Jennifer Yarden - Academia.edu (original) (raw)

Papers by Jennifer Yarden

Research paper thumbnail of Association of tumour necrosis factor alpha variants with the CF pulmonary phenotype

Thorax, 2005

Background: The pulmonary phenotype in patients with cystic fibrosis (CF), even in those with the... more Background: The pulmonary phenotype in patients with cystic fibrosis (CF), even in those with the same CF transmembrane conductance regulator (CFTR) genotype, is variable and must therefore be influenced by secondary genetic factors as well as environmental factors. Possible candidate genes that modulate the CF lung phenotype may include proinflammatory cytokines. One such protein is tumour necrosis factor a (TNFa), a member of the immune system. Methods: Three polymorphic loci in the promoter (2851c/t, 2308g/a, 2238g/a) and one polymorphic locus in intron 1 (+691g ins/del) of the TNFa gene were typed by a single nucleotide primer extension assay in CF patients and healthy controls. Spirometric data and first age of infection with Pseudomonas aeruginosa were collected retrospectively from patients' medical records. Results: An association was found between the TNFa +691g ins/del polymorphic locus and severity of CF lung disease. Patients heterozygous for +691g ins and +691g del were more likely to have better pulmonary function (mean (SD) forced expiratory volume in 1 second (FEV 1 ) 79.7 (12.8)% predicted) than patients homozygous for +691g ins (mean (SD) FEV 1 67.5 (23.0)% predicted; p = 0.008, mean difference 12.2%, 95% CI 3.5 to 21.0). Also, patients heterozygous for +691g ins and +691g del were more likely to have an older first age of infection with P aeruginosa (mean (SD) 11.4 (6.0) years) than patients homozygous for +691g ins (mean (SD) 8.3 (4.6) years; p = 0.018, mean difference 3.1 years, 95% CI 0.5 to 5.6). An association was also found with the 2851c/t polymorphic locus. In the group of patients with more severe FEV 1 % predicted, a higher proportion of patients were homozygous for the 2851c allele than in the other group of patients (p = 0.04, likelihood ratio x 2 , odds ratio = 2.4). Conlusion: TNFa polymorphisms are associated with the severity of CF lung disease in Czech and Belgian patients with CF.

Research paper thumbnail of Serum anti-glycan antibodies predict complicated Crohn's disease behavior: A cohort study

Inflammatory Bowel Diseases, 2009

Background:A high proportion of patients with Crohn's disease (CD) over time develop complication... more Background:A high proportion of patients with Crohn's disease (CD) over time develop complications like fistulae and strictures, requiring surgery. We tested a panel of antiglycan antibodies for predicting the occurrence of complications and CD-related surgery in an adult patient cohort.A high proportion of patients with Crohn's disease (CD) over time develop complications like fistulae and strictures, requiring surgery. We tested a panel of antiglycan antibodies for predicting the occurrence of complications and CD-related surgery in an adult patient cohort.Methods:Serum samples of 149 CD patients of the German inflammatory bowel disease (IBD) network were tested for the presence of anti-laminarin IgA (Anti-L), anti-chitin IgA (Anti-C), anti-chitobioside IgA (ACCA), anti-laminaribioside IgG (ALCA), anti-mannobioside IgG (AMCA), and anti-Saccaromyces cerevisiae IgG (gASCA) carbohydrate antibodies by enzyme-linked immunosorbent assay (ELISA) (IBDX® panel, Glycominds, Lod, Israel) in a blinded fashion. Clinical data were available on occurrence of complicated disease or CD-related surgery as well as disease activity, onset, and location.Serum samples of 149 CD patients of the German inflammatory bowel disease (IBD) network were tested for the presence of anti-laminarin IgA (Anti-L), anti-chitin IgA (Anti-C), anti-chitobioside IgA (ACCA), anti-laminaribioside IgG (ALCA), anti-mannobioside IgG (AMCA), and anti-Saccaromyces cerevisiae IgG (gASCA) carbohydrate antibodies by enzyme-linked immunosorbent assay (ELISA) (IBDX® panel, Glycominds, Lod, Israel) in a blinded fashion. Clinical data were available on occurrence of complicated disease or CD-related surgery as well as disease activity, onset, and location.Results:The median follow-up of the patients without any previous complication or surgery at time of sample procurement was 53.7 months. Overall, 26.3% developed a complication and 17.1% underwent CD-related surgery, respectively. Positivity for gASCA, AMCA, ACCA, and Anti-L alone or an increasing frequency of positive serum antibodies independently predicted a faster progression toward a more severe disease course. Once a complication or surgery had occurred only positivity for Anti-L or more than 3 markers out of the whole panel indicated progression to an additional surgery or complication. The antibody status of most patients remained stable over time.The median follow-up of the patients without any previous complication or surgery at time of sample procurement was 53.7 months. Overall, 26.3% developed a complication and 17.1% underwent CD-related surgery, respectively. Positivity for gASCA, AMCA, ACCA, and Anti-L alone or an increasing frequency of positive serum antibodies independently predicted a faster progression toward a more severe disease course. Once a complication or surgery had occurred only positivity for Anti-L or more than 3 markers out of the whole panel indicated progression to an additional surgery or complication. The antibody status of most patients remained stable over time.Conclusions:This is the first study showing the clinical value of serum antiglycan antibodies for prediction of a more complicated disease course in adult patients with CD. (Inflamm Bowel Dis 2010)This is the first study showing the clinical value of serum antiglycan antibodies for prediction of a more complicated disease course in adult patients with CD. (Inflamm Bowel Dis 2010)

