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1.
Int J Mol Sci ; 23(23)2022 Dec 03.
Artigo em Inglês | MEDLINE | ID: mdl-36499587

RESUMO

SARS-CoV-2, a positive-strand RNA virus has caused devastating effects. The standard method for COVID diagnosis is based on polymerase chain reaction (PCR). The method needs expensive reagents and equipment and well-trained personnel and takes a few hours to be completed. The search for faster solutions has led to the development of immunological assays based on antibodies that recognize the viral proteins that are faster and do not require any special equipment. Here, we explore an innovative analytical approach based on the sandwich oligonucleotide hybridization which can be adapted to several biosensing devices including thermal lateral flow and electrochemical devices, as well as fluorescent microarrays. Polypurine reverse-Hoogsteen hairpins (PPRHs) oligonucleotides that form high-affinity triplexes with the polypyrimidine target sequences are used for the efficient capture of the viral genome. Then, a second labeled oligonucleotide is used to detect the formation of a trimolecular complex in a similar way to antigen tests. The reached limit of detection is around 0.01 nM (a few femtomoles) without the use of any amplification steps. The triplex enhanced nucleic acid detection assay (TENADA) can be readily adapted for the detection of any pathogen requiring only the knowledge of the pathogen genome sequence.


Assuntos
COVID-19 , Ácidos Nucleicos , Humanos , SARS-CoV-2/genética , COVID-19/diagnóstico , Oligonucleotídeos/química , Reação em Cadeia da Polimerase , RNA Viral/genética , RNA Viral/análise , Técnicas de Amplificação de Ácido Nucleico/métodos
2.
Clin Exp Rheumatol ; 37 Suppl 119(4): 41-48, 2019.
Artigo em Inglês | MEDLINE | ID: mdl-30767873

RESUMO

OBJECTIVES: To evaluate the clinical features and survival of patients with positive anti-RNA polymerase III (anti-RNAP III) in a Spanish single centre. METHODS: We analysed 221 patients with SSc according to LeRoy and Medsger criteria. Twenty-six patients with positivity for anti-RNAP III antibodies were compared with 195 negative patients. Epidemiological, clinical, immunological features and survival were analysed. RESULTS: In patients with anti-RNAP III positivity diffuse cutaneous SSc (dcSSc) subset was the most prevalent (20, 76.9% vs. 35, 17.9%, p < 0.001), with shorter diagnosis delay (4.11 ± 7.34 years vs. 6.77 ± 9.22 years, p = 0.005). Patients with anti-RNAP III antibodies had higher frequency of arterial hypertension (13, 50% vs. 55, 28.2%, p = 0.024), scleroderma renal crisis (SRC) (3, 11.5% vs. 3, 1.5%, p = 0.023), arthritis (9, 34.6% vs. 35, 17.9%, p = 0.046), tendon friction rubs (4, 15.4% vs. 1, 0.5%, p = 0.001) and contractures (5, 19.2% vs. 10, 5.1%, p = 0.02). There were no differences found in the presence of cancer or in global survival. In the multivariate survival analysis, severe interstitial lung disease (ILD) (HR: 8.61, 95%CI 3.40 - 21.81), pulmonary arterial hypertension (PAH) (HR: 4.05, 95%CI 1.42 - 11.61) and SRC (HR: 17.27, 95%CI 3.36 - 88.97) were the only factors associated with poor prognosis. CONCLUSIONS: In this cohort anti-RNAP III antibodies are related with dcSSc subset, shorter diagnostic delay and higher prevalence of musculoskeletal involvement, arterial hypertension and SRC. ILD, PAH and SRC were independent prognostic factors.


Assuntos
Autoanticorpos/imunologia , Doenças Pulmonares Intersticiais , RNA Polimerase III/imunologia , Escleroderma Sistêmico , Adulto , Autoanticorpos/sangue , Diagnóstico Tardio , Feminino , Humanos , Doenças Pulmonares Intersticiais/diagnóstico , Doenças Pulmonares Intersticiais/imunologia , Doenças Pulmonares Intersticiais/metabolismo , Masculino , Pessoa de Meia-Idade , Escleroderma Sistêmico/diagnóstico , Escleroderma Sistêmico/imunologia , Escleroderma Sistêmico/metabolismo , Espanha
3.
Rheumatology (Oxford) ; 57(2): 388-396, 2018 02 01.
Artigo em Inglês | MEDLINE | ID: mdl-29149307

