Ulcerative Colitis: Dassopoulos T

Nguyen GC, Harris ML, Dassopoulos T. · Division of Gastroenterology, The Johns Hopkins Hospital, 600 North Wolfe Street/Blalock 461, Baltimore, MD 21287, USA. · Curr Gastroenterol Rep. · Pubmed #17105689 No free full text.

Abstract: Immunomodulators are a class of drugs that attenuate the underlying inflammatory processes of Crohn's disease (CD) and ulcerative colitis (UC), the two major inflammatory bowel diseases (IBD). These agents play a prominent role in the management of refractory and steroid-dependent IBD. The immunomodulatory drugs in the IBD arsenal include azathioprine, 6-mercaptopurine, methotrexate, cyclosporine, and tacrolimus. Azathioprine and 6-mercaptopurine are considered first-line immunosuppressants due to their proven efficacy in both CD and UC and their safety profile, whereas cyclosporine occupies a niche as a surgery-sparing agent in the acute management of severe, steroid-refractory UC. Immunomodulators also appear to have a role as adjunctive therapy when used with infliximab or other biologic agents to reduce immunogenicity. Although data have been limited to observational studies, azathioprine and 6-mercaptopurine may be used during pregnancy.

Dassopoulos T. · Department of Medicine, Meyerhoff Inflammatory Bowel Disease Center, Johns Hopkins University, 600 North Wolfe Street/Blalock 463, Baltimore, MD 21287, USA. · Curr Gastroenterol Rep. · Pubmed #11696287 No free full text.

Abstract: The two major inflammatory bowel diseases, Crohn's disease (CD) and ulcerative colitis (UC), represent clinicopathologic entities that traditionally have been diagnosed on the basis of a combination of clinical, radiologic, endoscopic, and histologic features. Serum perinuclear antineutrophil cytoplasmic antibodies (pANCA) and anti-Saccharomyces cerevisiae antibodies (ASCA) have recently been added to our diagnostic armamentarium. Several studies have demonstrated that UC-associated pANCAs recognize nuclear antigens. Additional studies have demonstrated that the pANCA human monoclonal antibody (mAb) Fab 5-3 reacts with histone H1 and with bacterial and mycobacterial antigens. Several reports have suggested that, in CD, pANCA and ASCA are correlated with colonic and small bowel disease respectively. One study found that higher ASCA levels were correlated with more aggressive CD. Serology may prove to be useful in predicting the evolution of indeterminate colitis. Magnetic resonance imaging (MRI) and leukocyte scintigraphy hold promise in identifying inflammatory CD. MRI enteroclysis is useful in identifying both luminal small bowel disease and extraluminal complications. A recent study of surveillance colonoscopy in extensive Crohn's colitis showed a high risk of dysplasia and cancer.

Hanauer SB, Dassopoulos T. · Department of Medicine, Section of Gastroenterology, University of Chicago, Chicago, Illinois, USA. · Annu Rev Med. · Pubmed #11160781 No free full text.

Abstract: Crohn's disease and ulcerative colitis are idiopathic inflammatory bowel diseases characterized by dysregulated intestinal immune responses in genetically susceptible hosts. Conventional approaches to the medical therapy of ulcerative colitis and Crohn's disease can now be directed at either induction or maintenance of remission to improve therapeutic efficacy while minimizing complications. Newer approaches have expanded the utility of conventional therapies by improving both safety and efficacy and highlight the importance of specific targets along the immunoinflammatory pathways. The combination of conventional and novel approaches now offers the potential of modifying the natural history of these diseases.

Nguyen GC, Frick KD, Dassopoulos T. · Mount Sinai Hospital IBD Centre, University of Toronto, Toronto, Ontario, Canada. · Gastrointest Endosc. · Pubmed #19249771 No free full text.

