genética , MicroRNAs/genética , Vasculite Sistêmica/genética , Vasculite Associada a Anticorpo Anticitoplasma de Neutrófilos/genética , Síndrome de Behçet/genética , Biomarcadores , Epigenômica , Regulação da Expressão Gênica/genética , Arterite de Células Gigantes/genética , Humanos , Síndrome de Linfonodos Mucocutâneos/genética , Púrpura de Schoenlein-Henoch/genética
7.
Rev Med Interne ; 38(10): 670-678, 2017 Oct.
Artigo em Francês | MEDLINE | ID: mdl-28800947

RESUMO

Giant cell arteritis (GCA) is the most common vasculitis in adults. GCA is a granulomatous large-vessel vasculitis involving the aorta and its major branches in people>50 years. Glucocorticoids (GC) remain the cornerstone of GCA treatment. Prednisone is usually started at 0.7 or 1mg/kg/day depending on the occurrence of ischemic complications. Then, GC are progressively tapered and stopped after a mean duration of 18 months. GC are very efficient but relapses often occur during their tapering. Moreover, GC-related side effects are very common during this long term GC therapy. Thus, it can be assumed that GC are not the ideal treatment for GCA and that GC-sparing strategies have to be developed. The pathogenesis of GCA is not fully understood but major advances have been achieved in the recent years. If the trigger of GCA, which is suspected to be infectious, is still not identified, mechanisms triggering the granulomatous inflammation of the arterial wall and the progressive vascular remodeling leading to the occurrence of ischemic events have been better and better deciphered. Thanks to these advances in the knowledge of GCA pathogenesis, new therapeutic targets have emerged such as blockade of the activation of T cells or inhibition of the interleukin-6 (IL-6), IL-12/23 or IL-1ß pathways.


Assuntos
Anti-Inflamatórios/uso terapêutico , Drogas em Investigação/uso terapêutico , Arterite de Células Gigantes/tratamento farmacológico , Arterite de Células Gigantes/etiologia , Abatacepte/uso terapêutico , Anticorpos Monoclonais Humanizados/uso terapêutico , Arterite de Células Gigantes/genética , Glucocorticoides/uso terapêutico , Humanos , Terapia de Alvo Molecular/métodos , Terapia de Alvo Molecular/tendências , Ustekinumab/uso terapêutico
8.
Ann Rheum Dis ; 76(9): 1624-1634, 2017 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-28606962

RESUMO

BACKGROUND: Giant-cell arteritis (GCA) is an inflammatory disease of large/medium-sized arteries, frequently involving the temporal arteries (TA). Inflammation-induced vascular remodelling leads to vaso-occlusive events. Circulating endothelin-1 (ET-1) is increased in patients with GCA with ischaemic complications suggesting a role for ET-1 in vascular occlusion beyond its vasoactive function. OBJECTIVE: To investigate whether ET-1 induces a migratory myofibroblastic phenotype in human TA-derived vascular smooth muscle cells (VSMC) leading to intimal hyperplasia and vascular occlusion in GCA. METHODS AND RESULTS: Immunofluorescence/confocal microscopy showed increased ET-1 expression in GCA lesions compared with control arteries. In inflamed arteries, ET-1 was predominantly expressed by infiltrating mononuclear cells whereas ET receptors, particularly ET-1 receptor B (ETBR), were expressed by both mononuclear cells and VSMC. ET-1 increased TA-derived VSMC migration in vitro and α-smooth muscle actin (αSMA) expression and migration from the media to the intima in cultured TA explants. ET-1 promoted VSMC motility by increasing activation of focal adhesion kinase (FAK), a crucial molecule in the turnover of focal adhesions during cell migration. FAK activation resulted in Y397 autophosphorylation creating binding sites for Src kinases and the p85 subunit of PI3kinases which, upon ET-1 exposure, colocalised with FAK at the focal adhesions of migrating VSMC. Accordingly, FAK or PI3K inhibition abrogated ET-1-induced migration in vitro. Consistently, ET-1 receptor A and ETBR antagonists reduced αSMA expression and delayed VSMC outgrowth from cultured GCA-involved artery explants. CONCLUSIONS: ET-1 is upregulated in GCA lesions and, by promoting VSMC migration towards the intimal layer, may contribute to intimal hyperplasia and vascular occlusion in GCA.