RESUMO

Objectives: To analyse the influence of genetic alterations and differential expression of transcription intermediary factor 1 (TIF1) genes in the pathophysiology of cancer-associated myositis (CAM). Methods: Paired blood and tumour DNA samples from patients with anti-TIF1γ-positive CAM and from controls were analysed by whole-exome sequencing for the presence of somatic mutations and loss of heterozygosity (LOH) in their TIF1 genes. The genesis and maintenance of the autoimmune process were investigated immunohistochemically by studying TIF1γ expression in the different tissues involved in CAM (skin, muscle and tumour) based on the immunohistochemical H-score. Results: From seven patients with anti-TIF1γ-positive CAM, we detected one somatic mutation and five cases of LOH in one or more of the four TIF1 genes compared with just one case of LOH in tumours from TIF1γ-negative myositis patients (86% vs 17%; P = 0.03). Compared with type-matched control tumours from non-myositis patients, TIF1γ staining was more intense in tumours from anti-TIF1γ-positive patients (H-score 255 vs 196; P = 0.01). Also, TIF1γ staining in muscle was slightly more intense in anti-TIF1γ-positive than in anti-TIF1γ-negative myositis (H-score 22 vs 5; P = 0.03). In contrast, intense TIF1γ staining was detected in the skin of both myositis and control patients. Conclusion: Tumours from paraneoplastic anti-TIF1γ-positive patients showed an increased number of genetic alterations, such as mutations and LOH, in TIF1 genes. These genetic alterations, in the context of a high expression of TIF1γ in the tumour, muscle and skin of these patients may be key to understanding the genesis of paraneoplastic myositis.


Assuntos
Perda de Heterozigosidade/genética , Mutação , Miosite/genética , Neoplasias/genética , Fatores de Transcrição/genética , Adulto , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Músculo Esquelético/metabolismo , Pele/metabolismo , Sequenciamento do Exoma
4.
Clin Exp Rheumatol ; 32(1): 113-6, 2014.
Artigo em Inglês | MEDLINE | ID: mdl-24238281

RESUMO

We determined the expression of Integrin alpha L chain (ITGAL), Perforin 1 (PRF1), and CD70 and studied the associations with laboratory and clinical parameters. CD4+ T cells were isolated from 35 SLE patients and 30 healthy controls. The transcript levels of ITGAL, PRF1, and CD70 were quantified by real-time reverse-transcription polymerase chain reaction (RT-PCR). The SLE patients had significantly elevated transcript levels of ITGAL (18.61±22.17 vs. 7.33±9.17, p=0.042), PRF1 (21.67±26.34 vs. 10.67±11.65, p=0.039), and CD70 (1.45±1.63 vs. 0.67± 0.28, p=0.011). Patients with anti-microsomal and/or anti-thyroglobulin antibodies showed high levels of ITGAL (33.41±30.14 vs. 13.58±16.43, p=0.044; and 34.01±27.66 vs. 11.90±16.17, p=0.007, respectively). No association was seen either for the typical antibodies of SLE or for the disease activity. Although ITGAL, PRF1, and CD70 are overexpressed in SLE CD4+ T cells, their expression is not linked to the typical clinical and serological parameters associated with the disease. The role that ITGAL may play in autoimmune thyroiditis deserves further investigation.


Assuntos
Antígeno CD11a/genética , Ligante CD27/genética , Linfócitos T CD4-Positivos/imunologia , Lúpus Eritematoso Sistêmico/imunologia , Proteínas Citotóxicas Formadoras de Poros/genética , Adulto , Idoso , Biomarcadores/sangue , Estudos de Casos e Controles , Células Cultivadas , Feminino , Humanos , Lúpus Eritematoso Sistêmico/sangue , Lúpus Eritematoso Sistêmico/diagnóstico , Masculino , Pessoa de Meia-Idade , Perforina , Valor Preditivo dos Testes , RNA Mensageiro/análise , Reação em Cadeia da Polimerase em Tempo Real , Reação em Cadeia da Polimerase Via Transcriptase Reversa , Testes Sorológicos , Regulação para Cima , Adulto Jovem
5.
Ann Rheum Dis ; 71(6): 993-6, 2012 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-22294626

RESUMO

BACKGROUND: A new myositis-specific autoantibody (anti-p155) directed against transcriptional intermediary factor 1 γ (TIF1γ) has been described as a good marker of cancer-associated myositis (CAM). OBJECTIVE: To analyse the feasibility of detecting this autoantibody in patient serum samples using new assays with commercially available recombinant TIF1γ. METHODS: The study included 90 Spanish patients with dermatomyositis (DM), classified as clinically amyopathic DM, CAM, or DM without cancer. Anti-TIF1γ antibodies were detected by ELISA and immunoblot techniques and compared with anti-p155 antibody detection by protein immunoprecipitation assays with radiolabelled HeLa cells. The κ coefficient was used to compare the agreement between the different tests. RESULTS: Serum samples from 23 (25.6%) and 20 (22.2%) patients with DM recognised TIF1γ by ELISA and immunoblot, respectively. ELISA (κ=0.91) and immunoblot (κ=0.88) showed excellent agreement with immunoprecipitation analysis (anti-p155). Good concordance (κ=0.91) was also seen between ELISA and immunoblot. CONCLUSIONS: Excellent agreement was found between anti-p155 detected by immunoprecipitation and anti-TIF1γ detected by ELISA or immunoblot. These data indicate that identification of this autoantibody can be reliably performed in a standard laboratory setting, with potential application in clinical practice for cancer screening in adult patients with DM.


