Ulcerative Colitis: Landers C

McGovern DP, Taylor KD, Landers C, Derkowski C, Dutridge D, Dubinsky M, Ippoliti A, Vasiliauskas E, Mei L, Mengesha E, King L, Pressman S, Targan SR, Rotter JI. · Medical Genetics Institute & Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, Los Angeles, California 90048, USA. · Inflamm Bowel Dis. · Pubmed #18720471 No free full text.

Abstract: BACKGROUND: Despite recent advances the majority of inflammatory bowel disease (IBD) susceptibility 'genes' remain undiscovered. Recent data suggest that autoimmune conditions may 'share' susceptibility loci. Epidemiological evidence indicates an association between celiac disease and IBD and both conditions demonstrate increased gut permeability. MAGI2, recently implicated in ulcerative colitis (UC) and celiac disease, encodes a scaffolding protein involved in epithelial integrity. Our aim was to test MAGI2 variants for association with IBD and also their role in determining intermediate hereditary phenotypes defined by antibody production to microbial antigens. METHODS: We genotyped 113 MAGI2 single nucleotide polymorphisms (SNPs) in 681 cases of Crohn's disease (CD), 259 UC cases, and 195 controls. RESULTS: The most significant IBD association was in intron 6 (rs2160322, P = 0.009) and both UC (P = 0.006) and CD (P = 0.03) contributed to this association. The most significant CD association was with an intron 2 haplotype (rs7785088/rs323149/rs13246026, P = 0.002). We observed highly significant associations with UC in intron 6 (rs7803276/rs7803705, P = 0.002) and also significant associations in introns 2, 6, and 20. Significant associations were seen with: immunoglobulin G (IgG) anti-Saccharomyces cerevisiae antibodies (ASCA)-positive CD in intron 3 (P = 0.003), intron 6 (P = 0.003), and intron 20 (P = 0.001); anti-CBir1-positive CD in intron 3 (P = 0.0001) and intron 6 (P = 0.008); and anti-outer membrane porin C (OmpC)-positive CD in intron 3 (P = 0.0009), and intron 9 (P = 0.007). Quantitative antibody levels were also associated with variants in intron 4 (anti-IgA ASCA, P = 0.0003 and anti-IgG ASCA, P = 0.0002). CONCLUSIONS: These findings support the significance of the epithelial barrier in IBD pathogenesis.

Fleshner P, Ippoliti A, Dubinsky M, Vasiliauskas E, Mei L, Papadakis KA, Rotter JI, Landers C, Targan S. · Division of Colon and Rectal Surgery, Inflammatory Bowel Disease Center, Cedars-Sinai Medical Center, Los Angeles, California, USA. · Clin Gastroenterol Hepatol. · Pubmed #18378498 No free full text.

Abstract: BACKGROUND & AIMS: Acute pouchitis (AP) and chronic pouchitis (CP) are common after ileal pouch-anal anastomosis (IPAA) for ulcerative colitis. The aim of this study was to assess associations of preoperative perinuclear antineutrophil cytoplasmic antibody (pANCA) and anti-CBir1 flagellin on AP or CP development. METHODS: Patients were assessed prospectively for clinically and endoscopically proven AP (antibiotic responsive) or CP (antibiotic-dependent or refractory to antibiotic therapy). Sera from 238 patients were analyzed for ANCA and anti-CBir1 using an enzyme-linked immunosorbent assay. pANCA(+) patients were substratified into high-level (>100 EU/mL) and low-level (<100 EU/mL) groups. RESULTS: After a median follow-up period of 47 months, 72 patients (30%) developed pouchitis. Pouchitis developed in 36% of pANCA(+) patients versus 16% of pANCA(-) patients (P = .005), 46% of anti-CBir1(+) patients versus 26% of anti-CBir1(-) patients (P = .02), and 54% of 35 pANCA(+)/anti-CBir1(+) patients versus 31% of 136 pANCA(+)/anti-CBir1(-) patients (P = .02). AP developed in 37 pANCA(+) patients (22%) versus 6 pANCA(-) patients (9%) (P = .02), and 12 anti-CBir1(+) patients (26%) versus 31 anti-CBir1(-) patients (16%) (P = .1). Although AP was not influenced by pANCA level, AP was seen in 38% of low-level pANCA(+)/anti-CBir1(+) patients versus 18% low-level pANCA(+)/anti-CBir1(-) patients (P = .03). CP was seen in 29% of high-level pANCA(+) patients versus 11% of low-level pANCA(+) patients (P = .03). CONCLUSIONS: Both pANCA and anti-CBir1 expression are associated with pouchitis after IPAA. Anti-CBir1 increases the incidence of AP only in patients who have low-level pANCA expression, and increases the incidence of CP only in patients who have high-level pANCA expression. Diverse patterns of reactivity to microbial antigens may manifest as different forms of pouchitis after IPAA.

