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1.
Nat Commun ; 10(1): 4955, 2019 Oct 31.
Artigo em Inglês | MEDLINE | ID: mdl-31672989

RESUMO

Systemic sclerosis (SSc) is an autoimmune disease that shows one of the highest mortality rates among rheumatic diseases. We perform a large genome-wide association study (GWAS), and meta-analysis with previous GWASs, in 26,679 individuals and identify 27 independent genome-wide associated signals, including 13 new risk loci. The novel associations nearly double the number of genome-wide hits reported for SSc thus far. We define 95% credible sets of less than 5 likely causal variants in 12 loci. Additionally, we identify specific SSc subtype-associated signals. Functional analysis of high-priority variants shows the potential function of SSc signals, with the identification of 43 robust target genes through HiChIP. Our results point towards molecular pathways potentially involved in vasculopathy and fibrosis, two main hallmarks in SSc, and highlight the spectrum of critical cell types for the disease. This work supports a better understanding of the genetic basis of SSc and provides directions for future functional experiments.

2.
J Vis Exp ; (146)2019 04 30.
Artigo em Inglês | MEDLINE | ID: mdl-31107440

RESUMO

Pulmonary fibrosis is a hallmark of several human lung diseases with a different etiology. Since current therapies are rather limited, mouse models continue to be an essential tool for developing new antifibrotic strategies. Here we provide an effective method to investigate in vivo antifibrotic activity of human mesenchymal stromal cells obtained from whole umbilical cord (hUC-MSC) in attenuating bleomycin-induced lung injury. C57BL/6 mice receive a single endotracheal injection of bleomycin (1.5 U/kg body weight) followed by a double infusion of hUC-MSC (2.5 x 105) into the tail vein, 24 h and 7 days after the bleomycin administration. Upon sacrifice at days 8, 14, or 21, inflammatory and fibrotic changes, collagen content, and hUC-MSC presence in explanted lung tissue are analyzed. The injection of bleomycin into the mouse trachea allows the direct targeting of the lungs, leading to extensive pulmonary inflammation and fibrosis. The systemic administration of a double dose of hUC-MSC results in the early blunting of the bleomycin-induced lung injury. Intravenously infused hUC-MSC are transiently engrafted into the mouse lungs, where they exert their anti-inflammatory and antifibrotic activity. In conclusion, this protocol has been successfully applied for the preclinical testing of hUC-MSC in an experimental mouse model of human pulmonary fibrosis. However, this technique can be easily extended both to study the effect of different endotracheally administered substances on the pathophysiology of the lungs and to validate new anti-inflammatory and antifibrotic systemic therapies.

3.
Autoimmun Rev ; 18(1): 93-106, 2019 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-30408582

RESUMO

Autoimmune rheumatic diseases are characterised by an abnormal immune system response, complement activation, cytokines dysregulation and inflammation. In last years, despite many progresses in managing these patients, it has been shown that clinical remission is reached in less than 50% of patients and a personalised and tailored therapeutic approach is still lacking resulting in a significant gap between guidelines and real-world practice. In this context, the need for biomarkers facilitating early diagnosis and profiling those individuals at the highest risk for a poor outcome has become of crucial interest. A biomarker generally refers to a measured characteristic which may be used as an indicator of some biological state or condition. Three different types of medical biomarkers has been suggested: i. mechanistic markers; ii. clinical disease markers; iii. therapeutic markers. A combination of biomarkers from these different groups could be used for an ideal more accurate diagnosis and treatment. However, although a growing body of evidence is focused on improving biomarkers, a significant amount of this information is not integrated on standard clinical care. The overarching aim of this work was to clarify the meaning of specific biomarkers during autoimmune diseases; their possible role in confirming diagnosis, predicting outcome and suggesting specific treatments.


