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Increased expression of CCL20 in human inflammatory bowel disease.

Inflammatory bowel disease (IBD) constituting Crohn's disease (CD) and ulcerative colitis (UC) is related to a dysregulated T cell response. CCL20 attracts memory T lymphocytes and dendritic cells. We asked whether CCL20 expression is altered in IBD. Colonic biopsies were obtained from 114 subjects with IBD, non-IBD colitis, irritable bowel syndrome, and healthy controls. CCL20 and CCR6 mRNA expression was measured by Taqman-PCR, and protein secretion from colonic explant cultures (CEC) and its regulation by TNF-alpha by ELISA. CCL20, CCR6, and Langerin were identified by immunohistochemistry and immunofluorescence. CCL20 mRNA and protein were severalfold increased in involved CD and UC but not in non-IBD colitis. TNF-alpha increased and anti-TNF-alpha decreased CCL20 release in healthy control CEC but not in involved IBD colonic specimens. CCL20 localized to follicle-associated epithelium, and CCR6 to the adjacent mantle zone of lymphoid follicles. Furthermore, abundant numbers of Langerin(+) immature dendritic cells were identified in the subepithelial space of IBD specimens. CCL20 might regulate the attraction of T lymphocytes and dendritic cells in IBD.

Adult↗

Glucocorticoid receptors are down-regulated in inflamed colonic mucosa but not in peripheral blood mononuclear cells from patients with inflammatory bowel disease.

BACKGROUND: Growing evidence indicates that the immune system and the hypothalamic-pituitary-adrenal system are linked by several mechanisms, for example intracellular glucocorticoid receptors (hGR). Glucocorticoids are the standard treatment of acute attacks of inflammatory bowel disease (IBD). Binding of glucocorticoids to hGR down-regulates the transcription of inflammatory genes that can propagate IBD. PATIENTS AND METHODS: IBD patients were either treated with 5-60 mg of prednisolone for more than 1 week or were without glucocorticoid treatment for more than 4 weeks. hGR levels were determined from isolated cytosol of peripheral blood mononuclear cells (PBMCs) or mucosal biopsies using a radioassay with [3H]-dexamethasone. Interleukin (IL) 6 levels were determined by enzyme-linked immunosorbent assay (ELISA). RESULTS: The systemic (PBMC) hGR levels of corticosteroid-treated IBD patients were significantly lower than those of control subjects (59.6 +/- 57.1 dpm mg-1 cytosol protein vs. 227.0 +/- 90.8 dpm mg-1 cytosol protein, P = 0.007) and IBD patients not receiving glucocorticoid treatment (179.7 +/- 171.3 dpm mg-1 cytosol protein, P = 0.002). Systemic hGR levels in untreated IBD patients did not differ significantly from those in control subjects. In patients with connective tissue diseases, systemic hGR levels were also found to be decreased in the absence of glucocorticoid treatment. Systemic hGR levels in patients with Crohn's disease (CD) treated with steroids (66.6 +/- 61.0 dpm mg-1 cytosol protein) were not different from those in patients with ulcerative colitis (UC) (56.1 +/- 51.6 dpm mg-1 cytosol protein). In contrast to these findings, mucosal hGR levels were significantly decreased in both steroid-treated (18.0 +/- 15.5) and not steroid-treated (37.8 +/- 30.5) patients compared with control subjects (125.6 +/- 97.1; P = 0.00009 and P = 0.0008 respectively). IL-6 levels in all IBD groups with and without steroids were significantly different from those in control subjects. CONCLUSION: In IBD there is no difference in systemic hGR levels between not steroid-treated patients and control subjects, in spite of inflammatory activity (IL-6). Mucosal hGR levels were decreased independently of treatment, probably leading to a decreased protection against NF-kappaB action in the intestinal mucosa.

Binding, Competitive↗

Dietary calcium intake and its relation to bone mineral density in patients with inflammatory bowel disease.

OBJECTIVES: To investigate calcium intake and its association with bone mineral density (BMD) and the type and extent of the disease in patients with inflammatory bowel disease (IBD). SETTING: University hospital clinic. SUBJECTS: A total of 152 unselected IBD patients and 73 healthy controls. MEASUREMENTS: Dietary calcium intake was assessed with a food frequency questionnaire and BMD of the lumbar spina and proximal femur was measured. RESULTS: The IBD patients had lower dietary calcium intake (1034 [SD 493] mg) than the controls (1334 [514] mg, P < 0.001). The difference was significant in the males (1047 [552] mg and 1575 [586] mg, respectively, P < 0.001), but not in the females (1020 [422] mg and 1112 [303] mg). The dietary daily calcium intake was below 1000 mg in 53% of the patients and 27% of the controls (P = 0.0004) and below 400 mg in 9.2% of the patients and none of the controls (P = 0.007). The calcium intake was not associated with the severity or the type of IBD. Seventy-one (47%) patients and eight (11%) controls avoided lactose in their diet (P < 0.001). In the IBD patients, no association between the calcium intake and BMD was detected, whereas in the controls a positive correlation between the calcium intake and the BMD of the proximal femur was found. CONCLUSIONS: Calcium intakes below the recommendations are seen more often in the IBD patients than in the healthy controls, but in the IBD patients the calcium intake is not associated with BMD in a cross-sectional study. A low-lactose diet is common among IBD patients. To reduce the risk of inadequate calcium intake, unnecessary dietary restrictions concerning, e.g. milk products, should be avoided for these patients.

