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1.
Arthritis Rheumatol ; 2019 Sep 11.
Artigo em Inglês | MEDLINE | ID: mdl-31509349

RESUMO

OBJECTIVE: Pulmonary arterial hypertension (PAH), one of the major complications of systemic sclerosis (SSc), is a rare disease with unknown etiopathogenesis and non curative treatments. As PSGL-1-/- mice develop a spontaneous SSc-like syndrome, the objective of this work was to analyze whether they develop PAH and molecular mechanisms involved. METHODS: Doppler echocardiography was used to estimate pulmonary pressure; immunohistochemistry, to assess vascular remodeling; myography of dissected pulmonary artery rings, to analyze vascular reactivity. ELISA, to quantify the levels of AngII; Western blot, to measure AT1R, AT2R, eNOS and p-eNOS expression in lung lysates and Flow cytometry to determine cytokine production of immune cells and NO production by endothelial cells. In all cases, n = 4-8 mice per experimental group. RESULTS: PSGL-1-/- mice present lung vessel wall remodeling and reduced expression of pulmonary AT2R (>18-month-old female mice: WT 0.337±0.094 vs KO 0.189±0.072). With aging, PSGL-1-/- females have impaired up-regulation of ERα and develop lung vascular endothelial dysfunction coinciding with an increase in pulmonary AngII levels (WT 48.70±5.13 vs KO 78.02±28.09 pg/g lung tissue) and a decrease in eNOS phosphorylation, driving to reduced endothelial NO production. These events lead to reduction in PAAT/ET ratio in 33% of aged PSGL-1-/- females, indicating pulmonary hypertension. Importantly, we found expanded populations of IFN-γ-producing PSGL-1-/- T cells and B cells and reduced presence of regulatory T cells. CONCLUSION: PSGL-1 absence induces reduction of Treg, NO production and ERα expression and the increase of Angiotensin II in the lungs of female mice, favoring the development of PAH.

2.
J Invest Dermatol ; 138(10): 2123-2132, 2018 Oct.
Artigo em Inglês | MEDLINE | ID: mdl-29689251

RESUMO

Systemic sclerosis (SSc) is an autoimmune disorder with high morbidity and mortality, is difficult to diagnose early, and has no curative treatment. PSGL-1 is a leukocyte receptor whose deficiency in mice promotes an SSc-like disease. ADAM8, a metalloprotease that cleaves PSGL-1, is implicated in inflammatory processes. Our goal was to evaluate whether PSGL-1 and ADAM8 contribute to the pathogenesis of human SSc. We found that patients with SSc presented increased PSGL-1 expression on monocytes, dendritic cells, and T cells and decreased expression of PSGL-1 on B cells. PSGL-1 on monocytes from SSc patients failed to induce Syk phosphorylation or IL-10 production after interaction with P-selectin. Up to 60% of the IL-10-producing B cells expressed PSGL-1, pointing to a regulatory role for PSGL-1 in B cells, and PSGL-1+ B cells from SSc patients had decreased IL-10 production. ADAM8 expression was increased on antigen-presenting cells and T lymphocytes of SSc patients. Patients treated with calcium antagonists had lower levels of ADAM8 on APCs and T lymphocytes. Multivariate analysis indicated that the high percentage of ADAM8-expressing plasmacytoid dendritic cells discriminated patients from healthy donors. High PSGL-1 expression on dendritic cells was associated with the presence of interstitial lung disease.