Research paper thumbnail of 390 The Novel Anti-Glycan Antibodies Anti-L and AntiC in Conjunction with ALCA, ACCA, gASCA and AMCA Predict Early Development of Fistulae, Stenoses and Surgery in Patients with Crohn's Disease: A Prospective Analysis

Research paper thumbnail of Association of the novel serologic anti-glycan antibodies anti-laminarin and anti-chitin with complicated Crohn's disease behavior

Inflammatory Bowel Diseases, 2009

Background:We tested a panel of novel serological anti-glycan antibodies including the previously... more Background:We tested a panel of novel serological anti-glycan antibodies including the previously unpublished anti-laminarin IgA (Anti-L) and anti-chitin IgA (Anti-C) carbohydrate antibodies for the presence in Crohn's disease (CD) patients, diagnosis and differentiation of CD, association with complicated disease behavior, and marker stability over time.We tested a panel of novel serological anti-glycan antibodies including the previously unpublished anti-laminarin IgA (Anti-L) and anti-chitin IgA (Anti-C) carbohydrate antibodies for the presence in Crohn's disease (CD) patients, diagnosis and differentiation of CD, association with complicated disease behavior, and marker stability over time.Methods:The presence of Anti-L, Anti-C, anti-chitobioside IgA (ACCA), anti-laminaribioside IgG (ALCA), anti-mannobioside IgG (AMCA), and anti-Saccaromyces cervisiae IgG (gASCA) carbohydrate antibodies were tested in serum samples from 824 participants (363 CD, 130 ulcerative colitis [UC], 74 other gastrointestinal diseases, and 257 noninflammatory bowel/gastrointestinal disease controls) of the German IBD-network by enzyme-linked immunosorbent assay (ELISA; Glycominds, Lod, Israel) and for perinuclear antineutrophil cytoplasmic antibody (pANCA) by immunofluorescence.The presence of Anti-L, Anti-C, anti-chitobioside IgA (ACCA), anti-laminaribioside IgG (ALCA), anti-mannobioside IgG (AMCA), and anti-Saccaromyces cervisiae IgG (gASCA) carbohydrate antibodies were tested in serum samples from 824 participants (363 CD, 130 ulcerative colitis [UC], 74 other gastrointestinal diseases, and 257 noninflammatory bowel/gastrointestinal disease controls) of the German IBD-network by enzyme-linked immunosorbent assay (ELISA; Glycominds, Lod, Israel) and for perinuclear antineutrophil cytoplasmic antibody (pANCA) by immunofluorescence.Results:In all, 77.4% of the CD patients were positive for at least 1 of the anti-glycan antibodies. gASCA or the combination of gASCA/pANCA remained most accurate for the diagnosis of CD, but the combined use of the antibodies improved differentiation of CD from UC. Several single markers as well as an increasing antibody response were independently linked to a severe disease phenotype, as shown for the occurrence of complications, CD-related surgery, early disease onset, and ileal disease location. This was observed for both quantitative and qualitative antibody responses. The antibody status remained stable over time in most IBD patients.In all, 77.4% of the CD patients were positive for at least 1 of the anti-glycan antibodies. gASCA or the combination of gASCA/pANCA remained most accurate for the diagnosis of CD, but the combined use of the antibodies improved differentiation of CD from UC. Several single markers as well as an increasing antibody response were independently linked to a severe disease phenotype, as shown for the occurrence of complications, CD-related surgery, early disease onset, and ileal disease location. This was observed for both quantitative and qualitative antibody responses. The antibody status remained stable over time in most IBD patients.Conclusions:A panel of anti-glycan antibodies including the novel Anti-L and Anti-C may aid in differentiation of CD from UC, is associated with complicated CD behavior and IBD-related surgery, and is stable over time in a large patient cohort. Inflamm Bowel Dis 2009A panel of anti-glycan antibodies including the novel Anti-L and Anti-C may aid in differentiation of CD from UC, is associated with complicated CD behavior and IBD-related surgery, and is stable over time in a large patient cohort. Inflamm Bowel Dis 2009