Assuntos
Movimento Celular/genética , Endotelina-1/genética , Arterite de Células Gigantes/genética , Músculo Liso Vascular/metabolismo , Miócitos de Músculo Liso/metabolismo , Remodelação Vascular/genética , Actinas/efeitos dos fármacos , Actinas/genética , Actinas/metabolismo , Idoso , Western Blotting , Estudos de Casos e Controles , Movimento Celular/efeitos dos fármacos , Antagonistas dos Receptores de Endotelina/farmacologia , Endotelina-1/metabolismo , Endotelina-1/farmacologia , Feminino , Imunofluorescência , Quinase 1 de Adesão Focal/antagonistas & inibidores , Quinase 1 de Adesão Focal/metabolismo , Arterite de Células Gigantes/metabolismo , Arterite de Células Gigantes/patologia , Humanos , Hiperplasia , Técnicas In Vitro , Leucócitos Mononucleares , Masculino , Microscopia Confocal , Músculo Liso Vascular/citologia , Miócitos de Músculo Liso/citologia , Miócitos de Músculo Liso/efeitos dos fármacos , Fosfatidilinositol 3-Quinases/antagonistas & inibidores , Fosfatidilinositol 3-Quinases/metabolismo , Fosforilação , Receptor de Endotelina A/efeitos dos fármacos , Receptor de Endotelina A/metabolismo , Receptor de Endotelina B/metabolismo , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Túnica Íntima/patologia , Remodelação Vascular/efeitos dos fármacos , Quinases da Família src/metabolismo
9.
Autoimmun Rev ; 16(8): 833-844, 2017 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-28564617

RESUMO

Giant cell arteritis (GCA) is a granulomatous vasculitis affecting large arteries, especially the aorta and the extracranial branches of the external carotid artery. Its exact pathogenesis is not fully understood but major progress has been made in recent years, leading to new therapeutic targets like inhibition of the interleukin-6 pathway or the modulation of immune checkpoints. The cause of GCA has not been clearly identified but it is thought that GCA occurs on a genetic background and is triggered by unknown environmental factors that could activate and lead to the maturation of dendritic cells localized in the adventitia of normal arteries. These activated dendritic cells then produce chemokines which trigger the recruitment of CD4+ T cells, which in turn become activated, proliferate and polarize into Th1 and Th17 cells, which produce IFN-γ and IL-17, respectively. Exposed to IFN-γ, endothelial cells and vascular smooth muscle cells produce chemokines leading to the recruitment of further Th1 cells, CD8+ T cells and monocytes. The latter differentiate into macrophages, which, when persistently exposed to IFN-γ, form giant cells, the histological hallmark of GCA. With the contribution of vascular smooth muscle cells, immune cells then trigger the destruction and remodeling of the arterial wall, thus leading to the formation of a neo-intima resulting in progressive occlusion of the arterial lumen, which is responsible for the ischemic symptoms of GCA. In this paper, we review recent progress in our understanding of GCA pathogenesis in the fields of genetics, epigenetics, infections, immunology and vascular remodeling.


Assuntos
Arterite de Células Gigantes/etiologia , Animais , Linfócitos B/imunologia , Epigênese Genética , Arterite de Células Gigantes/genética , Arterite de Células Gigantes/imunologia , Humanos , Infecção/complicações , Interleucina-6/imunologia , Neutrófilos/imunologia , Receptores Notch/imunologia
10.
Rev Med Interne ; 38(10): 663-669, 2017 Oct.
Artigo em Francês | MEDLINE | ID: mdl-28457683