Assuntos
Doenças Autoimunes/imunologia , Biomarcadores/metabolismo , Prática Clínica Baseada em Evidências/métodos , Doenças Reumáticas/imunologia , Diagnóstico Precoce , Guias como Assunto , Humanos
4.
PLoS One ; 13(6): e0196048, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29856737

RESUMO

Lung fibrosis is a severe condition resulting from several interstial lung diseases (ILD) with different etiologies. Current therapy of ILD, especially those associated with connective tissue diseases, is rather limited and new anti-fibrotic strategies are needed. In this study, we investigated the anti-fibrotic activity in vivo of human mesenchymal stromal cells obtained from whole umbilical cord (hUC-MSC). Adult immunocompetent C57BL/6 mice (n. = 8 for each experimental condition) were injected intravenously with hUC-MSC (n. = 2.5 × 105) twice, 24 hours and 7 days after endotracheal injection of bleomycin. Upon sacrifice at days 8, 14, 21, collagen content, inflammatory cytokine profile, and hUC-MSC presence in explanted lung tissue were analyzed. Systemic administration of a double dose of hUC-MSC significantly reduced bleomycin-induced lung injury (inflammation and fibrosis) in mice through a selective inhibition of the IL6-IL10-TGFß axis involving lung M2 macrophages. Only few hUC-MSC were detected from explanted lungs, suggesting a "hit and run" mechanism of action of this cellular therapy. Our data indicate that hUC-MSC possess strong in vivo anti-fibrotic activity in a mouse model resembling an immunocompetent human subject affected by inflammatory ILD, providing proof of concept for ad-hoc clinical trials.


Assuntos
Sangue Fetal/metabolismo , Transplante de Células-Tronco Mesenquimais , Células-Tronco Mesenquimais/metabolismo , Fibrose Pulmonar/terapia , Animais , Citocinas/metabolismo , Modelos Animais de Doenças , Feminino , Xenoenxertos , Humanos , Pulmão/metabolismo , Pulmão/patologia , Macrófagos/metabolismo , Macrófagos/patologia , Células-Tronco Mesenquimais/patologia , Camundongos , Fibrose Pulmonar/metabolismo , Fibrose Pulmonar/patologia
5.
BMJ Case Rep ; 20182018 May 18.
Artigo em Inglês | MEDLINE | ID: mdl-29776943

RESUMO

We present the case of a 44-year-old woman affected by systemic sclerosis (SSc) who was admitted to our department for abdominal pain, nausea, vomiting and fever. Imaging studies showed the presence of a thickened colon wall involving the descending colon and the sigma, while a subsequent endoscopy revealed multiple serpiginous ulcers covered with fibrin and exudates. Under the hypothesis of drug-induced colitis, mycophenolate mofetil (MMF), which she was taking for SSc-related interstitial lung disease (ILD), was readily suspended, with a rapid recovery without further treatment. A follow-up colonoscopy showed the complete resolution of the ulcers. This is the first case of MMF-induced colitis in a patient being treated for SSc-ILD.


Assuntos
Colite/induzido quimicamente , Doenças Pulmonares Intersticiais/tratamento farmacológico , Ácido Micofenólico/efeitos adversos , Escleroderma Sistêmico/complicações , Adulto , Feminino , Humanos , Doenças Pulmonares Intersticiais/etiologia
6.
Free Radic Biol Med ; 125: 90-97, 2018 09.
Artigo em Inglês | MEDLINE | ID: mdl-29694853

RESUMO

Systemic sclerosis (SSc) is an autoimmune disease characterized by damage of small vessels, immune abnormalities and exaggerated production of extracellular matrix. The etiology of the disease is unknown and the pathogenesis ill defined. However, there is consistent evidence that oxidative stress contributes to the establishment and progression of the disease. This review examines the most relevant research regarding the involvement of free radicals and of nicotinamide adenine dinucleotide phosphate oxidases (NADPH oxidases; NOX) in the pathogenesis of systemic sclerosis.


