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2.
Clin Exp Immunol ; 203(2): 304-314, 2021 02.
Artigo em Inglês | MEDLINE | ID: mdl-33089489

RESUMO

Natural killer T (NKT) cells are an abundant subset of liver lymphocytes activated by lipid antigens presented on CD1d molecules that are expressed by cholangiocytes. We aimed to determine if bile from patients with chronic liver diseases contains antigenic lipids that can activate NKT cells. Using murine invariant (24.7, 24.8 and DN32.D3) and non-invariant (14S.6, 14S.7 and 14S.10) NKT hybridomas we investigated the presence of lipid antigens in bile collected from the gallbladder of patients undergoing liver transplantation due to end-stage liver disease. Biliary microbiota profiles were generated using 16S rRNA amplicon sequencing. We found that the patient bile samples contain antigens that activate both invariant and non-invariant NKT hybridomas (24.7, 24.8, DN32.D3, 14S.6, 14S.7 and 14S.10), as demonstrated by activation of at least one hybridoma by eight of 10 bile samples. Activation at high dilutions suggests that some antigens are highly potent. We used the non-invariant NKT hybridoma 14S.6 to screen 21 additional patient bile samples for NKT-reactivity and demonstrated that 12 of 21 bile samples resulted in activation, three of which gave a strong activation. Four of 12 activating bile samples contained microbial DNA. Our results reveal an immunological pathway that could be of critical importance in biliary immunology.


Assuntos
Antígenos/imunologia , Bile/imunologia , Lipídeos/imunologia , Hepatopatias/imunologia , Ativação Linfocitária/imunologia , Células T Matadoras Naturais/imunologia , Animais , Antígenos CD1d/imunologia , Linhagem Celular , Humanos , Células Matadoras Naturais/imunologia , Fígado/imunologia , Camundongos , RNA Ribossômico 16S/imunologia
3.
Sci Rep ; 9(1): 167, 2019 01 17.
Artigo em Inglês | MEDLINE | ID: mdl-30655568

RESUMO

Common variable immunodeficiency (CVID) patients have reduced gut microbial diversity compared to healthy controls. The reduced diversity is associated with gut leakage, increased systemic inflammation and ten "key" bacteria that capture the gut dysbiosis (dysbiosis index) in CVID. Rifaximin is a broad-spectrum non-absorbable antibiotic known to reduce gut leakage (lipopolysaccharides, LPS) in liver disease. In this study, we explored as a 'proof of concept' that altering gut microbial composition could reduce systemic inflammation, using CVID as a disease model. Forty adult CVID patients were randomized, (1:1) to twice-daily oral rifaximin 550 mg versus no treatment for 2 weeks in an open-label, single-centre study. Primary endpoints were reduction in plasma/serum levels of soluble (s) CD14, sCD25, sCD163, neopterin, CRP, TNF, LPS and selected cytokines measured at 0, 2 and 8 weeks. Secondary endpoint was changes in intra-individual bacterial diversity in stool samples. Rifaximin-use did not significantly change any of the inflammation or gut leakage markers, but decreased gut microbial diversity compared with no treatment (p = 0.002). Importantly, the gut bacteria in the CVID dysbiosis index were not changed by rifaximin. The results suggest that modulating gut microbiota by rifaximin is not the chosen intervention to affect systemic inflammation, at least not in CVID.


Assuntos
Biomarcadores/análise , Imunodeficiência de Variável Comum/tratamento farmacológico , Disbiose/tratamento farmacológico , Microbioma Gastrointestinal/efeitos dos fármacos , Inflamação/tratamento farmacológico , Rifaximina/uso terapêutico , Adolescente , Adulto , Idoso , Antibacterianos/uso terapêutico , Feminino , Fármacos Gastrointestinais/uso terapêutico , Humanos , Masculino , Pessoa de Meia-Idade , Estudo de Prova de Conceito , Estudos Prospectivos , Adulto Jovem
4.
Mucosal Immunol ; 11(6): 1582-1590, 2018 11.
Artigo em Inglês | MEDLINE | ID: mdl-30115993

RESUMO

Cholangiocytes function as antigen-presenting cells with CD1d-dependent activation of natural killer T (NKT) cells in vitro. NKT cells may act both pro- and anti-inflammatory in liver immunopathology. We explored this immune pathway and the antigen-presenting potential of NKT cells in the bile ducts by challenging wild-type and Cd1d-/- mice with intrabiliary injection of the NKT cell activating agent oxazolone. Pharmacological blocking of CD1d-mediated activation was performed with a monoclonal antibody. Intrabiliary oxazolone injection in wild-type mice caused acute cholangitis with significant weight loss, elevated serum levels of alanine transaminase, aspartate transaminase, alkaline phosphatase and bilirubin, increased histologic grade of cholangitis and number of T cells, macrophages, neutrophils and myofibroblasts per portal tract after 7 days. NKT cells were activated after intrabiliary injection of oxazolone with upregulation of activation markers. Cd1d-/- and wild-type mice pretreated with antibody blocking of CD1d were protected from disease. These findings implicate that cells in the bile ducts function as antigen-presenting cells in vivo and activate NKT cells in a CD1d-restricted manner. The elucidation of this biliary immune pathway opens up for potentially new therapeutic approaches for cholangiopathies.