Research paper thumbnail of 392 Specific Levels and Combinations of the Anti-Glycan Antibodies Anti-L, AntiC, ALCA, ACCA, gASCA and AMCA Contribute to Diagnosis and Differential Diagnosis of Patients with Crohn's Disease and Are Associated with Complicated Disease and Surgery

Research paper thumbnail of T1289 Anti-Glycan Antibodies are Associated With Disabling Disease Course and Complicated Disease Behavior in Patients With Crohn's Disease

Gastroenterology, 2010

proportional hazards regression was performed to find predictors for surgery-free survival.

R... more proportional hazards regression was performed to find predictors for surgery-free survival.

Results: In our study cohort (mean age 60.2 ±11.8 years, 57.5 % females, 17 % current smokers, median follow up 292 days), 135 patients underwent 340 endoscopic stricture dilations (159 primary and 181 anastomotic). The median intervention-free (repeat dilation or surgery) period was 140 days and there were total of 4 complications (3 perforations, 1 major bleeding). There was no difference between primary or anastomotic strictures with respect to need for surgery (p=0.17, , intervention-free period (p= 0.24) or perforation rate (0.7% versus 1.2%, p= 0.57). 36 patients (26.7%) underwent surgery in the follow-up period. Multivariate Cox regression analysis showed that inflamed mucosa (hazard ratio [HR] 2.3, p=0.04) and colonic location (HR, 2.5, p=0.03) were significantly associated with increased risk for future surgery while intramucosal steroid injection did not confer any benfit.

Conclusion: In this largest experience reported so far, we have found that endoscopic dilation is very safe and effective for CD patients with anastomotic as well as non-anastomotic strictures. Future studies should aim to investigate endoscopic and pharmacologic interventions that can prolong the intervention-free period and improve longterm outcomes.

Research paper thumbnail of Serum anti-GAGA4 IgM antibodies differentiate relapsing remitting and secondary progressive multiple sclerosis from primary progressive multiple sclerosis and other neurological diseases

Journal of Neuroimmunology, 2009

The serum level of IgM antibodies against Glc(alpha1,4)Glc(alpha) (GAGA4) is higher in relapsing ... more The serum level of IgM antibodies against Glc(alpha1,4)Glc(alpha) (GAGA4) is higher in relapsing remitting multiple sclerosis (RRMS) compared to other neurological disease (OND) patients and healthy controls (HC). Detecting the level of anti-GAGA4 antibody by enzyme immunoassay and total IgM, we confirmed that anti-GAGA4 IgM can differentiate RRMS from OND patients and HC. Moreover, secondary progressive MS (SPMS) and RRMS patients have similar levels of anti-GAGA4 demonstrating the biomarker's presence throughout the disease. Interestingly, the anti-GAGA4 assay may also differentiate between primary progressive MS (PPMS) and RRMS/SPMS patients, since nearly all PPMS patients were negative for the assay.

Research paper thumbnail of Polymorphisms in the mannose binding lectin gene affect the cystic fibrosis pulmonary phenotype

Journal of Medical Genetics, 2004

Research paper thumbnail of The TNFα receptor TNFRSF1A and genes encoding the amiloride-sensitive sodium channel ENaC as modulators in cystic fibrosis

Human Genetics, 2006

The CFTR mutations in cystic fibrosis (CF) lead to ion transport anomalities which predispose to ... more The CFTR mutations in cystic fibrosis (CF) lead to ion transport anomalities which predispose to chronic infection and inflammation of CF airways as the major determinants for morbidity and mortality in CF. Discordant clinical phenotypes of siblings with identical CFTR mutations and the large variability of clinical manifestations of patients who are homozygous for the most common mutation F508del suggest that both environment and genes other than CFTR contribute substantially to CF disease. The prime candidates for genetic modifiers in CF are elements of host defence such as the TNFα receptor and of ion transport such as the amiloride-sensitive epithelial sodium channel ENaC, both of which are encoded side by side on 12p13 (TNFRSF1A, SCNN1A) and 16p12 (SCNN1B, SCNN1G). Thirty-seven families with F508del-CFTR homozygous siblings exhibiting extreme clinical phenotypes that had been selected from the 467 pairs of the European CF Twin and Sibling Study were genotyped at 12p13 and 16p12 markers. The ENaC was identified as a modulator of CF by transmission disequilibrium at SCNN1G and association with CF phenotype intrapair discordance at SCNN1B. Family-based and case-control analyses and sequencing of SCNN1A and TNFRSF1A uncovered an association of the TNFRSF1A intron 1 haplotype with disease severity. Carriers of risk haplotypes were underrepresented suggesting a strong impact of both loci on survival. The finding that TNFRSF1A, SCNN1B and SCNN1G are clinically relevant modulators of CF disease supports current concepts that the depletion of airway surface liquid and inadequate host inflammatory responses trigger pulmonary disease in CF.