Assuntos
Fibrose/complicações , NADPH Oxidases/metabolismo , Estresse Oxidativo , Escleroderma Sistêmico/etiologia , Animais , Humanos , Oxirredução , Espécies Reativas de Oxigênio/metabolismo , Escleroderma Sistêmico/metabolismo , Escleroderma Sistêmico/patologia
7.
Onco Targets Ther ; 11: 833-842, 2018.
Artigo em Inglês | MEDLINE | ID: mdl-29497315

RESUMO

Lartruvo® (olaratumab) is a fully human immunoglobulin G subclass 1 (IgG1) monoclonal antibody that inhibits platelet-derived growth factor receptor alpha (PDGFRα). The antitumor activity of olaratumab has been tested in vitro and in vivo, and inhibition of tumor growth has been observed in cancer cell lines, including glioblastoma and leiomyosarcoma cells. It represents the first-in-class antibody to be approved by regulatory authorities for the treatment of advanced soft-tissue sarcomas (STSs) in combination with doxorubicin, based on the results of the Phase Ib/II trial by Tap et al. The median progression-free survival (PFS), which was the primary end point of the study, was improved for patients treated with olaratumab plus doxorubicin compared to those treated with doxorubicin monotherapy (6.6 vs 4.1 months, respectively; HR 0.672, 95% CI 0.442-1.021, p=0.0615). Moreover, final analysis of overall survival (OS) showed a median OS of 26.5 months with olaratumab plus doxorubicin vs 14.7 months with doxorubicin, with a gain of 11.8 months (HR 0.46, 95% CI 0.30-0.71, p=0.0003). In October 2016, olaratumab was admitted in the Accelerated Approval Program by the US Food and Drug Administration (FDA) for use in combination with doxorubicin for the treatment of adult patients with STSs. In November 2016, the European Medicines Agency (EMA) granted conditional approval for olaratumab in the same indication under its Accelerated Assessment Program. A double-blind, placebo-controlled, randomized Phase III study (ANNOUNCE trial, NCT02451943) is being performed in order to confirm the survival advantage of olaratumab and to provide definitive drug confirmation by regulators. The study is ongoing, but enrollment is closed. The purpose of this review was to evaluate the rationale of olaratumab in the treatment of advanced STSs and its emerging role in clinical practice.

8.
Immunol Lett ; 195: 83-87, 2018 03.
Artigo em Inglês | MEDLINE | ID: mdl-29032187

RESUMO

Systemic sclerosis (SSc) is characterized by microangiopathy, excessive fibrosis, and the presence of circulating autoantibodies to several cellular and extracellular components. The role of autoimmunity in generating the clinical and pathologic phenotypes in SSc has been long debated and is still matter of controversy. Distinct specificities of antinuclear antibodies (ANAs) are selectively detected in SSc patients and are associated with unique disease manifestations, but do not have a proven pathogenic role. A new group of autoantibodies reactive with cell surface receptors have been identified in SSc patients. They have been shown to directly activate pathways that may contribute to tissue and vascular damage. As such, they are proposed to have a role as agonistic autoantibodies in SSc. According to Koch's third postulate, the autoantibodies in question should cause disease when introduced into a healthy subject. Therefore, our review will focus on those autoantibodies for which agonistic activity has already been demonstrated not only in vitro, but, at least partly, also in vivo. These include the antibodies anti-endothelial cells (AECA), anti-Platelet-Derived Growth Factor Receptor (PDGFR), anti-Angiotensin II type 1 receptor (AT1R) and anti-endothelin-1 type A receptor (ETaR). In this review, we will discuss also a class of antagonistic autoantibodies, the anti-muscarinic-3 receptor (M3R) antibodies, since they seem to fulfill the aforementioned requirements.


Assuntos
Autoanticorpos/metabolismo , Vasos Sanguíneos/patologia , Pulmão/patologia , Receptor Muscarínico M3/imunologia , Escleroderma Sistêmico/imunologia , Animais , Fibrose , Humanos , Receptor Tipo 1 de Angiotensina/imunologia , Receptor de Endotelina A/imunologia , Receptor beta de Fator de Crescimento Derivado de Plaquetas/imunologia , Transdução de Sinais
9.
Curr Pharm Biotechnol ; 18(12): 1008-1016, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-29278213

RESUMO

BACKGROUND: The use of biologic agents in systemic immune-mediated diseases has dramatically increased in recent years, replacing conventional immunosuppressive strategies that are characterized by unspecific mechanisms of action and burdened with serious adverse effects. Biologic drugs have selective action towards specific targets, with considerable steroid-sparing effect. They are used nowadays to induce remission or treat specific organ involvements in systemic autoimmune diseases. CONCLUSION: In this review, we will discuss the scientific evidence supporting the use of biologics in these diseases, with a particular emphasis on their efficacy and safety profile compared to the conventional drugs.