Adult↗

Chronic narcotic use in inflammatory bowel disease patients: prevalence and clinical characteristics.

BACKGROUND: Narcotic addiction can be a significant problem in inflammatory bowel disease (IBD). However, there are few published reports about this problem. METHODS: All patients prescribed narcotics chronically in the absence of demonstrable organic pathology were identified on the computerized Brisbane IBD Research Group database (n=332 patients with informative data as of 1 January 1999). Individual case records were reviewed with regard to clinical, psychiatric and social characteristics of these patients, and the prevalence of psychiatric disorders were compared with a control group of IBD patients. RESULTS: Eleven patients were identified. Nine had complete datasets, eight with Crohn's disease (CD), of which six had previous stricturing ileal disease, and one patient had ulcerative colitis, making a prevalence of 2.7% of IBD patients and 5.1% of CD patients. A 67% prevalence of a psychiatric disorder in narcotic users was significantly greater than the 8% prevalence in the control group of IBD patients (odds ratio 22, 95% CI 3.24-177). CONCLUSIONS: A significant proportion of IBD patients without demonstrable organic pathology were chronic narcotic users. Psychiatric disorders are common in this subgroup, as with chronic functional abdominal pain syndromes. It is suggested that inappropriate narcotic use in IBD patients can be reduced by appreciating that narcotics are a temporary therapy only for IBD patients, and awareness of pre-existing social and psychiatric disorders, which not only impact on clinical presentation of pain, but also help define the subgroup of patients who are at risk of narcotic misuse.

Adolescent↗

Spatial distribution and histogenesis of colorectal Paneth cell metaplasia in idiopathic inflammatory bowel disease.

BACKGROUND AND AIM: Colorectal Paneth cell metaplasia (PCM) is known to be a sign of idiopathic inflammatory bowel disease (IBD), although its distribution and histogenesis are not fully understood. Objectives of this research were to investigate the spatial distribution of PCM in IBD and other forms of colitis (non-IBD), and to find stimuli causing PCM. METHODS: We studied multiple biopsy specimens from 181 patients with ulcerative colitis (UC), 159 with Crohn's disease (CD), 448 with non-IBD, and 78 normal controls. Paneth cell metaplasia frequency, at each colorectal site, was evaluated to find possible differences among diseases, phases of activity, and extents of disease. RESULTS: In non-IBD and controls, PCM was rarely (0-1.9%) seen at distal sites, but frequently (up to 48.7%) found at the ascending colon and cecum (P < 0.001). Paneth cell metaplasia frequency was significantly higher in IBD than in non-IBD patients and controls at distal sites (P < 0.001), but did not differ significantly between UC and CD, or among active, resolving, and quiescent phases. In UC, proctitis and left-sided colitis rarely displayed PCM at unaffected sites. Multiple logistic regression analysis revealed that PCM was positively associated with crypt distortion and mononuclear cell infiltration (P < 0.005), but negatively or not significantly associated with crypt atrophy, mucin depletion, acute inflammation, or phase of activity. CONCLUSIONS: Paneth cell metaplasia is a non-specific phenomenon in the proximal colon, but distal PCM, which occurs exclusively in affected mucosa, is a useful marker indicating IBD, even in the inactive phase. Regression analysis suggests that repair and regeneration may be the most potent stimuli causing PCM.

Adult↗

Inflammatory bowel disease in spouses and their offspring.

BACKGROUND & AIMS: The rarity of inflammatory bowel disease (IBD) in both husband and wife is often given as an argument against an infectious origin. We registered conjugal instances of IBD in Northern France and in Belgium between 1989 and 2000. METHODS: Couples were assigned to group A if both partners had symptoms of IBD before cohabitation, to group B if one spouse had IBD before cohabitation and the other experienced first symptoms afterwards, and to group C if both partners got the disease after cohabitation. Risk of IBD was assessed in their offspring. RESULTS: Thirty conjugal instances were registered. Seventeen were concordant for Crohn's disease and 3 for ulcerative colitis; 10 were mixed. Two belonged to group A, 6 to group B, and 22 to group C. In group C, IBD occurred in the first affected spouse an average of 9 years after cohabitation and in the second spouse an average of 8.5 years later. Group C conjugal forms were more frequent than expected by chance (P < 0.02). Fifty-four children were born to 25 couples; among them 9, of whom 4 were siblings, developed Crohn's disease at a median age of 15 years. CONCLUSIONS: The frequency of conjugal forms of IBD suggests an etiologic role for environmental factors. Offspring of 2 affected parents have a high risk of developing IBD.