RESUMO

Knowledge of the natural history and epidemiology of giant cell arteritis (GCA) is growing. With the recent conceptual change, GCA is no longer considered a disease with mandatory cranial symptoms but, rather, a larger disease spectrum also including idiopathic aortitis in people older than 50 and polymyalgia rheumatica with large-vessel involvement. The incidence peak between age 70 and 80 years, greater frequency in females and greater occurrence in Nordic countries are well-established epidemiological characteristics. Conversely, the notion that the incidence of GCA is increasing is challenged by several recent population-based studies suggesting a trend reversal for about 15 to 20 years. The known link with the allele HLA-DRB1*04 was confirmed by a genome-wide association study that also found associations with two other genetic polymorphisms. Recent studies indicating a link with varicella zoster virus infection have invigorated the hypothesis of an infectious cause for GCA. Smoking is the most solidly recognized environmental risk factor, but other traditional cardiovascular risk factors do not seem to predispose to GCA. Evidence is mounting that overall mortality in GCA patients is at best slightly higher than expected in relation to general population mortality data, but GCA is associated with an increase in morbidity and mortality specifically related to aortic aneurysm or other cardiovascular causes. Further studies are needed to integrate the current knowledge into a single etiological model.


Assuntos
Arterite de Células Gigantes/epidemiologia , Arterite de Células Gigantes/patologia , Progressão da Doença , Predisposição Genética para Doença , Arterite de Células Gigantes/genética , Humanos , Incidência , Prognóstico , Fatores de Risco
11.
Sci Rep ; 7: 43953, 2017 03 09.
Artigo em Inglês | MEDLINE | ID: mdl-28277489

RESUMO

Giant cell arteritis (GCA) and Takayasu's arteritis (TAK) are major forms of large-vessel vasculitis (LVV) that share clinical features. To evaluate their genetic similarities, we analysed Immunochip genotyping data from 1,434 LVV patients and 3,814 unaffected controls. Genetic pleiotropy was also estimated. The HLA region harboured the main disease-specific associations. GCA was mostly associated with class II genes (HLA-DRB1/HLA-DQA1) whereas TAK was mostly associated with class I genes (HLA-B/MICA). Both the statistical significance and effect size of the HLA signals were considerably reduced in the cross-disease meta-analysis in comparison with the analysis of GCA and TAK separately. Consequently, no significant genetic correlation between these two diseases was observed when HLA variants were tested. Outside the HLA region, only one polymorphism located nearby the IL12B gene surpassed the study-wide significance threshold in the meta-analysis of the discovery datasets (rs755374, P = 7.54E-07; ORGCA = 1.19, ORTAK = 1.50). This marker was confirmed as novel GCA risk factor using four additional cohorts (PGCA = 5.52E-04, ORGCA = 1.16). Taken together, our results provide evidence of strong genetic differences between GCA and TAK in the HLA. Outside this region, common susceptibility factors were suggested, especially within the IL12B locus.


Assuntos
Predisposição Genética para Doença , Arterite de Células Gigantes/genética , Antígenos HLA/genética , Arterite de Takayasu/genética , Feminino , Genótipo , Humanos , Masculino , Polimorfismo Genético
12.
Am J Hum Genet ; 100(1): 64-74, 2017 Jan 05.
Artigo em Inglês | MEDLINE | ID: mdl-28041642

RESUMO

Giant cell arteritis (GCA) is the most common form of vasculitis in individuals older than 50 years in Western countries. To shed light onto the genetic background influencing susceptibility for GCA, we performed a genome-wide association screening in a well-powered study cohort. After imputation, 1,844,133 genetic variants were analyzed in 2,134 case subjects and 9,125 unaffected individuals from ten independent populations of European ancestry. Our data confirmed HLA class II as the strongest associated region (independent signals: rs9268905, p = 1.94 × 10-54, per-allele OR = 1.79; and rs9275592, p = 1.14 × 10-40, OR = 2.08). Additionally, PLG and P4HA2 were identified as GCA risk genes at the genome-wide level of significance (rs4252134, p = 1.23 × 10-10, OR = 1.28; and rs128738, p = 4.60 × 10-9, OR = 1.32, respectively). Interestingly, we observed that the association peaks overlapped with different regulatory elements related to cell types and tissues involved in the pathophysiology of GCA. PLG and P4HA2 are involved in vascular remodelling and angiogenesis, suggesting a high relevance of these processes for the pathogenic mechanisms underlying this type of vasculitis.