3.
Sci Rep ; 7: 41841, 2017 02 02.
Artigo em Inglês | MEDLINE | ID: mdl-28150814

RESUMO

Mice deficient in P-Selectin presented altered immunity/tolerance balance. We have observed that the absence of P-Selectin promotes splenomegaly with reduced naïve T cell population, elevated activated/effector T cell subset, increased germinal center B and Tfh populations and high production of autoreactive antibodies. Moreover, 1.5-3-month-old P-selectin KO mice showed reduced IL-10-producing leukocytes in blood and a slightly reduced Treg population in the skin. With aging and, coinciding with disease severity, there is an increase in the IL17+ circulating and dermal T cell subpopulations and reduction of dermal Treg. As a consequence, P-Selectin deficient mice developed a progressive autoimmune syndrome showing skin alterations characteristic of lupus prone mice and elevated circulating autoantibodies, including anti-dsDNA. Similar to human SLE, disease pathogenesis was characterized by deposition of immune complexes in the dermoepidermal junction and renal glomeruli, and a complex pattern of autoantibodies. More important, skin biopsies of cutaneous lupus erythematosus patients did not show increased expression of P-Selectin, as described for other inflammatory diseases, and the number of vessels expressing P-Selectin was reduced.


Assuntos
Tolerância Imunológica , Lúpus Eritematoso Cutâneo/genética , Selectina-P/genética , Animais , Autoanticorpos/sangue , Feminino , Centro Germinativo/patologia , Humanos , Interleucina-10/metabolismo , Interleucina-17/metabolismo , Lúpus Eritematoso Cutâneo/imunologia , Subpopulações de Linfócitos , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Selectina-P/metabolismo , Pele/irrigação sanguínea , Pele/metabolismo , Baço/patologia , Linfócitos T/imunologia
4.
Expert Rev Clin Immunol ; 9(7): 599-621, 2013 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-23899231

RESUMO

Abatacept is approved for the treatment of moderate-to-severe active rheumatoid arthritis (RA) patients with inadequate response to one or more disease-modifying antirheumatic drugs (DMARDs), including methotrexate or a TNF antagonist, and can be used either as monotherapy or concomitantly with nonbiologic DMARDs. It can be administered either intravenously or subcutaneously. It has demonstrated to improve signs and symptoms of RA, physical function and health-related quality of life, and it inhibits radiographic progression of structural damage across a wide range of early and long-standing RA populations. The safety profile appears good and close to RA patients treated with nonbiologic DMARDs. Meta-analysis and real-world studies support these findings. This article reviews published data on clinical and radiographic efficacy as well as the safety of this drug, incorporating recent relevant information reported at scientific meetings.


Assuntos
Artrite Reumatoide/tratamento farmacológico , Imunoconjugados/uso terapêutico , Imunossupressores/uso terapêutico , Articulações/efeitos dos fármacos , Abatacepte , Animais , Antirreumáticos , Artrografia , Ensaios Clínicos como Assunto , Progressão da Doença , Resistência a Medicamentos , Humanos , Imunoconjugados/farmacologia , Imunossupressores/farmacologia , Articulações/patologia , Fator de Necrose Tumoral alfa/antagonistas & inibidores
5.
Hum Mol Genet ; 22(19): 4021-9, 2013 Oct 01.
Artigo em Inglês | MEDLINE | ID: mdl-23740937

RESUMO

Systemic sclerosis (SSc) and systemic lupus erythematosus (SLE) are two archetypal systemic autoimmune diseases which have been shown to share multiple genetic susceptibility loci. In order to gain insight into the genetic basis of these diseases, we performed a pan-meta-analysis of two genome-wide association studies (GWASs) together with a replication stage including additional SSc and SLE cohorts. This increased the sample size to a total of 21,109 (6835 cases and 14,274 controls). We selected for replication 19 SNPs from the GWAS data. We were able to validate KIAA0319L (P = 3.31 × 10(-11), OR = 1.49) as novel susceptibility loci for SSc and SLE. Furthermore, we also determined that the previously described SLE susceptibility loci PXK (P = 3.27 × 10(-11), OR = 1.20) and JAZF1 (P = 1.11 × 10(-8), OR = 1.13) are shared with SSc. Supporting these new discoveries, we observed that KIAA0319L was overexpressed in peripheral blood cells of SSc and SLE patients compared with healthy controls. With these, we add three (KIAA0319L, PXK and JAZF1) and one (KIAA0319L) new susceptibility loci for SSc and SLE, respectively, increasing significantly the knowledge of the genetic basis of autoimmunity.


