RESUMO
ITGAM-ITGAX (rs11150612, rs11574637), VAV3 rs17019602, CARD9 rs4077515, DEFA (rs2738048, rs10086568), and HORMAD2 rs2412971 are mucosal immune defence polymorphisms, that have an impact on IgA production, described as risk loci for IgA nephropathy (IgAN). Since IgAN and Immunoglobulin-A vasculitis (IgAV) share molecular mechanisms, with the aberrant deposit of IgA1 being the main pathophysiologic feature of both entities, we assessed the potential influence of the seven abovementioned polymorphisms on IgAV pathogenesis. These seven variants were genotyped in 381 Caucasian IgAV patients and 997 matched healthy controls. No statistically significant differences were observed in the genotype and allele frequencies of these seven polymorphisms when the whole cohort of IgAV patients and those with nephritis were compared to controls. Similar genotype and allele frequencies of all polymorphisms were disclosed when IgAV patients were stratified according to the age at disease onset or the presence/absence of gastrointestinal or renal manifestations. Likewise, no ITGAM-ITGAX and DEFA haplotype differences were observed when the whole cohort of IgAV patients, along with those with nephritis and controls, as well as IgAV patients, stratified according to the abovementioned clinical characteristics, were compared. Our results suggest that mucosal immune defence polymorphisms do not represent novel genetic risk factors for IgAV pathogenesis.
Assuntos
Glomerulonefrite por IGA , Vasculite por IgA , Imunidade nas Mucosas , Nefrite , Humanos , Antígeno CD11c , Frequência do Gene , Genótipo , Glomerulonefrite por IGA/genética , Vasculite por IgA/genética , Polimorfismo Genético , Imunidade nas Mucosas/genéticaRESUMO
OBJECTIVES: Interferon regulatory factor 5 (IRF5) is a major regulator of type I interferon induction and is also critical to produce pro-inflammatory cytokines. An influence of IRF5 genetic variants on the increased risk of immune-mediated diseases has been described. Accordingly, we aimed to evaluate the implication of IRF5 in the pathogenesis of Immunoglobulin-A vasculitis (IgAV), an inflammatory vascular pathology. METHODS: Three tag genetic variants (rs2004640, rs2070197 and rs10954213), representative of 3 different haplotype blocks within IRF5, were genotyped in 372 Caucasian patients with IgAV and 876 sex and ethnically matched healthy controls by TaqMan assays. RESULTS: No significant differences in the genotype and allele frequencies between patients with IgAV and healthy controls were observed when each IRF5 polymorphism was evaluated independently. Likewise, no significant differences between patients with IgAV and healthy controls were found when we assessed the three IRF5 polymorphisms combined, conforming haplotypes. In addition, there were no significant differences in genotype, allele and haplotype frequencies of IRF5 when patients with IgAV were stratified according to the age at disease onset or to the presence/absence of gastrointestinal or renal manifestations. CONCLUSIONS: Our results do not support an influence of IRF5 on the pathogenesis of IgAV.
Assuntos
Predisposição Genética para Doença , Imunoglobulina A , Fatores Reguladores de Interferon/genética , Vasculite/genética , Estudos de Casos e Controles , Genótipo , Haplótipos , Humanos , Polimorfismo de Nucleotídeo ÚnicoRESUMO
OBJECTIVES: Cytokines signaling pathway genes represent a key component of the genetic network implicated in the pathogenesis of immunoglobulin-A vasculitis (IgAV), an inflammatory vascular pathology. Interleukin (IL)17A is described as a genetic risk locus for some autoimmune diseases, such as giant cell arteritis and spondyloarthritis. Accordingly, we aimed to determine the potential influence of IL17A on the pathogenesis of IgAV. METHODS: Five IL17A tag polymorphisms (rs4711998, rs8193036, rs3819024, rs2275913 and rs7747909), which cover the major variability of this gene, were genotyped in 360 Caucasian patients with IgAV and 1,003 sex and ethnically matched healthy controls using TaqMan probes. RESULTS: No statistically significant differences between patients with IgAV and healthy controls were observed when each IL17A genetic variant was analysed independently. Similarly, no statistically significant differences between patients with IgAV and healthy controls were found when the five IL17A polymorphisms were evaluated combined conforming haplotypes. In addition, there were no statistically significant differences in genotype, allele and haplotype frequencies of IL17A when patients with IgAV were stratified according to the age at disease onset or to the presence/absence of gastrointestinal or renal manifestations. CONCLUSIONS: Our results do not support an influence of IL17A on the pathogenesis of IgAV.