Assuntos
Alelos , Predisposição Genética para Doença/genética , Variação Genética , Estudo de Associação Genômica Ampla , Arterite de Células Gigantes/genética , Plasminogênio/genética , Prolil Hidroxilases/genética , Idoso , Idoso de 80 Anos ou mais , Estudos de Coortes , Europa (Continente)/etnologia , Feminino , Humanos , Masculino , Neovascularização Fisiológica , Polimorfismo de Nucleotídeo Único/genética , Risco
13.
Proc Natl Acad Sci U S A ; 114(6): E970-E979, 2017 02 07.
Artigo em Inglês | MEDLINE | ID: mdl-28115719

RESUMO

Giant cell arteritis (GCA) causes autoimmune inflammation of the aorta and its large branches, resulting in aortic arch syndrome, blindness, and stroke. CD4+ T cells and macrophages form organized granulomatous lesions in the walls of affected arteries, destroy the tunica media, and induce ischemic organ damage through rapid intimal hyperplasia and luminal occlusion. Pathogenic mechanisms remain insufficiently understood; specifically, it is unknown whether the unopposed activation of the immune system is because of deficiency of immunoinhibitory checkpoints. Transcriptome analysis of GCA-affected temporal arteries revealed low expression of the coinhibitory ligand programmed death ligand-1 (PD-L1) concurrent with enrichment of the programmed death-1 (PD-1) receptor. Tissue-residing and ex vivo-generated dendritic cells (DC) from GCA patients were PD-L1lo, whereas the majority of vasculitic T cells expressed PD-1, suggesting inefficiency of the immunoprotective PD-1/PD-L1 immune checkpoint. DC-PD-L1 expression correlated inversely with clinical disease activity. In human artery-SCID chimeras, PD-1 blockade exacerbated vascular inflammation, enriched for PD-1+ effector T cells, and amplified tissue production of multiple T-cell effector cytokines, including IFN-γ, IL-17, and IL-21. Arteries infiltrated by PD-1+ effector T cells developed microvascular neoangiogenesis as well as hyperplasia of the intimal layer, implicating T cells in the maladaptive behavior of vessel wall endogenous cells. Thus, in GCA, a breakdown of the tissue-protective PD1/PD-L1 checkpoint unleashes vasculitic immunity and regulates the pathogenic remodeling of the inflamed arterial wall.


Assuntos
Artérias/metabolismo , Arterite de Células Gigantes/genética , Inflamação/genética , Linfócitos T/metabolismo , Idoso , Idoso de 80 Anos ou mais , Animais , Artérias/patologia , Antígeno B7-H1/genética , Antígeno B7-H1/metabolismo , Células Cultivadas , Citocinas/genética , Citocinas/metabolismo , Feminino , Perfilação da Expressão Gênica/métodos , Arterite de Células Gigantes/metabolismo , Humanos , Inflamação/metabolismo , Masculino , Camundongos Endogâmicos NOD , Camundongos Knockout , Camundongos SCID , Pessoa de Meia-Idade , Receptor de Morte Celular Programada 1/genética , Receptor de Morte Celular Programada 1/metabolismo
17.
Ann Rheum Dis ; 75(8): 1527-33, 2016 08.
Artigo em Inglês | MEDLINE | ID: mdl-26342092

