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• W2107965805 abstract "Background & Aims: Some patients with Crohn’s disease (CD) develop antibodies against mannan, a component of the yeast Saccharomyces cerevisiae cell wall. Mannan-binding lectin (MBL), a component of the innate immune system, can bind to S. cerevisiae. MBL concentration depends on genetic polymorphisms. The aim of this study was to evaluate whether low MBL contributes to anti-S. cerevisiae antibody (ASCA) production. Methods: ASCA and MBL concentrations in sera from patients with CD (n = 74), ulcerative colitis (UC) (n = 22), and healthy controls (n = 32) were measured by an enzyme-linked immunosorbent assay (ELISA). Genetic MBL variants were determined from 58 CD patients, 18 UC patients, and 47 controls by DNA sequencing. Lymphocytes were tested for proliferative response after stimulation with mannan. Results: ASCA were found in 47% of the patients with CD and in 0% of the controls. More ASCA-positive patients (52%) had low serum MBL concentrations compared with ASCA-negative patients (4%) (P < 0.0001). T-cell proliferation in response to mannan stimulation was observed in ASCA-positive patients and could be inhibited by the addition of MBL. These patients had significantly lower MBL serum concentrations than patients whose lymphocytes did not proliferate on mannan stimulation (P < 0.0001). Homozygous or compound heterozygous MBL mutations in the exon 1 and promoter occurred in 12 patients with cellular or humoral immune reactivity to mannan as compared with only 1 nonreactive patient (P < 0.0001). Conclusions: A subgroup of CD patients is characterized by ASCA positivity, T-cell proliferation on mannan stimulation, and mutations in the MBL gene that result in MBL deficiency. Thus, we propose that enhanced mannan exposure stimulates specific immune responses in a subgroup of CD patients with genetically determined low MBL concentrations. This enhanced exposure contributes to the generation of ASCA. Background & Aims: Some patients with Crohn’s disease (CD) develop antibodies against mannan, a component of the yeast Saccharomyces cerevisiae cell wall. Mannan-binding lectin (MBL), a component of the innate immune system, can bind to S. cerevisiae. MBL concentration depends on genetic polymorphisms. The aim of this study was to evaluate whether low MBL contributes to anti-S. cerevisiae antibody (ASCA) production. Methods: ASCA and MBL concentrations in sera from patients with CD (n = 74), ulcerative colitis (UC) (n = 22), and healthy controls (n = 32) were measured by an enzyme-linked immunosorbent assay (ELISA). Genetic MBL variants were determined from 58 CD patients, 18 UC patients, and 47 controls by DNA sequencing. Lymphocytes were tested for proliferative response after stimulation with mannan. Results: ASCA were found in 47% of the patients with CD and in 0% of the controls. More ASCA-positive patients (52%) had low serum MBL concentrations compared with ASCA-negative patients (4%) (P < 0.0001). T-cell proliferation in response to mannan stimulation was observed in ASCA-positive patients and could be inhibited by the addition of MBL. These patients had significantly lower MBL serum concentrations than patients whose lymphocytes did not proliferate on mannan stimulation (P < 0.0001). Homozygous or compound heterozygous MBL mutations in the exon 1 and promoter occurred in 12 patients with cellular or humoral immune reactivity to mannan as compared with only 1 nonreactive patient (P < 0.0001). Conclusions: A subgroup of CD patients is characterized by ASCA positivity, T-cell proliferation on mannan stimulation, and mutations in the MBL gene that result in MBL deficiency. Thus, we propose that enhanced mannan exposure stimulates specific immune responses in a subgroup of CD patients with genetically determined low MBL concentrations. This enhanced exposure contributes to the generation of ASCA. Crohn’s disease (CD) is a chronic inflammatory disorder characterized by a dysregulated mucosal immune response. The exact pathogenesis of CD remains unknown. It is currently thought that the disease arises owing to a complex array of genetic, environmental, and immunologic susceptibility factors. The interaction of the immune system with bacterial antigens also is thought to play an important role in the cause of CD.It has been suggested that in patients with CD, a loss of immune tolerance toward resident bacterial flora is one factor in the perpetuation of disease.1Duchmann R. Kaiser I. Hermann E. Mayet W. Ewe K. Meyer zum Buschenfelde K.H. Tolerance exists towards resident intestinal flora but is broken in active inflammatory bowel disease (IBD).Clin Exp Immunol. 