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BACKGROUND & AIMS: In children with autoimmune hepatitis, uncertainties include outcomes associated with type 2 hepatitis, the possibility of and criteria for attempting withdrawal of treatment, and long-term outcomes. We report our experience on these issues. METHODS: From 1973 to 2002, 117 children with type 1 (n = 65) or type 2 (n = 52) hepatitis, excluding fulminant hepatitis, were treated, primarily with prednisone and azathioprine. Median follow-up was 20 years in survivors. RESULTS: Normalisation of aminotransferases and prothrombin ratio were observed in 93% and 84% of children, respectively; sustained remission after treatment withdrawal was recorded in 24% of the entire population, with a median follow-up of 7 years. Sustained treatment-free remission was obtained in 11 of 24 children with follow-ups of 4-22 years based on durable normalisation of aminotransferases (without histological assessment). Gastrointestinal bleeding from varices and the emergence of extrahepatic autoimmune disorders occurred in 10 and 22 patients, respectively. Liver transplantation was performed in 23 patients at a median age of 21 years. The 30-year probabilities of overall and native liver survival were 81% and 61%, respectively. No differences were observed between type 1 and 2 hepatitis for any of the component parts of outcome. In the multivariate analysis, a persistent abnormal prothrombin ratio was associated with worse probabilities of overall and native liver survival. CONCLUSIONS: In terms of liver outcome, type 2 hepatitis is not different from type 1. Withdrawal of treatment is possible without prior liver histology. A persistent abnormal prothrombin ratio identifies patients who will require liver transplantation in adolescence or early adulthood. IMPACT AND IMPLICATIONS: In children with autoimmune hepatitis, there are conflicting reports on the differences in outcome between type 1 and type 2 hepatitis, and on the possibility of treatment withdrawal, before which liver histology is required; data concerning >10-year overall and native liver survival rates are limited. In this study, we found no differences in outcomes between type 1 and 2 hepatitis; a durable treatment-free state was achieved in 19% of all patients throughout childhood and early adulthood, and in 45% of children for whom treatment withdrawal was attempted without prior liver histology; prothrombin was found to be predictive of 30-year overall and native liver survival. The results allow for a less-strict approach to treatment withdrawal in children, avoiding the risks of a liver biopsy, and they provide a tool to help anticipate the need for liver transplantation before complications occur.
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Hepatite Autoimune , Imunossupressores , Criança , Adolescente , Humanos , Adulto , Adulto Jovem , Imunossupressores/uso terapêutico , Hepatite Autoimune/diagnóstico , Hepatite Autoimune/tratamento farmacológico , Hepatite Autoimune/patologia , Protrombina , Azatioprina/efeitos adversos , TransaminasesRESUMO
INTRODUCTION: Recurrent miscarriages are defined as three or more early miscarriages before 12 weeks of gestation. The aim of this study was to describe a cohort of women with unexplained recurrent miscarriages, evaluate several potential biomarkers of immune origin, and describe the outcome of pregnancies under immunomodulatory therapies. METHODS: Women having a history of at least 3 early miscarriages without any etiology were recruited from 3 university hospitals. RESULTS: Among 101 women with recurrent miscarriages, overall, 652 pregnancies have been included in the analysis. Women which experienced miscarriages were older (33.3 ± 5.4 versus 31.9 ± 6.7; p = 0.03), with history of more pregnancies (4 (2-6) versus 3.5 (1-5.75); p 0.0008), and less frequently the same partner (406 (74%) versus 79 (86%); p=0.01). There was no difference in the level and frequencies of biomarkers of immune origin (NK, lymphocyte, gamma globulins and blood cytokine levels and endometrial uNK activation status), except the higher rates of positive antinuclear antibodies in women with live birth (12 (13%) versus 36 (7%); p=0.03). Among the 652 pregnancies, 215 (33%) have been treated and received either aspirin/low weighted molecular heparin (LMWH) and/or combined to different lines of immunomodulatory treatment. Patients with pregnancy under treatment had a significantly higher rate of cumulative live birth rate than those with untreated ones (43.0% vs 34.8%; p = 0.04). When compared to patients with untreated pregnancies, patients with steroids during the pregnancy had twice more chances to obtain live birth (OR 2.0, CI95% 1.1 - 3.7, p = 0.02). CONCLUSIONS: Unexplained recurrent miscarriages could have improved obstetrical outcome under immunomodulatory therapies and in particular steroids.