Assuntos
Anticorpos Monoclonais/uso terapêutico , Doenças Autoimunes/tratamento farmacológico , Produtos Biológicos/uso terapêutico , Terapia Biológica/métodos , Fator de Necrose Tumoral alfa/antagonistas & inibidores , Anticorpos Monoclonais/administração & dosagem , Anticorpos Monoclonais/efeitos adversos , Doenças Autoimunes/imunologia , Produtos Biológicos/administração & dosagem , Produtos Biológicos/efeitos adversos , Ensaios Clínicos como Assunto , Humanos , Resultado do Tratamento
12.
J Neuroinflammation ; 14(1): 88, 2017 04 21.
Artigo em Inglês | MEDLINE | ID: mdl-28427412

RESUMO

BACKGROUND: The majority of Parkinson's disease (PD) cases are sporadic and idiopathic suggesting that this neurodegenerative disorder is the result of both environmental and genetic factors. Stress and neuroinflammation are among the factors being investigated for their possible contributions to PD. Experiments in rodents showed that severe chronic stress can reduce the number of dopaminergic neurons in the substantia nigra pars compacta (SNc); the same cells that are lost in PD. These actions are at least in part mediated by increased oxidative stress. Here, we tested the hypothesis that the interleukin-13 receptor alpha 1 (IL-13Rα1), a cytokine receptor whose activation increases the vulnerability of dopaminergic neurons to oxidative damage, participates in the stress-dependent damage of these neurons. METHODS: Mice were subject to daily sessions of 8 h (acute) stress for 16 weeks (5 days a week), a procedure previously showed to induce loss of dopaminergic neurons in the SNc. The source and the kinetics of interleukin-13 (IL-13), the endogenous ligand of IL-13Rα1, were evaluated 0, 1, 3, 6, and 8 h and at 16 weeks of stress. Identification of IL-13 producing cell-type was performed by immunofluorescent and by in situ hybridization experiments. Markers of oxidative stress, microglia activation, and the number of dopaminergic neurons in IL-13Rα1 knock-out animals (Il13ra1 Y/ - ) and their wild-type littermates (Il13ra1 Y/+ ) were evaluated at 16 weeks of stress and at 20 weeks, following a 4 week non-stressed period and compared to non-stressed mice. RESULTS: IL-13 was expressed in microglial cells within the SN and in a fraction of the tyrosine hydroxylase-positive neurons in the SNc. IL-13 levels were elevated during daily stress and peaked at 6 h. 16 weeks of chronic restraint stress significantly reduced the number of SNc dopaminergic neurons in Il13ra1 Y/+ mice. Neuronal loss at 16 weeks was significantly lower in Il13ra1 Y/- mice. However, the loss of dopaminergic neurons measured at 20 weeks, after 4 weeks of non-stress following the 16 weeks of stress, was similar in Il13ra1 Y/+ and Il13ra1 Y/- mice. CONCLUSIONS: IL-13, a cytokine previously demonstrated to increase the susceptibility of SNc dopaminergic neurons to oxidative stress, is elevated in the SN by restraint stress. Lack of IL-13Rα1 did not prevent nor halted but delayed neuronal loss in the mouse model of chronic restraint stress. IL-13/IL-13Rα1 may represent a target to reduce the rate of DA neuronal loss that can occur during severe chronic restraint stress.


Assuntos
Neurônios Dopaminérgicos/metabolismo , Subunidade alfa1 de Receptor de Interleucina-13/deficiência , Estresse Oxidativo/fisiologia , Estresse Psicológico/metabolismo , Animais , Contagem de Células/métodos , Neurônios Dopaminérgicos/patologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Estresse Psicológico/patologia , Substância Negra/metabolismo , Substância Negra/patologia
13.
Anal Biochem ; 528: 26-33, 2017 Jul 01.
Artigo em Inglês | MEDLINE | ID: mdl-28450104