1995; 102: 448-455Crossref PubMed Scopus (854) Google Scholar However, luminal antigens consist not only of bacteria, but also of yeast. The importance of luminal antigens in the pathogenesis of inflammatory bowel disease has been shown by the fact that animal models for colitis kept in a germ-free environment do not develop disease. Furthermore, it has been shown that T cells from CD patients react to their own bacterial flora.1Duchmann R. Kaiser I. Hermann E. Mayet W. Ewe K. Meyer zum Buschenfelde K.H. Tolerance exists towards resident intestinal flora but is broken in active inflammatory bowel disease (IBD).Clin Exp Immunol. 1995; 102: 448-455Crossref PubMed Scopus (854) Google Scholar Recently, results of positional cloning and candidate gene analysis of chromosome 16 have identified nucleotide oligomerization domain 2 as a gene linked to CD. Nucleotide oligomerization domain 2, otherwise known as CARD15, is thought to play an important role in the cellular reactivity to bacterial antigens.2Hugot J.P. Chamaillard M. Zouali H. Lesage S. Cezard J.P. Belaiche J. Almer S. Tysk C. O’Morain C.A. Gassull M. Binder V. Finkel Y. Cortot A. Modigliani R. Laurent-Puig P. Gower-Rousseau C. Macry J. Colombel J.F. Sahbatou M. Thomas G. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn’s disease.Nature. 2001; 411: 599-603Crossref PubMed Scopus (4630) Google Scholar, 3Hampe J. Cuthbert A. Croucher P.J. Mirza M.M. Mascheretti S. Fisher S. Frenzel H. King K. Hasselmeyer A. MacPherson A.J. Bridger S. van Deventer S. Forbes A. Nikolaus S. Lennard-Jones J.E. Foelsch U.R. Krawczak M. Lewis C. Schreiber S. Mathew G. Association between insertion mutation in NOD2 gene and Crohn’s disease in German and British populations.Lancet. 2001; 357: 1925-1928Abstract Full Text Full Text PDF PubMed Scopus (1008) Google Scholar This provides yet an additional clue to the importance of genetically determined disturbances of the immune system toward luminal antigens. The generation of other antibodies such as perinuclear antineutrophil cytoplasmic antibodies in patients with ulcerative colitis (UC) may be owing to a cross-reactivity with bacterial antigens and thus reflect the immune response to bacteria in inflammatory bowel disease.4Seibold F. Brandwein S. Simpson S. Terhorst C. Elson C.O. pANCA represent a crossreactivity to enteric bacterial antigens.J Clin Immunol. 1998; 18: 153-160Crossref PubMed Scopus (85) Google Scholar Furthermore, a proportion of patients with CD develop antibodies against mannan, a cell-wall component of the yeast Saccharomyces cerevisiae (anti-S. cerevisiae antibodies [ASCA]). These antibodies are sensitive and specific for CD. ASCA are not found in healthy controls, but are found in a proportion of healthy relatives of patients with CD.5Quinton J.F. Sendid B. Reumaux D. Duthilleul P. Cortot A. Grandbastien B. Charrier G. Targan S.R. Colombel J.F. Poulain D. Anti-Saccharomyces cerevisiae mannan antibodies combined with antineutrophil cytoplasmic autoantibodies in inflammatory bowel disease prevalence and diagnostic role.Gut. 1998; 42: 788-791Crossref PubMed Scopus (529) Google Scholar, 6Seibold F. Stich O. Hufnagl R. Kamil S. Scheurlen M. Anti-Saccharomyces cerevisiae antibodies in inflammatory bowel disease a family study.Scand J Gastroenterol. 