Assuntos
Autoanticorpos/sangue , Dermatomiosite/diagnóstico , Dermatomiosite/imunologia , Fatores de Transcrição/imunologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Autoanticorpos/imunologia , Biomarcadores/sangue , Ensaio de Imunoadsorção Enzimática/métodos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Neoplasias/diagnóstico , Neoplasias/imunologia
6.
J Clin Immunol ; 31(4): 584-7, 2011 Aug.
Artigo em Inglês | MEDLINE | ID: mdl-21509625

RESUMO

OBJECTIVES: Xenotropic murine leukemia virus-related virus (XMRV)-specific proviral DNA has been recently detected in peripheral blood mononuclear cells of patients with chronic fatigue syndrome. Since chronic fatigue is commonly reported in patients with systemic lupus erythematosus (SLE) we aimed at testing the presence of this virus in these patients. METHODS: Ninety-five SLE patients, 45 of whom had a Fatigue Severity Scale score higher than 3, were included. Molecular analyses were performed by PCR from DNA obtained from the whole blood of both SLE patients and 50 healthy controls. RESULTS: None of the 145 samples analyzed yielded the specific XMRV PCR product. CONCLUSIONS: We conclude that XMRV is not detected in blood neither from SLE patients nor from healthy controls. It leads to infer that other environmental and biological triggers (different from XMRV) may account for the increased levels of fatigue over the course of SLE.


Assuntos
Fadiga/virologia , Lúpus Eritematoso Sistêmico/virologia , Vírus Relacionado ao Vírus Xenotrópico da Leucemia Murina/imunologia , Vírus Relacionado ao Vírus Xenotrópico da Leucemia Murina/isolamento & purificação , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Anticorpos Antivirais/sangue , DNA Viral/sangue , DNA Viral/isolamento & purificação , Feminino , Humanos , Leucócitos Mononucleares/virologia , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Masculino , Pessoa de Meia-Idade , Infecções por Retroviridae/sangue , Infecções por Retroviridae/virologia
7.
Rheumatol Int ; 31(4): 537-41, 2011 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-19851769

RESUMO

The association of common variable immunodeficiency (CVID) and systemic lupus erythematosus (SLE) is infrequent. Mannose-binding lectin (MBL) has been shown to play a role in CVID and SLE. The purpose of this study is to describe two cases of CVID who presented as SLE and also evaluate the presence of MBL polymorphisms and MBL serum levels in those patients. In both patients, SLE was the first manifestation of CVID. In these patients the SLE immunological markers and disease activity disappeared after the development of CVID. They carried the very infrequent MBL haplotype 4Q-57Glu. One of them had a homozygous genotype, whereas the other patient was heterozygous and also presented the haplotype 4P-57Glu that had never been previously detected. Interestingly, this last patient was presenting frequent respiratory tract infections, developed bronchiectasis and had low levels of circulating MBL. These results may support the role of MBL in the development of autoimmunity in CVID. Further genetic studies are needed to clarify the role of the MBL polymorphisms in the development of autoimmunity in CVID.


Assuntos
Imunodeficiência de Variável Comum/complicações , Imunodeficiência de Variável Comum/genética , Lúpus Eritematoso Sistêmico/etiologia , Lectina de Ligação a Manose/genética , Polimorfismo Genético , Adolescente , Autoimunidade , Imunodeficiência de Variável Comum/sangue , Feminino , Genótipo , Humanos , Lectina de Ligação a Manose/sangue
8.
Rev Med Virol ; 19(5): 273-86, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19714703