Research paper thumbnail of The TNFa receptor TNFRSF1A and genes encoding the amiloride-sensitive sodium channel ENaC as modulators in cystic fibrosis

Research paper thumbnail of Genes that determine immunology and inflammation modify the basic defect of impaired ion conductance in cystic fibrosis epithelia

Journal of Medical Genetics, 2010

Background The cystic fibrosis (CF) basic defect, caused by dysfunction of the apical chloride ch... more Background The cystic fibrosis (CF) basic defect, caused by dysfunction of the apical chloride channel CFTR in the gastrointestinal and respiratory tract epithelia, has not been employed so far to support the role of CF modifier genes. Methods Patients were selected from 101 families with a total of 171 F508del-CFTR homozygous CF patients to identify CF modifying genes. A candidate gene based association study of 52 genes on 16 different chromosomes with a total of 182 genetic markers was performed. Differences in haplotype and/or diplotype distribution between case and reference CF subpopulations were analysed. Results Variants at immunologically relevant genes were associated with the manifestation of the CF basic defect (0.01<Praw<0.0001 at IL1B, TLR9, TNFa, CD95, STAT3 and TNFR). The intragenic background of F508del-CFTR chromosomes determined disease severity and manifestation of the basic defect (Praw¼0.0009). Allele distributions comparing transmitted and non-transmitted alleles were distorted at several loci unlinked to CFTR. Conclusions The inherited capabilities of the innate and adaptive immune system determine the manifestation of the CF basic defect. Variants on F508del-CFTR chromosomes contribute to the observed patient-topatient variability among F508del-CFTR homozygotes. A survivor effect, manifesting as a transmission disequilibrium at many loci, is consistent with the improvement of clinical care over the last decades, resulting in a depletion of risk alleles at modifier genes. Awareness of non-genetic factors such as improvement of patient care over time is crucial for the interpretation of CF modifier studies. < Supplementary material and tables are published online only. To view these files please visit the journal online

Research paper thumbnail of 17 The TNFα receptor TNFRSF1A and genes encoding the amiloride-sensitive sodium channel ENaC as modulators in Cystic Fibrosis

Journal of Cystic Fibrosis, 2006

The CFTR mutations in cystic fibrosis (CF) lead to ion transport anomalities which predispose to ... more The CFTR mutations in cystic fibrosis (CF) lead to ion transport anomalities which predispose to chronic infection and inflammation of CF airways as the major determinants for morbidity and mortality in CF. Discordant clinical phenotypes of siblings with identical CFTR mutations and the large variability of clinical manifestations of patients who are homozygous for the most common mutation F508del suggest that both environment and genes other than CFTR contribute substantially to CF disease. The prime candidates for genetic modifiers in CF are elements of host defence such as the TNFa receptor and of ion transport such as the amiloride-sensitive epithelial sodium channel ENaC, both of which are encoded side by side on 12p13 (TNFRSF1A, SCNN1A) and 16p12 (SCNN1B, SCNN1G). Thirty-seven families with F508del-CFTR homozygous siblings exhibiting extreme clinical phenotypes that had been selected from the 467 pairs of the European CF Twin and Sibling Study were genotyped at 12p13 and 16p12 markers. The ENaC was identified as a modulator of CF by transmission disequilibrium at SCNN1G and association with CF phenotype intrapair discordance at SCNN1B. Family-based and case-control analyses and sequencing of SCNN1A and TNFRSF1A uncovered an association of the TNFRSF1A intron 1 haplotype with disease severity. Carriers of risk haplotypes were underrepresented suggesting a strong impact of both loci on survival. The finding that TNFRSF1A, SCNN1B and SCNN1G are clinically relevant modulators of CF disease supports current concepts that the depletion of airway surface liquid and inadequate host inflammatory responses trigger pulmonary disease in CF.