Abstract: BACKGROUND: Management of unifocal, flat, low-grade dysplasia (LGD) in ulcerative colitis (UC) remains controversial. OBJECTIVE: To compare the relative costs and effectiveness of immediate colectomy and enhanced colonoscopic surveillance for the management of LGD. DESIGN AND SETTING: Medical decision analysis by using state-transition Markov models. Transition probabilities and health utilities were derived from the literature, and costs were derived from national hospital data sets and Medicare and/or Medicaid reimbursement schedules. PATIENTS: Two simulated cohorts of 10,000 patients with longstanding UC who were newly diagnosed with unifocal, flat LGD on initial surveillance colonoscopy. INTERVENTIONS: Immediate colectomy or enhanced surveillance (repeated colonoscopy at 3, 6, and 12 months, and then annually). MAIN OUTCOME MEASUREMENTS: Costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios. RESULTS: Immediate colectomy dominated over enhanced surveillance and yielded higher QALYs (20.1 vs 19.9 years) and lower costs ($75,900 vs $83,900). These findings were robust to variations in model parameters, with immediate colectomy remaining dominant in 90% of simulations in sensitivity analysis. Varying postcolectomy health utility outside the range in the probabilistic sensitivity analysis rendered enhanced surveillance cost effective. When the health utility was below 0.77, the incremental cost-effectiveness ratio was $50,000 per QALY. LIMITATIONS: Data based on observational studies and analyses rely on model assumptions. CONCLUSIONS: Our analysis showed that immediate colectomy was preferable to enhanced surveillance. Health preference toward the postcolectomy state is, however, an influential factor. This decision analysis model provides a conceptual framework for physicians and patients to understand the relative benefits and costs of both interventions.

Wu F, Zikusoka M, Trindade A, Dassopoulos T, Harris ML, Bayless TM, Brant SR, Chakravarti S, Kwon JH. · The Harvey M. and Lyn P. Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, Division of Gastroenterology, The Johns Hopkins University Medical Institutions, Baltimore, Maryland 21205-2195, USA. · Gastroenterology. · Pubmed #18835392 No free full text.

Abstract: BACKGROUND & AIMS: Chronic inflammatory bowel diseases such as ulcerative colitis (UC) are associated with differential expression of genes involved in inflammation and tissue remodeling. MicroRNAs (miRNAs), which direct mRNA degradation and translational inhibition, influence a number of disease processes. We examined whether miRNAs are differentially expressed in UC tissues and are associated with expression of genes that regulate inflammation. METHODS: miRNA expression was assessed in patients with active UC, inactive UC, Crohn's disease, irritable bowel syndrome, infectious colitis, and microscopic colitis, as well as in healthy subjects by microarray, quantitative reverse transcription-polymerase chain reaction and in situ hybridization analyses. Colonic epithelial cell (HT29) expression of miRNAs was assessed. Regulation of gene expression by miRNAs was assessed by luciferase reporter construct assays and transfection of specific miRNA mimics. RESULTS: Active UC was associated with the differential expression of 11 miRNAs; 3 were significantly decreased and 8 were significantly increased in UC tissues. In situ hybridization analysis indicated that miR-192, an miRNA with decreased expression in active UC, was predominantly localized to colonic epithelial cells. Macrophage inflammatory peptide (MIP)-2 alpha, a chemokine expressed by epithelial cells, was identified as a target of miR-192. In colon epithelial cells, induction of MIP-2 alpha expression by tumor necrosis factor-alpha was accompanied by a concomitant reduction in miR-192 expression and miR-192 was observed to regulate the expression of MIP-2 alpha. CONCLUSIONS: These findings expand the known roles of miRNAs, indicating that tissues from patients with UC, and possibly other chronic inflammatory diseases, have altered miRNA expression patterns. These findings also demonstrate that miRNAs regulate colonic epithelial cell-derived chemokine expression.