Assuntos
Ductos Biliares/patologia , Colangite/imunologia , Células Epiteliais/imunologia , Células T Matadoras Naturais/imunologia , Animais , Anticorpos Bloqueadores/administração & dosagem , Apresentação de Antígeno , Antígenos CD1d/genética , Antígenos CD1d/imunologia , Antígenos CD1d/metabolismo , Células Cultivadas , Feminino , Humanos , Imunização , Ativação Linfocitária , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Oxazolona/administração & dosagem
5.
Aliment Pharmacol Ther ; 48(2): 179-189, 2018 07.
Artigo em Inglês | MEDLINE | ID: mdl-29851098

RESUMO

BACKGROUND: Primary sclerosing cholangitis is a progressive liver disease with a remarkably variable course. Biomarkers of disease activity or prognostic models predicting outcome at an individual level are currently not established. AIM: To evaluate the prognostic utility of four biomarkers of basement membrane and interstitial extracellular matrix remodeling in patients with primary sclerosing cholangitis. METHODS: Serum samples were available from 138 large-duct primary sclerosing cholangitis patients (of which 102 [74%] with IBD) recruited 2008-2012 and 52 ulcerative colitis patients (controls). The median follow-up time was 2.2 (range 0-4.3) years. Specific biomarkers of type III and V collagen formation (PRO-C3 and PRO-C5, respectively) and type III and IV collagen degradation (C3M and C4M, respectively) were assessed. The Enhanced Liver Fibrosis test, including procollagen type III N-terminal peptide, tissue inhibitor of metalloproteinase-1 and hyaluronic acid was assessed for comparison. RESULTS: All markers were elevated in primary sclerosing cholangitis compared to ulcerative colitis patients (P < 0.001). PRO-C3 showed the largest difference between the two groups with a threefold increase in primary sclerosing cholangitis compared to ulcerative colitis patients. Patients with high baseline serum levels of all markers, except C3M, had shorter survival compared to patients with low baseline serum levels (P < 0.001). Combining PRO-C3 and PRO-C5 the odds ratio for predicting transplant-free survival was 47 compared to the Enhanced Liver Fibrosis test's odds ratio of 11. CONCLUSIONS: Extracellular matrix remodeling is elevated in primary sclerosing cholangitis patients compared to ulcerative colitis patients. Furthermore, the interstitial matrix marker PRO-C3 was identified as a potent prognostic marker and an independent predictor of transplant-free survival in primary sclerosing cholangitis.


Assuntos
Biomarcadores/sangue , Colangite Esclerosante/diagnóstico , Colangite Esclerosante/mortalidade , Matriz Extracelular/metabolismo , Adolescente , Adulto , Idoso , Colangite Esclerosante/sangue , Colangite Esclerosante/terapia , Colite Ulcerativa/sangue , Colite Ulcerativa/diagnóstico , Colite Ulcerativa/mortalidade , Progressão da Doença , Matriz Extracelular/patologia , Feminino , Humanos , Ácido Hialurônico/sangue , Cirrose Hepática/sangue , Cirrose Hepática/diagnóstico , Cirrose Hepática/mortalidade , Cirrose Hepática/terapia , Transplante de Fígado , Masculino , Pessoa de Meia-Idade , Fragmentos de Peptídeos/sangue , Valor Preditivo dos Testes , Pró-Colágeno/sangue , Prognóstico , Análise de Sobrevida , Inibidor Tecidual de Metaloproteinase-1/sangue , Adulto Jovem
6.
Am J Transplant ; 18(4): 952-963, 2018 04.
Artigo em Inglês | MEDLINE | ID: mdl-28925583