Research paper thumbnail of Association of tumour necrosis factor alpha variants with the CF pulmonary phenotype

Thorax, 2005

Background: The pulmonary phenotype in patients with cystic fibrosis (CF), even in those with the... more Background: The pulmonary phenotype in patients with cystic fibrosis (CF), even in those with the same CF transmembrane conductance regulator (CFTR) genotype, is variable and must therefore be influenced by secondary genetic factors as well as environmental factors. Possible candidate genes that modulate the CF lung phenotype may include proinflammatory cytokines. One such protein is tumour necrosis factor a (TNFa), a member of the immune system. Methods: Three polymorphic loci in the promoter (2851c/t, 2308g/a, 2238g/a) and one polymorphic locus in intron 1 (+691g ins/del) of the TNFa gene were typed by a single nucleotide primer extension assay in CF patients and healthy controls. Spirometric data and first age of infection with Pseudomonas aeruginosa were collected retrospectively from patients' medical records. Results: An association was found between the TNFa +691g ins/del polymorphic locus and severity of CF lung disease. Patients heterozygous for +691g ins and +691g del were more likely to have better pulmonary function (mean (SD) forced expiratory volume in 1 second (FEV 1 ) 79.7 (12.8)% predicted) than patients homozygous for +691g ins (mean (SD) FEV 1 67.5 (23.0)% predicted; p = 0.008, mean difference 12.2%, 95% CI 3.5 to 21.0). Also, patients heterozygous for +691g ins and +691g del were more likely to have an older first age of infection with P aeruginosa (mean (SD) 11.4 (6.0) years) than patients homozygous for +691g ins (mean (SD) 8.3 (4.6) years; p = 0.018, mean difference 3.1 years, 95% CI 0.5 to 5.6). An association was also found with the 2851c/t polymorphic locus. In the group of patients with more severe FEV 1 % predicted, a higher proportion of patients were homozygous for the 2851c allele than in the other group of patients (p = 0.04, likelihood ratio x 2 , odds ratio = 2.4). Conlusion: TNFa polymorphisms are associated with the severity of CF lung disease in Czech and Belgian patients with CF.

Research paper thumbnail of Serum anti-glycan antibodies predict complicated Crohn's disease behavior: A cohort study

Inflammatory Bowel Diseases, 2009

Background:A high proportion of patients with Crohn's disease (CD) over time develop complication... more Background:A high proportion of patients with Crohn's disease (CD) over time develop complications like fistulae and strictures, requiring surgery. We tested a panel of antiglycan antibodies for predicting the occurrence of complications and CD-related surgery in an adult patient cohort.A high proportion of patients with Crohn's disease (CD) over time develop complications like fistulae and strictures, requiring surgery. We tested a panel of antiglycan antibodies for predicting the occurrence of complications and CD-related surgery in an adult patient cohort.Methods:Serum samples of 149 CD patients of the German inflammatory bowel disease (IBD) network were tested for the presence of anti-laminarin IgA (Anti-L), anti-chitin IgA (Anti-C), anti-chitobioside IgA (ACCA), anti-laminaribioside IgG (ALCA), anti-mannobioside IgG (AMCA), and anti-Saccaromyces cerevisiae IgG (gASCA) carbohydrate antibodies by enzyme-linked immunosorbent assay (ELISA) (IBDX® panel, Glycominds, Lod, Israel) in a blinded fashion. Clinical data were available on occurrence of complicated disease or CD-related surgery as well as disease activity, onset, and location.Serum samples of 149 CD patients of the German inflammatory bowel disease (IBD) network were tested for the presence of anti-laminarin IgA (Anti-L), anti-chitin IgA (Anti-C), anti-chitobioside IgA (ACCA), anti-laminaribioside IgG (ALCA), anti-mannobioside IgG (AMCA), and anti-Saccaromyces cerevisiae IgG (gASCA) carbohydrate antibodies by enzyme-linked immunosorbent assay (ELISA) (IBDX® panel, Glycominds, Lod, Israel) in a blinded fashion. Clinical data were available on occurrence of complicated disease or CD-related surgery as well as disease activity, onset, and location.Results:The median follow-up of the patients without any previous complication or surgery at time of sample procurement was 53.7 months. Overall, 26.3% developed a complication and 17.1% underwent CD-related surgery, respectively. Positivity for gASCA, AMCA, ACCA, and Anti-L alone or an increasing frequency of positive serum antibodies independently predicted a faster progression toward a more severe disease course. Once a complication or surgery had occurred only positivity for Anti-L or more than 3 markers out of the whole panel indicated progression to an additional surgery or complication. The antibody status of most patients remained stable over time.The median follow-up of the patients without any previous complication or surgery at time of sample procurement was 53.7 months. Overall, 26.3% developed a complication and 17.1% underwent CD-related surgery, respectively. Positivity for gASCA, AMCA, ACCA, and Anti-L alone or an increasing frequency of positive serum antibodies independently predicted a faster progression toward a more severe disease course. Once a complication or surgery had occurred only positivity for Anti-L or more than 3 markers out of the whole panel indicated progression to an additional surgery or complication. The antibody status of most patients remained stable over time.Conclusions:This is the first study showing the clinical value of serum antiglycan antibodies for prediction of a more complicated disease course in adult patients with CD. (Inflamm Bowel Dis 2010)This is the first study showing the clinical value of serum antiglycan antibodies for prediction of a more complicated disease course in adult patients with CD. (Inflamm Bowel Dis 2010)