2001; 36: 196-201Crossref PubMed Scopus (80) Google Scholar It is possible that ASCA also are caused by a cross-reactivity with bacteria expressing mannans on their surface or caused by an immune reactivity to frequently ingested yeast antigens. Furthermore, we and others showed a proliferative response of T cells to yeast antigens in patients with CD.7Konrad A. Rütten C. Scheurlen M. Göke B. Seibold F. Immune sensitization to yeast antigens in ASCA-positive patients with Crohn’s disease.Inflamm Bowel Dis. 2004; 10: 97-105Crossref PubMed Scopus (40) Google Scholar, 8van den Bogaerde J. Kamm M.A. Knight S.C. Immune sensitization to food, yeast and bacteria in Crohn’s disease.Aliment Pharmacol Ther. 2001; 15: 1647-1653Crossref PubMed Scopus (39) Google Scholar Yeast phosphopeptidomannans are not typical T-cell antigens, but there is increasing evidence that mannans influence the innate immune system and also may interact with T cells.9Oka H. Emori Y. Ohya O. Kobayashi N. Sasaki H. Tanaka Y. Hayashi Y. Nomoto K. An immunomodulatory arabinomannan extracted from Mycobacterium tuberculosis, Z-100, restores the balance of Th1/Th2 cell responses in tumor bearing mice.Immunol Lett. 1999; 70: 109-117Crossref PubMed Scopus (25) Google ScholarMannan-binding lectin (MBL) is a member of the collectin family and is an important component of the innate immune response. It is an acute-phase reactant and the only collectin known to activate the complement system. Mammalian lectins are a group of proteins that bind selectively to carbohydrates. Binding to these carbohydrates can contribute to cell-cell recognition if the lectin is bound to the cell surface. Others have evolved to recognize the surface sugar moieties of microbes, which are their binding targets, for subsequent clearance by phagocytosis without the involvement of antibodies. MBL binds multivalently to terminal carbohydrates such as mannose, glucose, and fucose, as well as to repetitive mannose residues on yeast cells, gram-negative bacteria, and several parasites.10Petersen S.V. Thiel S. Jensenius J.C. The mannan-binding lectin pathway of complement activation biology and disease association.Mol Immunol. 2001; 38: 133-149Crossref PubMed Scopus (257) Google Scholar MBL is able to eliminate potential pathogens by activating the complement cascade or by opsonization.10Petersen S.V. Thiel S. Jensenius J.C. The mannan-binding lectin pathway of complement activation biology and disease association.Mol Immunol. 2001; 38: 133-149Crossref PubMed Scopus (257) Google Scholar In most infections the presence of MBL increases resistance to disease and a low concentration of MBL in serum is associated with increased susceptibility to certain infectious diseases, especially in early childhood, owing to reduced opsonization.11De Miranda Santos I. Costa C. Krieger H. Feitose M. Zurakowski D. Fardin B. Gomes R. Weiner D. Harn D. Ezekowitz R. Epstein J. Mannan-binding lectin enhances susceptibility to visceral leishmaniasis.Infect Immun. 2001; 69: 5212-5215Crossref PubMed Scopus (138) Google Scholar, 12Super M. Thiel S. Lu J. Levinsky R.J. Turner M.W. Association of low levels of mannan-binding protein with a common defect in opsonization.Lancet. 1989; i: 1236-1239Abstract Scopus (461) Google Scholar Nevertheless, many individuals with low MBL levels are asymptomatic and clinical symptoms are apparent only when additional immune defects are present.The serum MBL concentration varies considerably among individuals and has been shown to be influenced by mutations in the coding and the promoter region of the gene.13Madsen H.O. Garred P. Thiel S. Kurtzhals J.A. Lamm L.U. Ryder L.P. Svejgaard A. Interplay between promoter and structural gene variants control basal serum levels of mannan-binding protein.J Immunol. 1995; 155: 3013-3030PubMed Google Scholar The human gene for MBL is located on chromosome 10q 11.2–21 and comprises 4 exons.14Taylor M. Brickell P. Craig R. Summerfiled J. Structure and evolutionary origin of the gene encoding a human serum mannan-binding protein promotor.J Biochem. 1999; 262: 763-771Google Scholar Three different MBL alleles in the coding exon 1 (point mutations in codons 52, 54, and 57) result in low serum levels of MBL.15Turner M.W. Mannan-binding lectin the pluripotent molecule of the innate immune system.Immunol Today. 1996; 17: 532-540Abstract Full Text PDF PubMed Scopus (674) Google Scholar Additionally, mutations in the promoter of the MBL gene have been described that also influence the expression of MBL.16Jüliger S. Luckner D. Mordmüller B. May J. Weierich A. Lell B. Luty A. Kremsner P. Kun J. Promoter variants of the human mannose-binding lectin gene show different binding abilities.Biochem Biophys Res Commun. 