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OBJECTIVE: The aim was to evaluate the most relevant cell populations involved in vascular homeostasis as potential biomarkers of SLE-related cardiovascular disease (CVD). METHODS: Low-density granulocytes (LDGs), monocyte subsets, endothelial progenitor cells, angiogenic T (Tang) cells, CD4+CD28null and Th1/Th17 lymphocytes and serum cytokine levels were quantified in 109 SLE patients and 33 controls in relationship to the presence of subclinical carotid atheromatosis or cardiovascular disease. A second cohort including 31 recent-onset SLE patients was also included. RESULTS: Raised monocyte and LDG counts, particularly those LDGs negative for CD16/CD14 expression (nLDGs), in addition to the ratios of monocytes and nLDGs to high-density lipoprotein-cholesterol (HDLc) molecules (MHR and nLHR, respectively), were present in SLE patients with traditional risk factors or subclinical atheromatosis but not in those who were CV-free, thus revealing their value in the identification of patients at risk of CVD, even at the onset of disease. Accordingly, nLDGs were correlated positively with carotid intima-media thickness (cIMT) and with inflammatory markers (CRP and IL-6). A bias towards more differentiated monocyte subsets, related to increased IFN-α and IL-17 serum levels, was also observed in patients. Intermediate monocytes were especially expanded, but independently of their involvement in CVD. Finally, CD4+CD28null, Th17 and Th1 lymphocytes were increased, with CD4+CD28null and Th17 cells being associated with cIMT, whereas endothelial progenitor and Tang cell levels were reduced in all SLE patients. CONCLUSION: The present study highlights the potential use of MHR and nLHR as valuable biomarkers of CVD risk in SLE patients, even at diagnosis. The increased amounts of nLDGs, monocytes, Th17 and senescent-CD28null subsets, coupled with reduced pro-angiogenic endothelial progenitor cells and Tang cells, could underlie the development of atheromatosis in SLE.
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Enfermedades Cardiovasculares/etiología , Granulocitos , Lupus Eritematoso Sistémico/sangre , Monocitos , Adulto , Biomarcadores/sangre , Enfermedades Cardiovasculares/sangre , Estudios de Casos y Controles , Citocinas/sangre , Femenino , Humanos , Lupus Eritematoso Sistémico/complicaciones , Masculino , Persona de Mediana EdadRESUMEN
BACKGROUND: Overexpression of autologous proteins can lead to the formation of autoantibodies and autoimmune diseases. MHC class I polypeptide-related sequence A (MICA) is highly expressed in the enterocytes of patients with celiac disease, which arises in response to gluten. The aim of this study was to investigate anti-MICA antibody formation in patients with celiac disease and its association with other autoimmune processes. METHODS: We tested serum samples from 383 patients with celiac disease, obtained before they took up a gluten-free diet, 428 patients with diverse autoimmune diseases, and 200 controls for anti-MICA antibodies. All samples were also tested for anti-endomysium and anti-transglutaminase antibodies. RESULTS: Antibodies against MICA were detected in samples from 41.7% of patients with celiac disease but in only 3.5% of those from controls (P <0.0001) and 8.2% from patients with autoimmune disease (P <0.0001). These antibodies disappeared after the instauration of a gluten-free diet. Anti-MICA antibodies were significantly prevalent in younger patients (P <0.01). Fifty-eight patients with celiac disease (15.1%) presented a concomitant autoimmune disease. Anti-MICA-positive patients had a higher risk of autoimmune disease than MICA antibody-negative patients (P <0.0001; odds ratio = 6.11). The risk was even higher when we also controlled for age (odds ratio = 11.69). Finally, we found that the associated risk of developing additional autoimmune diseases was 16 and 10 times as high in pediatric patients and adults with anti-MICA, respectively, as in those without. CONCLUSIONS: The development of anti-MICA antibodies could be related to a gluten-containing diet, and seems to be involved in the development of autoimmune diseases in patients with celiac disease, especially younger ones.