Research paper thumbnail of 390 The Novel Anti-Glycan Antibodies Anti-L and AntiC in Conjunction with ALCA, ACCA, gASCA and AMCA Predict Early Development of Fistulae, Stenoses and Surgery in Patients with Crohn's Disease: A Prospective Analysis

Research paper thumbnail of Association of the novel serologic anti-glycan antibodies anti-laminarin and anti-chitin with complicated Crohn's disease behavior

Inflammatory Bowel Diseases, 2009

Background:We tested a panel of novel serological anti-glycan antibodies including the previously... more Background:We tested a panel of novel serological anti-glycan antibodies including the previously unpublished anti-laminarin IgA (Anti-L) and anti-chitin IgA (Anti-C) carbohydrate antibodies for the presence in Crohn's disease (CD) patients, diagnosis and differentiation of CD, association with complicated disease behavior, and marker stability over time.We tested a panel of novel serological anti-glycan antibodies including the previously unpublished anti-laminarin IgA (Anti-L) and anti-chitin IgA (Anti-C) carbohydrate antibodies for the presence in Crohn's disease (CD) patients, diagnosis and differentiation of CD, association with complicated disease behavior, and marker stability over time.Methods:The presence of Anti-L, Anti-C, anti-chitobioside IgA (ACCA), anti-laminaribioside IgG (ALCA), anti-mannobioside IgG (AMCA), and anti-Saccaromyces cervisiae IgG (gASCA) carbohydrate antibodies were tested in serum samples from 824 participants (363 CD, 130 ulcerative colitis [UC], 74 other gastrointestinal diseases, and 257 noninflammatory bowel/gastrointestinal disease controls) of the German IBD-network by enzyme-linked immunosorbent assay (ELISA; Glycominds, Lod, Israel) and for perinuclear antineutrophil cytoplasmic antibody (pANCA) by immunofluorescence.The presence of Anti-L, Anti-C, anti-chitobioside IgA (ACCA), anti-laminaribioside IgG (ALCA), anti-mannobioside IgG (AMCA), and anti-Saccaromyces cervisiae IgG (gASCA) carbohydrate antibodies were tested in serum samples from 824 participants (363 CD, 130 ulcerative colitis [UC], 74 other gastrointestinal diseases, and 257 noninflammatory bowel/gastrointestinal disease controls) of the German IBD-network by enzyme-linked immunosorbent assay (ELISA; Glycominds, Lod, Israel) and for perinuclear antineutrophil cytoplasmic antibody (pANCA) by immunofluorescence.Results:In all, 77.4% of the CD patients were positive for at least 1 of the anti-glycan antibodies. gASCA or the combination of gASCA/pANCA remained most accurate for the diagnosis of CD, but the combined use of the antibodies improved differentiation of CD from UC. Several single markers as well as an increasing antibody response were independently linked to a severe disease phenotype, as shown for the occurrence of complications, CD-related surgery, early disease onset, and ileal disease location. This was observed for both quantitative and qualitative antibody responses. The antibody status remained stable over time in most IBD patients.In all, 77.4% of the CD patients were positive for at least 1 of the anti-glycan antibodies. gASCA or the combination of gASCA/pANCA remained most accurate for the diagnosis of CD, but the combined use of the antibodies improved differentiation of CD from UC. Several single markers as well as an increasing antibody response were independently linked to a severe disease phenotype, as shown for the occurrence of complications, CD-related surgery, early disease onset, and ileal disease location. This was observed for both quantitative and qualitative antibody responses. The antibody status remained stable over time in most IBD patients.Conclusions:A panel of anti-glycan antibodies including the novel Anti-L and Anti-C may aid in differentiation of CD from UC, is associated with complicated CD behavior and IBD-related surgery, and is stable over time in a large patient cohort. Inflamm Bowel Dis 2009A panel of anti-glycan antibodies including the novel Anti-L and Anti-C may aid in differentiation of CD from UC, is associated with complicated CD behavior and IBD-related surgery, and is stable over time in a large patient cohort. Inflamm Bowel Dis 2009