RESUMO

OBJECTIVES: There is increasing evidence that microRNAs (miRNAs) are deregulated in autoimmune and cardiovascular diseases. The present study aimed to identify if miRNAs are deregulated in giant cell arteritis (GCA), a vasculitis affecting large-sized and medium-sized arteries, and to determine if miRNA levels might allow to discriminate between patients with GCA and those without. METHODS: 58 patients who had temporal artery biopsy (TAB) for suspected GCA were included in the study and divided into three groups: patients with TAB-positive GCA showing a transmural inflammation (n=27), patients with TAB-negative GCA (n=8) and TAB-negative non-GCA patients with a final diagnosis different from GCA (n=23). To identify candidate miRNAs deregulated in GCA, we profiled the expression of 1209 miRNAs in inflamed TABs and normal TABs. Selected miRNAs were then validated by real-time PCRs and in situ hybridisation (ISH). RESULTS: MiR-146b-5p, -146a, -155, -150, -21 and -299-5p were significantly more expressed in inflamed TABs from patients with GCA. miRNAs were mainly deregulated at the tissue level because peripheral blood mononuclear cells and polymorphonuclear cells from the three groups of patients and age-matched healthy controls had similar levels of miRNAs. ISH showed that miR-21 was mainly expressed by cells in the medial and intimal layers of inflamed TABs. Patients with TAB-negative GCA had a miRNA profile similar to TAB-negative non-GCA patients. CONCLUSIONS: MiR-146b-5p, -146a, -21, -150, -155, -299-5p are overexpressed in the presence of inflammation in TABs from patients with GCA.


Assuntos
Arterite de Células Gigantes/genética , MicroRNAs/genética , Artérias Temporais/patologia , Remodelação Vascular/genética , Idoso , Idoso de 80 Anos ou mais , Biomarcadores/metabolismo , Biópsia , Estudos de Casos e Controles , Feminino , Regulação da Expressão Gênica/efeitos dos fármacos , Arterite de Células Gigantes/diagnóstico , Arterite de Células Gigantes/patologia , Glucocorticoides/farmacologia , Humanos , Hibridização In Situ , Masculino , MicroRNAs/metabolismo , Artérias Temporais/metabolismo , Transcriptoma
18.
Int J Surg Pathol ; 24(1): 78-84, 2016 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-26353853

RESUMO

Giant cell arteritis (GCA) is an immunologically mediated vasculitis of large and medium-sized vessels, typically affecting the cranial arteries and usually occurring in the elderly. GCA of the female genital tract is extremely rare with only 31 cases reported in the English literature. An 83-year-old white female with postmenopausal vaginal bleeding revealed an endometrial polyp on pelvic ultrasonography following which polypectomy and subsequently hysterectomy with bilateral salpingo-oophorectomy was done. Microscopy revealed a well-differentiated endometrioid adenocarcinoma. Interestingly, classic GCA involving numerous small to medium-sized arteries of the cervix, myometrium, bilateral fallopian tubes, and ovaries was also identified. Hematologic evaluation revealed marginal zone lymphoma with an exceptionally rare 20q deletion. Bilateral temporal artery biopsy was done subsequently, which exhibited GCA on microscopy. Corticosteroid was started that improved her polymyalgia rheumatica symptoms. The patient is on follow-up for 3 years and is doing well. To our knowledge, this is the first case of GCA of the female genital tract associated with a lymphoma and the second case of marginal zone lymphoma with the novel 20q deletion.


Assuntos
Deleção Cromossômica , Doenças dos Genitais Femininos/patologia , Arterite de Células Gigantes/patologia , Linfoma de Zona Marginal Tipo Células B/patologia , Idoso de 80 Anos ou mais , Cromossomos Humanos Par 20 , Feminino , Doenças dos Genitais Femininos/complicações , Doenças dos Genitais Femininos/genética , Arterite de Células Gigantes/complicações , Arterite de Células Gigantes/genética , Humanos , Linfoma de Zona Marginal Tipo Células B/complicações , Linfoma de Zona Marginal Tipo Células B/genética
19.
J Hum Genet ; 61(1): 27-32, 2016 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-26178430