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Autoanticuerpos/sangre , Enfermedades Autoinmunes/sangre , Enfermedades Autoinmunes/diagnóstico , Enfermedad Celíaca/sangre , Enfermedad Celíaca/diagnóstico , Antígenos de Histocompatibilidad Clase I/sangre , Adolescente , Adulto , Enfermedades Autoinmunes/dietoterapia , Enfermedad Celíaca/dietoterapia , Niño , Preescolar , Comorbilidad , Dieta Sin Gluten/métodos , Femenino , Glútenes/administración & dosificación , Glútenes/efectos adversos , Humanos , Masculino , Factores de Riesgo , Adulto JovenRESUMEN
Little information exists about the association of anti-SSA/Ro60 and anti-Ro52/TRIM21 with systemic lupus erytematosus (SLE) features. In this work, we analysed the associations of both anti-Ro reactivities with clinical and immunological manifestations in 141 SLE patients. Photosensitivity and xerophtalmia/xerostomia were found to be positively associated with both anti-SSA/Ro60 (P = 0.024 and P = 0.019, resp.) and anti-Ro52/TRIM21 (P = 0.026 and P = 0.022, resp.). In contrast, a negative association was detected regarding anti-phospholipid antibodies, anti-SSA/Ro60 having a stronger effect (P = 0.014) than anti-Ro52/TRIM21. Anti-SSA/Ro60 showed a specific positive association with hypocomplementemia (P = 0.041), mainly with low C4 levels (P = 0.008), whereas anti-Ro52/TRIM21 was found to be positively associated with Raynaud's phenomenon (P = 0.026) and cytopenia (P = 0.048) and negatively associated with anti-dsDNA (P = 0.013). Lymphocytes are involved in the relationship between anti-Ro52/TRIM21 and cytopenia since positive patients showed lower cell levels than negative patients (P = 0.036). In conclusion, anti-SSA/Ro60 and anti-Ro52/TRIM21 showed both common and specific associations in SLE. These data thus increase evidence of the different associations of the two anti-Ro specificities even in a particular disease.
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Anticuerpos Antinucleares/inmunología , Lupus Eritematoso Sistémico/inmunología , Ribonucleoproteínas/inmunología , Adulto , Anticuerpos Antinucleares/sangre , Anticuerpos Antifosfolípidos/sangre , Complemento C3/deficiencia , Complemento C4/deficiencia , Femenino , Humanos , Inhibidor de Coagulación del Lupus/análisis , Lupus Eritematoso Sistémico/sangre , Lupus Eritematoso Sistémico/complicaciones , Linfopenia/etiología , Linfopenia/inmunología , Masculino , Úlceras Bucales/etiología , Úlceras Bucales/inmunología , Fenotipo , Trastornos por Fotosensibilidad/etiología , Trastornos por Fotosensibilidad/inmunología , Enfermedad de Raynaud/etiología , Enfermedad de Raynaud/inmunología , Xeroftalmia/etiología , Xeroftalmia/inmunología , Xerostomía/etiología , Xerostomía/inmunología , Adulto JovenRESUMEN
OBJECTIVES: The aim of the study was to analyze the diagnostic performance of anti-deamidated gliadin peptide (dGp) immunoglobulin (Ig) G and IgA regarding the age at celiac disease (CD) diagnosis and the anti-dGp IgG usefulness for diagnosing CD IgA-deficient patients. METHODS: Anti-dGp IgG and IgA and anti-native gliadin (nGlia) IgA were determined by enzyme fluoroimmunoassay in 100 newly diagnosed anti-tissue transglutaminase (tTG) IgA-positive pediatric and adult patients with CD and in 100 age-matched patients with other digestive pathologies. Anti-dGp IgG was evaluated in 6 CD IgA-deficient patients. RESULTS: When analyzing all of the patients, the anti-dGp IgG assay showed higher diagnostic accuracy (area under receiver operating characteristic curve), specificity, and positive predictive value than anti-dGp IgA and anti-nGlia IgA. All of the diagnostic parameters corresponding to anti-dGp IgG reached the same values as anti-tTG IgA in children 7 years or younger. In older patients, both anti-dGp isotypes showed an inverse behavior, IgG having a higher specificity and positive predictive value but a lower sensitivity and negative predictive value than IgA. Anti-dGp levels were associated with the severity of intestinal lesions, and an inverse association was found regarding age at diagnosis. Both anti-dGp IgG and IgA were found to be positive in the 9 patients with minimal intestinal changes included in the study. All of the patients with CD with IgA deficiency were positive for anti-dGp IgG. CONCLUSIONS: The diagnostic performance of anti-dGp depends on the antibody isotype and on the age at CD diagnosis, anti-dGp IgG being a serological marker at least as useful as anti-tTG IgA for detecting CD in children ages 7 years or younger. Our data also indicate that anti-dGp IgG can improve the diagnosis of IgA-deficient patients.