Assuntos
Predisposição Genética para Doença , Peptídeos e Proteínas de Sinalização Intracelular/genética , Lúpus Eritematoso Sistêmico/genética , Proteínas de Neoplasias/genética , Proteínas do Tecido Nervoso/genética , Proteínas Nucleares/genética , Proteínas Serina-Treonina Quinases/genética , Escleroderma Sistêmico/genética , Estudos de Casos e Controles , Loci Gênicos , Variação Genética , Estudo de Associação Genômica Ampla , Humanos , Lúpus Eritematoso Sistêmico/imunologia , Polimorfismo de Nucleotídeo Único , Receptores de Superfície Celular , Reprodutibilidade dos Testes , Fatores de Risco , Escleroderma Sistêmico/imunologia
6.
Arthritis Res Ther ; 14(6): R273, 2012 Dec 27.
Artigo em Inglês | MEDLINE | ID: mdl-23270786

RESUMO

INTRODUCTION: Potassium voltage-gated channel shaker-related subfamily member 5 (KCNA5) is implicated in vascular tone regulation, and its inhibition during hypoxia produces pulmonary vasoconstriction. Recently, a protective association of the KCNA5 locus with systemic sclerosis (SSc) patients with pulmonary arterial hypertension (PAH) was reported. Hence, the aim of this study was to replicate these findings in an independent multicenter Caucasian SSc cohort. METHODS: The 2,343 SSc cases (179 PAH positive, confirmed by right-heart catheterization) and 2,690 matched healthy controls from five European countries were included in this study. Rs10744676 single-nucleotide polymorphism (SNP) was genotyped by using a TaqMan SNP genotyping assay. RESULTS: Individual population analyses of the selected KCNA5 genetic variant did not show significant association with SSc or any of the defined subsets (for example, limited cutaneous SSc, diffuse cutaneous SSc, anti-centromere autoantibody positive and anti-topoisomerase autoantibody positive). Furthermore, pooled analyses revealed no significant evidence of association with the disease or any of the subsets, not even the PAH-positive group. The comparison of PAH-positive patients with PAH-negative patients showed no significant differences among patients. CONCLUSIONS: Our data do not support an important role of KCNA5 as an SSc-susceptibility factor or as a PAH-development genetic marker for SSc patients.


Assuntos
Predisposição Genética para Doença/genética , Hipertensão Pulmonar/genética , Canal de Potássio Kv1.5/genética , Polimorfismo de Nucleotídeo Único , Escleroderma Sistêmico/genética , Estudos de Coortes , Grupo com Ancestrais do Continente Europeu/genética , Frequência do Gene , Predisposição Genética para Doença/etnologia , Genótipo , Humanos , Hipertensão Pulmonar/complicações , Hipertensão Pulmonar/etnologia , Itália , Desequilíbrio de Ligação , Países Baixos , Razão de Chances , Escleroderma Sistêmico/complicações , Escleroderma Sistêmico/etnologia , Espanha , Suécia , Reino Unido
7.
Ann Rheum Dis ; 71(1): 114-9, 2012 Jan.
Artigo em Inglês | MEDLINE | ID: mdl-21926187