RESUMO

Cancer remains one of the most serious long-term complications after liver transplantation (LT). Data for all adult LT patients between 1982 and 2013 were extracted from the Nordic Liver Transplant Registry. Through linkage with respective national cancer-registry data, we calculated standardized incidence ratios (SIRs) based on country, sex, calendar time, and age-specific incidence rates. Altogether 461 cancers were observed in 424 individuals of the 4246 LT patients during a mean 6.6-year follow-up. The overall SIR was 2.22 (95% confidence interval [CI], 2.02-2.43). SIRs were especially increased for colorectal cancer in recipients with primary sclerosing cholangitis (4.04) and for lung cancer in recipients with alcoholic liver disease (4.96). A decrease in the SIR for cancers occurring within 10 years post-LT was observed from the 1980s: 4.53 (95%CI, 2.47-7.60), the 1990s: 3.17 (95%CI, 2.70-3.71), to the 2000s: 1.76 (95%CI, 1.51-2.05). This was observed across age- and indication-groups. The sequential decrease for the SIR of non-Hodgkin lymphoma was 25.0-12.9-7.53, and for nonmelanoma skin cancer 80.0-29.7-10.4. Cancer risk after LT was found to be decreasing over time, especially for those cancers that are strongly associated with immunosuppression. Whether immunosuppression minimization contributed to this decrease merits further study.


Assuntos
Neoplasias Colorretais/epidemiologia , Neoplasias Hepáticas/epidemiologia , Transplante de Fígado/efeitos adversos , Neoplasias Pulmonares/epidemiologia , Sistema de Registros/estatística & dados numéricos , Adulto , Estudos de Coortes , Neoplasias Colorretais/etiologia , Neoplasias Colorretais/prevenção & controle , Feminino , Seguimentos , Humanos , Incidência , Neoplasias Hepáticas/etiologia , Neoplasias Hepáticas/prevenção & controle , Neoplasias Pulmonares/etiologia , Neoplasias Pulmonares/prevenção & controle , Masculino , Pessoa de Meia-Idade , Prognóstico , Fatores de Risco , Países Escandinavos e Nórdicos/epidemiologia
7.
HLA ; 90(4): 228-233, 2017 10.
Artigo em Inglês | MEDLINE | ID: mdl-28695657

RESUMO

Primary sclerosing cholangitis (PSC) is strongly associated with several human leukocyte antigen (HLA) haplotypes. Due to extensive linkage disequilibrium and multiple polymorphic candidate genes in the HLA complex, identifying the alleles responsible for these associations has proven difficult. We aimed to evaluate whether studying populations of admixed or non-European descent could help in defining the causative HLA alleles. When assessing haplotypes carrying HLA-DRB1*13:01 (hypothesized to specifically increase the susceptibility to chronic cholangitis), we observed that every haplotype in the Scandinavian PSC population carried HLA-DQB1*06:03. In contrast, only 65% of HLA-DRB1*13:01 haplotypes in an admixed/non-European PSC population carried this allele, suggesting that further assessments of the PSC-associated haplotype HLA-DRB1*13:01-DQA1*01:03-DQB1*06:03 in admixed or multi-ethnic populations could aid in identifying the causative allele.


Assuntos
Colangite Esclerosante/genética , Predisposição Genética para Doença , Cadeias beta de HLA-DQ/genética , Cadeias HLA-DRB1/genética , Haplótipos , Alelos , Colangite Esclerosante/etnologia , Colangite Esclerosante/imunologia , Etnicidade , Expressão Gênica , Frequência do Gene , Cadeias beta de HLA-DQ/classificação , Cadeias beta de HLA-DQ/imunologia , Cadeias HLA-DRB1/classificação , Cadeias HLA-DRB1/imunologia , Humanos , Desequilíbrio de Ligação , Países Escandinavos e Nórdicos , População Branca
8.
Eur J Clin Nutr ; 71(8): 995-1001, 2017 08.
Artigo em Inglês | MEDLINE | ID: mdl-28378853

RESUMO

BACKGROUND/OBJECTIVES: Fatty liver disease (FLD) is an important intermediate trait along the cardiometabolic disease spectrum and strongly associates with type 2 diabetes. Knowledge of biological pathways implicated in FLD is limited. An untargeted metabolomic approach might unravel novel pathways related to FLD. SUBJECTS/METHODS: In a population-based sample (n=555) from Northern Germany, liver fat content was quantified as liver signal intensity using magnetic resonance imaging. Serum metabolites were determined using a non-targeted approach. Partial least squares regression was applied to derive a metabolomic score, explaining variation in serum metabolites and liver signal intensity. Associations of the metabolomic score with liver signal intensity and FLD were investigated in multivariable-adjusted robust linear and logistic regression models, respectively. Metabolites with a variable importance in the projection >1 were entered in in silico overrepresentation and pathway analyses. RESULTS: In univariate analysis, the metabolomics score explained 23.9% variation in liver signal intensity. A 1-unit increment in the metabolomic score was positively associated with FLD (n=219; odds ratio: 1.36; 95% confidence interval: 1.27-1.45) adjusting for age, sex, education, smoking and physical activity. A simplified score based on the 15 metabolites with highest variable importance in the projection statistic showed similar associations. Overrepresentation and pathway analyses highlighted branched-chain amino acids and derived gamma-glutamyl dipeptides as significant correlates of FLD. CONCLUSIONS: A serum metabolomic profile was associated with FLD and liver fat content. We identified a simplified metabolomics score, which should be evaluated in prospective studies.