RESUMO

Eight per cent of the human genome is derived from the integration of retroviral sequences that were incorporated in our DNA more than 25 million years ago. Although some of these elements show mutations and deletions, some HERVs are transcriptionally active and produce functional proteins. Different mechanisms have been described which link HERVs to some chronic diseases such as several cancers, nervous system diseases and autoimmune rheumatic and connective tissue diseases. They could cause disease because of their capacity for being moved and inserted next to certain genes whose expression would be consequentially altered. Another way in which disease could potentially arise is when HERV-encoded proteins are expressed. These proteins would be considered as [foreign] and they could trigger B-cells to produce antibodies against them, which, in turn, might cross-react with other proteins of our bodies. This mechanism could give rise to autoimmune diseases such as rheumatoid arthritis (RA), lupus erythematosus, Sjögren's syndrome (SJS), mixed connective tissue diseases and inflammatory neurological disease. Furthermore, it should be pointed out that HERV-proteins may act as superantigens. Interestingly, some environmental agents seem to induce the expression of HERVs. Thus, ultraviolet light and several chemical agents could reactivate such sequences by altering their structure without modifying their nucleotide composition when the methylation pattern is changed. Therefore, the epigenetic changes observed in pathological conditions such as systemic lupus erythematosus (SLE) or cancer could be translated into an effect on the activation of some of the retroelements present in our genome which ultimately could have a direct or indirect role on the initiation and clinical evolution of certain chronic diseases.


Assuntos
Doenças Autoimunes/genética , Doenças Autoimunes/virologia , Retrovirus Endógenos/genética , Retrovirus Endógenos/imunologia , Retroelementos/genética , Integração Viral , Reações Cruzadas , Epigênese Genética , Genoma Humano/genética , Genoma Viral/genética , Humanos , Proteínas dos Retroviridae/imunologia , Proteínas dos Retroviridae/metabolismo , Superantígenos/imunologia , Superantígenos/metabolismo
9.
Rheumatol Int ; 30(12): 1601-4, 2010 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19844716

RESUMO

The objective of the study is to determine whether the activity of DNase1 is associated to the presence of nephropathy in patients with SLE. Forty-five patients affected with SLE and renal involvement were analyzed. The type of renal involvement was type III or IV glomerulonephritis. At least two serum samples were withdrawn from each patient, one obtained in a renal flare and the other obtained in a period of clinical stability. C3 and C4 complement levels and anti-DNA antibodies were determined. DNase1 activity was measured using a radial enzyme-diffusion method. Results suggest that when comparison of DNase1 activity was established between samples obtained during a phase of active renal involvement and those obtained in the clinically stable phase, we did not find statistically significant differences. When the comparison was performed with matched samples of the same patient, DNase1 activity was lower when patients had active renal involvement than when samples were taken in clinically stable phase (21.21 µg/ml ± 16.47 vs. 25.62 µg/ml ± 18.81, p < 0.05). No difference in DNase1 activity was observed between samples positive or negative for anti-DNA antibodies. No difference in DNase1 activity was found in patients with normal or decreased levels of C3 (25.09 µg/ml ± 17.78 vs. 20.01 µg/ml ± 16.15, p = 0.073) or C4 (23.52 µm/ml ± 16.60 vs. 19.62 µg/ml ± 17.54, p = 0.060). We conclude that low DNase1 activity is associated to the active phase of type III or IV nephropathy. Therefore, it is possible that this enzyme plays an important role in the development of SLE nephropathy.


Assuntos
Desoxirribonuclease I/sangue , Nefrite Lúpica/enzimologia , Anticorpos Antinucleares/sangue , Complemento C3/análise , Complemento C4/análise , Feminino , Nível de Saúde , Humanos , Rim/enzimologia , Rim/patologia , Nefrite Lúpica/sangue , Nefrite Lúpica/fisiopatologia , Masculino , Índice de Gravidade de Doença
10.
Br J Haematol ; 147(3): 289-96, 2009 Nov.
Artigo em Inglês | MEDLINE | ID: mdl-19659549

RESUMO

The possibility of a genetic predisposition to develop antiphospholipid syndrome (APS) and to produce anticardiolipin antibodies and lupus anticoagulant has been addressed by family studies and population studies. Various studies suggest a familial occurrence of anticardiolipin antibodies and lupus anticoagulant, with or without clinical evidence of APS. This familial tendency could be genetically determined. Multiple human leucocyte antigen-DR or -DQ associations with antiphospholipid antibodies have been described. Genetic studies of a representative antigen, beta2-glycoprotein-I (beta(2)GPI), have been carried-out and a particular valine(247)/leucine polymorphism could be a genetic risk for presenting anti-beta(2)GPI antibodies and APS. Many other thrombosis-related genetic factors have been investigated in APS, but no additional risk for thrombosis has been indicated in affected patients. Although the mechanisms and pathophysiology of thrombosis in APS are highly heterogeneous and multifactorial, different genes and acquired factors seem to be involved. In this review, we will focus on those genetic variants that could contribute to the development of thrombosis in APS.