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Aborto Habitual/tratamento farmacológico , Aspirina/administração & dosagem , Heparina de Baixo Peso Molecular/administração & dosagem , Fatores Imunológicos/administração & dosagem , Imunomodulação , Aborto Habitual/sangue , Aborto Habitual/epidemiologia , Adulto , Biomarcadores/sangue , Feminino , Humanos , Gravidez , Estudos RetrospectivosRESUMO
INTRODUCTION: Recurrent implantation failure is defined as the absence of pregnancy after at least three transfers of good-quality embryos after in vitro fecundation/intracytoplasic sperm injection. AIM: The aim of this study was to describe a multicentre cohort of women with unexplained RIF, to analyse the factors associated with clinical pregnancy and to evaluate the immunomodulatory therapies efficacy. METHODS: Women were consecutively recruited from university departments with unexplained RIF. RESULTS: Sixty-four women were enrolled with mean age 36 ± 3 years. The rates of clinical pregnancy in 64 women were compared in untreated and treated cycles and according to therapies used during the last prospectively followed embryo transfer. A clinical pregnancy after the transfer was noted in 56 % pregnancies on intralipids and in 50 % on prednisone, versus 5 % in untreated ones (p < 0.001). The 340 embryo transfers of these 64 women resulted in 68 clinical pregnancies and 18 live births. Clinical pregnancies were significantly more frequent in treated versus untreated embryo transfers (44 % vs 9 %; p < 0.001) with odds ratio at 8.13 (95 % CI 4.49-14.72, p < 0.0001). Cumulative pregnancy rates were higher for steroid-treated transfers than for untreated transfers when considering overall transfers before and after using steroids and also only those under steroids. Cumulative pregnancy rates were not different from steroid- and intralipid-treated embryo transfers CONCLUSIONS: In this multicentre study of women with unexplained RIF, use of immunomodulatory treatments before embryo transfer resulted in higher clinical pregnancy. Randomised, well-designed studies in well-defined population of RIF women are necessary to confirm our preliminary data.
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Implantação do Embrião/imunologia , Transferência Embrionária/estatística & dados numéricos , Infertilidade Feminina/terapia , Injeções de Esperma Intracitoplásmicas/estatística & dados numéricos , Adulto , Biomarcadores/análise , Transferência Embrionária/métodos , Feminino , Humanos , Infertilidade Feminina/diagnóstico , Infertilidade Feminina/imunologia , Gravidez , Taxa de Gravidez , Medição de Risco/estatística & dados numéricos , Injeções de Esperma Intracitoplásmicas/métodos , Falha de TratamentoRESUMO
INTRODUCTION: In retrospective cohort study of women with unexplained recurrent implantation failure (RIF) and miscarriage (RM), we analyzed the efficacy and safety of intralipid therapy to obtain a live birth. PATIENTS AND METHODS: Women with unexplained RM and/or RIF were included from 2015 to 2018 from three French university hospitals. RESULTS: Among 187 women treated for unexplained recurrent miscarriages and implantation failures, 26 women with median age of 36 years (29-43) received intralipid therapy. Among these 26 women, 10 women with a median age of 33 years (31-40) had a history of spontaneous recurrent miscarriages, with a median of 5 (4-8) previous miscarriages. Live births occurred in 7 (70 %) pregnancies under intralipids and were significantly more frequent than in women with recurrent miscarriages who did not receive intralipid therapy (n = 20, p = 0.02). Age, number of previous miscarriages, and additional therapies did not significantly differ between the two groups. Among the 26 included women, 16 had a history of recurrent implantation failures, with median age of 37 years (29-43) and median 9.5 (3-19) embryo transfers. Clinical pregnancy occurred in 9 (56 %) women receiving intralipids after embryo transfers under intralipids among which 5 (55 %) resulted in a live birth. Comparing successful pregnancies under intralipids with those with fetal loss, no significant differences have been noted. CONCLUSION: Intralipids could be an effective and safe therapy in women with unexplained recurrent miscarriages and infertility.