Melmed GY, Fleshner PR, Bardakcioglu O, Ippoliti A, Vasiliauskas EA, Papadakis KA, Dubinsky M, Landers C, Rotter JI, Targan SR. · Division of Gastroenterology, Department of Medicine, Cedars-Sinai Medical Center, Los Angeles, CA 90048, USA. · Dis Colon Rectum. · Pubmed #18085333 links to  free full text

Abstract: PURPOSE: Approximately 5 to 10 percent of patients undergoing ileal pouch-anal anastomosis with a diagnosis of ulcerative colitis are subsequently diagnosed with Crohn's disease. Preoperative predictors for Crohn's disease post-ileal pouch-anal anastomosis have not been prospectively defined. METHODS: A total of 238 consecutive patients with ulcerative colitis or indeterminate colitis undergoing ileal pouch-anal anastomosis were prospectively enrolled into a longitudinal database. Clinical factors were assessed perioperatively. Serum drawn preoperatively was assayed for anti-Saccharomyces cerevisiae, antiouter membrane porin-C, anti-CBir1, and perinuclear antineutrophil cytoplasmic antibody using enzyme-linked immunosorbent assay. Crohn's disease was defined by small bowel inflammation proximal to the ileal pouch or a perianal fistula identified at least three months after ileostomy closure. Predictors were assessed in a multivariate Cox proportional hazards model to predict the rate of Crohn's disease after ileostomy closure. RESULTS: Sixteen patients (7 percent) were diagnosed with Crohn's disease; median time to Crohn's disease was 19 (range, 1-41) months. Significant factors for postoperative Crohn's disease after ileal pouch-anal anastomosis included family history of Crohn's disease (hazard ratio, 8.4; 95 percent confidence interval, 2.96-24.1; P < 0.0001) and anti-Saccharomyces cerevisiae immunoglobulin-A seropositivity (hazard ratio, 3.14; 95 percent confidence interval, 1.1-9.81; P = 0.04). Crohn's disease developed in only 8 of 198 patients (4 percent) without these predictors vs. 8 of 40 patients (20 percent) in those with at least one of these factors (P = 0.002). The cumulative risk of Crohn's disease among patients with two risk factors (67 percent) was higher than in patients with either risk factor (18 percent) or neither risk factor (4 percent, P < 0.001). CONCLUSIONS: Patients with ulcerative colitis and indeterminate colitis with a family history of Crohn's disease or preoperative anti-Saccharomyces cerevisiae immunoglobulin-A seropositivity are more likely to be diagnosed with Crohn's disease after ileal pouch-anal anastomosis.

Melmed GY, Elashoff R, Chen GC, Nastaskin I, Papadakis KA, Vasiliauskas EA, Liu W, Landers C, Ippoliti AF, Targan SR. · Inflammatory Bowel Disease Center, Division of Gastroenterology, Department of Medicine, Cedars-Sinai Medical Center, David Geffen School of Medicine, University of California Los Angeles, California, USA. · Clin Gastroenterol Hepatol. · Pubmed #17478347 No free full text.

Abstract: BACKGROUND & AIMS: Some patients diagnosed with UC undergo a change in diagnosis to CD. Identification of predictors of a diagnostic change could potentially impact the management of patients with colonic inflammation. Our aim was to characterize clinical and serologic predictors of a change in diagnosis from UC to CD. METHODS: A nested, case-controlled study was performed to compare individuals with a change in diagnosis from UC to CD (cases) with age-matched UC and CD controls; primary analysis compared cases with UC controls. Subjects underwent chart review for clinical "red flags" identified by gastroenterologists with expertise in IBD. Serum collected at the time of database enrollment was tested for antibodies to oligomannan (anti-Saccharomyces cerevisiae), Pseudomonas fluorescens-related protein, Escherichia coli outer membrane porin C, CBir1 flagellin, and perinuclear antineutrophil cytoplasmic antibodies. RESULTS: Twenty-one cases, 52 UC controls, and 56 CD controls were assessed. Three red flags, but no serologic markers, differed between cases and UC controls. At initial colonoscopy, cases were more likely to have extensive colonic involvement than UC controls (P = .008). Multivariate regression identified non-bloody diarrhea at initial presentation (P = .01) and weight loss >10% at presentation (P = .007) as independent predictors of diagnostic change. Serologic markers did not add to the contribution of these 2 clinical factors in predicting a change in diagnosis from UC to CD. Diagnostic change was evident in 6 of 6 (100%) patients with both predictors, compared with 8 of 50 (16%) with neither of these factors (P < .0001). CONCLUSIONS: Patients with a diagnosis of UC with initial non-bloody diarrhea or weight loss have an increased likelihood of subsequent change in diagnosis to CD and might thus warrant further diagnostic work-up.