Assuntos
Fígado Gorduroso Alcoólico/sangue , Metabolismo dos Lipídeos , Fígado/metabolismo , Hepatopatia Gordurosa não Alcoólica/sangue , Idoso , Consumo de Bebidas Alcoólicas/efeitos adversos , Bancos de Espécimes Biológicos , Biomarcadores/sangue , Estudos de Coortes , Biologia Computacional , Estudos Transversais , Dipeptídeos/sangue , Sistemas Inteligentes , Fígado Gorduroso Alcoólico/diagnóstico por imagem , Fígado Gorduroso Alcoólico/metabolismo , Fígado Gorduroso Alcoólico/fisiopatologia , Feminino , Ácido Glutâmico/análogos & derivados , Ácido Glutâmico/sangue , Humanos , Fígado/diagnóstico por imagem , Fígado/fisiopatologia , Imageamento por Ressonância Magnética , Masculino , Metabolômica/métodos , Pessoa de Meia-Idade , Hepatopatia Gordurosa não Alcoólica/diagnóstico por imagem , Hepatopatia Gordurosa não Alcoólica/metabolismo , Autorrelato , Índice de Gravidade de Doença
9.
Pediatr Transplant ; 21(2)2017 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-27957786

RESUMO

Biliary atresia (BA) is the most common indication for LT in children. We investigated whether this diagnosis per se, compared to other chronic liver diseases (OCLD), had an influence on patient survival. Data from 421 Scandinavian children, 194 with BA and 227 with OCLD, listed for LT between 1990 and 2010 were analyzed. The intention-to-treat survival and influencing risk factors were studied. Patients with BA had higher risk of death after listing than patients with OCLD. The youngest (<1 year) and smallest (<10 kg) children with the highest bilirubin (>510 µmol/L), highest INR (>1.6), and highest PELD score (>20) listed during 1990s had the worst outcome. Given the same PELD score, patients with BA had higher risk of death than patients with OCLD. For adolescents, low weight/BMI was the only prognostic marker. Impaired intention-to-treat survival in patients with BA was mainly explained by more advanced liver disease in younger ages and higher proportion of young children in the BA group rather than diagnosis per se. PELD score predicted death, but seemed to underestimate the severity of liver disease in patients with BA. Poor nutritional status and severe cholestasis had negative impact on survival, supporting the "sickest children first" allocation policy and correction of malnutrition before surgery.


Assuntos
Atresia Biliar/mortalidade , Atresia Biliar/cirurgia , Falência Hepática/mortalidade , Falência Hepática/cirurgia , Transplante de Fígado , Adolescente , Índice de Massa Corporal , Criança , Pré-Escolar , Feminino , Sobrevivência de Enxerto , Humanos , Lactente , Recém-Nascido , Análise de Intenção de Tratamento , Coeficiente Internacional Normatizado , Masculino , Análise Multivariada , Estado Nutricional , Prognóstico , Estudos Prospectivos , Sistema de Registros , Fatores de Risco , Países Escandinavos e Nórdicos , Tempo para o Tratamento , Resultado do Tratamento
10.
Mucosal Immunol ; 9(6): 1455-1465, 2016 11.
Artigo em Inglês | MEDLINE | ID: mdl-26982597

RESUMO

Common variable immunodeficiency (CVID) is the most common symptomatic primary immunodeficiency characterized by low immunoglobulin (Ig)G and IgA, and/or IgM. In addition to bacterial infections, a large subgroup has noninfectious inflammatory and autoimmune complications. We performed 16S ribosomal RNA-based profiling of stool samples in 44 CVID patients, 45 patients with inflammatory bowel disease (disease controls), and 263 healthy controls. We measured plasma lipopolysaccharide (LPS) and markers of immune cell activation (i.e., soluble (s) CD14 and sCD25) in an expanded cohort of 104 patients with CVID and in 30 healthy controls. We found a large shift in the microbiota of CVID patients characterized by a reduced within-individual bacterial diversity (alpha diversity, P<0.001) without obvious associations to antibiotics use. Plasma levels of both LPS (P=0.001) and sCD25 (P<0.0001) were elevated in CVID, correlating negatively with alpha diversity and positively with a dysbiosis index calculated from the taxonomic profile. Low alpha diversity and high dysbiosis index, LPS, and immune markers were most pronounced in the subgroup with inflammatory and autoimmune complications. Low level of IgA was associated with decreased alpha diversity, but not independently from sCD25 and LPS. Our findings suggest a link between immunodeficiency, systemic immune activation, LPS, and altered gut microbiota.