RESUMO

Takayasu arteritis (TAK) is an immune-mediated vasculitis affecting large arteries first reported in 1908 from Japan. Case reports of familial onset of TAK from Japan and other countries indicated genetic contribution to TAK onset beyond ethnicity. Genetic studies of TAK have been performed mainly addressing the human leukocyte antigen (HLA) locus. HLA genetic studies of TAK that have previously been reported are reviewed in this manuscript. HLA-B*52:01 is associated with TAK beyond population. Many of the associations other than HLA-B*52:01 can be explained by a haplotype with HLA-B*52:01. HLA-B*67:01 is a novel susceptibility HLA-B allele to TAK confirmed in the Japanese population. Further independent associations are suggested in the HLA locus. Involvement of the 171st and 67th amino acid residues with TAK onset has been indicated. The 67th amino acid may explain the difference in susceptibility effects to TAK and Behçet's disease between HLA-B*52:01 and *51:01. HLA-B*52:01 is associated not only with TAK susceptibility but also with clinical phenotypes. Recent genome-wide association studies of TAK revealed multiple non-HLA susceptibility genes. In particular, the IL12B region seems to have a central role in TAK onset and its progression. Whether TAK and giant cell arteritis (GCA), the other vasculitis affecting large arteries, are the same disease is an interesting question to address in spite of different clinical manifestations between the two diseases. GCA is associated with HLA-DR4, which is not associated with TAK. GCA is not associated with HLA-Bw52. These two diseases seem not to share non-HLA susceptibility loci based on the recent genetic studies.


Assuntos
Antígenos HLA/genética , Arterite de Takayasu/genética , Predisposição Genética para Doença , Arterite de Células Gigantes/genética , Humanos
20.
Ann Rheum Dis ; 75(6): 1196-202, 2016 06.
Artigo em Inglês | MEDLINE | ID: mdl-26038090

RESUMO

OBJECTIVE: To investigate the inflammatory response in giant cell arteritis (GCA) by characterising the DNA methylation pattern within the temporal artery microenvironment. METHODS: Twelve patients with non-equivocal histological evidence for GCA and 12 age-matched, sex-matched and ethnicity-matched controls with normal biopsies were studied. DNA was extracted from the affected portions of temporal artery tissue in patients with GCA and from histologically confirmed normal arteries in controls. Genome-wide DNA methylation status was evaluated using the Illumina Infinium HumanMethylation450 BeadChip Array. Differentially methylated loci between affected and unaffected arterial tissues were identified, and subsequent bioinformatic analysis performed. Immunohistochemistry was used to examine tissue expression patterns in temporal artery biopsies. RESULTS: We identified 1555 hypomethylated CG sites (853 genes) in affected temporal artery tissue from patients with GCA compared with normal controls. Gene ontology enrichment analysis of hypomethylated genes revealed significant representation in T cell activation and differentiation pathways, including both TH1 and TH17 signatures. Our DNA methylation data suggest a role for increased activity of the calcineurin/nuclear factor of activated T cells (NFAT) signalling pathway in GCA, confirmed by immunohistochemistry showing increased expression and nuclear localisation of NFAT1. NFAT signalling downstream targets such as interleukin (IL)-21/IL-21R and CD40L were overexpressed in GCA-affected arteries. Further, proinflammatory genes including TNF, LTA, LTB, CCR7, RUNX3, CD6, CD40LG, IL2, IL6, NLRP1, IL1B, IL18, IL21, IL23R and IFNG were hypomethylated in the cellular milieu of GCA arteries. CONCLUSIONS: We characterised the inflammatory response in GCA-affected arteries using 'epigenetic immunophenotyping' and identified molecules and pathways relevant to disease pathogenesis in GCA.


Assuntos
Metilação de DNA , Arterite de Células Gigantes/genética , Artérias Temporais/metabolismo , Idoso , Idoso de 80 Anos ou mais , Biópsia , Estudos de Casos e Controles , Citocinas/metabolismo , Feminino , Regulação da Expressão Gênica/imunologia , Arterite de Células Gigantes/imunologia , Arterite de Células Gigantes/patologia , Humanos , Imunofenotipagem , Mediadores da Inflamação/metabolismo , Ativação Linfocitária/genética , Ativação Linfocitária/imunologia , Masculino , Linfócitos T/imunologia , Artérias Temporais/imunologia , Artérias Temporais/patologia
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