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Enfermedad Celíaca/diagnóstico , Enfermedad Celíaca/inmunología , Gliadina/inmunología , Deficiencia de IgA/complicaciones , Inmunoglobulina A/sangre , Inmunoglobulina G/sangre , Adolescente , Adulto , Factores de Edad , Anciano , Anciano de 80 o más Años , Área Bajo la Curva , Enfermedad Celíaca/complicaciones , Niño , Preescolar , Femenino , Humanos , Lactante , Masculino , Persona de Mediana Edad , Valor Predictivo de las Pruebas , Curva ROC , Estudios Retrospectivos , Estadísticas no Paramétricas , Transglutaminasas/inmunología , Adulto JovenRESUMEN
INTRODUCTION: Impaired high-density lipoprotein (HDL) levels and antioxidant functionality of HDL, mainly attributed to a decreased paraoxonase-1 (PON1) functionality, have been described in autoimmune conditions. In this setting, a role for humoral response in cardiovascular disease is emerging. This study evaluates the role of immunoglobulin G (IgG) antibodies against HDL and disease-related autoantibodies on HDL dysfunction in immune-driven diseases. METHODS: Serum IgG anti-HDL antibodies, PON1 activity, and total antioxidant capacity (TAC) were quantified in 381 patients with different immune-driven diseases [18 mixed connective tissue disease (MCTD), 35 primary Sjögren syndrome (pSS), 38 systemic sclerosis (SSc), 33 ANCA-associated vasculitis (AAV), 60 diabetes mellitus 1, 29 autoimmune B12 deficiency/pernicious anemia, 29 primary biliary cirrhosis, 46 IBD/Crohn, 54 IBD/UC, and 39 celiac disease (CD)] and 138 healthy controls. RESULTS: IgG anti-HDL antibodies were increased in MCTD, pSS, AAV, and inflammatory bowel disease (IBD) [Crohn and ulcerative colitis (UC)], even after correcting for total IgG levels, but not in organ-specific autoimmune diseases. Anti-HDL antibodies were negatively associated with PON1 activity in MCTD (r = -0.767, p < 0.001) and AAV (r = -0.478, p = 0.005), whereas both anti-HDL and anti-neutrophil cytoplasm antibod levels were related to an impaired PON1 activity and TAC in IBD/UC. In SSc, anti-centromere antibodies correlated PON1 activity. anti-Saccharomyces cerevisiae antibodies levels were negatively associated with PON1 activity (r = -0.257, p = 0.012) and PON1/TAC ratio (r = -0.261, p = 0.009) in IBD/Crohn. HDL dysfunction in CD was only related to anti-transglutaminase levels. CONCLUSION: IgG anti-HDL antibodies and HDL dysfunction are common hallmarks of systemic autoimmunity. Anti-HDL and disease-related autoantibodies account for the HDL antioxidant dysfunction in immune-driven conditions, mainly in systemic autoimmune disorders.
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Dermatomyositis causes inflammation and damage of muscle and skin, and sometimes involves internal organs, especially lung parenchyma. Patients with dermatomyositis still represent a diagnostic challenge because of the rarity of this disease and the lack of specificity of some of its cutaneous manifestations. Herein, we describe the case of a patient with dermatomyositis, initially diagnosed as psoriatic arthritis, in which the performance of anti-melanoma differentiation-associated gene 5 (MDA5) antibodies was decisive to establish a definitive diagnosis.
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Artritis Psoriásica/diagnóstico , Autoanticuerpos/sangre , Dermatomiositis/diagnóstico , Helicasa Inducida por Interferón IFIH1/inmunología , Adulto , Biomarcadores/sangre , Dermatomiositis/sangre , Dermatomiositis/inmunología , Diagnóstico Diferencial , Errores Diagnósticos , Femenino , HumanosRESUMEN
The present study aimed to evaluate the possible role of immunoglobulin G (IgG) antibodies against high-density lipoproteins (HDL) and paraoxonase 1 (PON1) as possible biomarkers of cardiovascular disease (CVD) in systemic lupus erythematosus (SLE). To this end, levels of these autoantibodies, PON1 activity and total antioxidant capacity were quantified in serum samples from 198 SLE patients, 100 healthy controls (HC) and 42 non-autoimmune individuals with traditional cardiovascular risk factors. PON1 rs662 polymorphism was analysed in a subgroup of patients and controls. Subclinical CVD were determined by Doppler ultrasound in 118 SLE patients and 30 HC, analysing carotid intima-media thickness (IMT) and blood flow parameters in internal carotid, middle cerebral and basilar arteries. Serum levels of both anti-HDL and anti-PON1 antibodies were increased in SLE patients compared with HC (p < 0.001); however, only anti-PON1 antibodies, in addition to disease activity, were significant predictors of the impaired PON1 function in SLE (ß = -0.143, p = 0.045). Conversely, anti-HDL antibodies were associated with higher risk of CVD (odds ratio: 3.69; p = 0.012) and lower HDL levels at disease onset (ρ = -0.324, p = 0.044). Finally, anti-PON1 antibodies were associated with carotid IMT in SLE (ß = 0.201, p = 0.008) and inversely related to cranial arteries blood flow velocities in patients with clinical and subclinical CVD (all p < 0.001). In sum, these findings allowed us to propose serum levels of anti-PON1 and anti-HDL antibodies as potential early biomarkers of endothelial damage and premature atherosclerosis in SLE, thus constituting useful therapeutic targets for the prevention of future CVD in these patients.