Adolescent↗

Peripheral and intestinal regulatory CD4+ CD25(high) T cells in inflammatory bowel disease.

BACKGROUND & AIMS: Regulatory CD25+ T cells (T(reg)) are effective in the prevention and down-regulation of inflammatory bowel disease (IBD) in animal models. Functional T(reg) cells are characterized by the expression of the transcription factor FOXP3 and show a CD4+ CD25(high) phenotype in humans. The aim of this study was to determine whether disease activity in IBD correlates with changes in frequency of T(reg) cells and their distribution in the intestinal mucosa. METHODS: T(reg) cells were analyzed from peripheral blood and from biopsy specimens of IBD patients, inflammatory controls, and healthy volunteers by flow cytometry (CD4+ CD25(high)), immunochemistry (FOXP3), and real-time PCR (FOXP3). Regulatory properties of purified peripheral CD4+ CD25(high) T(reg) cells were determined by their suppressive effect on the proliferation of CD4+ CD25- T cells. RESULTS: In peripheral blood, CD4+ CD25(high) T cells from IBD patients retain their suppressive activity. CD4+ CD25(high) and FOXP3+ T(reg) cells are increased during remission but decreased during active disease. This contrasts with their strong increase in peripheral blood of patients with acute diverticulitis. Different than peripheral blood, inflamed IBD mucosa contains an increased number of CD4+ CD25(high) T cells, FOXP3+ T cells, and transcripts for FOXP3 compared with noninflamed mucosa. However, the increase of FOXP3+ T cells in IBD lesions is significantly lower compared with inflammatory controls. CONCLUSIONS: The frequency of CD4+ CD25+ T(reg) cells varies with IBD activity. Active IBD is not associated with a functional defect but with a contraction of the peripheral blood T reg pool and an only moderate expansion in intestinal lesions. Thus, compensatory mechanisms, numerically, are not successfully achieved in these diseases.

Adolescent↗

Fatigue in patients with primary sclerosing cholangitis.

BACKGROUND: The occurrence of fatigue in primary sclerosing cholangitis (PSC), its impact on quality of life and the role of concomitant inflammatory bowel disease (IBD) and coexisting irritable bowel syndrome (IBS) is unexplored. METHODS: Ninety-three patients with PSC, associated with IBD in 80% of cases and 77 patients with IBD alone, were enrolled in the study. The patients completed the following questionnaires: the Fatigue Impact Scale (FIS), the Psychological General Well-Being Index (PGWB), the Gastrointestinal Symptom Rating Scale (GSRS), the Beck Depression Inventory (BDI) and diagnostic criteria for IBS. Questionnaire data were related to liver tests and the latest liver biopsy in the PSC patients. Two sex- and age matched controls from the general population (GP) were assigned to each PSC patient and these controls completed the FIS and the BDI. RESULTS: Total fatigue score did not differ significantly between patients with PSC and IBD alone. Median total fatigue score among GP subjects was 39 (13-72), which was higher than in PSC (19 (6-52) (P = 0.02)) and in IBD patients (19 (5-35) (P < 0.0001)). PGWB and GSRS scores did not differ between patients with PSC and IBD alone. Depression and general health (PGWB) were independent predictors for total fatigue score in PSC. No correlation was observed between fatigue in PSC and the severity of the liver disease. CONCLUSIONS: Fatigue in patients with PSC is related to depression but not to the severity of the liver disease. Both the PSC and IBD patients had lower total fatigue scores than subjects from the general population. This argues against fatigue as a specific symptom of PSC and IBD patients.

Adaptation, Psychological↗

Nutrition and inflammatory bowel disease: an update.

BACKGROUND: Inflammatory bowel disease (IBD) is a chronic inflammatory process, the aetiology of which remains unknown. Nutrition may play an important role in the pathogenesis and treatment of IBD. The evidence regarding the role of specific dietary components in the pathogenesis of IBD is still inconclusive. Many studies have been subject to methodological limitations; studies of better design are necessary to confirm the hypothesis that nutritional factors may indeed play a role in the development of IBD. Several studies have reported nutritional and functional deficiencies in IBD patients, especially in Crohn's disease. It is, however, hard to discriminate between disease-induced and malnutrition-induced changes in nutritional parameters. Maintaining adequate nutritional status has been suggested to be beneficial to the course of the disease in IBD. Studies have provided further insight into the possible beneficial effects of nutritional supplementation as primary and adjunctive therapy in IBD. The effects of specific nutritional therapy may be caused by alterations in intestinal flora and hence in the production of intraluminal proinflammatory substances. Immunonutrients such as n-3 fatty acids and antioxidants may also play a role in the treatment of IBD. In this paper, the relation between nutritional aetiological factors, nutritional status and nutritional therapy is discussed in detail.