Hui T, Landers C, Vasiliauskas E, Abreu M, Dubinsky M, Papadakis KA, Price J, Lin YC, Huiying Y, Targan S, Fleshner P. · Division of Colon and Rectal Surgery, Cedars-Sinai Medical Center, Los Angeles, California, USA. · Dis Colon Rectum. · Pubmed #15868228 No free full text.

Abstract: PURPOSE: Although acute pouchitis after ileal pouch-anal anastomosis is common and easily treated, continuous pouch inflammation seen clinically as chronic, antibiotic-dependent pouchitis, and/or Crohn's disease remains a difficult management problem. Compared with ulcerative colitis, indeterminate colitis patients undergoing ileal pouch-anal anastomosis have a higher incidence of continuous pouch inflammation, which may represent persistent immune reactivity to microbial antigens. Antibody responses to three microbial antigens (oligomannan anti-Saccharomyces cerevisiae, outer membrane porin C of Escherichia coli, and an antigen (I2) from Pseudomonas flourescens) are more commonly seen in Crohn's disease, whereas antibodies to a cross-reactive antigen (perinuclear antineutrophil cytoplasmic antibodies) is more suggestive of ulcerative colitis. We examined whether preoperative serologic responses to these antigens were associated with Crohn's disease in indeterminate colitis patients after ileal pouch-anal anastomosis. METHODS: Twenty-eight indeterminate colitis patients undergoing ileal pouch-anal anastomosis were prospectively assessed for the development of pouchitis or Crohn's disease. Serologic responses were determined by enzyme-linked immunosorbent assay and immunofluorescence. Patients were classified based on four predominant profiles of antibody expression. Antibody profiles were determined before knowledge of clinical outcome. RESULTS: Median follow-up was 38 (range, 3-75) months. Of 16 patients (61 percent) who developed pouch inflammation, 4 (25 percent) had acute pouchitis and 12 (75 percent) had continuous pouch inflammation (9 had chronic pouchitis, 3 had Crohn's disease). No preoperative clinical factor predicted the development of these pouch complications. Overall, 16 patients (57 percent) had a positive antibody reactivity profile. Serologic expression of any marker alone did not predict the development of continuous pouch inflammation. However, continuous pouch inflammation developed in 10 of 16 patients (63 percent) who had a positive antibody reactivity profile compared with only 2 of 12 patients (17 percent) who had a negative antibody reactivity profile (P = 0.015). CONCLUSIONS: Indeterminate colitis patients who have a positive antibody reactivity profile before ileal pouch-anal anastomosis have a significantly higher incidence of continuous pouch inflammation after surgery than those with a negative profile.

Papadakis KA, Prehn J, Zhu D, Landers C, Gaiennie J, Fleshner PR, Targan SR. · Inflammatory Bowel Disease Center and Burns and Allen Research Institute, Los Angeles, CA 90048, USA. · Inflamm Bowel Dis. · Pubmed #15626897 No free full text.