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Aborto Habitual , Fosfolipídeos , Óleo de Soja , Aborto Habitual/terapia , Adulto , Implantação do Embrião , Emulsões , Feminino , Humanos , Nascido Vivo/epidemiologia , Gravidez , Estudos RetrospectivosRESUMO
INTRODUCTION: Patients with phospholipase A2 receptor (PLA2R)-associated membranous nephropathy and stage 4 or 5 chronic kidney disease are at high risk of end-stage kidney disease. In recent years, rituximab (RTX) emerged as a safe and efficient treatment for patients with PLA2R-associated membranous nephropathy. Whether its use is also appropriate in patients with an estimated glomerular filtration rate <30 ml/min per 1.73 m2 has not been investigated. METHODS: We retrospectively reviewed characteristics and outcome of 13 patients with PLA2R-associated membranous nephropathy and stage 4 or 5 chronic kidney disease who received a total of 14 consecutive RTX treatments from January 2012 to March 2018. The treatment regimen consisted of either 2 weekly infusions of 375 mg/m2 or 2 RTX infusions of 1 g/d two weeks apart. When needed, the regimen was repeated to achieve immunological remission. RESULTS: The mean estimated glomerular filtration rate, serum albumin level, and urinary protein level at the first RTX infusion were 18 ± 7 ml/min per 1.73 m2, 25.2 ± 5.4 g/l, and 13.2 ± 7.5 g/d, respectively, with all patients being tested positive for serum PLA2R antibodies. Ten treatment courses led to an increase in estimated glomerular filtration rate and remission of nephrotic syndrome after a median follow-up of 40.8 months (interquartile range, 14.8-46.8). Conversely, 4 RTX treatments were unsuccessful, with patients requiring chronic hemodialysis within 1 year. The urinary albumin-to-protein ratio before treatment was predictive of renal response. Immunological remission occurred after 11 treatment courses and was associated with clinical response in 10 of 11 patients. Three patients experienced severe adverse events. CONCLUSION: RTX seems effective and reasonably safe in PLA2R-associated membranous nephropathy with stage 4 or 5 chronic kidney disease. Immunological remission is associated with a good clinical outcome.
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In this study, we aimed to analyze the value of annexin-A5 anticoagulant ratio (A5R) and non-criteria antibodies for the diagnosis of APS in patients with clinical seronegative APS. Three groups were defined, including 21 seronegative APS patients with unexplained obstetrical adverse events or thrombosis history, 15 confirmed APS patients with triple aPL positivity, and a control group of 20 healthy patients without any history of thrombosis or pregnancy complications. Seronegative APS patients have similar levels of A5R in comparison to healthy controls (202% [171%-238%] versus 191% [178%-221%]; p = 0.65), whereas triple-positive APS patients have significantly more reduced A5R in comparison to both seronegative and healthy patients (149% [138%-158%] versus 202% [171%-238%] and 191% [178%-221%], respectively, p < 0.001). The non-criteria aPL were found in 24% of seronegative APS: anti-PE IgM in 3 cases (14%) and anti-PS/PT IgG and anti-PS/PT IgM in 1 (5%) case each. The frequency of non-criteria APL was significantly more frequent in comparison to healthy controls (p = 0.048). All triple-positive APS patients have at least one non-criteria aPL, and the non-criteria aPL were significantly more frequent in these patients compared to seronegative APS and healthy controls (p < 0.001). Whereas A5R levels do not allow to discriminate seronegative APS from healthy controls, our results demonstrate that non-criteria aPL can help to APS diagnosis in clinical seronegative APS.Key points⢠Annexin-A5 resistance testing does not help for the diagnosis of seronegative APS.⢠The non-criteria antiphospholipid antibodies can contribute to APS diagnosis in patients without conventional antibodies.