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Arildialquilfosfatasa/inmunología , Autoanticuerpos/sangre , Enfermedades de las Arterias Carótidas/sangre , Inmunoglobulina G/sangre , Lipoproteínas HDL/inmunología , Lupus Eritematoso Sistémico/sangre , Adulto , Antioxidantes/análisis , Arildialquilfosfatasa/genética , Biomarcadores/sangre , Enfermedades de las Arterias Carótidas/diagnóstico por imagen , Enfermedades de las Arterias Carótidas/epidemiología , Enfermedades de las Arterias Carótidas/inmunología , Grosor Intima-Media Carotídeo , Estudios de Casos y Controles , Femenino , Humanos , Lupus Eritematoso Sistémico/diagnóstico , Lupus Eritematoso Sistémico/epidemiología , Lupus Eritematoso Sistémico/inmunología , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Valor Predictivo de las Pruebas , Prevalencia , Factores de Riesgo , España/epidemiología , Ultrasonografía DopplerRESUMEN
Asturias is an autonomous region in the north of Spain with historical and anthropologic peculiarities. In the current report, we examine the main clinical and immunologic features of 363 patients with systemic lupus erythematosus (SLE), virtually the entire population of SLE patients in Asturias. We constructed a database with the clinical and immunologic features of all patients fulfilling the American College of Rheumatology criteria, based on the review of hospital records corresponding to blood samples received for antinuclear antibodies testing since 1992. Arthritis was the most frequently observed main clinical feature and neuropathy was the rarest. Male patients had a disease more frequently characterized by serositis (p<0.05) and neurologic disorder (p<0.01) than females, while children presented malar rash (p<0.05), fever (p<0.05), and kidney involvement (p<0.01) more often than adults. Late-onset patients were characterized by lower frequencies of malar rash (p<0.01), neurologic disorder (p<0.05), alopecia (p<0.01), and lymphadenopathy (p<0.05) than young adults. Numerous direct and inverse significant associations were found among clinical and immunologic features. The most relevant significant associations were neurologic disorder with lupus anticoagulant (p<0.01); kidney involvement with serositis (p<0.01) and DNA antibodies (p<0.05); and thrombosis with DNA antibodies (p<0.05), cardiolipin antibodies (p<0.01), and lupus anticoagulant (p<0.01). A low mortality was found in our series, although kidney involvement (p<0.05) and cardiolipin antibodies (p<0.05) are factors associated with poor survival.
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Anticuerpos Antinucleares/sangre , Lupus Eritematoso Sistémico/diagnóstico , Lupus Eritematoso Sistémico/epidemiología , Adolescente , Adulto , Factores de Edad , Edad de Inicio , Niño , Ensayo de Inmunoadsorción Enzimática , Femenino , Humanos , Lupus Eritematoso Sistémico/sangre , Lupus Eritematoso Sistémico/fisiopatología , Enfermedades Linfáticas/fisiopatología , Masculino , Persona de Mediana Edad , Pronóstico , Ribonucleoproteínas/sangre , Ribonucleoproteínas/inmunología , Estudios Seroepidemiológicos , Serositis/fisiopatología , Factores Sexuales , España/epidemiología , Análisis de SupervivenciaRESUMEN
This study aims to analyze in depth the role of IFNα in the upregulation of BLyS in different leukocyte populations and the possible relationship of these molecules with IL-17 and other pathogenic cytokines in SLE. Thus, IFNAR1 and membrane BLyS (mBLyS) expression was upregulated on various blood cell types from patients and closely correlated in all individuals. Moreover, BLyS serum levels associated positively with IFNα and IL-17A amounts, as well as with mBLyS on B cells and neutrophils. Interestingly, mBLyS on neutrophils was also correlated with IL-17A levels. Additionally, intracellular IL-17A expression was increased in both CD4(+) lymphocytes and neutrophils from patients, and IL-17(+)CD4(+) T cell frequency was associated with serum IFNα and IFNRA1 expression on B cells. Finally, in vitro assays support an IFNα role in the activation of Th17 cells in SLE. In conclusion, these data suggest that IFNα, BLyS and IL-17 could form a pathological axis in SLE, involving T and B lymphocytes, monocytes, DCs and neutrophils, which act in a vicious circle that encourage the preexisting inflammation and propagate the disease process.