Research paper thumbnail of 392 Specific Levels and Combinations of the Anti-Glycan Antibodies Anti-L, AntiC, ALCA, ACCA, gASCA and AMCA Contribute to Diagnosis and Differential Diagnosis of Patients with Crohn's Disease and Are Associated with Complicated Disease and Surgery

Research paper thumbnail of T1289 Anti-Glycan Antibodies are Associated With Disabling Disease Course and Complicated Disease Behavior in Patients With Crohn's Disease

Gastroenterology, 2010

proportional hazards regression was performed to find predictors for surgery-free survival.

R... more proportional hazards regression was performed to find predictors for surgery-free survival.

Results: In our study cohort (mean age 60.2 ±11.8 years, 57.5 % females, 17 % current smokers, median follow up 292 days), 135 patients underwent 340 endoscopic stricture dilations (159 primary and 181 anastomotic). The median intervention-free (repeat dilation or surgery) period was 140 days and there were total of 4 complications (3 perforations, 1 major bleeding). There was no difference between primary or anastomotic strictures with respect to need for surgery (p=0.17, , intervention-free period (p= 0.24) or perforation rate (0.7% versus 1.2%, p= 0.57). 36 patients (26.7%) underwent surgery in the follow-up period. Multivariate Cox regression analysis showed that inflamed mucosa (hazard ratio [HR] 2.3, p=0.04) and colonic location (HR, 2.5, p=0.03) were significantly associated with increased risk for future surgery while intramucosal steroid injection did not confer any benfit.

Conclusion: In this largest experience reported so far, we have found that endoscopic dilation is very safe and effective for CD patients with anastomotic as well as non-anastomotic strictures. Future studies should aim to investigate endoscopic and pharmacologic interventions that can prolong the intervention-free period and improve longterm outcomes.

Research paper thumbnail of Serum anti-GAGA4 IgM antibodies differentiate relapsing remitting and secondary progressive multiple sclerosis from primary progressive multiple sclerosis and other neurological diseases

Journal of Neuroimmunology, 2009

The serum level of IgM antibodies against Glc(alpha1,4)Glc(alpha) (GAGA4) is higher in relapsing ... more The serum level of IgM antibodies against Glc(alpha1,4)Glc(alpha) (GAGA4) is higher in relapsing remitting multiple sclerosis (RRMS) compared to other neurological disease (OND) patients and healthy controls (HC). Detecting the level of anti-GAGA4 antibody by enzyme immunoassay and total IgM, we confirmed that anti-GAGA4 IgM can differentiate RRMS from OND patients and HC. Moreover, secondary progressive MS (SPMS) and RRMS patients have similar levels of anti-GAGA4 demonstrating the biomarker&amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;amp;#39;s presence throughout the disease. Interestingly, the anti-GAGA4 assay may also differentiate between primary progressive MS (PPMS) and RRMS/SPMS patients, since nearly all PPMS patients were negative for the assay.

Research paper thumbnail of Polymorphisms in the mannose binding lectin gene affect the cystic fibrosis pulmonary phenotype

Journal of Medical Genetics, 2004

Research paper thumbnail of The TNFα receptor TNFRSF1A and genes encoding the amiloride-sensitive sodium channel ENaC as modulators in cystic fibrosis

Human Genetics, 2006

The CFTR mutations in cystic fibrosis (CF) lead to ion transport anomalities which predispose to ... more The CFTR mutations in cystic fibrosis (CF) lead to ion transport anomalities which predispose to chronic infection and inflammation of CF airways as the major determinants for morbidity and mortality in CF. Discordant clinical phenotypes of siblings with identical CFTR mutations and the large variability of clinical manifestations of patients who are homozygous for the most common mutation F508del suggest that both environment and genes other than CFTR contribute substantially to CF disease. The prime candidates for genetic modifiers in CF are elements of host defence such as the TNFα receptor and of ion transport such as the amiloride-sensitive epithelial sodium channel ENaC, both of which are encoded side by side on 12p13 (TNFRSF1A, SCNN1A) and 16p12 (SCNN1B, SCNN1G). Thirty-seven families with F508del-CFTR homozygous siblings exhibiting extreme clinical phenotypes that had been selected from the 467 pairs of the European CF Twin and Sibling Study were genotyped at 12p13 and 16p12 markers. The ENaC was identified as a modulator of CF by transmission disequilibrium at SCNN1G and association with CF phenotype intrapair discordance at SCNN1B. Family-based and case-control analyses and sequencing of SCNN1A and TNFRSF1A uncovered an association of the TNFRSF1A intron 1 haplotype with disease severity. Carriers of risk haplotypes were underrepresented suggesting a strong impact of both loci on survival. The finding that TNFRSF1A, SCNN1B and SCNN1G are clinically relevant modulators of CF disease supports current concepts that the depletion of airway surface liquid and inadequate host inflammatory responses trigger pulmonary disease in CF.