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Anexina A5/química , Anticorpos Antifosfolipídeos/sangue , Anticoagulantes/química , Síndrome Antifosfolipídica/diagnóstico , Complicações Cardiovasculares na Gravidez/sangue , Trombose/sangue , Adulto , Anexina A5/imunologia , Síndrome Antifosfolipídica/sangue , Síndrome Antifosfolipídica/imunologia , Estudos de Casos e Controles , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Gravidez , Complicações Cardiovasculares na Gravidez/imunologia , Trombose/imunologiaRESUMO
INTRODUCTION: Autoimmune and autoinflammatory diseases (AIDs) represent a socioeconomic burden as the second cause of chronic illness in Western countries. In this context, the TRANSIMMUNOM clinical protocol is designed to revisit the nosology of AIDs by combining basic, clinical and information sciences. Based on classical and systems biology analyses, it aims to uncover important phenotypes that cut across diagnostic groups so as to discover biomarkers and identify novel therapeutic targets. METHODS AND ANALYSIS: TRANSIMMUNOM is an observational clinical protocol that aims to cross-phenotype a set of 19 AIDs, six related control diseases and healthy volunteers . We assembled a multidisciplinary cohort management team tasked with (1) selecting informative biological (routine and omics type) and clinical parameters to be captured, (2) standardising the sample collection and shipment circuit, (3) selecting omics technologies and benchmarking omics data providers, (4) designing and implementing a multidisease electronic case report form and an omics database and (5) implementing supervised and unsupervised data analyses. ETHICS AND DISSEMINATION: The study was approved by the institutional review board of Pitié-Salpêtrière Hospital (ethics committee Ile-De-France 48-15) and done in accordance with the Declaration of Helsinki and good clinical practice. Written informed consent is obtained from all participants before enrolment in the study. TRANSIMMUNOM's project website provides information about the protocol (https://www.transimmunom.fr/en/) including experimental set-up and tool developments. Results will be disseminated during annual scientific committees appraising the project progresses and at national and international scientific conferences. DISCUSSION: Systems biology approaches are increasingly implemented in human pathophysiology research. The TRANSIMMUNOM study applies such approach to the pathophysiology of AIDs. We believe that this translational systems immunology approach has the potential to provide breakthrough discoveries for better understanding and treatment of AIDs. TRIAL REGISTRATION NUMBER: NCT02466217; Pre-results.
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Doenças Autoimunes/patologia , Inflamação/patologia , Adolescente , Adulto , Doenças Autoimunes/diagnóstico , Biomarcadores , Protocolos Clínicos , Feminino , Humanos , Inflamação/diagnóstico , Masculino , Pessoa de Meia-Idade , Adulto JovemRESUMO
The prevalence, clinical characteristics, and outcomes of patients with antimitochondrial antibodies (AMAs), but no clinical evidence of primary biliary cholangitis (PBC), are largely unknown. A prospective study of AMA incidence was conducted through a nation-wide network of 63 French immunology laboratories. Clinical data from 720 of 1,318 AMA-positive patients identified in 1 year were collected. Patients were categorized as either newly diagnosed with PBC (n = 275), previously diagnosed with PBC (n = 216), or with nonestablished diagnosis of PBC (n = 229). The latter group was specifically evaluated. Follow-up data were collected for up to 7 years after detection of AMAs. Prevalence of AMA-positive patients without evidence of PBC was 16.1 per 100,000. These patients had the following characteristics: 78% female; median age 58 years; median AMA titer 1:160; extrahepatic autoimmune disorders 46%; normal serum alkaline phosphatases (ALP) 74%; ALP above 1.5 times the upper limit of normal 13%; and cirrhosis 6%. Compared to those newly diagnosed with PBC, the patients were slightly younger, had lower AMA titers, and lower sex-ratio imbalance. Among the patients with normal ALP and no evidence of cirrhosis, the 5-year incidence rate of PBC was 16%. Whereas no patients died from PBC, the 5-year survival rate was 75%, as compared to 90% in a control, standardized population matched for age and sex (P < 0.05). CONCLUSION: Nearly half of the newly detected AMAs in clinical practice does not lead to a diagnosis of PBC. PBC is unrecognized in 13% of those cases. Only 1 in 6 patients with AMAs and normal ALP will develop PBC after 5 years. The mortality of AMA-positive patients without PBC is increased irrespective of the risk of PBC development. (Hepatology 2017;65:152-163).