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Factor Activador de Células B/sangre , Interferón-alfa/sangre , Interleucina-17/sangre , Lupus Eritematoso Sistémico/metabolismo , Adulto , Linfocitos B/metabolismo , Femenino , Humanos , Lupus Eritematoso Sistémico/sangre , Masculino , Persona de Mediana Edad , Neutrófilos/metabolismo , Células Th17/metabolismo , Regulación hacia ArribaRESUMEN
BACKGROUND: Genetic variations in the interleukin (IL)-10 gene promoter have been associated with levels of induced production of IL-10, disease susceptibility, and allograft rejection. Small amounts of this cytokine are constitutively produced and are important in maintaining the physiologic function of the cytokine network. In this study, we evaluated the distribution of IL-10 basal levels and its genetic regulation in a healthy Spanish population. METHODS: Polymorphisms at the -1,082, -819, and -512 positions of the IL-10 promoter were analyzed by polymerase chain reaction amplification and hybridization with fluorescent-labeled allele-specific probes in 183 Spanish people. Levels of IL-10 messenger (m)RNA were tested by real-time reverse transcription-polymerase chain reaction in 123 healthy donors. Serum concentrations of IL-10 were measured by a highly sensitive ELISA, whereas protein amounts in lipopolysaccharide culture supernatants were quantified by an in-house ELISA. RESULTS: The frequency of IL-10 promoter alleles and haplotypes in our population showed remarkable differences from other Caucasian populations. Large interindividual variations were found in mRNA and protein constitutive levels of IL-10, which allowed its classification in low and intermediate/high producers. We found statistical differences in mRNA concentration between the polymorphic variant GCC/GCC and the low producer genotypes. The G allele at position -1082 was the most important genetic factor in the regulation of constitutive IL-10 mRNA levels. Similarly, we also found an association of this polymorphic position with serum concentration greater than 2 pg/mL. CONCLUSIONS: Constitutive levels of IL-10 (mRNA and serum protein) displayed remarkable interindividual variations, which are genetically controlled by polymorphic variants at the cytokine gene promoter.
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Interleucina-10/genética , Interleucina-10/metabolismo , Polimorfismo Genético/fisiología , ARN Mensajero/metabolismo , Alelos , Frecuencia de los Genes , Genotipo , Haplotipos , Humanos , Lipopolisacáridos/farmacología , Concentración Osmolar , Regiones Promotoras Genéticas/fisiologíaRESUMEN
Anti-Golgi antibodies are a type of anticytoplasmic autoantibody rarely found during routine examination of pathological samples. Although they have been mostly associated with connective autoimmune diseases, they are also present in other clinical conditions, including few cases of liver dysfunction. In this report, we describe for the first time the presence of high titres of anti-Golgi antibodies in a patient with virus-C-induced hepatocellular carcinoma (HCC). By immunofluorescence, the patient's serum yielded a characteristic fluorescence pattern that corresponded to the presence of Golgi reactivity. On immunoblot, the serum disclosed three reactive bands of approximately 105, 79 and 59 kDa. In addition, we retrospectively analysed the presence of anti-Golgi antibodies in sera from 95 patients with chronic hepatitis C, in 32 patients with chronic hepatitis B, in 35 patients with HCC associated with either virus C (27 cases), virus B (five cases) or both virus C and virus B (three cases), and in 18 patients with HCC induced by alcoholism. We found an additional positive patient, beside the patient presented herein, with HCC induced by B virus infection, whereas all patients without HCC were negative. Thus, the overall frequency of anti-Golgi antibodies in our series of patients with virus-induced HCC was 5.5% (two cases out of 36). The mechanism involved in the appearance of anti-Golgi antibodies in HCC is discussed, along with a review of the reported cases of liver diseases associated with the appearance of Golgi autoantibodies.
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Autoanticuerpos/sangre , Carcinoma Hepatocelular/inmunología , Aparato de Golgi/inmunología , Neoplasias Hepáticas/inmunología , Anciano , Anciano de 80 o más Años , Carcinoma Hepatocelular/virología , Técnica del Anticuerpo Fluorescente Indirecta , Hepatitis C Crónica/complicaciones , Hepatitis C Crónica/inmunología , Humanos , Immunoblotting , Neoplasias Hepáticas/virología , MasculinoRESUMEN
Clinical associations of anti-SSA/Ro60 and anti-Ro52/TRIM21 antibodies are not yet fully established. In order to analyse the diagnostic utility of their separate detection, we retrospectively revised the clinical data of 200 anti-SSA/Ro60 and/or anti-Ro52/TRIM21 positive patients identified by line immunoassay during ANA routine detection. Anti-SSA/Ro60 positive patients showed a significantly higher prevalence of autoimmune diseases (AIDs) independently on the presence of anti-Ro52/TRIM21 (OR 3.13, 95% CI 1.10-8.88, p = 0.032). Anti-SSA/Ro60 was independently associated with systemic lupus erythematosus (SLE) when comparing with Sjögren's syndrome (SS) and other systemic AIDs (OR 3.46, 95% CI 1.08-11.06, p = 0.036). The more frequent specificity found in cutaneous lupus erythematosus (CLE) was also anti-SSA/Ro60. In contrast, detection of isolated anti-Ro52/TRIM21 was characteristic of SS (7/35, 20.0%), diffuse cutaneous systemic sclerosis (dcSSc) (3/4, 75.0%), primary biliary cirrhosis (PBC) (4/5, 80.0%) and, specially, of polymyositis/dermatomyositis (PM/DM) (6/6, 100%). In fact, anti-Ro52/TRIM21 was the only antibody detected in 4 out of the 6 PM/DM patients. Malignancies mainly account for the observed high prevalence of mono-specific anti-Ro52/TRIM21 in patients with non-AIDs (10/15, 62.5%). In conclusion, this retrospective study supports the routine distinction of anti-SSA/Ro60 and anti-Ro52/TRIM21 due to their different clinical associations.