Nguyen GC, Tuskey A, Dassopoulos T, Harris ML, Brant SR. · Harvey M. and Lyn P. Meyerhoff Inflammatory Bowel Disease Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. · Inflamm Bowel Dis. · Pubmed #17828784 links to  free full text

Abstract: BACKGROUND: Recent epidemiological studies suggest that the prevalences of Crohn's disease (CD) and ulcerative colitis (UC) are increasing in the United States. We sought to determine whether nationwide rates of inflammatory bowel disease (IBD) hospitalizations have increased in response to temporal trends in prevalence. METHODS: We identified all admissions with a primary diagnosis of CD or UC, or 1 of their complications in the Nationwide Inpatient Sample between 1998 and 2004. National estimates of hospitalization rates and rates of surgery were determined using the U.S. Census population as the denominator. RESULTS: There were an estimated 359,124 and 214,498 admissions for CD and UC, respectively. The overall hospitalization rate for CD was 18.0 per 100,000 and that for UC was 10.8 per 100,000. There was a 4.3% annual relative increase in hospitalization rate for CD (P < 0.0001) and a 3.0% annual increase for UC (P < 0.0001). Surgery rates were 3.4 bowel resections per 100,000 for CD and 1.2 colectomies per 100,000 for UC and remained stable. There were no temporal patterns for average length of stay for CD (5.8 days) or for UC (6.8 days). The national estimate of total inpatient charges attributable to CD increased from $762 million to $1,330 million between 1998 and 2004, and that for UC increased from $592 million to $945 million.CONCLUSIONS: Hospitalization rates for IBD, particularly CD, have increased within a 7-year period, incurring a substantial rise in inflation-adjusted economic burden. The findings reinforce the need for effective treatment strategies to reduce IBD complications.

De Jager PL, Franchimont D, Waliszewska A, Bitton A, Cohen A, Langelier D, Belaiche J, Vermeire S, Farwell L, Goris A, Libioulle C, Jani N, Dassopoulos T, Bromfield GP, Dubois B, Cho JH, Brant SR, Duerr RH, Yang H, Rotter JI, Silverberg MS, Steinhart AH, Daly MJ, Podolsky DK, Louis E, Hafler DA, Rioux JD, Anonymous00242, Anonymous00243. · Department of Neurology, Center for Neurologic Diseases, Brigham & Women's Hospital and Harvard Medical School, Boston, MA, USA. · Genes Immun. · Pubmed #17538633 No free full text.

Abstract: The intestinal flora has long been thought to play a role either in initiating or in exacerbating the inflammatory bowel diseases (IBD). Host defenses, such as those mediated by the Toll-like receptors (TLR), are critical to the host/pathogen interaction and have been implicated in IBD pathophysiology. To explore the association of genetic variation in TLR pathways with susceptibility to IBD, we performed a replication study and pooled analyses of the putative IBD risk alleles in NFKB1 and TLR4, and we performed a haplotype-based screen for association to IBD in the TLR genes and a selection of their adaptor and signaling molecules. Our genotyping of 1539 cases of IBD and pooled analysis of 4805 cases of IBD validates the published association of a TLR4 allele with risk of IBD (odds ratio (OR): 1.30, 95% confidence interval (CI): 1.15-1.48; P=0.00017) and Crohn's disease (OR: 1.33, 95% CI: 1.16-1.54; P=0.000035) but not ulcerative colitis. We also describe novel suggestive evidence that TIRAP (OR: 1.16, 95% CI: 1.04-1.30; P=0.007) has a modest effect on risk of IBD. Our analysis, therefore, offers additional evidence that the TLR4 pathway - in this case, TLR4 and its signaling molecule TIRAP - plays a role in susceptibility to IBD.

Dassopoulos T, Nguyen GC, Bitton A, Bromfield GP, Schumm LP, Wu Y, Elkadri A, Regueiro M, Siemanowski B, Torres EA, Gregory FJ, Kane SV, Harrell LE, Franchimont D, Achkar JP, Griffiths A, Brant SR, Rioux JD, Taylor KD, Duerr RH, Silverberg MS, Cho JH, Steinhart AH. · Johns Hopkins University Meyerhoff Inflammatory Bowel Disease Center, Baltimore MD, USA. · Inflamm Bowel Dis. · Pubmed #17427244 links to  free full text