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Autoanticorpos/sangue , Colangite/sangue , Colangite/imunologia , Mitocôndrias/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Criança , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Estudos Prospectivos , Adulto JovemRESUMO
We report here the case of a 50-years-old man treated for mixed connective tissue disease (MCTD) positive for anti-U1 ribonucleoprotein (U1RNP) antibodies who secondarily developed a granulomatosis with polyangiitis (GPA) associated with anti-proteinase 3 anti-neutrophil cytoplasmic antibodies (PR3-ANCA). We then evaluated the frequency of the association between anti-U1RNP and anti-PR3-ANCA antibodies by a systematic retrospective study in ten European hospitals. Overall, out of 11,921 samples analyzed for both auto-antibodies, 18 cases of anti-U1RNP and anti-PR3-ANCA double positivity were found and only one patient presented with both MCTD and GPA symptoms. Our retrospective analysis indicates that anti-U1RNP and anti-PR3-ANCA antibodies double positivity is infrequent and very rarely associated with both MTCD and GPA. Our observation describes for the first time the coexistence of MTCD and severe GPA in a Caucasian patient. Association of anti-U1RNP and ANCA antibodies was rarely reported in the literature. Eleven cases of MCTD and ANCA vasculitis have been reported to date, with only two cases with anti-PR3-ANCA association, and only one vasculitis. The seven other cases reported in the literature presented with an association of MCTD and microscopic polyangiitis which appears to be a more frequent presentation than MTCD associated with GPA.
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Autoanticorpos/sangue , Granulomatose com Poliangiite/epidemiologia , Doença Mista do Tecido Conjuntivo/epidemiologia , Mieloblastina/imunologia , Ribonucleoproteínas Nucleares Pequenas/imunologia , Astenia , Europa (Continente)/epidemiologia , Granulomatose com Poliangiite/complicações , Granulomatose com Poliangiite/diagnóstico , Hospitais , Humanos , Vasculite por IgA , Masculino , Programas de Rastreamento , Pessoa de Meia-Idade , Doença Mista do Tecido Conjuntivo/complicações , Doença Mista do Tecido Conjuntivo/diagnóstico , Prevalência , Redução de PesoRESUMO
BACKGROUND: A few children with acute or chronic liver disease display histological features compatible with autoimmune hepatitis, but lack specific serological markers. AIM: To describe features, management and outcome of childhood seronegative autoimmune hepatitis. METHODS: From 1988 to 2010, 38 children were included under the following criteria: negative virological studies, no serum autoantibodies, exclusion of other causes of liver diseases, and liver histology compatible with autoimmune hepatitis. RESULTS: Four groups were identified: (1) 12 with increased serum gamma globulin concentrations; (2) 10 with normal or low serum gamma globulins and no combined blood disease; (3) 10 with combined aplastic anemia; and (4) 6 with peripheral thrombocytopenia with/without neutropenia. Immunosuppressive treatment was associated with aminotransferases normalization in all but one child who required liver transplantation. Relapses occurred in 10 children. Lymphocytopenia was found at the time of the diagnosis of hepatitis in 13 children, 12 in groups 3 or 4. All 38 children are alive after 4-17 years, 18 still under immunosuppression. CONCLUSIONS: Childhood seronegative autoimmune hepatitis includes a spectrum of disorders. Early liver histology is recommended and, if compatible with autoimmune hepatitis, immunosuppressive treatment should be started. Initial lymphocytopenia may indicate future hematological complication.