Assuntos
Imunodeficiência de Variável Comum/imunologia , Imunodeficiência de Variável Comum/microbiologia , Disbiose/imunologia , Microbioma Gastrointestinal/imunologia , Lipopolissacarídeos/imunologia , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Biodiversidade , Biomarcadores , Estudos de Casos e Controles , Feminino , Humanos , Imunoglobulina A/imunologia , Doenças Inflamatórias Intestinais/imunologia , Doenças Inflamatórias Intestinais/microbiologia , Subunidade alfa de Receptor de Interleucina-2/metabolismo , Ativação Linfocitária/imunologia , Masculino , Pessoa de Meia-Idade , Linfócitos T/imunologia , Linfócitos T/metabolismo , Adulto Jovem
11.
J Crohns Colitis ; 10(3): 330-7, 2016 Mar.
Artigo em Inglês | MEDLINE | ID: mdl-26526357

RESUMO

BACKGROUND AND AIMS: There is an unexplained association between ulcerative colitis [UC] and primary sclerosing cholangitis [PSC], with the intestinal microbiota implicated as an important factor. The study aim was to compare the structure of the intestinal microbiota of patients with UC with and without PSC. METHODS: UC patients with PSC [PSC-UC] and without PSC [UC] were identified from biobanks at Oslo University Hospital, Foothills Hospital Calgary and Mount Sinai Hospital Toronto. Microbial DNA was extracted from colonic tissue and sequencing performed of the V4 region of the 16S rRNA gene on Illumina MiSeq. Sequences were assigned to operational taxonomic units [OTUs] using Quantitative Insights Into Microbial Ecology [QIIME]. Microbial alpha diversity, beta diversity, and relative abundance were compared between PSC-UC and UC phenotypes. RESULTS: In all, 31 PSC-UC patients and 56 UC patients were included. Principal coordinate analysis [PCoA] demonstrated that city of sample collection was the strongest determinant of taxonomic profile. In the Oslo cohort, Chao 1 index was modestly decreased in PSC-UC compared with UC [p = 0.04] but did not differ significantly in the Calgary cohort. No clustering by PSC phenotype was observed using beta diversity measures. For multiple microbial genera there were nominally significant differences between UC and PSC-UC, but results were not robust to false-discovery rate correction. CONCLUSIONS: No strong PSC-specific microbial associations in UC patients consistent across different cohorts were identified. Recruitment centre had a strong effect on microbial composition. Future studies should include larger cohorts to increase power and the ability to control for confounding factors.


Assuntos
Colangite Esclerosante/microbiologia , Colite Ulcerativa/microbiologia , Microbioma Gastrointestinal , Adolescente , Adulto , Idoso , Biodiversidade , Estudos de Casos e Controles , Criança , Colangite Esclerosante/complicações , Colite Ulcerativa/complicações , Feminino , Humanos , Masculino , Pessoa de Meia-Idade , Fenótipo , Análise de Componente Principal , Adulto Jovem
12.
J Intern Med ; 277(6): 717-26, 2015 Jun.
Artigo em Inglês | MEDLINE | ID: mdl-25382824

RESUMO

OBJECTIVES: Recent metabolomic, experimental and clinical studies have demonstrated that trimethylamine-N-oxide (TMAO), a microbiota-dependent metabolite from dietary phosphatidylcholine and carnitine, is a strong predictor of coronary artery disease (CAD). This finding suggests a link between the gut microbiota and atherosclerosis. The potential impact of TMAO in chronic heart failure (HF) is unknown. We hypothesized that TMAO levels would provide prognostic information about adverse outcomes in chronic HF. DESIGN: Prospective, observational study including 155 consecutive patients with chronic HF. In addition, 100 patients with stable CAD without HF and 33 matched healthy individuals were included as controls. Plasma levels of TMAO and its precursors choline and betaine were measured, and associations with symptoms, aetiology and transplant-free survival in the patients with HF were explored. RESULTS: Plasma levels of TMAO (P = 0.01), choline (P < 0.001) and betaine (P < 0.001) were elevated in patients with chronic HF compared to control subjects, with the highest levels in patients with New York Heart Association (NYHA) classes III and IV. Furthermore, TMAO levels were highest in individuals with ischaemic HF, followed by those with stable CAD and nonischaemic HF. TMAO, but not choline or betaine, was associated with reduced transplant-free survival: approximately 50% of patients in the upper tertile of TMAO levels died or received a heart transplant during 5.2 years of follow-up (unadjusted Cox-regression: hazard ratio 2.24, 95% confidence interval 1.28-3.92, P = 0.005). CONCLUSIONS: TMAO levels were elevated in patients with HF and associated with NYHA class, ischaemic aetiology and adverse outcomes. Future studies should focus on gut microbiota, dietary composition and intestinal dysfunction in relation to TMAO levels and clinical outcome in HF.