RESUMO

Systemic sclerosis (SSc) is a chronic autoimmune disease of the connective tissue. The variety and clinical relevance of autoantibodies in SSc patients have been extensively studied, eventually identifying agonistic autoantibodies targeting the platelet-derived growth factor receptor alpha (PDGFRα), and representing potential biomarkers for SSc. We used a resonant mirror biosensor to characterize the binding between surface-blocked PDGFRα and PDGFRα-specific recombinant human monoclonal autoantibodies (mAbs) produced by SSc B cells, and detect/quantify serum autoimmune IgG with binding characteristics similar to the mAbs. Kinetic data showed a conformation-specific, high-affinity interaction between PDGFRα and mAbs, with equilibrium dissociation constants in the low-to-high nanomolar range. When applied to total serum IgG, the assay discriminated between SSc patients and healthy controls, and allowed the rapid quantification of autoimmune IgG in the sera of SSc patients, with anti-PDGFRα IgG falling in the range 3.20-4.67 neq/L of SSc autoantibodies. The test was validated by comparison to direct and competitive anti-PDGFRα antibody ELISA. This biosensor assay showed higher sensibility with respect to ELISA, and other major advantages such as the specificity, rapidity, and reusability of the capturing surface, thus representing a feasible approach for the detection and quantification of high affinity, likely agonistic, SSc-specific anti-PDGFRα autoantibodies.


Assuntos
Autoanticorpos/sangue , Autoanticorpos/imunologia , Biomarcadores/sangue , Técnicas Biossensoriais/métodos , Receptor alfa de Fator de Crescimento Derivado de Plaquetas/imunologia , Escleroderma Sistêmico/imunologia , Adulto , Idoso , Linfócitos B/imunologia , Feminino , Humanos , Limite de Detecção , Masculino , Pessoa de Meia-Idade , Escleroderma Sistêmico/diagnóstico , Sensibilidade e Especificidade
14.
Front Immunol ; 8: 75, 2017.
Artigo em Inglês | MEDLINE | ID: mdl-28228756

RESUMO

One of the earliest events in the pathogenesis of systemic sclerosis (SSc) is microvasculature damage with intimal hyperplasia and accumulation of cells expressing PDGF receptor. Stimulatory autoantibodies targeting PDGF receptor have been detected in SSc patients and demonstrated to induce fibrosis in vivo and convert in vitro normal fibroblasts into SSc-like cells. Since there is no evidence of the role of anti-PDGF receptor autoantibodies in the pathogenesis of SSc vascular lesions, we investigated the biologic effect of agonistic anti-PDGF receptor autoantibodies from SSc patients on human pulmonary artery smooth muscle cells and the signaling pathways involved. The synthetic (proliferation, migration, and type I collagen gene α1 chain expression) and contractile (smooth muscle-myosin heavy chain and smooth muscle-calponin expression) profiles of human pulmonary artery smooth muscle cells were assessed in vitro after incubation with SSc anti-PDGF receptors stimulatory autoantibodies. The role of reactive oxygen species, NOX isoforms, and mammalian target of rapamycin (mTOR) was investigated. Human pulmonary artery smooth muscle cells acquired a synthetic phenotype characterized by higher growth rate, migratory activity, gene expression of type I collagen α1 chain, and less expression of markers characteristic of the contractile phenotype such as smooth muscle-myosin heavy chain and smooth muscle-calponin when stimulated with PDGF and autoantibodies against PDGF receptor, but not with normal IgG. This phenotypic profile is mediated by increased generation of reactive oxygen species and expression of NOX4 and mTORC1. Our data indicate that agonistic anti-PDGF receptor autoantibodies may contribute to the pathogenesis of SSc intimal hyperplasia.