Assuntos
Síndrome Antifosfolipídica/genética , Trombose/genética , Predisposição Genética para Doença , Antígenos HLA-DQ/genética , Antígenos HLA-DR/genética , Humanos , Fenótipo , Fatores de Risco
11.
Med Clin (Barc) ; 132(20): 767-71, 2009 May 30.
Artigo em Inglês | MEDLINE | ID: mdl-19403146

RESUMO

BACKGROUND AND OBJECTIVE: Livedo reticularis racemosa and cerebrovascular lesions characterize Sneddon's syndrome. We report 23 patients with livedo racemosa and describe the association with thrombotic events. Our objective was to determine whether livedo racemosa may be an independent clinical marker for the development of thrombotic events in patients who test negative for anti-phospholipid antibodies. METHODS: Twenty-three patients with widespread livedo racemosa were studied. None of the patients were positive for anti-phospholipid antibodies. The clinical protocol included a register of thrombotic events, fetal death or miscarriages, hypertension, and valvular heart disease. Cerebral MRI and echocardiography were systematically performed in all patients. RESULTS: Nineteen patients (82.60%) had thrombotic events. Fifteen (65.21%) had arterial thrombosis and eleven (47.82%) presented venous occlusions. Seven patients (30.43%) had both arterial and venous thrombosis. Fetal losses were recorded in seven cases (30.43%), with a total number of 33; five patients had 3 or more fetal losses. Eleven out of 23 patients (47.82%) had valvular heart disease. Arterial hypertension was detected in 16 (69.56%) patients. Four patients did not have thrombotic events but had other clinical manifestations. After anti-coagulation therapy was withdrawn, a new thrombotic event was observed in 9 out of the 14 treated patients (64.28%). CONCLUSIONS: Livedo racemosa seems to be a good clinical marker for the detection of hypercoagulable states even in the absence of anti-phospholipid antibodies or other known biologic markers of thrombosis. Long-term anti-coagulation is probably warranted in patients with livedo racemosa and a previous thrombotic event.


Assuntos
Livedo Reticular/etiologia , Trombose/complicações , Anticorpos Antifosfolipídeos , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Recidiva , Fatores de Risco , Trombose/diagnóstico
12.
Immunology ; 124(3): 339-47, 2008 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-18194272

RESUMO

Global DNA hypomethylation in CD4(+) T cells has been detected in systemic lupus erythematosus (SLE) and it seems to be linked to its pathogenesis. We investigated the relationship between overall DNA methylation and the expression of three DNA (cytosine-5) methyltransferases involved in the DNA methylation process. The DNA deoxymethylcytosine (dmC) content of purified CD4(+) T cells from 29 SLE patients and 30 healthy controls was measured by means of an enzyme-linked immunosorbent assay (ELISA). The transcript levels of DNA cytosine-5-methyltransferase 1 (DNMT1), DNA cytosine-5-methyltransferase 3A (DNMT3A) and DNA cytosine-5-methyltransferase 3B (DNMT3B) were quantified by real-time reverse transcription-polymerase chain reaction (RT-PCR). Association studies were also carried out with several laboratory parameters, as well as with the patients' clinical manifestations. SLE patients had a significantly lower CD4(+) T-cell DNA dmC content than controls (0.802 +/- 0.134 versus 0.901 +/- 0.133) (P = 0.007). No differences in transcript levels were observed for DNMT1, DNMT3A and DNMT3B between patients and controls. The simultaneous association of low complement counts with lymphopenia, high titres of anti-double-stranded DNA (anti-dsDNA), or an SLE disease activity index (SLEDAI) of > 5, resulted in the increase of at least one of the three DNA methyltransferases. It is possible that patients were reacting indirectly to an underlying DNA hypomethylation status by increasing the mRNA levels of DNA methyltransferases when the disease was being definitely active.


Assuntos
Linfócitos T CD4-Positivos/enzimologia , DNA (Citosina-5-)-Metiltransferases/biossíntese , Lúpus Eritematoso Sistêmico/genética , Adulto , Anticorpos Antinucleares/análise , Linfócitos T CD4-Positivos/imunologia , Complemento C3/análise , DNA (Citosina-5-)-Metiltransferases/genética , Metilação de DNA , DNA Metiltransferase 3A , Feminino , Expressão Gênica , Humanos , Lúpus Eritematoso Sistêmico/complicações , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/imunologia , Linfopenia/etiologia , Linfopenia/imunologia , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/genética , Proteínas Repressoras/biossíntese , Proteínas Repressoras/genética , Reação em Cadeia da Polimerase Via Transcriptase Reversa/métodos , Índice de Gravidade de Doença , Transcrição Gênica , DNA Metiltransferase 3B
13.
Autoimmun Rev ; 7(5): 345-51, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-18486920