2000; 275: 617-622Crossref PubMed Scopus (29) Google Scholar The high frequency of structural mutations in many populations may reflect a selection advantage for reduced activities of MBL-associated immune mechanisms in certain environments.We propose that the immune reactivity against mannans in CD may be related to the MBL concentration, and therefore to polymorphisms in the MBL gene because MBL recognizes repetitive mannose residues on yeast cells. In detail, a low MBL level may be a factor contributing to the generation of ASCA and the proliferative response to mannans. To test this hypothesis, we examined the relationship between the T-cell response to mannans and the occurrence of ASCA, with MBL concentrations and polymorphisms in patients with CD, UC, and in healthy individuals.Materials and methodsPatientsSeventy-four patients with CD (35 women, 39 men), 22 patients with UC (12 women, 10 men), and 32 healthy controls were included in the study for determination of MBL and ASCA. Diagnosis of CD and UC was established by endoscopic, histologic, and clinical criteria.17Best W.R. Becktel J.M. Singleton J.W. Kern Jr, F. Development of a Crohn’s disease activity index. National Cooperative Crohn’s Disease Study.Gastroenterology. 1976; 70: 439-444Abstract Full Text PDF PubMed Scopus (2974) Google Scholar None of the patients with CD had a high disease activity (CD activity index [CDAI] > 150), 21 patients had a CDAI ranging between 100 and 150 points, and 53 patients had a CDAI less than 100 points. Twenty-nine of the patients with CD received no therapy, 27 patients received an immunosuppressive therapy (either azathioprine, 6-mercapto-purine, or methotrexate), and 18 patients were treated with steroids (<20 mg of prednisone) or mesalazine. Of the 22 patients with UC, 5 patients received no therapy, 12 patients received mesalazine, 4 patients were treated with an immunosuppressive therapy (either azathioprine or 6-mercapto-purine), and 1 patient received steroids.A subgroup of 58 patients with CD, 18 patients with UC, and 47 healthy controls, were analyzed for MBL gene mutations. Fifty-three patients with CD, all 18 patients with UC, and 10 of the healthy controls additionally were investigated for the proliferative response to mannan.Blood was drawn simultaneously for several tests: the antibody detection, the MBL determination, and to obtain peripheral lymphocytes. The study was approved by the local ethics committee. Sera were stored at −20°C until use.Enzyme-linked immunosorbent assay for detection of ASCA and MBL measurementEnzyme-linked immunosorbent assay (ELISA) plates (Nunc, Wiesbaden, Germany) were coated with mannan (0.5 μg/mL in bicarbonate buffer, pH 9.6) for 24 hours at 4°C. Phosphopeptidomannans from S. cerevisiae were extracted as described elsewhere.18Kocourek J. Ballou C.E. Method for fingerprinting yeast cell wall mannans.J Bacteriol. 1969; 100: 1175-1181Crossref PubMed Google Scholar After washing the plates in phosphate-buffered saline (pH 7.4) containing 0.5% bovine serum albumin, serial dilutions (in wash buffer) of sera were added for 24 hours. Plates were washed again in phosphate-buffered saline containing 0.5% bovine serum albumin and 0.05 Tween. Peroxidase-conjugated polyvalent anti-human immunoglobulin (100 μL, 1:1000) was added for 1 hour at room temperature. After washing, the plates were developed by 50 μL TMB substrate (TMB Microwell; Kirkegaard and Perry Laboratories, Gaithersburg, MD), and the reaction was stopped with 50 μL of 25% sulfuric acid. Plates were read by an ELISA reader (Dynatech MR 5000; Dynatech, Worthing, UK). Serial dilutions of a high positive marker serum were used as standard.Serum MBL concentrations were determined by using a commercial ELISA (Antibody Shop, Copenhagen, Denmark). Low MBL concentrations were defined as serum levels <500 ng/mL and MBL deficiency as <100 ng/mL according to the recommendations of the manufacturer. To evaluate the changes of MBL concentrations for the period of 6 and 12 months, 15 sera of 5 patients were tested by MBL ELISA.Isolation of lymphocytes and proliferation assayLymphocytes were isolated from peripheral blood by centrifugation using a gradient (Ficoll-Hypaque, Pharmacia, Uppsala, Sweden). Adherent cells were obtained after incubation on Petri dishes for 4 hours and used as antigen-presenting cells. Cells were cultured in RPMI 1640 medium (Life Technologies, Basel, Switzerland) supplemented