Assuntos
Betaína/sangue , Colina/sangue , Insuficiência Cardíaca/diagnóstico , Intestinos/microbiologia , Lipotrópicos/sangue , Metilaminas/sangue , Microbiota , Oxidantes/sangue , Idoso , Biomarcadores/sangue , Doença Crônica , Feminino , Insuficiência Cardíaca/sangue , Insuficiência Cardíaca/metabolismo , Insuficiência Cardíaca/mortalidade , Humanos , Mucosa Intestinal/metabolismo , Masculino , Pessoa de Meia-Idade , Valor Preditivo dos Testes , Prognóstico , Estudos Prospectivos , Medição de Risco , Fatores de Risco , Sensibilidade e Especificidade , Índice de Gravidade de Doença , Análise de Sobrevida
13.
Aliment Pharmacol Ther ; 39(3): 282-301, 2014 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-24372568

RESUMO

BACKGROUND: Despite considerable advances over the last two decades in the molecular understanding of cholestasis and cholestatic liver disease, little improvement has been made in diagnostic tools and therapeutic strategies. AIMS: To critically review controversial aspects of the scientific basis for common clinical practice in primary biliary cirrhosis (PBC) and primary sclerosing cholangitis (PSC) and to discuss key ongoing challenges to improve patient management. METHODS: We performed a literature search using PubMed and by examining the reference lists of relevant review articles related to the clinical management of PBC and PSC. Articles were considered on the background of the European Association for the Study of the Liver (EASL) and the American Association for the Study of Liver Diseases (AASLD) practice guidelines and clinical experience of the authors. RESULTS: Ongoing challenges in PBC mainly pertain to the improvement of medical therapy, particularly for patients with a suboptimal response to ursodeoxycholic acid. In PSC, development of medical therapies and sensitive screening protocols for cholangiocarcinoma represent areas of intense research. To rationally improve patient management, a better understanding of pathogenesis, including complications like pruritis and fatigue, is needed and there is a need to identify biomarker end-points for treatment effect and prognosis. Timing of liver transplantation and determining optimal regimens of immunosuppression post-liver transplantation will also benefit from better appreciation of pre-transplant disease mechanisms. CONCLUSION: Controversies in the management of PBC and PSC relate to topics where evidence for current practice is weak and further research is needed.


Assuntos
Colangite Esclerosante/terapia , Cirrose Hepática Biliar/terapia , Transplante de Fígado/métodos , Neoplasias dos Ductos Biliares/diagnóstico , Neoplasias dos Ductos Biliares/patologia , Ductos Biliares Intra-Hepáticos/patologia , Colangiocarcinoma/diagnóstico , Colangiocarcinoma/patologia , Colangite Esclerosante/diagnóstico , Colangite Esclerosante/fisiopatologia , Humanos , Terapia de Imunossupressão/métodos , Cirrose Hepática Biliar/diagnóstico , Cirrose Hepática Biliar/fisiopatologia , Prognóstico , Fatores de Tempo , Ácido Ursodesoxicólico/uso terapêutico
14.
Genes Immun ; 10(6): 601-5, 2009 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-19387457

RESUMO

We reported earlier that two mitochondrial gene polymorphisms, UCP2 -866 G/A (rs659366) and mtDNA nt13708 G/A (rs28359178), are associated with multiple sclerosis (MS). Here we aim to investigate whether these functional polymorphisms contribute to other eight chronic inflammatory diseases, including rheumatoid arthritis (RA), systemic lupus erythematosus (SLE), Wegener' granulomatosis (WG), Churg-Strauss syndrome (CSS), Crohn's disease (CD), ulcerative colitis (UC), primary sclerosing cholangitis (PSC) and psoriasis. Compared with individual control panels, the UCP2 -866 G/A polymorphism was associated with RA and SLE, and the mtDNA nt13708 G/A polymorphism with RA. Compared with combined controls, the UCP2 -866 G/A polymorphism was associated with SLE, WG, CD and UC. When all eight disease panels and the original MS panel were combined in a meta-analysis, the UCP2 was associated with chronic inflammatory diseases in terms of either alleles (odds ratio (OR)=0.91, 95% confidence interval (95% CI): 0.86-0.96), P=0.0003) or genotypes (OR=0.88, (95% CI: 0.82-0.95), P=0.0008), with the -866A allele associated with a decreased risk to diseases. As the -866A allele increases gene expression, our findings suggest a protective role of the UCP2 protein in chronic inflammatory diseases.