Abstract: Chemokine receptors play an important role in the recruitment of activated T cells to inflammatory sites. The aim of this study was to analyze the expression of the chemokine receptor CXCR3 on T lymphocytes in intestinal lymphoid tissues and to document the altered disposition of these cells in patients with inflammatory bowel disease (IBD). The expression and regulation of CXCR3 on mucosal lymphoid tissue and peripheral blood lymphocytes (PBLs) were analyzed by flow cytometry and Northern blotting. The migration of lamina propria lymphocytes (LPLs) and PBLs to interferon (IFN)-gamma-inducible protein (IP)-10 (or CXCL10) was evaluated by chemotaxis assays. IFN-gamma and interleukin-4-producing T lymphocytes were quantitated by intracellular staining, and IFN-gamma was measured in culture supernatants by enzyme-linked immunosorbent assay. CXCR3 is expressed on the majority of CD4 lamina propria (LP) T cells and correlates with a T-helper (Th) type 1/Th-0 cytokine phenotype on LP and mesenteric lymph node (MLN) CD4 T lymphocytes. IP-10/CXCL10 is more chemotactic in vitro for both CD4 and CD8 T cells that have been isolated from the LP compared with peripheral blood. CXCR3 protein, but not messenger RNA, expression was lower in inflamed LPLs compared with uninvolved LPLs in patients with ulcerative colitis but not in those with Crohn's disease. However, CXCR3 was expressed on a higher percentage of MLN CD4 T cells isolated from inflamed intestinal tissue, and CXCR3 expression could be induced in vitro with T-cell activation in MLN CD4 T cells. In summary, most CXCR3 T lymphocytes in normal intestinal tissues are Th-1/Th-0 effector/memory cells. Activation-dependent receptor regulation and alteration in receptor-bearing cells, primarily in MLN draining inflamed intestinal tissue, suggest an important role for this T-cell subset in the pathogenesis of human IBD.

Sutton CL, Kim J, Yamane A, Dalwadi H, Wei B, Landers C, Targan SR, Braun J. · Department of Pathology and Laboratory Medicine, University of California, Los Angeles, California, USA. · Gastroenterology. · Pubmed #10889151 No free full text.

Abstract: BACKGROUND & AIMS: Enteric microorganisms are implicated in the pathogenesis of Crohn's disease (CD), but no clear bacterial or viral species has been identified. In this study, representational difference analysis (RDA) was used to isolate DNA segments preferentially abundant in lamina propria mononuclear cells of lesional mucosa vs. adjacent uninvolved mucosa. METHODS: Two RDA-derived microbial sequences were isolated (I1 and I2) and identified as novel homologues of the ptxR and tetR bacterial transcription-factor families. RESULTS: Quantitative competitive polymerase chain reaction of paraffin-embedded intestinal specimens from 212 patients showed that I2 DNA was present in many CD colonic lesions (43%), but was infrequent in other colonic specimens (9% of ulcerative colitis lesions and 5% of non-inflammatory bowel disease diseases; P<0.0001). I2 was prevalent in ileal specimens, regardless of disease status (43%-54%). Enzyme-linked immunosorbent assay analysis of 150 individuals with an I2 glutathione-S-transferase fusion protein showed frequent immunoglobulin A seroreactivity in CD (54% of patients), but infrequent seroreactivity in patients with ulcerative colitis, other inflammatory enteric diseases, or normals (10%, 19%, and 4%, respectively; P<0.001 to 0.00001). CONCLUSIONS: These findings relate CD to a novel lesion-localized and immunologically associated bacterial sequence, suggesting that the microorganism expressing the I2 gene product may be related to CD pathogenesis.

Cohavy O, Harth G, Horwitz M, Eggena M, Landers C, Sutton C, Targan SR, Braun J. · Department of Pathology and Laboratory Medicine, Los Angeles, California 90095, USA. · Infect Immun. · Pubmed #10569769 links to  free full text

Abstract: pANCA is a marker antibody associated with inflammatory bowel disease (IBD), including most patients with ulcerative colitis and a subset with Crohn's disease. This study addressed the hypothesis that pANCA reacts with an antigen(s) of microbial agents potentially relevant to IBD pathogenesis. Using a pANCA monoclonal antibody, we have previously identified the C-terminal basic random-coil domain of histone H1 as a pANCA autoantigen. BLAST analysis of the peptide databases revealed H1 epitope homologues in open reading frames of the Mycobacterium tuberculosis genome. Western analysis of extracts from six mycobacterial species directly demonstrated reactivity to a single, conserved approximately 32-kDa protein. Direct protein sequencing, followed by gene cloning, revealed a novel 214-amino-acid protein, an iron-regulated protein recently termed HupB. Sequence analysis demonstrated its homology with the mammalian histone H1 gene family, and recombinant protein expression confirmed its reactivity with the 5-3 pANCA monoclonal antibody. Binding activity of patient serum immunoglobulin G (IgG) to HupB did not correlate with reactivity to histone H1 or pANCA, indicating the complex character of the pANCA antigen. However, anti-HupB IgA was strongly associated with Crohn's disease (P < 0.001). These findings indicate that the 5-3 pANCA monoclonal antibody detects a structural domain recurrent among mycobacteria and cross-reactive with a DNA-binding domain of histone H1. The association of HupB-binding serum IgA with IBD provides new evidence for the association of a mycobacterial species with Crohn's disease.