Assuntos
Predisposição Genética para Doença , Imunoglobulina A , Interleucina-17/genética , Vasculite/genética , Estudos de Casos e Controles , Redes Reguladoras de Genes , Haplótipos , Humanos , Polimorfismo de Nucleotídeo Único , Vasculite/patologiaRESUMO
BACKGROUND: Early cerebral hypoperfusion and ischemia occur after subarachnoid hemorrhage (SAH) and influence clinical prognosis. Pathophysiological mechanisms possibly involve inflammatory mediators. TNF-α has been associated with complications and prognosis after SAH. We investigated the relation of perfusion parameters and ischemic lesions, with levels of TNF-α main receptor, TNF-R1, after SAH, and their association with prognosis. METHODS: We included consecutive SAH patients admitted within the first 72 h of SAH onset. Blood samples were simultaneously collected from a peripheral vein and from the parent artery of the aneurysm. Levels of TNF-R1 were measured using ELISA (R&D Systems Inc., USA). CT perfusion and MRI studies were performed in the first 72 h. Correlation and logistic regression analysis were used to identify outcome predictors. RESULTS: We analyzed 41 patients. Increased levels of TNF-R1 correlated with increased Tmax (arterial: r = -0.37, p = 0.01) and prolonged MTT (arterial: r = 0.355, p = 0.012; venous: r = 0.306, p = 0.026). Increased levels of both arterial and venous TNF-R1 were associated with increased number of lesions on DWI (p = 0.006). In multivariate analysis, venous TNFR1 levels > 1742.2 pg/mL (OR 1.78; 95%CI 1.18-2.67; p = 0.006) and DWI lesions (OR 14.01; 95%CI 1.19-165.3; p = 0.036) were both independent predictors of poor outcome (mRS ≥ 3) at 6 months. CONCLUSION: Increased levels of TNF-R1 in arterial and venous blood correlate with worse cerebral perfusion and with increased burden of acute ischemic lesions in the first 72 h after SAH. Venous levels of TNF-R1 and DWI lesions were associated with poor outcome at 6 months. These results highlight the pathophysiological role of TNF-α pathways in SAH and suggest a possible role of combined imaging and laboratorial markers in determining prognosis in acute SAH.
Assuntos
Isquemia Encefálica , Circulação Cerebrovascular , Hemorragia Subaracnóidea , Isquemia Encefálica/diagnóstico por imagem , Isquemia Encefálica/etiologia , Humanos , Isquemia , Perfusão , Receptores Tipo I de Fatores de Necrose Tumoral , Hemorragia Subaracnóidea/complicações , Hemorragia Subaracnóidea/diagnóstico por imagemRESUMO
CD40, BLK and BANK1 genes involved in the development and signaling of B-cells are identified as susceptibility loci for numerous inflammatory diseases. Accordingly, we assessed the potential influence of CD40, BLK and BANK1 on the pathogenesis of immunoglobulin-A vasculitis (IgAV), predominantly a B-lymphocyte inflammatory condition. Three genetic variants within CD40 (rs1883832, rs1535045, rs4813003) and BLK (rs2254546, rs2736340, rs2618476) as well as two BANK1 polymorphisms (rs10516487, rs3733197), previously associated with inflammatory diseases, were genotyped in 382 Caucasian patients with IgAV and 955 sex- and ethnically matched healthy controls. No statistically significant differences were observed in the genotype and allele frequencies of CD40, BLK and BANK1 when IgAV patients and healthy controls were compared. Similar results were found when CD40, BLK and BANK1 genotypes or alleles frequencies were compared between patients with IgAV stratified according to the age at disease onset or to the presence/absence of gastrointestinal or renal manifestations. Moreover, no CD40, BLK and BANK1 haplotype differences were disclosed between patients with IgAV and healthy controls and between patients with IgAV stratified according to the clinical characteristics mentioned above. Our findings indicate that CD40, BLK and BANK1 do not contribute to the genetic background of IgAV.