Abstract: BACKGROUND: The NIDDK IBD Genetics Consortium (IBDGC) collects DNA and phenotypic data from inflammatory bowel disease (IBD) subjects to provide a resource for genetic studies. No previous studies have been performed on the reliability and validity of phenotypic determinations in either Crohn's disease (CD) or ulcerative colitis (UC) using primary records. Our aim was to determine the reliability and validity of these phenotypic assessments. METHODS: The de-identified records of 30 IBD patients were reviewed by 2 phenotypers per center using a standard protocol for phenotypic assessment. Each phenotyper evaluated 10 charts on 2 occasions 5 months apart. Reliability was expressed as the kappa (kappa) statistic. Performance characteristics were determined by comparison to a consensus-derived "gold standard" and by generation of receiver operating characteristic (ROC) curves. RESULTS: Agreement for diagnosis was excellent (kappa = 0.82; 95% confidence interval [CI]: 0.71-0.92). Agreement for CD location was good for jejunal, ileal, colorectal, and perianal disease with kappa between 0.60 and 0.74 but was fair for esophagogastroduodenal (kappa = 0.36). Agreement for UC extent (kappa = 0.67; 95% CI: 0.48-0.85), and CD behavior (kappa = 0.67; 95% CI: 0.49-0.83) were very good. Area under the ROC curves was greater than 0.84 for diagnosis, CD behavior, UC extent, and ileal and colonic CD location. CONCLUSIONS: IBD phenotype classification using a standard protocol exhibited very good to excellent inter- and intrarater agreement and validity. This study highlights the importance of standard protocols in generating reliable and valid phenotypic assessments. The data will facilitate estimates of phenotyping misclassification rates that should be considered when making inferences from IBD genotype-phenotype studies.

Wu F, Dassopoulos T, Cope L, Maitra A, Brant SR, Harris ML, Bayless TM, Parmigiani G, Chakravarti S. · Department of Medicine (Gastroenterology Division), Johns Hopkins University School of Medicine, Baltimore, Maryland 21205, USA. · Inflamm Bowel Dis. · Pubmed #17262812 links to  free full text

Abstract: BACKGROUND: Ulcerative colitis (UC) and Crohn's disease (CD) are inflammatory bowel diseases (IBD) with variable, overlapping clinical features and complex pathophysiologies. METHODS: To identify pathogenic processes underlying these disease subtypes, we used single endoscopic pinch biopsies to elucidate patterns of gene expression in active and inactive areas of UC and CD and compared these to infectious colitis and healthy control samples. RESULTS: Unsupervised classification of a total of 36 samples yielded promising separation between the affected IBD, unaffected IBD, non-IBD colitis, and normal control samples, suggesting each sample type had a distinctive gene expression pattern. Genes differentially expressed in the CD samples compared to in the controls were related to IFNgamma-inducible TH1 processes (IFITM1, IFITM3, STAT1, and STAT3) and antigen presentation (TAP1, PSME2, PSMB8). The most noticeable change in the UC samples was reduced expression of genes regulating biosynthesis, metabolism, and electrolyte transport (HNF4G, KLF5, AQP8, ATP2B1, and SLC16A). Twenty-five percent of genes down-regulated in the UC samples were also down-regulated in the infectious colitis samples. Unaffected biopsy samples of IBD patients also registered differences expression of genes compared to in the normal controls. Of these differentially expressed genes, only 2 were up-regulated, PSKH1, a regulator of mRNA processing, and PPID, a suppressor of apoptosis. CONCLUSIONS: The study shows that the gene expression patterns of IBD, CD in particular, are quite different from those of infectious colitis, highlighting distinctive expression of genes and pathways in UC and CD.