with 5% heat-inactivated fetal bovine serum and 100 U/mL antibiotic/antimycotic solution (Life Technologies) in a 96-well plate at 37°C in an atmosphere of 5% CO2. T cells (106/mL) were co-cultured either with antigen-presenting cells, mannan (0.01–1 mg/mL), ovalbumin (0.01–1 mg/mL), 4 μg/mL anti-CD3 (Pharmingen, Basel, Switzerland), or 3 μg/mL of the T-cell mitogen Concanavalin A (Con A; Böhringer, Mannheim, Germany). Antigen-presenting cells were treated with the antigen at 2 × 107 cells/5 mL at 37°C overnight, irradiated with 25 Gy, washed twice, and reconstituted at 2 × 106 cells/mL in complete RPMI 1640 medium. T cells of each patient were co-cultured with their own preincubated antigen-presenting cells and proliferation was determined by thymidine incorporation (Amersham, Bucks, UK). Cells were pulsed with thymidine at day 4, harvested 18 hours later (Skatron, Lier, Norway), and measured by a scintillation counter (Beckmann, Krefeld, Germany). In 3 patients the experiment was performed as described earlier, but T cells were preincubated with MBL (150 μg/mL; Statens Serum Institute, Copenhagen, DK) for 30 minutes.Investigation of the promoter region and exon 1 in the gene codon for MBLDNA of a subgroup of 58 patients with CD, 18 patients with UC, and 47 healthy controls was isolated from peripheral blood using a purification kit (Qiagen, Hilden, Germany).Fragments of the polymorphic regions of exon 1 of the MBL gene were amplified by polymerase chain reaction (PCR) using the primers MBL for 63: 5′-GAGGCCAGGGATGGGTCATC-3′, and MBL rev + 268: 5′-CCA ACA CGT ACC TGG TTC CC-3′.To amplify the promoter fragment, the primers BaR: 5′- GATGAGCAGTGGGGATCCTAAGGA-3′ and MBL kurz: 5′- GGCTAGGCTGCTGAGGTTTC-3′ were used (all primers were purchased from Interactiva, Ulm, Germany). PCR condition after an initial denaturation step for both primer pairs and after an initial incubation at 94°C for 4 minutes was as follows: 38 cycles were performed at 94°C for 1 minute, 56°C for 45 seconds, and 72°C for 1 minute. The PCR was followed by a final extension step of 10 minutes at 72°C. The obtained PCR fragments were purified with a PCR cycle kit (peqlab Biotechnologie GmbH, Erlangen, Germany) according to the manufacturer’s instructions and eluted in 30 μL of distilled H2O. The sequencing reaction was performed with 10 μL of the purified PCR product with 4 μL BigDye Terminator Cycle Sequencing Extract (PerkinElmer, Foster City, CA) and 40 ng of primer. The DNA sequences were analyzed on an automated sequencer (ABI Prism 373; PerkinElmer).Statistical analysisThe results were expressed as the mean ± the standard error of the mean. The statistical significance was determined by unpaired Student t tests (GraphPad Prism 3.0 software, San Diego, CA), Fisher exact tests, Bonferroni corrections, and Kruskall-Wallis tests. STATA software (College Station, TX), SPSS (Munich, Germany), or StatView (Cary, NC) were used.ResultsMBL concentration in serumBecause MBL is an important constituent of the innate immune system, we analyzed MBL concentrations in CD, UC, and in healthy controls. Low MBL levels (defined as <500 ng/mL) were found in 21 of 74 (28%) of patients with CD, in 4 (18%) of 22 patients with UC, and in 7 (22%) of 32 of the healthy controls (not significant). MBL deficiency (defined as <100 ng/mL) was found in 3 healthy controls (9%), 1 patient with UC (4.5%), and 12 (16%) patients with CD (not significant).Serum MBL concentrations remained unchanged when serum samples drawn every 6 months were analyzed (Figure 1).Antibody and T-Cell response to mannan correlates with MBL concentrationIn 35 of 74 (47%) patients with CD, ASCA were found, whereas this antibody was not detectable in 22 patients with UC, or in the 32 healthy controls. The ASCA titers ranged from 201 to 3390 U/mL (median, 490 U/mL; mean, 767 U/mL). Significantly more ASCA-positive patients had low MBL serum concentrations or were MBL deficient compared with ASCA-negative persons (P < 0.0001; Kruskall-Wallis test) (Figure 2). However, when the level of ASCA titer and MBL concentration was correlated, we found a weak correlation with a coefficient of only −0.18.Figure 2MBL concentrations measured by ELISA in 74 sera of patients with CD, 22 patients with UC, and 32 healthy controls (con). Patients were divided according to their ASCA antibody status (+, ASCA positive; −, ASCA negative). The MBL concentration of ASCA-positive CD patients (CD+) was significantly lower than in healthy controls (con), in patients with UC, and ASCA-negative patients with CD (P < 0.0001, Kruskall-Wallis test).View Large Image Figure ViewerDownload (PPT)The proliferative response of T cells to mannan was investigated in a subgroup of 27 ASCA-positive and 26 ASCA-negative patients. Eleven of 27 ASCA-positive patients were MBL deficient (MBL < 100 ng/mL), and 14 ASCA-positive patients had low MBL levels (MBL < 500 ng/mL). A proliferative response with a proliferative index >5 (the proliferation index was evaluated as the ratio of antigen-stimulated culture − control culture/control culture) to mannan was seen in 16 of the 53 patients with CD. With the exception of a single patient, all proliferating patients were ASCA positive. Proliferative response was associated with the ASCA status and low MBL values (Figure 3, Figure 4). Patients with CD whose lymphocytes proliferated on stimulation with mannan had significantly lower MBL serum concentrations than patients with CD (P < 0.0001; t test), UC patients, or controls whose lymphocytes did not proliferate on stimulation with mannan. In the ASCA-negative group, only 1 of 26 patients was MBL deficient. Their lymphocytes, with the exception of a single CD patient with high MBL concentrations, did not proliferate after stimulation with mannan (Figure 4). Lymphocytes from patients with UC or from healthy controls did not proliferate on stimulation with mannan. The mean of MBL concentration in patients with CD was significantly higher in patients whose lymphocytes did not proliferate on stimulation with mannan compared with a high proliferative response to mannan that was associated with low MBL concentrations (P < 0.0001, t test).Figure 3Proliferative response to mannan and MBL concentrations measured by ELISA in patients with UC, CD, and healthy controls. No significant proliferation of T cells after stimulation with mannan were observed in (A) healthy controls, (B) patients with UC, or (C) ASCA-negative patients with CD. (D) This is in contrast to a strong proliferative response seen in MBL-deficient ASCA-positive patients.View Large Image Figure ViewerDownload (PPT)Figure 4Proliferative response of lymphocytes on stimulation with mannan in patients with CD. Association of proliferative response with ASCA status and MBL negativity. (ASCA−, patient with CD and negative for ASCA; ASCA+, patients with CD and positive for ASCA; MBL−, MBL concentration <500 ng/mL; MBL+, MBL concentration >500 ng/mL). ◊, ASCA−/MBL+; ▾, ASCA−/MBL−; ×, ASCA+/MBL+; ▵, ASCA+/MBL−.View Large Image Figure ViewerDownload (PPT)To investigate the functional significance of MBL in the context of T-cell proliferation to mannans, we performed an inhibition test with MBL in 3 patients. The proliferative response to mannan could be inhibited significantly by preincubation of lymphocytes with mannan-binding lectin (proliferation rate, 5492 ± 1134 cpm vs. 2300 ± 173 cpm; P < 0.05; Fisher exact test). The proliferative response to anti-CD3 or Con A was not influenced by preincubation with MBL.Analysis of gene mutations in exon and promoter of MBLBecause MBL concentrations are determined by genetic polymorphisms, we investigated for MBL mutations in the promoter and exon. From 58 patients with CD, 18 patients with UC, and 47 healthy controls, MBL polymorphisms were determined. The 8 most common haplotypes were found in the samples and controls (Table 1, Table 2). The frequency of individuals homozygous and compound heterozygous in the codons 52 and 54 of exon 1 of patients suffering from CD or UC differed significantly from the healthy controls (P = 0.0143; Fisher exact test; Table 1, Table 2). If only CD patients and controls were considered, the P value decreased further (P = 0.005; Fisher exact test). When all haplotypes of the promoter region and exon 1 were analyzed, no significant difference was observed. When single haplotypes were compared against all others only the LYPA allele was found in higher frequency in the control group compared with CD (P = 0.041; Fisher exact test). No single point mutation or coding region analyzed