Assuntos
Artrite Reumatoide/genética , DNA Mitocondrial/genética , Canais Iônicos/genética , Lúpus Eritematoso Sistêmico/genética , Proteínas Mitocondriais/genética , Polimorfismo de Nucleotídeo Único/genética , Artrite Reumatoide/epidemiologia , Artrite Reumatoide/imunologia , Estudos de Casos e Controles , Colangite Esclerosante/epidemiologia , Colangite Esclerosante/genética , Colangite Esclerosante/imunologia , Doença Crônica , Síndrome de Churg-Strauss/epidemiologia , Síndrome de Churg-Strauss/genética , Síndrome de Churg-Strauss/imunologia , Colite Ulcerativa/epidemiologia , Colite Ulcerativa/genética , Colite Ulcerativa/imunologia , Doença de Crohn/epidemiologia , Doença de Crohn/genética , Doença de Crohn/imunologia , Genótipo , Alemanha/epidemiologia , Humanos , Lúpus Eritematoso Sistêmico/epidemiologia , Lúpus Eritematoso Sistêmico/imunologia , Metanálise como Assunto , Esclerose Múltipla/epidemiologia , Esclerose Múltipla/genética , Esclerose Múltipla/imunologia , Psoríase/epidemiologia , Psoríase/genética , Psoríase/imunologia , Fatores de Risco , Países Escandinavos e Nórdicos/epidemiologia , Proteína Desacopladora 2
15.
Ann Rheum Dis ; 67(9): 1287-91, 2008 Sep.
Artigo em Inglês | MEDLINE | ID: mdl-18065500

RESUMO

BACKGROUND AND OBJECTIVES: The Fc receptor-like 3 (FCRL3) gene -169T>C single nucleotide polymorphism (SNP) has been reported to be associated with several autoimmune diseases (AIDs) in Japanese populations. However, association results in other populations have been conflicting. Therefore, we investigated this SNP in a Scandinavian panel of AIDs. METHODS: We genotyped patients with rheumatoid arthritis (RA; n = 708), juvenile idiopathic arthritis (JIA; n = 524), systemic lupus erythaematosus (SLE; n = 166), ulcerative colitis (UC; n = 335), primary sclerosing cholangitis (PSC; n = 365), Crohn disease (CD; n = 149), a healthy control group (n = 1030) and 425 trio families with type 1 diabetes (T1D). Statistical analysis consisted of case-control and family-based association tests. RESULTS: RA was associated with the C allele (odds ratio (OR) = 1.16, 95% CI 1.01 to 1.33) and the CC genotype (OR = 1.30, 95% CI 1.01 to 1.67) of the FCRL3 -169T>C SNP in our material. Suggestive evidence for association was also found for JIA (CC genotype: OR = 1.30, 95% CI 0.99 to 1.70), and clinical subgroup analysis indicated that this was connected to the polyarticular subgroup. No significant association was found with SLE, UC, CD, PSC or T1D. In patients with RA, we found no significant interaction between the FCRL3 -169T>C and PTPN22 1858C>T SNPs, nor between the FCRL3 -169CC genotype and IgM-rheumatoid factor or anti-cyclic citrullinated peptide titre levels. CONCLUSION: We found an association between the FCRL3 -169T>C SNP and RA, and suggestive evidence for involvement with JIA, in a Norwegian population. These findings lend support for a role for this SNP in RA across ethnically diverse populations, and warrant follow-up studies in JIA.


Assuntos
Artrite Juvenil/genética , Artrite Reumatoide/genética , Polimorfismo de Nucleotídeo Único , Receptores Imunológicos/genética , Doenças Autoimunes/genética , Frequência do Gene , Predisposição Genética para Doença , Genótipo , Humanos , Noruega
17.
Genes Immun ; 8(3): 275-8, 2007 Apr.
Artigo em Inglês | MEDLINE | ID: mdl-17301827

RESUMO

Approximately 80% of patients with primary sclerosing cholangitis (PSC) of Northern European origin have inflammatory bowel disease (IBD), the majority ulcerative colitis (UC). An inherent problem in interpreting positive findings in genetic association studies of PSC is thus to distinguish between factors associated with hepatobiliary versus intestinal pathology. We aimed to clarify to what extent human leukocyte antigen (HLA) class II associations in UC patients with and without PSC differ. High-resolution DRB1 and DQB1 typing was performed in 365 Scandinavian PSC patients, an independent cohort of 330 Norwegian UC patients and 368 healthy controls. HLA associations found in PSC were mostly distinct from those seen in UC, and no significant differences were noted between PSC patients with concurrent UC and PSC patients without IBD. This suggests different HLA associated genetic susceptibility to PSC and UC, and supports notions that UC in PSC may represent a distinct UC phenotype.