RESUMO
BAFF, APRIL and BAFF-R are key proteins involved in the development of B-lymphocytes and autoimmunity. Additionally, BAFF, APRIL and BAFFR polymorphisms were associated with immune-mediated conditions, being BAFF GCTGT>A a shared insertion-deletion genetic variant for several autoimmune diseases. Accordingly, we assessed whether BAFF, APRIL and BAFFR represent novel genetic risk factors for Immunoglobulin-A vasculitis (IgAV), a predominantly B-lymphocyte inflammatory condition. BAFF rs374039502, which colocalizes with BAFF GCTGT>A, and two tag variants within APRIL (rs11552708 and rs6608) and BAFFR (rs7290134 and rs77874543) were genotyped in 386 Caucasian IgAV patients and 806 matched healthy controls. No genotypes or alleles differences were observed between IgAV patients and controls when BAFF, APRIL and BAFFR variants were analysed independently. Likewise, no statistically significant differences were found in the genotype and allele frequencies of BAFF, APRIL or BAFFR when IgAV patients were stratified according to the age at disease onset or to the presence/absence of gastrointestinal (GI) or renal manifestations. Similar results were disclosed when APRIL and BAFFR haplotypes were compared between IgAV patients and controls and between IgAV patients stratified according to the clinical characteristics mentioned above. Our results suggest that BAFF, APRIL and BAFFR do not contribute to the genetic network underlying IgAV.
Assuntos
Doenças Autoimunes , Fator Ativador de Células B/genética , Receptor do Fator Ativador de Células B/genética , Imunoglobulina A/imunologia , Polimorfismo de Nucleotídeo Único , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/genética , Vasculite , Adulto , Doenças Autoimunes/genética , Doenças Autoimunes/imunologia , Fator Ativador de Células B/imunologia , Receptor do Fator Ativador de Células B/imunologia , Feminino , Humanos , Masculino , Membro 13 da Superfamília de Ligantes de Fatores de Necrose Tumoral/imunologia , Vasculite/genética , Vasculite/imunologiaRESUMO
Cytokines signalling pathway genes are crucial factors of the genetic network underlying the pathogenesis of Immunoglobulin-A vasculitis (IgAV), an inflammatory vascular condition. An influence of the interleukin (IL)33- IL1 receptor like (IL1RL)1 signalling pathway on the increased risk of several immune-mediated diseases has been described. Accordingly, we assessed whether the IL33-IL1RL1 pathway represents a novel genetic risk factor for IgAV. Three tag polymorphisms within IL33 (rs3939286, rs7025417 and rs7044343) and three within IL1RL1 (rs2310173, rs13015714 and rs2058660), that also were previously associated with several inflammatory diseases, were genotyped in 380 Caucasian IgAV patients and 845 matched healthy controls. No genotypes or alleles differences were observed between IgAV patients and controls when IL33 and IL1RL1 variants were analysed independently. Likewise, no statistically significant differences were found in IL33 or IL1RL1 genotype and allele frequencies when IgAV patients were stratified according to the age at disease onset or to the presence/absence of gastrointestinal (GI) or renal manifestations. Similar results were disclosed when IL33 and IL1RL1 haplotypes were compared between IgAV patients and controls and between IgAV patients stratified according to the clinical characteristics mentioned above. Our results suggest that the IL33-IL1RL1 signalling pathway does not contribute to the genetic network underlying IgAV.