RESUMO

Systemic lupus erythematosus (SLE) is a systemic autoimmune disease of unknown etiology with a complex genetic basis that includes many susceptibility genes on multiple chromosomes. As complex human diseases like SLE involve multiple, interacting genetic and environmental determinants, identifying genes for complex traits is challenging and has had limited success so far. Several key approaches that are necessary to identify disease susceptibility genes in common diseases such as SLE are now available. Collectively, these approaches will allow the prioritization of candidate genes based on available knowledge of map position and biologic relevance. They will also allow us to obtain the genomic structure of these genes as well as to study sequence variants that will facilitate the identification of genes that are important in the development and expression (severity) of lupus and associated phenotypes. Although it is still a labor-intensive and expensive project to identify susceptibility genes in common diseases such as SLE, the new techniques that are now being used will undoubtedly improve gene mapping in such a kind of diseases. In this review we highlight the current findings in the genetics of human SLE after using these approaches.


Assuntos
Predisposição Genética para Doença , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/imunologia , Antígenos CD/genética , Antígeno B7-H1 , Antígeno CTLA-4 , Proteínas do Sistema Complemento/genética , Humanos , Imunogenética , Fatores Reguladores de Interferon/genética , Complexo Principal de Histocompatibilidade , Lectina de Ligação a Manose/genética , Receptores Fc/genética
14.
Autoimmun Rev ; 7(5): 359-63, 2008 May.
Artigo em Inglês | MEDLINE | ID: mdl-18486922

RESUMO

Systemic lupus erythematosus (SLE) is an autoimmune disease of unknown aetiology with a complex genetic basis that includes many susceptibility genes on multiple chromosomes. As many complex human diseases, SLE involves multiple, interacting genetic and environmental determinants, and identifying genes and enzymes for complex traits is challenging and has had limited success so far. DNase1 has been implicated in the pathophysiology of SLE since the 1950s. The importance of DNase1 has grown up since the description that apoptotic cells can be the source of self-antigens in SLE. Many articles have focused in disturbed apoptosis and in the defects of the apoptotic cell debris as the origin of nucleosomes against which the immune response can be induced. The enzyme DNase1 plays a role in the clearance of apoptotic debris, and is therefore of capital interest in this process. In this review we highlight the current findings in the pathophysiology, genetics, and therapeutical role of DNase1 in SLE.


Assuntos
Desoxirribonuclease I/metabolismo , Lúpus Eritematoso Sistêmico/enzimologia , Animais , Apoptose , Desoxirribonuclease I/química , Desoxirribonuclease I/genética , Desoxirribonuclease I/uso terapêutico , Humanos , Lúpus Eritematoso Sistêmico/tratamento farmacológico , Lúpus Eritematoso Sistêmico/genética , Lúpus Eritematoso Sistêmico/imunologia
15.
Thromb Res ; 121(6): 727-34, 2008.
Artigo em Inglês | MEDLINE | ID: mdl-17869328

RESUMO

INTRODUCTION: The thrombotic risk associated with protein Z (PZ) deficiency is unclear. Anti-protein Z (anti-PZ) has been described as a risk factor in unexplained embryo demise. The aim of our study was to evaluate a possible PZ deficiency and presence of anti-PZ antibodies on thrombotic diseases. MATERIAL AND METHODS: We performed a case-control study on 114 patients with preexisting arterial or venous thrombosis (50 and 64, respectively). Thrombosis was studied based on etiology (creating factor risk subgroups) and on specific thrombotic disease. RESULTS: PZ levels of patients were significantly lower compared to controls (1709+-761.3 ng/mL vs. 2437+-964.7 ng/mL P=0.001). The high arterial risk factor subgroup showed the lowest PZ level (1267.5+-609 ng/mL) whereas the rest of arterial and venous etiological subgroups presented similar PZ levels. Patients with peripheral artery disease had the lowest PZ level (1022+-966 ng/mL). The rest of arterial and venous thrombotic diseases presented similar PZ levels. A significant increased risk for arterial and venous thrombosis for the lowest (<1685 ng/mL) quartile of PZ has been founded (OR:52, P=0.001 and OR:18, P=0.007, respectively). Anti-PZ antibodies were negative in the majority of patients, although mean anti-PZ IgG antibody levels in the arterial thrombosis group were significantly higher compared to venous thrombosis and control groups (P=0.05 and P=0.005, respectively). CONCLUSIONS: The results suggest that both arterial and venous thrombotic events are related to low PZ levels and that low PZ concentrations are associated with thrombosis in our study. In arterial thrombosis our findings strengthen previous studies that related low PZ levels to atherosclerotic disease. Anti-PZ antibodies do not seem to play a potent role in thrombosis.