Duerr RH, Taylor KD, Brant SR, Rioux JD, Silverberg MS, Daly MJ, Steinhart AH, Abraham C, Regueiro M, Griffiths A, Dassopoulos T, Bitton A, Yang H, Targan S, Datta LW, Kistner EO, Schumm LP, Lee AT, Gregersen PK, Barmada MM, Rotter JI, Nicolae DL, Cho JH. · Division of Gastroenterology, Hepatology and Nutrition, Department of Medicine, School of Medicine, University of Pittsburgh, University of Pittsburgh Medical Center Presbyterian, Mezzanine Level, C-Wing, 200 Lothrop Street, Pittsburgh, PA 15213, USA. · Science. · Pubmed #17068223 links to  free full text

Abstract: The inflammatory bowel diseases Crohn's disease and ulcerative colitis are common, chronic disorders that cause abdominal pain, diarrhea, and gastrointestinal bleeding. To identify genetic factors that might contribute to these disorders, we performed a genome-wide association study. We found a highly significant association between Crohn's disease and the IL23R gene on chromosome 1p31, which encodes a subunit of the receptor for the proinflammatory cytokine interleukin-23. An uncommon coding variant (rs11209026, c.1142G>A, p.Arg381Gln) confers strong protection against Crohn's disease, and additional noncoding IL23R variants are independently associated. Replication studies confirmed IL23R associations in independent cohorts of patients with Crohn's disease or ulcerative colitis. These results and previous studies on the proinflammatory role of IL-23 prioritize this signaling pathway as a therapeutic target in inflammatory bowel disease.

Ginsburg PM, Dassopoulos T. · Yale University School of Medicine, New Haven, Connecticut, USA. · Inflamm Bowel Dis. · Pubmed #16954812 links to  free full text

This publication has no abstract.

Nguyen GC, Torres EA, Regueiro M, Bromfield G, Bitton A, Stempak J, Dassopoulos T, Schumm P, Gregory FJ, Griffiths AM, Hanauer SB, Hanson J, Harris ML, Kane SV, Orkwis HK, Lahaie R, Oliva-Hemker M, Pare P, Wild GE, Rioux JD, Yang H, Duerr RH, Cho JH, Steinhart AH, Brant SR, Silverberg MS. · Harvey M. and Lyn P. Meyerhoff Inflammatory Bowel Disease Center, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA. · Am J Gastroenterol. · Pubmed #16696785 No free full text.

Abstract: OBJECTIVES: Inflammatory bowel disease (IBD), comprising primarily of Crohn's disease (CD) and ulcerative colitis (UC), is increasingly prevalent in racial and ethnic minorities. This study was undertaken to characterize racial differences in disease phenotype in a predominantly adult population. METHODS: Phenotype data on 830 non-Hispanic white, 127 non-Hispanic African American, and 169 Hispanic IBD patients, recruited from six academic centers, were abstracted from medical records and compiled in the NIDDK-IBD Genetics Consortium repository. We characterized racial differences in family history, disease location and behavior, surgical history, and extraintestinal manifestations (EIMs) using standardized definitions. RESULTS: African American CD patients were more likely than whites to develop esophagogastroduodenal CD (OR = 2.8; 95% CI: 1.4-5.5), colorectal disease (OR = 1.9; 95% CI: 1.1-3.4), perianal disease (OR = 1.7; 95% CI: 1.03-2.8), but less likely to have ileal involvement (OR = 0.55; 95% CI: 0.32-0.96). They were also at higher risk for uveitis (OR = 5.5; 95% CI: 2.3-13.0) and sacroiliitis (OR = 4.0; 95% CI: 1.55-10.1). Hispanics had higher prevalence of perianal CD (OR = 2.9; 95% CI: 1.8-4.6) and erythema nodosum (3.3; 95% CI: 1.7-6.4). Among UC patients, Hispanics had more proximal disease extent. Both African American and Hispanic CD patients, but not UC patients, had lower prevalences of family history of IBD than their white counterparts. CONCLUSIONS: There are racial differences in IBD family history, disease location, and EIMs that may reflect underlying genetic variations and have important implications for diagnosis and management of disease. These findings underscore the need for further studies in minority populations.

Achkar JP, Dassopoulos T, Silverberg MS, Tuvlin JA, Duerr RH, Brant SR, Siminovitch K, Reddy D, Datta LW, Bayless TM, Zhang L, Barmada MM, Rioux JD, Steinhart AH, McLeod RS, Griffiths AM, Cohen Z, Yang H, Bromfield GP, Schumm P, Hanauer SB, Cho JH, Nicolae DL. · Center for Inflammatory Bowel Disease, Department of Gastroenterology, Cleveland Clinic Foundation, Cleveland, OH, USA. · Am J Gastroenterol. · Pubmed #16542294 No free full text.