Assuntos
Vasculite por IgA/genética , Vasculite por IgA/imunologia , Imunoglobulina A/metabolismo , Proteína 1 Semelhante a Receptor de Interleucina-1/genética , Proteína 1 Semelhante a Receptor de Interleucina-1/imunologia , Interleucina-33/genética , Interleucina-33/imunologia , Adolescente , Estudos de Casos e Controles , Criança , Feminino , Frequência do Gene , Redes Reguladoras de Genes , Predisposição Genética para Doença , Genótipo , Haplótipos , Humanos , Vasculite por IgA/etiologia , Masculino , Polimorfismo de Nucleotídeo Único , Transdução de Sinais/genética , Transdução de Sinais/imunologia , Adulto JovemRESUMO
BACKGROUND: The prevalence of pneumonia in infants with high fever without source (FWS; temperature, > or =39.0 degrees C) and a white blood cell (WBC) count greater than 20 x 10(9)/L (occult pneumonia) has been reported to be 20% before the introduction of the 7-valent pneumococcal conjugated vaccine (PCV7). This is the main reason for carrying out chest x-ray (CXR) on infants with high FWS. The aims of this study were to establish the prevalence of occult pneumonia in well-appearing infants with high FWS (temperature, > or =39.0 degrees C) and a WBC count greater than 20 x 10(9)/L in the era of PCV7 and to analyze the value of WBC, absolute neutrophil count (ANC), and C-reactive protein (CRP) level as predictors of the risk of occult pneumonia in these patients. PATIENTS AND METHODS: We conducted a multicenter prospective study in 4 pediatric emergency departments including children younger than 36 months with FWS (temperature, > or =39.0 degrees C) and a WBC count higher than 20 x 10(9)/L on whom a CXR was performed in the absence of respiratory findings. Physicians completed a questionnaire when observing the infant, and the attending physician or, when in doubt, the radiologist interpreted the CXR. Multivariable binary logistic regression was used to estimate the adjusted relative influences of the aforementioned factors on the prevalence of radiological pneumonia. RESULTS: During an entire year (September 2006 to September 2007), we included 188 infants (aged 1-36 months; 56.2% were males) with high FWS and a WBC count greater than 20 x 10(9)/L (range, 20-44.7 x 10(9)/L) on whom a CXR was performed. Of the 188 chest radiographs obtained, 37 (19.7%) were interpreted by the radiologist. Consolidation in the chest radiographs was detected in 25 (13.3%). The probability of an infant with high FWS and WBC of 20 x 10(9)/L or greater having pneumonia was related to 3 of the studied variables: age, ANC, and serum CRP level. The incidence of pneumonia increased with age (odds ratio [OR] of 2.62 for infants >12 months; 95% confidence interval [95% CI], 1.04-6.60), CRP level greater than 100 mg/L (OR, 3.18; 95% CI, 1.19-8.51), and ANC greater than 20 x 10(9)/L (OR, 3.52; 95% CI, 1.37-9.06). White blood cell count was not predictive of occult pneumonia when ANC was taken into account. CONCLUSIONS: In the era of PCV7, the incidence of pneumonia in infants younger than 36 months with high FWS and WBC count greater than 20 x 10(9)/L seems to be lower than that previously reported. However, this is not a uniform group because the incidence of pneumonia increases in infants older than 12 months and with higher ANC and serum CRP level.
Assuntos
Febre de Causa Desconhecida/epidemiologia , Pneumonia/epidemiologia , Proteína C-Reativa/análise , Comorbidade , Feminino , Febre de Causa Desconhecida/sangue , Humanos , Incidência , Lactente , Contagem de Leucócitos , Masculino , Neutrófilos , Pneumonia/sangue , Estudos ProspectivosRESUMO
Acute generalized exanthematous pustulosis (AGEP) comprises a group of eruptions characterized by several small sterile pustules over an erythematous-edematous skin. These eruptions are usually drug induced and show some characteristics that suggest an immunologic background. Treatment is based on withdrawal of the drug causing the eruption. Prognosis is generally good and the skin lesions usually resolve in a few days with characteristic postpustular pin-point desquamation. We report three cases of AGEP induced by omeprazole, a drug with a good safety profile. Some adverse cutaneous reactions have been described as secondary effects. However, to our knowledge, no cases of omeprazole-induced AGEP have previously been reported. AGEP related to other proton pump inhibitors is exceptional.