Assuntos
Autoanticorpos/sangue , Proteínas Sanguíneas/análise , Trombose/sangue , Artérias , Proteínas Sanguíneas/deficiência , Proteínas Sanguíneas/imunologia , Estudos de Casos e Controles , Ensaio de Imunoadsorção Enzimática , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Reprodutibilidade dos Testes , Fatores de Risco , Trombose/imunologia , Veias
16.
J Leukoc Biol ; 81(6): 1609-16, 2007 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-17360956

RESUMO

Global DNA hypomethylation in CD4+ T cells has been detected in systemic lupus erythematosus (SLE), and it seems to be linked to its pathogenesis. We investigated the relationship between overall DNA methylation and the expression of two methyl CpG-binding domain (MBD) proteins. DNA deoxymethylcytosine (d(m)C) content of purified CD4(+) T cells from 29 SLE patients and 30 healthy controls was measured by means of an ELISA. Transcript levels of two methyl CpG-binding proteins (MBD2 and MBD4) were quantified by real-time RT-PCR. Association studies were also carried out with several laboratory parameters, as well as with the patients' clinical manifestations. SLE patients had significantly less CD4+ T cell DNA d(m)C content than controls (0.802+/-0.134 vs. 0.901+/-0.133; P=0.007). MBD2 and MBD4 mRNA levels were considerably higher in the patients' group: 0.975 +/- 0683 versus 0.604 +/- 0.614 (P=0.004) and 0.359 +/- 0.330 versus 0.092 +/- 0.169, respectively (P<0.0005). It is interesting that SLE patients showed a negative correlation between methylation indices and MBD2 (r=-0.609, P<0.0005) and MBD4 (r=-0.395, P=0.034) transcript levels. MBD2 and MBD4 transcript overexpression and inverse correlations with DNA methylation indices indicate that both enzymes may really have a direct and active role on the genome-wide DNA hypomethylation observed in CD4+ T cells from SLE patients.


Assuntos
Linfócitos T CD4-Positivos/metabolismo , Proteínas de Ligação a DNA/biossíntese , Endodesoxirribonucleases/biossíntese , Lúpus Eritematoso Sistêmico/metabolismo , Adulto , Metilação de DNA , Proteínas de Ligação a DNA/genética , Endodesoxirribonucleases/genética , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , RNA Mensageiro/metabolismo
17.
Ann N Y Acad Sci ; 1108: 127-36, 2007 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-17893979

RESUMO

Several studies have indicated the importance of DNA hypomethylation in the etiology of systemic lupus erythematosus (SLE). Different enzymes linked to the DNA methylation process have been described. The identification of all these enzymes means that cells have the capacity to modify their methylation patterns. Therefore, to obtain a deeper understanding of the role this epigenetic mechanism may have on SLE, the enzymes involved in the DNA methylation mechanism must be thoughtfully analyzed. In fact, studies of enzymes (other than DNMT1) in this autoimmune disease are still lacking. We have recently investigated the simultaneous gene expression of DNMT1, DNMT3A, DNMT3B, MBD2, and MBD4 in SLE patients. Here we review some of the studies that focus on the relationship between DNA methylation and SLE as well as we report our recent findings in this field. We suggest some alternative hypothesis that could help to understand the causes of the global DNA hypomethylation observed in the CD4+ T cells of these patients.


Assuntos
Linfócitos T CD4-Positivos/fisiologia , DNA (Citosina-5-)-Metiltransferases/metabolismo , Metilação de DNA , Lúpus Eritematoso Sistêmico/genética , Animais , Epigênese Genética , Humanos
18.
Clin Rheumatol ; 26(6): 947-9, 2007 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-16941203

RESUMO

Pulmonary arterial hypertension is a recognized clinical component of systemic autoimmune diseases, especially systemic sclerosis. Mutations in the bone morphogenetic protein receptor 2 gene reported in sporadic and familial primary pulmonary arterial hypertension have failed to be detected in patients with either scleroderma spectrum disease or underlying connective tissue diseases. Activin receptor-like kinase 1 (ALK-1) gene has recently been linked to the pathogenesis of pulmonary hypertension in patients with hereditary hemorrhagic telangiectasia, which has some resemblance with the CREST syndrome. The presence of mutations in the ALK-1 gene in ten patients with underlying connective tissue diseases was investigated.