Assuntos
Colangite Esclerosante/complicações , Colangite Esclerosante/imunologia , Colite Ulcerativa/complicações , Colite Ulcerativa/imunologia , Antígenos HLA-DQ , Antígenos HLA-DR , Adolescente , Adulto , Idoso , Idoso de 80 Anos ou mais , Alelos , Estudos de Casos e Controles , Criança , Pré-Escolar , Colangite Esclerosante/genética , Colite Ulcerativa/genética , Feminino , Frequência do Gene , Predisposição Genética para Doença , Antígenos HLA-DQ/genética , Cadeias beta de HLA-DQ , Antígenos HLA-DR/genética , Cadeias HLA-DRB1 , Humanos , Masculino , Pessoa de Meia-Idade , Noruega , Suécia
18.
Tissue Antigens ; 69(2): 161-9, 2007 Feb.
Artigo em Inglês | MEDLINE | ID: mdl-17257319

RESUMO

Primary sclerosing cholangitis (PSC) is associated with the human leukocyte antigen (HLA)-DRB1*0301-DQA1*0501-DQB1*0201 (DR3) and HLA-DRB1*1301-DQA1*0103-DQB1*0603 (DR6) haplotypes. Recently, the extended HLA class I region has been found to harbour genes that modulate or confer susceptibility independently of the HLA class II genes in several immune-mediated diseases. The aim of the present study was to evaluate the influence of genes in the extended HLA class I region on susceptibility to PSC. Seven microsatellite markers (MIB, D6S265, D6S2222, D6S464, D6S2223, D6S2225 and D6S2239) were analysed together with HLA class II alleles in 219 Norwegian patients with PSC and 282 random controls. To control for associations because of linkage disequilibrium (LD), 142 HLA-DR3 homozygous and 187 DR6-positive controls were included. The unstratified analysis showed significant associations with the alleles MIB*349 [odds ratio (OR) = 3.0, corrected P value (P(c)) = 3 x 10(-12)], D6S265*122 (OR = 1.7, P(c)= 0.004), D6S464*209 (OR = 1.8, P(c)= 0.03) and D6S2225*147 (OR = 2.7, P(c)= 4 x 10(-6)), which were mainly secondary to the DR3 association. When stratifying for DR6, an association with the D6S265*122 allele was still observed (OR = 3.7, P(c)= 0.0004). In the presence of the D6S265*122 allele, the risk to develop PSC conferred by DR6 was increased four times compared with the risk conferred by DR6 alone. In addition, a novel negative association of PSC with DR11 was observed (OR = 0.21, P(c)= 2 x 10(-4)). In conclusion, our study shows that a gene in LD with D6S265 contributes to susceptibility to develop PSC in individuals carrying DR6. Moreover, we found that the PSC-associated DR3 haplotype extends more telomeric than that previously reported. We also report a possible protective effect of DR11 on development of PSC.


Assuntos
Colangite Esclerosante/imunologia , Antígeno HLA-DR3/genética , Antígeno HLA-DR6/genética , Antígenos de Histocompatibilidade Classe I/genética , Adolescente , Adulto , Idoso , Alelos , Estudos de Casos e Controles , Criança , Colangite Esclerosante/genética , Cromossomos Humanos Par 6/genética , Marcadores Genéticos , Predisposição Genética para Doença , Haplótipos , Antígenos de Histocompatibilidade Classe II/genética , Humanos , Desequilíbrio de Ligação , Repetições de Microssatélites , Pessoa de Meia-Idade
20.
Tissue Antigens ; 68(1): 78-81, 2006 Jul.
Artigo em Inglês | MEDLINE | ID: mdl-16774544

RESUMO

CCR5 is a chemokine receptor expressed on T-cells and macrophages. A 32-base pair deletion in the chemokine receptor 5 gene (CCR5-Delta32) leads to a non-functional receptor. Conflicting evidence exists whether this deletion is associated with primary sclerosing cholangitis (PSC). We genotyped the CCR5-Delta32 variant in 363 PSC patients and 366 controls. No significant increase in the Delta32 allele frequency was detected in the PSC patients compared to controls (12.7% vs 10.7% OR = 1.22, 95% CI [0.88, 1.68], P = 0.23). Survival analysis did not reveal any significant effects from CCR5-Delta32 genotypes on disease progression. Thus, in this study (power > 90%, given OR = 2, alpha = 0.05), we were unable to replicate previous findings and our results do not support an involvement of CCR5-Delta32 in either PSC susceptibility or progression.


Assuntos
Colangite Esclerosante/etiologia , Deleção de Genes , Receptores CCR5/genética , Alelos , Pareamento de Bases , Estudos de Casos e Controles , Intervalos de Confiança , Progressão da Doença , Feminino , Frequência do Gene , Predisposição Genética para Doença , Humanos , Masculino , Razão de Chances , Países Escandinavos e Nórdicos/epidemiologia
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