16.
J Neurosci ; 36(18): 5170-80, 2016 05 04.
Artigo em Inglês | MEDLINE | ID: mdl-27147667

RESUMO

UNLABELLED: The proinflammatory cytokine IL-18 has central anorexigenic effects and was proposed to contribute to loss of appetite observed during sickness. Here we tested in the mouse the hypothesis that IL-18 can decrease food intake by acting on neurons of the bed nucleus of the stria terminalis (BST), a component of extended amygdala recently shown to influence feeding via its projections to the lateral hypothalamus (LH). We found that both subunits of the heterodimeric IL-18 receptor are highly expressed in the BST and that local injection of recombinant IL-18 (50 ng/ml) significantly reduced c-fos activation and food intake for at least 6 h. Electrophysiological experiments performed in BST brain slices demonstrated that IL-18 strongly reduces the excitatory input on BST neurons through a presynaptic mechanism. The effects of IL-18 are cell-specific and were observed in Type III but not in Type I/II neurons. Interestingly, IL-18-sensitve Type III neurons were recorded in the juxtacapsular BST, a region that contains BST-LH projecting neurons. Reducing the excitatory input on Type III GABAergic neurons, IL-18 can increase the firing of glutamatergic LH neurons through a disinhibitory mechanism. Imbalance between excitatory and inhibitory activity in the LH can induce changes in food intake. Effects of IL-18 were mediated by the IL-18R because they were absent in neurons from animals null for IL-18Rα (Il18ra(-/-)), which lack functional IL-18 receptors. In conclusion, our data show that IL-18 may inhibit feeding by inhibiting the activity of BST Type III GABAergic neurons. SIGNIFICANCE STATEMENT: Loss of appetite during sickness is a common and often debilitating phenomenon. Although proinflammatory cytokines are recognized as mediators of these anorexigenic effects, their mechanism and sites of action remain poorly understood. Here we show that interleukin 18, an anorexigenic cytokine, can act on neurons of the bed nucleus of the stria terminalis to reduce food intake via the IL-18 receptor. The findings identify a site and a mode of action that indicate targets for the treatment of cachexia or other eating disorders.


Assuntos
Comportamento Alimentar/fisiologia , Interleucina-18/fisiologia , Núcleos Septais/fisiologia , Animais , Fenômenos Eletrofisiológicos/fisiologia , Região Hipotalâmica Lateral/fisiologia , Interleucina-18/biossíntese , Interleucina-18/genética , Subunidade alfa de Receptor de Interleucina-18/genética , Subunidade alfa de Receptor de Interleucina-18/fisiologia , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Neurônios/fisiologia , Proteínas Recombinantes/farmacologia , Sinapses/efeitos dos fármacos , Ácido gama-Aminobutírico/fisiologia
17.
Arthritis Rheumatol ; 68(9): 2263-73, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27111463

RESUMO

OBJECTIVE: To describe a skin-SCID mouse chimeric model of systemic sclerosis (SSc; scleroderma) fibrosis based on engraftment of ex vivo-bioengineered skin using skin cells derived either from scleroderma patients or from healthy donors. METHODS: Three-dimensional bioengineered skin containing human keratinocytes and fibroblasts isolated from skin biopsy specimens from healthy donors or SSc patients was generated ex vivo and then grafted onto the backs of SCID mice. The features of the skin grafts were analyzed by immunohistochemistry, and the functional profile of the graft fibroblasts was defined before and after treatment with IgG from healthy controls or SSc patients. Two procedures were used to investigate the involvement of platelet-derived growth factor receptor (PDGFR): 1) nilotinib, a tyrosine kinase inhibitor, was administered to mice before injection of IgG from SSc patient sera (SSc IgG) into the grafts, and 2) human anti-PDGFR monoclonal antibodies were injected into the grafts. RESULTS: Depending on the type of bioengineered skin grafted, the regenerated human skin exhibited either the typical scleroderma phenotype or the healthy human skin architecture. Treatment of animals carrying healthy donor skin grafts with SSc IgG resulted in the appearance of a bona fide scleroderma phenotype, as confirmed by increased collagen deposition and fibroblast activation markers. Results of the experiments involving administration of nilotinib or monoclonal antibodies confirmed the involvement of PDGFR. CONCLUSION: Our results provide the first in vivo demonstration of the fibrotic properties of anti-PDGFR agonistic antibodies. This bioengineered skin-humanized mouse model can be used to test in vivo the progression of the disease and to monitor response to antifibrotic drugs.