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Hepatite Autoimune/sangue , Hepatite Autoimune/complicações , Hepatite Autoimune/terapia , gama-Globinas/análise , Adolescente , Anemia Aplástica/epidemiologia , Autoanticorpos/sangue , Criança , Pré-Escolar , Feminino , França , Humanos , Imunossupressores/uso terapêutico , Lactente , Itália , Fígado/patologia , Falência Hepática/epidemiologia , Transplante de Fígado , Masculino , Trombocitopenia/epidemiologia , Transaminases/sangueRESUMO
Anti-signal recognition particle (SRP) antibodies are important serological markers for the diagnosis and the prognosis of idiopathic inflammatory myopathy (IIM), especially to distinguish immune-mediated necrotizing myopathy (IMNM). This study was set up to investigate the phenotype associated with anti-SRP antibodies and to evaluate the methods for detecting these antibodies. Clinical and biological data were retrospectively obtained from 60 adult patients with anti-SRP antibodies detected by a dot immunoassay from 12 centers. Thirty-six (60 %) out of these 60 patients suffered from an IIM, and among them, 21 patients were diagnosed as IMNM. Among patients with a definite IIM, proximal weakness and myalgia were prominent symptoms at the time of diagnosis. Only few patients displayed severe extra-muscular symptoms such as cardiac involvement or severe myositis. Mean creatine kinase levels were high for all patients except for two of them. When testing by indirect immunofluorescence (IIF) on HEp2 cells, the fraction of patients displaying the typical anti-SRP fine speckled staining of the cytoplasm was higher in patients with IIM (30/36) (83 %) than in patients with non-IIM (3/24) (12.5 %) (p < 0.0001). Thirty (91 %) out of 33 patients with a positive immunodot and a characteristic IIF cytoplasmic staining suffered from a clinical definite myositis, whereas only 6 (22 %) out of 27 patients with a positive immunodot but a negative cytoplasmic pattern suffered from a myositis (p < 0.00001). This series highlights the strong heterogeneity of anti-SRP positivity that encompassed IMNM and non-IMNM and supports the necessity of considering both IIF and dot immunoassay to confirm the diagnosis of anti-SRP-associated myositis.
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Autoanticorpos/metabolismo , Miosite/diagnóstico , Adulto , Idoso , Linhagem Celular Tumoral , Feminino , Técnica Indireta de Fluorescência para Anticorpo , Humanos , Immunoblotting , Masculino , Pessoa de Meia-Idade , Mialgia , Miosite/imunologia , Necrose , Estudos Retrospectivos , Partícula de Reconhecimento de Sinal/imunologiaRESUMO
BACKGROUND: The challenging diagnosis and poor prognosis of cholangiocarcinoma require the determination of biomarkers. Autoantibodies could be used in the clinic as diagnostic markers for the early detection of tumours. By proteomic approaches, several autoantibodies were proposed as potential markers. We tried in this study, to perform a serological proteome analysis, using various antigenic substrates, including tumours and human liver. METHODS: Sera from patients (n = 13) and healthy donors (n = 10) were probed on immunoblots performed using 2-dimensionally separated proteins from cholangiocarcinoma cell lines (CCLP1 and CCSW1), from the liver of healthy subject and interestingly, from tumour and adjacent non-tumour liver tissues from five patients with cholangiocarcinoma and tested with their corresponding serum. Spots of interest were identified using mass spectrometry and classified according gene ontology analysis. RESULTS: A comparison of the whole immunoblotting patterns given by cholangiocarcinoma sera against those obtained with normal control sera enabled the definition of 862 spots. Forty-five different proteins were further analysed, corresponding to (1) spots stained with more than four of 13 (30 %) sera tested with the CCLP1 or the CCSW1 cell line and with the normal liver, and (2) to spots immunoreactive with at least two of the five sera probed with their tumour and non-tumour counter-part of cholangiocarcinoma. Immunoreactive proteins with catalytic activity as molecular function were detected at rates of 93 and 64 % in liver from healthy subjects or cholangiocarcinoma non-tumour tissues respectively, compared to 43, 33, 33 % in tumour tissues, or CCSW1 and CCLP1 cell lines. A second pattern was represented by structural proteins with rates of 7 and 7 % in normal liver or non-tumour tissues compared to 14, 33 and 67 % in tumour tissue, CCSW1 or CCLP1 cell lines. Proteins with a binding function were detected at rates of 7 % in non-tumour tissue and 14 % in tumour tissue. Using the extracted tumour tissue, serotransferrin was targeted by all cholangiocarcinoma-related sera. CONCLUSIONS: Immunological patterns depended on the type of antigen substrate used; i.e. tumour versus non tumour specimens. Nevertheless, a combination of multiple autoantibodies tested with the most appropriate substrate might be more sensitive and specific for the diagnosis of cholangiocarcinoma.