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Enfermedades Autoinmunes/inmunología , Ribonucleoproteínas/inmunología , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Enfermedades Autoinmunes/sangre , Enfermedades Autoinmunes/diagnóstico , Estudios de Cohortes , Femenino , Humanos , Técnicas para Inmunoenzimas , Modelos Logísticos , Masculino , Persona de Mediana Edad , Análisis Multivariante , Estudios Retrospectivos , Ribonucleoproteínas/sangre , Adulto JovenRESUMEN
Dermatomyositis causes inflammation and damage of muscle and skin, and sometimes involves internal organs, especially lung parenchyma. Patients with dermatomyositis still represent a diagnostic challenge because of the rarity of this disease and the lack of specificity of some of its cutaneous manifestations. Herein, we describe the case of a patient with dermatomyositis, initially diagnosed as psoriatic arthritis, in which the performance of anti-melanoma differentiation-associated gene 5 (MDA5) antibodies was decisive to establish a definitive diagnosis
La dermatomiositis causa inflamación y daño del músculo y la piel, y en ocasiones afecta a órganos internos, especialmente el parénquima pulmonar. Los pacientes con dermatomiositis representan todavía un reto diagnóstico debido a la rareza de esta enfermedad y la falta de especificidad de algunas de sus manifestaciones cutáneas. Describimos el caso de una paciente con dermatomiositis, inicialmente diagnosticada de artritis psoriásica, en la que la determinación de anticuerpos anti-MDA5 fue decisiva para establecer un diagnóstico definitivo
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Humanos , Femenino , Adulto , Helicasa Inducida por Interferón IFIH1/genética , Dermatomiositis/diagnóstico , Artritis Psoriásica/diagnóstico , Diagnóstico Diferencial , Alendronato/uso terapéutico , Tacrolimus/uso terapéuticoRESUMEN
OBJECTIVE: There are dysregulated levels of interleukin 10 (IL-10) and tumor necrosis factor-alpha (TNF-alpha) in rheumatoid arthritis (RA), and their role in the disease is controversial. We analyzed the association of functional polymorphisms of IL-10 and TNF-alpha with susceptibility and disease characteristics at the time of diagnosis, and we also evaluated their possible use as predictors of clinical response to treatments. METHODS: Patients with recent-onset RA (n = 162) and healthy controls (n = 373) were genotyped for -1082 IL-10 and -308 TNF-alpha polymorphisms and data were related to clinical and immunological measurements of patients at the time of diagnosis. Response to treatment after 6 months was determined in 125 patients by the absolute change in Disease Activity Score (DAS28) and the American College of Rheumatology criteria for improvement. RESULTS: We found a reduced frequency of the low IL-10 producer genotype (-1082AA) in patients with RA compared to controls (26.5% vs 38.9%; p = 0.006), while it is a risk factor for anticyclic citrullinated peptide antibodies (anti-CCP) positivity (p = 0.028). Evaluation of clinical response to treatments indicated that carriage of the high IL-10 genotype was associated with a favorable outcome (p = 0.009), specifically to prednisone therapy (p = 0.0003). No significant effects were observed with TNF-alpha polymorphism alone; however, in combination with the IL-10 genotype, it increased the strength of these associations. CONCLUSION: Results show an association between the low IL-10 producer genotype and protection from RA; nevertheless, when other specific genetic and/or environmental factors trigger onset of RA, this genotype may predispose to development of anti-CCP+ RA disease with reduced response to prednisone treatment.