Abstract: OBJECTIVES: The complete elucidation of genetic variants that contribute to inflammatory bowel disease (IBD) will likely include variants that increase risk to both Crohn's disease and ulcerative colitis as well as variants that increase risk for particular phenotypic subsets. The purpose of this study was to assess phenotypic subsets that contribute to the major IBD susceptibility loci. METHODS: This linkage study encompassed 904 affected relative pairs, representing the largest combined phenotyped cohort to date, and allowing for meaningful subset analyses. Genetic linkage data were stratified by disease location and age at diagnosis. RESULTS: We establish that some loci, notably the IBD3 and chromosome 3q linkage regions demonstrate contributions from both small intestine and colon cohorts, whereas others, notably the IBD1 (NOD2/CARD15) and IBD2 regions increase risk for small intestine or colon inflammation, respectively. The strongest linkage evidence in this study was for the subset of extensive ulcerative colitis in the region of IBD2 (lod 3.27; p < 0.001). Evidence for linkage in the region of NOD2/CARD15 (IBD1) was stronger for the subset of Crohn's patients with ileal disease (lod 2.56; p= 0.035) compared to the overall Crohn's group, consistent with previous findings that NOD2/CARD15 variants are associated with ileal disease. CONCLUSIONS: Analyses incorporating disease location in IBD increase the power and enhance the accuracy of genomic localization. Our data provide strong evidence that extensive ulcerative colitis represents a pathophysiologic subset of IBD.

Cuffari C, Dassopoulos T, Turnbough L, Thompson RE, Bayless TM. · Department of Pediatrics, The Johns Hopkins University and the Meyerhoff IBD Center at the Johns Hopkins Hospital, Baltimore, Maryland, USA. · Clin Gastroenterol Hepatol. · Pubmed #15118980 No free full text.

Abstract: Background & Aims: Genetic polymorphism in thiopurine methyltransferase (TPMT) activity may influence clinical responsiveness to azathioprine (AZA) therapy. Our aim was to determine if the measurement of erythrocyte TPMT enzyme activity could be used to optimize clinical responsiveness to AZA therapy in patients with inflammatory bowel disease (IBD). Methods: A total of 142 consecutive patients were studied. Forty-one patients (32 with Crohn's disease [CD] and 9 with ulcerative colitis [UC]) were enrolled in a 4-month prospective nonrandomized study with AZA, and 101 (65 with CD and 36 with UC) were on either maintenance AZA or 6-mercaptopurine (6-MP). Erythrocyte TPMT activity and AZA metabolite levels were measured blinded to the clinical response. Results: The response rate after 4 months of continuous AZA therapy was 69% (9/13) in those patients with below-average (</=12 U/mL blood) TPMT activity, and 29% (8/27) in patients with enzyme activity levels >12 U/mL blood (P < 0.001). Patients with TPMT activity </=12 achieved a mean (SEM) erythrocyte 6-thioguanine ribonucleotide (6-TGn) level of 394 +/- 29 pmol/8 x 10(8) red blood cells (RBCs); higher than in patients with TPMT activity >12 (218 +/- 28), despite similar mean (1.6 mg/kg/day) dosages of AZA (P < 0.001). By multivariate logistic regression analysis, patients with a TPMT level <15.3 U/mL blood were 6.2 times more likely to respond to AZA therapy. A 6-TGn level of >292 pmol/8 x 10(8) RBCs was associated with a positive predictive value of clinical response of 85.7%. Conclusions: Patients with higher than average TPMT activity (>12) may remain refractory to conventional dosages of AZA, and may require high (>292) 6-TGn levels. Prospective, randomized, controlled trials are needed to determine whether prior TPMT phenotype testing can be used to adjust the dose of AZA effectively to improve clinical response time and rate.