Assuntos
Autoanticorpos/administração & dosagem , Modelos Animais de Doenças , Receptores do Fator de Crescimento Derivado de Plaquetas/imunologia , Esclerodermia Localizada/imunologia , Escleroderma Sistêmico/imunologia , Animais , Fibrose/imunologia , Camundongos , Camundongos SCID , Esclerodermia Localizada/patologia , Escleroderma Sistêmico/patologia , Pele/imunologia
18.
Arthritis Rheumatol ; 68(9): 2338-44, 2016 09.
Artigo em Inglês | MEDLINE | ID: mdl-27111665

RESUMO

OBJECTIVE: Systemic sclerosis (SSc) and rheumatoid arthritis (RA) are autoimmune diseases that have similar clinical and immunologic characteristics. To date, several shared SSc-RA genetic loci have been identified independently. The aim of the current study was to systematically search for new common SSc-RA loci through an interdisease meta-genome-wide association (meta-GWAS) strategy. METHODS: The study was designed as a meta-analysis combining GWAS data sets of patients with SSc and patients with RA, using a strategy that allowed identification of loci with both same-direction and opposite-direction allelic effects. The top single-nucleotide polymorphisms were followed up in independent SSc and RA case-control cohorts. This allowed an increase in the sample size to a total of 8,830 patients with SSc, 16,870 patients with RA, and 43,393 healthy controls. RESULTS: This cross-disease meta-analysis of the GWAS data sets identified several loci with nominal association signals (P < 5 × 10(-6) ) that also showed evidence of association in the disease-specific GWAS scans. These loci included several genomic regions not previously reported as shared loci, as well as several risk factors that were previously found to be associated with both diseases. Follow-up analyses of the putatively new SSc-RA loci identified IRF4 as a shared risk factor for these 2 diseases (Pcombined = 3.29 × 10(-12) ). Analysis of the biologic relevance of the known SSc-RA shared loci identified the type I interferon and interleukin-12 signaling pathways as the main common etiologic factors. CONCLUSION: This study identified a novel shared locus, IRF4, for the risk of SSc and RA, and highlighted the usefulness of a cross-disease GWAS meta-analysis strategy in the identification of common risk loci.


Assuntos
Artrite Reumatoide/genética , Estudo de Associação Genômica Ampla , Fatores Reguladores de Interferon/genética , Escleroderma Sistêmico/genética , Loci Gênicos , Predisposição Genética para Doença , Humanos , Fatores de Risco
19.
Ann Rheum Dis ; 75(8): 1521-6, 2016 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-26338038

RESUMO

OBJECTIVES: TYK2 is a common genetic risk factor for several autoimmune diseases. This gene encodes a protein kinase involved in interleukin 12 (IL-12) pathway, which is a well-known player in the pathogenesis of systemic sclerosis (SSc). Therefore, we aimed to assess the possible role of this locus in SSc. METHODS: This study comprised a total of 7103 patients with SSc and 12 220 healthy controls of European ancestry from Spain, USA, Germany, the Netherlands, Italy and the UK. Four TYK2 single-nucleotide polymorphisms (V362F (rs2304256), P1104A (rs34536443), I684S (rs12720356) and A928V (rs35018800)) were selected for follow-up based on the results of an Immunochip screening phase of the locus. Association and dependence analyses were performed by the means of logistic regression and conditional logistic regression. Meta-analyses were performed using the inverse variance method. RESULTS: Genome-wide significance level was reached for TYK2 V362F common variant in our pooled analysis (p=3.08×10(-13), OR=0.83), while the association of P1104A, A928V and I684S rare and low-frequency missense variants remained significant with nominal signals (p=2.28×10(-3), OR=0.80; p=1.27×10(-3), OR=0.59; p=2.63×10(-5), OR=0.83, respectively). Interestingly, dependence and allelic combination analyses showed that the strong association observed for V362F with SSc, corresponded to a synthetic association dependent on the effect of the three previously mentioned TYK2 missense variants. CONCLUSIONS: We report for the first time the association of TYK2 with SSc and reinforce the relevance of the IL-12 pathway in SSc pathophysiology.


Assuntos
Interleucina-12/fisiologia , Polimorfismo de Nucleotídeo Único , Escleroderma Sistêmico/genética , TYK2 Quinase/genética , Estudos de Casos e Controles , Predisposição Genética para Doença , Estudo de Associação Genômica Ampla , Humanos , Mutação de Sentido Incorreto , Escleroderma Sistêmico/imunologia , Transdução de Sinais/genética , Transdução de Sinais/imunologia
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