on its own was distributed unequally between CD patients, UC patients, and controls (data not shown for UC). All homozygous or compound heterozygous mutations in the codon 52 or 54 were associated with MBL deficiency (<100 ng/mL). Furthermore, compound heterozygous mutations with A/0 genotype in codon 52 or 54 in combination with HY/LX or LX/LY promoter genotype had an MBL-deficient phenotype (P < 0.0001; Fisher exact test).Table 1Haplotype Distribution in the Individuals Suffering From CD and UC and the Healthy Control GroupTotalCD patientsUC patientsHealthy controlsTotal (%)Relative frequencyTotal (%)Relative frequencyTotal (%)Relative frequencyTotal (%)Relative frequencyHYPA74 (30.1).30131 (26.7).26715 (41.7).41728 (29.8).298HYPB1 (0.4).0040 (0.0).0000 (0.0).0001 (1.1).011HYPD23 (9.3).09316 (13.8).1381 (2.8).0286 (6.4).064LXPA51 (20.7).20726 (22.4).2248 (22.2).22217 (18.1).181LYPA31 (12.6).12610 (8.6).0864 (11.1).11117 (18.1).181LYPB29 (11.8).11819 (16.4).1642 (5.6).0568 (8.5).085LYQA36 (14.6).14614 (12.1).1216 (16.7).16716 (17.0).170LYQC1 (0.4).0040 (0.0).0000 (0.0).0001 (1.1).011Total246 (100)1.000116 (100)1.00036 (100)1.00094 (100)1.000NOTE. H/L for position −555 in the promoter, XY for position −222 in the promoter, PQ for position +4, and ABCD for mutations in codon 52 (D), 54 (B), and 57 (C). Open table in a new tab Table 2Frequency of Homozygous and Compound Heterozygous Individuals in a Healthy Population and in Patients Suffering From CDTotalCD patientsHealthy controlsTotal (%)Relative frequencyTotal (%)Relative frequencyTotal (%)Relative frequencyB/B, B/D, D/D9 (7).0739 (16).15500A/A114 (93).92749 (84).84547 (100)1.000Total123 (100)1.00058 (100)1.00047 (100)1.000NOTE. Mutations in codon 52 (D), in codon 54 (B), and in codon 57 (C) were analyzed. The difference of the frequency of exon 1 polymorphisms in patients with CD or UC compared with healthy controls is statistically significant (P = 0.0143). When only CD patients and healthy controls are compared the significance increases (P = 0.005). Open table in a new tab Genetic MBL variants predispose to an immune reactivity to mannanWe found that mutations in codons 52 and 54 of the exon occurred more frequently in ASCA-positive compared with ASCA-negative patients with CD (P = 0.0034; Fisher exact test; Table 3). Similarly, a higher frequency of mutations in the exon was found in the patient group with a proliferative response to mannan compared with patients whose lymphocytes did not proliferate after stimulation with mannan (P = 0.003; Fisher exact test; Table 4). All 9 B/B, D/D, or compound heterozygous B/D CD patients were ASCA positive (P = 0.00044; Fisher exact test) and proliferated after stimulation with mannan (P < 0.0001; Fisher exact test). Furthermore, 3 of the 4 patients who were compound heterozygous for mutations with the A/0 genotype in codon 52 and 54 in combination with HY/LX or LX/LY promoter genotype were ASCA positive, and proliferated after stimulation with mannan. To summarize, 12 of 13 patients with an MBL-deficient haplotype and phenotype were ASCA positive and proliferated after stimulation with mannan (P < 0.00024 [ASCA status; Fisher exact test], P < 0.0001 [proliferation; Fisher exact test]). Additionally, the majority of patients whose lymphocytes proliferated to mannan were homozygous (44%) or heterozygous (44%) for the 550 mutation. The LYPA allele was found significantly less frequently in CD patients (P = 0.042; Fisher exact test) and did not occur in ASCA-positive patients.Table 3Type of MBL Variant and ASCA Status: ABCD for Mutations in Codon 52 (D), 54 (B) in the Exon, H/L for Position −555 in the Promoter, XY for Position −222 in the Promoter, and CGGdel/AAA for Linked Mutations in −427, −349, and −336CD, allASCA negativeASCA positiveA/D14 (24%)4 (13%)10" @default.
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• W2107965805 date "2004-10-01" @default.
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• W2107965805 title "Genetic variants of the mannan-binding lectin are associated with immune reactivity to mannans in Crohn’s disease" @default.
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• W2107965805 doi "https://doi.org/10.1053/j.gastro.2004.07.056" @default.
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