Karban AS, Okazaki T, Panhuysen CI, Gallegos T, Potter JJ, Bailey-Wilson JE, Silverberg MS, Duerr RH, Cho JH, Gregersen PK, Wu Y, Achkar JP, Dassopoulos T, Mezey E, Bayless TM, Nouvet FJ, Brant SR. · Johns Hopkins University School of Medicine, 1503 E. Jefferson Street, Room B136, Baltimore, MD 21231, USA. · Hum Mol Genet. · Pubmed #14613970 links to  free full text

Abstract: Nuclear Factor-kappaB (NF-kappaB) is a major transcription regulator of immune response, apoptosis and cell-growth control genes, and is upregulated in inflammatory bowel disease (IBD), both ulcerative colitis (UC) and Crohn's disease. The NFKB1 gene encodes the NF-kappaB p105/p50 isoforms. Genome-wide screens in IBD families show evidence for linkage on chromosome 4q where NFKB1 maps. We sequenced the NFKB1 promoter, exon 1 and all coding exons in 10 IBD probands and two controls, and identified six nucleotide variants, including a common insertion/deletion promoter polymorphism (-94ins/delATTG). Using pedigree-based transmission disequilibrium tests, we observed modest evidence for linkage disequilibrium (LD), independent of linkage, between the -94delATTG allele and UC in 131 out of 235 IBD pedigrees with UC offspring (P=0.047-0.052). This allele was also more frequent in the 156 non-Jewish UC probands from the 235 IBD pedigrees than in 149 non-Jewish controls (P=0.015). The -94delATTG association with UC was replicated in a second set of 258 unrelated, non-Jewish UC cases and 653 new, non-Jewish controls (P=0.021). Nuclear proteins from normal human colon tissue and colonic cell lines, but not ileal tissue, showed significant binding to -94insATTG but not to -94delATTG containing oligonucleotides. NFKB1 promoter/exon 1 luciferase reporter plasmid constructs containing the -94delATTG allele and transfected into either HeLa or HT-29 cell lines showed less promoter activity than comparable constructs containing the -94insATTG allele. Therefore, we have identified the first potentially functional polymorphism of NFKB1 and demonstrated its genetic association with a common human disease, ulcerative colitis.

Boone DL, Dassopoulos T, Lodolce JP, Chai S, Chien M, Ma A. · Department of Medicine, Ben May Institute for Cancer Research, The University of Chicago, Illinois, USA. · Inflamm Bowel Dis. · Pubmed #11837936 No free full text.

Abstract: The intestinal lamina propria contains lymphocytes that are chronically activated by exposure to luminal antigens. Dysregulation of these cells is thought to be central to the pathogenesis of bowel inflammation in experimental models of inflammatory bowel disease. CD28 signals on peripheral T cells provide important costimulatory signals that enhance T-cell proliferation and activation responses to antigens. However, the role of CD28 signals in lamina propria T cells or models of inflammatory bowel disease have not been determined. Accordingly, we examined T lymphocyte activation and proliferation in CD28-deficient (CD28-/-) mice to examine the in vivo roles of CD28 signals in lamina propria T-cell homeostasis. We further generated CD28-/- interleukin (IL)-2-/- double mutant mice to assess the role of CD28 signals in supporting the spontaneously activated and pathogenic T cells that accumulate in IL-2-/- mice. CD28-/- lamina propria T cells displayed reduced activation markers, but were present in normal numbers and proliferated normally. IL-2-/- lymphocytes expressed high levels of bcl-xL, whereas CD28-/- IL-2-/- cells had substantially less bcl-xL. However, lymphadenopathy and ulcerative colitis-like disease occurred in both IL-2-/- and CD28-/- IL-2-/- mice. Thus, CD28 provides a functional costimulatory signal to lamina propria T cells but is not required for homeostasis of these cells. In addition, neither CD28 nor bcl-xL appears to be required for the spontaneous accumulation of T cells in IL-2-/- mice. This suggests that other costimulatory molecules or T-cell receptor ligation alone drive lymphocyte expansion in IL-2-deficient mice.