RESUMO

OBJECTIVE: Systemic sclerosis (SSc) and systemic lupus erythematosus (SLE) are related chronic autoimmune diseases of complex aetiology in which the interferon (IFN) pathway plays a key role. Recent studies have reported an association between IRF7 and SLE which confers a risk to autoantibody production. A study was undertaken to investigate whether the IRF7 genomic region is also involved in susceptibility to SSc and the main clinical features. METHODS: Two case-control sets of Caucasian origin from the USA and Spain, comprising a total of 2316 cases of SSc and 2347 healthy controls, were included in the study. Five single nucleotide polymorphisms (SNPs) in the PHRF1-IRF7-CDHR5 locus were genotyped using TaqMan allelic discrimination technology. A meta-analysis was performed to test the overall effect of these genetic variants on SSc. RESULTS: Four out of five analysed SNPs were significantly associated with the presence of anticentromere autoantibodies (ACA) in the patients with SSc in the combined analysis (rs1131665: p(FDR)=6.14 × 10(-4), OR=0.78; rs4963128: p(FDR)=6.14 × 10(-4), OR=0.79; rs702966: p(FDR)=3.83 × 10(-3), OR=0.82; and rs2246614: p(FDR)=3.83 × 10(-3), OR=0.83). Significant p values were also obtained when the disease was tested globally; however, the statistical significance was lost when the ACA-positive patients were excluded from the study, suggesting that these associations rely on ACA positivity. Conditional logistic regression and allelic combination analyses suggested that the functional IRF7 SNP rs1131665 is the most likely causal variant. CONCLUSIONS: The results show that variation in the IRF7 genomic region is associated with the presence of ACA in patients with SSc, supporting other evidence that this locus represents a common risk factor for autoantibody production in autoimmune diseases.


Assuntos
Anticorpos Antinucleares/sangue , Doenças Autoimunes/genética , Fator Regulador 7 de Interferon/genética , Escleroderma Sistêmico/genética , Anticorpos Antinucleares/biossíntese , Doenças Autoimunes/imunologia , Estudos de Casos e Controles , Feminino , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Masculino , Polimorfismo de Nucleotídeo Único , Escleroderma Sistêmico/imunologia
10.
Ann Rheum Dis ; 70(4): 638-41, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-21187296

RESUMO

OBJECTIVES: The aim of this study was to confirm the influence of TNFSF4 polymorphisms on systemic sclerosis (SSc) susceptibility and phenotypic features. METHODS: A total of 8 European populations of Caucasian ancestry were included, comprising 3014 patients with SSc and 3125 healthy controls. Four genetic variants of TNFSF4 gene promoter (rs1234314, rs844644, rs844648 and rs12039904) were selected as genetic markers. RESULTS: A pooled analysis revealed the association of rs1234314 and rs12039904 polymorphisms with SSc (OR 1.15, 95% CI 1.02 to 1.31; OR 1.18, 95% CI 1.08 to 1.29, respectively). Significant association of the four tested variants with patients with limited cutaneous SSc (lcSSc) was revealed (rs1234314 OR 1.22, 95% CI 1.07 to 1.38; rs844644 OR 0.91, 95% CI 0.83 to 0.99; rs844648 OR 1.10, 95% CI 1.01 to 1.20 and rs12039904 OR 1.20, 95% CI 1.09 to 1.33). Association of rs1234314, rs844648 and rs12039904 minor alleles with patients positive for anti-centromere antibodies (ACA) remained significant (OR 1.23, 95% CI 1.10 to 1.37; OR 1.12, 95% CI 1.01 to 1.25; OR 1.22, 95% CI 1.07 to 1.38, respectively). Haplotype analysis confirmed a protective haplotype associated with SSc, lcSSc and ACA positive subgroups (OR 0.88, 95% CI 0.82 to 0.96; OR 0.88, 95% CI 0.80 to 0.96; OR 0.86, 95% CI 0.77 to 0.97, respectively) and revealed a new risk haplotype associated with the same groups of patients (OR 1.14, 95% CI 1.03 to 1.26; OR 1.20, 95% CI 1.08 to 1.35; OR 1.23, 95% CI 1.07 to 1.42, respectively). CONCLUSIONS: The data confirm the influence of TNFSF4 polymorphisms in SSc genetic susceptibility, especially in subsets of patients positive for lcSSc and ACA.


Assuntos
Ligante OX40/genética , Polimorfismo de Nucleotídeo Único , Escleroderma Sistêmico/genética , Estudos de Casos e Controles , Frequência do Gene , Estudos de Associação Genética , Predisposição Genética para Doença , Haplótipos , Humanos , Regiões Promotoras Genéticas/genética
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