Assuntos
Toxidermias/etiologia , Exantema/induzido quimicamente , Omeprazol/efeitos adversos , Inibidores da Bomba de Prótons/efeitos adversos , Dermatopatias Vesiculobolhosas/induzido quimicamente , Doença Aguda , Idoso , Idoso de 80 Anos ou mais , Feminino , Humanos , Masculino , Pessoa de Meia-IdadeRESUMO
BACKGROUND AND OBJECTIVE: Calciphylaxis is a cutaneous ischaemic vascular disease of small vessels with high morbidity and mortality. To date very few series of patients with this disease have been published, none from a Spanish hospital. The main objectives of this work are to analyze the demographic, clinical and histological profile of patients diagnosed in our department to identify risk factors and potential therapeutic strategies. MATERIAL AND METHOD: We made a retrospective study of the cases seen in the dermatology department with a diagnosis of calciphylaxis and who had a confirmatory biopsy in the period between January 2010 to August 2015. RESULTS: Nine patients were studied, with an age range of 76-86 years. All had cardiovascular comorbidities and 67% had renal failure. A 33% mortality was observed. CONCLUSIONS: Faced with a possible diagnosis of calciphylaxis, a complete blood analysis is mandatory to rule out other causes of skin ulcers. The management of these patients should be undertaken by a multidisciplinary team. We emphasize the role of sodium thiosulfate in the treatment of this condition.
Assuntos
Calciofilaxia/diagnóstico , Idoso , Idoso de 80 Anos ou mais , Calciofilaxia/etiologia , Calciofilaxia/patologia , Calciofilaxia/terapia , Feminino , Seguimentos , Humanos , Masculino , Estudos Retrospectivos , Fatores de RiscoRESUMO
BACKGROUND AND AIMS: Chitotriosidase, a component of innate immunity, constitutes a sensitive parameter of macrophage activation and its elevated plasma activity reflects an inflammatory response. Given the deleterious effects of inflammation in brain ischemia, we aimed to assess the prognostic value of chitotriosidase activity in acute stroke patients. METHODS: The study comprised 159 acute stroke patients and 51 age-matched controls. Plasma chitotriosidase activity was serially determined by fluorometric assay. Short-term neurological outcome was determined at 48 h and functional outcome at three-months. Predictors of neurological and functional outcome were determined via multivariate analysis, and the additional predictive value of chitotriosidase was tested with the Integrated Discrimination Index and the Net Reclassification Improvement. RESULTS: Stroke patients showed increased levels of baseline chitotriosidase activity compared to controls [114·2 (74·65-182·95) nmol/ml/h vs. 54·4 (32·7-76·4); P < 0·0001]. Chitotriosidase activity (<118·75) was found to be an independent predictor of neurological improvement at 48 h (odds ratio: 3·25; 95% confidence interval: 1·54-6·85; P=0·002), and the addition of plasma chitotriosidase activity showed a better prediction of improvement at 48 h (Integrated Discrimination Index=5·7%, Net Reclassification Improvement=11·6%, P<0·05) over the predictive model constituted only with clinical information. Although patients disabled at three-months showed higher baseline chitotriosidase levels, it was not an independent predictor of long-term disability. CONCLUSIONS: Baseline chitotriosidase activity in acute stroke patients treated with tissue plasminogen activator (tPA) may constitute a prognostic predictor of short-term outcome, adding a moderate additional predictive value. Our results underline the deleterious role of inflammation in acute stroke patients.