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Autoanticorpos/sangue , Neoplasias dos Ductos Biliares/sangue , Neoplasias dos Ductos Biliares/imunologia , Colangiocarcinoma/sangue , Colangiocarcinoma/imunologia , Proteoma/metabolismo , Proteômica/métodos , Linhagem Celular Tumoral , Eletroforese em Gel Bidimensional , Eletroforese em Gel de Poliacrilamida , Ontologia Genética , Humanos , Immunoblotting , Fígado/metabolismo , Fígado/patologia , Reprodutibilidade dos TestesRESUMO
BACKGROUND: Heterogeneous nuclear ribonucleoprotein (hnRNP) A2/B1 is a target for antinuclear autoantibodies in systemic Lupus erythematosus (SLE), rheumatoid arthritis (RA), and autoimmune hepatitis (AIH). AIM: To monitor molecular interactions between peptides spanning the entire sequence of hnRNP A2/B1 and sera from patients and healthy controls. METHODS: Sera from 8 patients from each pathology and controls were passed across a surface plasmon resonance Imagery (SPRi) surface containing 39 overlapping peptides of 17 mers covering the human hnRNP B1. Interactions involving the immobilised peptides were followed in real time and dissociation rate constants k(off) for each interaction were calculated. RESULTS: Several significant interactions were observed: i) high stability (lower k(off) values) between P55â70 and the AIH sera compared to controls (p= 0.003); ii) lower stability (higher k(off) values) between P118â133 and P262â277 and SLE sera, P145â160 and RA sera compared to controls (p=0.006, p=0.002, p=0.007). The binding curves and k(off) values observed after the formation of complexes with anti-IgM and anti-IgG antibodies and after nuclease treatment of the serum indicate that i) IgM isotypes are prevalent and ii) nucleic acids participate in the interaction between anti-hnRNAP B1 and P55â70 and also between controls and the peptides studied. CONCLUSIONS: These results indicate that P55â70 of hnRNP B1 is a potential biomarker for AIH in immunological tests and suggest the role of circulating nucleic acids, (eg miRNA), present or absent according to the autoimmune disorders and involved in antigen-antibody stability.
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Artrite Reumatoide/metabolismo , Biomarcadores/metabolismo , Hepatite Autoimune/metabolismo , Ribonucleoproteínas Nucleares Heterogêneas Grupo A-B/metabolismo , Lúpus Eritematoso Sistêmico/metabolismo , Ressonância de Plasmônio de Superfície/métodos , Anticorpos Antinucleares/metabolismo , Eletroforese em Gel de Poliacrilamida , Técnica Indireta de Fluorescência para Anticorpo , Humanos , Immunoblotting , Peptídeos/metabolismo , Estatísticas não ParamétricasRESUMO
BACKGROUND: Autoimmune hepatitis (AIH) after liver transplantation has been defined histologically as a "hepatitic" pattern of injury, characterized by lymphoplasmacytic inflammation with necroinflammatory activity (NIA), comparable with findings seen in native livers. This definition, however, is difficult to apply in practice because specific histologic criteria are not clearly delineated. This study aimed to determine which histologic features correlated best with clinical and serologic features of dAIH. METHODS: Index liver biopsies from patients with autoimmune-like hepatitis transplanted for non-AIH in two centers (n=35 and 20) were reviewed. Histologic features were correlated with the clinical diagnosis of AIH based on a retrospective review of clinical and serologic data, including therapeutic response. RESULTS: A clinical diagnosis of AIH was retrospectively assigned to 24 of 35 (68%) and 18 of 20 (90%) patients, respectively (P=0.10). In multivariate analysis, centrilobular NIA and centrilobular plasma cell (PC) ratio of 30% to 50% were independently discriminating for a clinical diagnosis of AIH (P=0.04 and 0.05, respectively). The best level of predictability (99.6%) was mathematically achieved when severe centrilobular NIA and centrilobular PC ratio of 30% to 50% were both present. CONCLUSION: A histologic pattern of centrilobular injury including increased NIA and increased PC infiltration correlates with measurements of autoimmunity in liver recipients. It could be used to segregate cases for further study and introduced into the AIH scoring systems when applied in the context of liver transplantation.