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Artritis Reumatoide/tratamiento farmacológico , Artritis Reumatoide/genética , Glucocorticoides/uso terapéutico , Interleucina-10/genética , Polimorfismo Genético/genética , Factor de Necrosis Tumoral alfa/genética , Adulto , Anciano , Anciano de 80 o más Años , Anticuerpos/sangre , Artritis Reumatoide/inmunología , Estudios de Casos y Controles , Femenino , Predisposición Genética a la Enfermedad/genética , Genotipo , Humanos , Masculino , Persona de Mediana Edad , Péptidos Cíclicos/inmunología , Pronóstico , Índice de Severidad de la Enfermedad , Resultado del TratamientoRESUMEN
INTRODUCTION: The clinical associations of NuMA and HsEg5 antibodies, the main anti-mitotic spindle apparatus autoantibodies, remain unclear due to their extremely low prevalence. PATIENTS AND METHODS: We have analysed the clinical data of 40 anti-NuMA- (0.87 per thousand) and 7 anti-HsEg5- (0.15 per thousand) positive patients detected during routine immunofluorescence examination of 45,804 sera. NuMA reactivity was further confirmed by immunoblotting. RESULTS: Antibodies to HsEg5 did not associate with any specific pathology. NuMA positivity associated with a diagnosis of connective tissue disease (CTD) in 18 patients (45%), primary Sjögren or sicca syndrome and undifferentiated connective tissue disease being the most represented. Seven patients (17.5%) were diagnosed with different organ-specific autoimmune diseases, whereas in the other 15 patients (37.5%), no autoimmune pathology could be documented. CONCLUSIONS: Therefore, although both anti-mitotic spindle apparatus antibodies are not associated to a defined autoimmune pathology, the presence of NuMA antibodies, mainly at high titers, may be an indication for a more extensive screening of CTD.
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Antígenos Nucleares/inmunología , Autoanticuerpos/sangre , Autoantígenos/inmunología , Enfermedades del Tejido Conjuntivo/inmunología , Cinesinas/inmunología , Proteínas Asociadas a Matriz Nuclear/inmunología , Adulto , Anciano , Anciano de 80 o más Años , Proteínas de Ciclo Celular , Enfermedades del Tejido Conjuntivo/sangre , Femenino , Técnica del Anticuerpo Fluorescente , Humanos , Immunoblotting , Masculino , Persona de Mediana EdadRESUMEN
The appearance of autoantibodies is a common characteristic of ulcerative colitis (UC). Specifically, anti-neutrophil cytoplasmic antibodies (ANCA) are the most prevalent in this disease and their synthesis may be genetically conditioned. The aim of the present study was to test the influence on appearance of autoantibodies of IL-10 and TNFalpha genes promoter polymorphisms, which control cytokine levels. Genetic polymorphisms of TNFalpha (-308 G/A) and IL-10 (-1082 G/A) and ANCA and anti-goblet cells antibodies (GAB) presence were determined in 99 UC patients. The -308A* allele and -308AA/AGTNFalpha genotypes (high producer), clearly correlated with ANCA positivity (p = 0.004 and p = 0.007, respectively). Additionally, homozygous carriage of the -1082A*IL-10 allele (low producer) significantly associated with ANCA presence (p = 0.007). Furthermore, combination of both genotypes (low IL-10/high TNFalpha producer genotype) had a greater influence on ANCA positivity than each individual genotype (p = 0.008). ANCA production in UC thus appears to be conditioned by IL-10 and TNFalpha genotypes.
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Anticuerpos Anticitoplasma de Neutrófilos/sangre , Colitis Ulcerosa/sangre , Colitis Ulcerosa/genética , Interleucina-10/genética , Factor de Necrosis Tumoral alfa/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Niño , Colitis Ulcerosa/inmunología , Femenino , Técnica del Anticuerpo Fluorescente , Genotipo , Células Caliciformes/inmunología , Humanos , Masculino , Persona de Mediana Edad , Polimorfismo Genético , Regiones Promotoras GenéticasRESUMEN
Antimalarial agents have been widely used as disease-modifying antirheumatic drugs in the treatment of systemic lupus erythematosus (SLE) and other rheumatological diseases, although their mechanism of action has not yet been fully defined. It is known, however, that effective response to treatment is variable among patients. Thus, the identification of genetic predictors of treatment response would provide valuable information for therapeutic intervention. The aim of the present study was to analyze the effect of antimalarial treatment on tumor necrosis factor (TNF)alpha serum levels and evaluate the possible influence of TNFalpha and IL-10 functional genetic polymorphisms on the response to antimalarial drugs. To this end, TNFalpha serum levels were quantified in 171 SLE patients and 215 healthy controls by ELISA techniques and polymorphisms at positions -1,082 and -308 of the IL-10 and TNFalpha gene promoters were determined by PCR amplification followed by hybridization with fluorescent-labeled allele-specific probes in 192 SLE patients and 343 matched controls. Data were related to clinical features and treatment at the time of sampling and during the course of the disease. Results showed a significantly higher amount of serum TNFalpha in the entire SLE population compared with controls. However, TNFalpha serum levels correlated negatively with the use of antimalarial treatment during at least three months before sampling. Patients under single or combined treatment with these drugs had TNFalpha serum levels similar to healthy controls, whereas untreated patients and those under corticosteroid or immunosuppressive therapies had increased amounts of this cytokine. This suggests, however, that antimalarial-mediated inhibition of TNFalpha was only significant in patients who were genetically high TNFalpha or low IL-10 producers. In addition, evaluation of SLE patients administered antimalarial drugs for three or more years who did not require any other specific SLE treatment indicates that patients with the combined genotype low IL-10/high TNFalpha are the best responders to antimalarial therapy, developing mild disease with a good course under this treatment. In conclusion, we proposed that an antimalarial-mediated downregulation of TNFalpha levels in SLE patients is influenced by polymorphisms at IL-10 and TNFalpha promoters. Our results may thus find important clinical application through the identification of patients who are the most likely to benefit from antimalarial therapy.