Assuntos
Receptores de Activinas Tipo II/genética , Éxons/genética , Hipertensão Pulmonar/genética , Lúpus Eritematoso Sistêmico/genética , Esclerodermia Difusa/genética , Adulto , Idoso , Análise Mutacional de DNA , Feminino , Humanos , Hipertensão Pulmonar/complicações , Lúpus Eritematoso Sistêmico/complicações , Masculino , Pessoa de Meia-Idade , Mutação , Esclerodermia Difusa/complicações
19.
Clin Rheumatol ; 36(6): 1401-1406, 2017 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-28283766

RESUMO

Introduction/objectives autoantibodies to types I and IV collagen have been described in rheumatic fever and infective endocarditis. We tried to elucidate if an autoimmune response against collagens I and IV exists, associated with heart valve disease in systemic lupus erythematosus (SLE) and antiphospholipid syndrome (APS). A cohort of 172 patients with SLE (n = 79), primary APS (PAPS, n = 83), and secondary APS (n = 10) were assessed for valvulopathy by transthoracic echocardiograms. Autoantibodies to types I and IV collagen were assessed in patients and 50 controls, setting autoantibody positivity at two standard deviations above the mean antibody level of controls. Positive anticollagen IV antibody rate was significantly higher in SLE patients (17.7%) in respect to the rest of groups (PAPS 2.4%, controls 2%; P = 0.001). Percentage of positive autoantibodies to collagen I was similar in SLE and APS cohort of patients with and without valvular disease (48.4 vs 51.6%, respectively; P = 0.45). Percentage of positive autoantibodies to collagen IV was increased but not significantly in SLE and APS cohort of patients with respect to those without valvular disease (62.5 vs 37.5%, respectively; P = 0.08). Mean (standard deviation) levels of positive anticollagen I and IV antibodies did not differ between patients with and without valvular disease (85.6 ± 55 vs 81 ± 85 U/ml, respectively; P = 0.86 for anticollagen I) (0.05 ± 0.02 vs 0.12 ± 0.16 U/ml, respectively; P = 0.34 for anticollagen IV). Our data indicate a lack of association of autoantibodies to types I and IV collagen with heart valve disease in SLE and APS.


Assuntos
Síndrome Antifosfolipídica/complicações , Colágeno Tipo IV/imunologia , Colágeno Tipo I/imunologia , Doenças das Valvas Cardíacas/imunologia , Lúpus Eritematoso Sistêmico/complicações , Adulto , Idoso , Síndrome Antifosfolipídica/imunologia , Autoanticorpos/sangue , Estudos de Casos e Controles , Feminino , Humanos , Lúpus Eritematoso Sistêmico/imunologia , Masculino , Pessoa de Meia-Idade
20.
Am J Med ; 116(3): 165-73, 2004 Feb 01.
Artigo em Inglês | MEDLINE | ID: mdl-14749160

RESUMO

PURPOSE: We sought to assess the nephritogenic antibody profile of patients with systemic lupus erythematosus (SLE), and to determine which antibodies were most useful in identifying patients at risk of nephritis. METHODS: We studied 199 patients with SLE, 78 of whom had lupus nephritis. We assayed serum samples for antibodies against chromatin components (double-stranded deoxyribonucleic acid [dsDNA], nucleosome, and histone), C1q, basement membrane components (laminin, fibronectin, and type IV collagen), ribonucleoprotein, and phospholipids. Correlations of these antibodies with disease activity (SLE Disease Activity Index) and nephropathy were assessed. Patients with no initial evidence of nephropathy were followed prospectively for 6 years. RESULTS: Antibodies against dsDNA, nucleosomes, histone, C1q, and basement membrane components were associated with disease activity (P <0.05). In a multivariate analysis, anti-dsDNA antibodies (odds ratio [OR] = 6; 95% confidence interval [CI]: 2 to 24) and antihistone antibodies (OR = 9.4; 95% CI: 4 to 26) were associated with the presence of proliferative glomerulonephritis. In the prospective study, 7 (6%) of the 121 patients developed proliferative lupus glomerulonephritis after a mean of 6 years of follow-up. Patients with initial antihistone (26% [5/19] vs. 2% [2/95], P = 0.0004) and anti-dsDNA reactivity (6% [2/33] vs. 0% [0/67], P = 0.048) had a greater risk of developing proliferative glomerulonephritis than patients without these autoantibodies. CONCLUSION: In addition to routine anti-dsDNA antibody assay, antihistone antibody measurement may be useful for identifying patients at increased risk of proliferative glomerulonephritis.


Assuntos
Autoanticorpos/análise , DNA/imunologia , Histonas/imunologia , Nefrite Lúpica/imunologia , Adulto , Idoso , Feminino , Glomerulonefrite/imunologia , Humanos , Lúpus Eritematoso Sistêmico/imunologia , Masculino , Pessoa de Meia-Idade , Análise Multivariada , Estudos Prospectivos , Fatores de Risco
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