Research paper thumbnail of The TNFa receptor TNFRSF1A and genes encoding the amiloride-sensitive sodium channel ENaC as modulators in cystic fibrosis

Research paper thumbnail of Genes that determine immunology and inflammation modify the basic defect of impaired ion conductance in cystic fibrosis epithelia

Journal of Medical Genetics, 2010

Background The cystic fibrosis (CF) basic defect, caused by dysfunction of the apical chloride ch... more Background The cystic fibrosis (CF) basic defect, caused by dysfunction of the apical chloride channel CFTR in the gastrointestinal and respiratory tract epithelia, has not been employed so far to support the role of CF modifier genes. Methods Patients were selected from 101 families with a total of 171 F508del-CFTR homozygous CF patients to identify CF modifying genes. A candidate gene based association study of 52 genes on 16 different chromosomes with a total of 182 genetic markers was performed. Differences in haplotype and/or diplotype distribution between case and reference CF subpopulations were analysed. Results Variants at immunologically relevant genes were associated with the manifestation of the CF basic defect (0.01<Praw<0.0001 at IL1B, TLR9, TNFa, CD95, STAT3 and TNFR). The intragenic background of F508del-CFTR chromosomes determined disease severity and manifestation of the basic defect (Praw¼0.0009). Allele distributions comparing transmitted and non-transmitted alleles were distorted at several loci unlinked to CFTR. Conclusions The inherited capabilities of the innate and adaptive immune system determine the manifestation of the CF basic defect. Variants on F508del-CFTR chromosomes contribute to the observed patient-topatient variability among F508del-CFTR homozygotes. A survivor effect, manifesting as a transmission disequilibrium at many loci, is consistent with the improvement of clinical care over the last decades, resulting in a depletion of risk alleles at modifier genes. Awareness of non-genetic factors such as improvement of patient care over time is crucial for the interpretation of CF modifier studies. < Supplementary material and tables are published online only. To view these files please visit the journal online

Research paper thumbnail of 17 The TNFα receptor TNFRSF1A and genes encoding the amiloride-sensitive sodium channel ENaC as modulators in Cystic Fibrosis

Journal of Cystic Fibrosis, 2006

The CFTR mutations in cystic fibrosis (CF) lead to ion transport anomalities which predispose to ... more The CFTR mutations in cystic fibrosis (CF) lead to ion transport anomalities which predispose to chronic infection and inflammation of CF airways as the major determinants for morbidity and mortality in CF. Discordant clinical phenotypes of siblings with identical CFTR mutations and the large variability of clinical manifestations of patients who are homozygous for the most common mutation F508del suggest that both environment and genes other than CFTR contribute substantially to CF disease. The prime candidates for genetic modifiers in CF are elements of host defence such as the TNFa receptor and of ion transport such as the amiloride-sensitive epithelial sodium channel ENaC, both of which are encoded side by side on 12p13 (TNFRSF1A, SCNN1A) and 16p12 (SCNN1B, SCNN1G). Thirty-seven families with F508del-CFTR homozygous siblings exhibiting extreme clinical phenotypes that had been selected from the 467 pairs of the European CF Twin and Sibling Study were genotyped at 12p13 and 16p12 markers. The ENaC was identified as a modulator of CF by transmission disequilibrium at SCNN1G and association with CF phenotype intrapair discordance at SCNN1B. Family-based and case-control analyses and sequencing of SCNN1A and TNFRSF1A uncovered an association of the TNFRSF1A intron 1 haplotype with disease severity. Carriers of risk haplotypes were underrepresented suggesting a strong impact of both loci on survival. The finding that TNFRSF1A, SCNN1B and SCNN1G are clinically relevant modulators of CF disease supports current concepts that the depletion of airway surface liquid and inadequate host inflammatory responses trigger pulmonary disease in CF.