Asunto(s)
Antimaláricos/uso terapéutico , Interleucina-10/genética , Lupus Eritematoso Sistémico/tratamiento farmacológico , Lupus Eritematoso Sistémico/genética , Polimorfismo Genético , Factor de Necrosis Tumoral alfa/genética , Adulto , Anciano , Estudios de Casos y Controles , Quimioterapia Combinada , Femenino , Genotipo , Humanos , Lupus Eritematoso Sistémico/sangre , Masculino , Persona de Mediana Edad , Polimorfismo de Nucleótido Simple , Resultado del Tratamiento , Factor de Necrosis Tumoral alfa/antagonistas & inhibidores , Factor de Necrosis Tumoral alfa/metabolismoRESUMEN
A typical feature of Crohn's disease (CD) patients is the development of antibodies against self- (PAB) or exogenous (ASCA) antigens, a process in which mucosal cytokine expression pattern might be involved. On the other hand, mutations in CARD15, a genetic risk factor for CD, alter cytokine production in response to bacterial infection. In the present study, we evaluated the role of functionally relevant IL-10 and TNFalpha gene polymorphisms in the synthesis of these antibodies and their relationship with CARD15 mutations. In CARD15 wild type patients, high TNFalpha producer genotypes protect against IgA-ASCA development, whereas an inverse association was observed in autoantibody synthesis (PAB). These associations were not observed in patients with CARD15 mutations, probably due to the lack of TNFalpha release as a consequence of the failure of CARD15 protein to recognize the peptidoglycan. Thus, we proposed a CARD15-TNFalpha circuit that might play a role in mucosal immune surveillance.
Asunto(s)
Anticuerpos Antifúngicos/inmunología , Enfermedad de Crohn/genética , Enfermedad de Crohn/inmunología , Inmunoglobulina A/inmunología , Proteína Adaptadora de Señalización NOD2/genética , Saccharomyces cerevisiae/inmunología , Factor de Necrosis Tumoral alfa/genética , Adolescente , Adulto , Anciano , Anciano de 80 o más Años , Alelos , Anticuerpos Antifúngicos/biosíntesis , Anticuerpos Antifúngicos/sangre , Biomarcadores , Enfermedad de Crohn/epidemiología , Enfermedad de Crohn/metabolismo , Femenino , Genotipo , Humanos , Inmunoglobulina A/biosíntesis , Inmunoglobulina A/sangre , Interleucina-10/genética , Masculino , Persona de Mediana Edad , Mutación/genética , PrevalenciaRESUMEN
OBJECTIVES: An altered production of cytokines underlies inflammatory bowel disease (IBD) susceptibility. Various polymorphisms at the IL-10 and TNFalpha gene promoters control cytokine production levels. The influence of these polymorphisms on susceptibility to ulcerative colitis (UC) and Crohn's disease (CD) and their association with clinical features were analyzed. SUBJECTS AND METHODS: Genetic polymorphisms of TNFalpha (-308 G/A) and IL-10 (-1082 G/A, -812 C/T, and -592 C/A) were determined using the LightCycler system with hybridization probes matched with one sequence variant. The study population included 99 UC patients, 146 CD patients, and 343 matched controls. RESULTS: We did not find association between TNFalpha or IL-10 gene polymorphisms and UC or CD susceptibility, though a slight influence of -1082*G allele in UC appearance was observed. In a stratified analysis, a highly significant association between the -1082 AA IL-10 genotype and the steroid dependency was observed in IBD (p < 0.0001), contributing both UC (p = 0.004) and CD (p = 0.003) to this association. In contrast, TNFalpha genotypes did not influence steroid dependency in IBD. Further, the contribution of cytokine genotypes and of clinical features to the appearance of steroid-dependent status (dependent variable) was studied by multivariate analysis. The steroid-dependent phenotype correlated in UC with extensive disease (p = 0.010) and with the low producer -1082 AA IL-10 genotype (p = 0.002) and in CD with penetrating disease (p = 0.010), arthritis (p = 0.011), and the -1082 AA IL-10 genotype (p = 0.006). CONCLUSIONS: The main conclusion is that carriage of the -1082 AA IL-10 genotype (low producer) is a relevant risk factor for developing steroid-dependent IBD.