Antioxidants↗

Computation of the full likelihood function for estimating variance at a quantitative trait locus.

The proportion of alleles identical by descent (IBD) determines the genetic covariance between relatives, and thus is crucial in estimating genetic variances of quantitative trait loci (QTL). However, IBD proportions at QTL are unobservable and must be inferred from marker information. The conventional method of QTL variance analysis maximizes the likelihood function by replacing the missing IBDs by their conditional expectations (the expectation method), while in fact the full likelihood function should take into account the conditional distribution of IBDs (the distribution method). The distribution method for families of more than two sibs has not been obvious because there are n(n - 1)/2 IBD variables in a family of size n, forming an n x n symmetrical matrix. In this paper, I use four binary variables, where each indicates the event that an allele from one of the four grandparents has passed to the individual. The IBD proportion between any two sibs is then expressed as a function of the indicators. Subsequently, the joint distribution of the IBD matrix is derived from the distribution of the indicator variables. Given the joint distribution of the unknown IBDs, a method to compute the full likelihood function is developed for families of arbitrary sizes.

Alleles↗

Association between a complex insertion/deletion polymorphism in NOD1 (CARD4) and susceptibility to inflammatory bowel disease.

The identification of the role of genetic variants within NOD2 (CARD15) in Crohn's disease and ulcerative colitis susceptibility highlight the role of the innate immune system in inflammatory bowel disease (IBD) pathogenesis. NOD1 (CARD4) is located on chromosome 7p14.3, in a region of known linkage to IBD and encodes an intracellular bacterial pathogen-associated molecular pattern receptor that is closely related to NOD2. We have identified strong association between haplotypes in the terminal exons of NOD1 and IBD (multi-allelic P = 0.0000003) in a panel of 556 IBD trios. The deletion allele of a complex functional NOD1 indel polymorphism (ND(1) + 32656*1) was significantly associated with early-onset IBD (P = 0.0003) in unrelated cases and controls. ND1 + 32656*1 was also associated with extra-intestinal manifestations of IBD (P = 0.04). These findings in two independent populations provide strong evidence for a role for NOD1 variants in IBD susceptibility and reinforce the role of the innate immune system in IBD pathogenesis.

Adaptor Proteins, Signal Transducing↗

Polypoid dysplasia and adenomas in inflammatory bowel disease: a clinical, pathologic, and follow-up study of 89 polyps from 59 patients.

Dysplasia in inflammatory bowel disease (IBD) is categorized as either flat or associated with a raised lesion or mass (dysplasia-associated lesion or mass [DALM]). One specific subtype of a dysplasia-associated lesion or mass consists of isolated discrete nodules or polyps that are difficult to distinguish from sporadic adenomas. Because the clinical management of these two lesions is different, we performed this study to (1) evaluate the clinical presentation, pathologic features, and natural history of polypoid dysplastic lesions and sporadic adenomas in patients with IBD and (2) determine whether there are clinical, endoscopic, or pathologic findings useful in differentiating between these two lesions. The morphologic features of 89 benign polypoid epithelial neoplasms from 59 patients with IBD (51 with ulcerative colitis, 8 with Crohn's colitis) were evaluated and correlated with the clinical, endoscopic, and follow-up data. In a separate analysis, patients were categorized arbitrarily as having (1) a probable sporadic adenoma if the polypoid epithelial neoplasm was not located within areas of histologically proven colitis, (2) a probable IBD-associated polypoid dysplasia if the lesion developed within an area of colitis, and associated flat dysplasia or an adenocarcinoma was detected during follow-up evaluation or (3) an indeterminate polyp, which was seen in the remainder of the cases. The clinical, endoscopic, and histologic data were compared among these three patient and polyp subgroups. There were 35 males and 24 females (median age, 57 years; range, 27-85 years). Median duration of disease was 10 years. Forty-nine percent of the patients had pancolitis; 66% had histologically active disease at the time of presentation. Nearly 70% of patients had only one polyp; the majority occurred in either the left colon or the rectum (66%). Most polyps were described as a sessile nodule, whereas only 7 (7.8%) were pedunculated. Polyps ranged from 2 mm to 50 mm (median, 5 mm); most had a tubular architecture (84.3%) and contained low-grade dysplasia (64%). In addition, most polyps had mildly increased lamina propria and intraepithelial neutrophilic and mononuclear inflammation. At follow-up evaluation (40 patients; median follow-up time, 13 months; range, 1-78 months), a further neoplastic lesion developed in 20%; low-grade flat dysplasia was seen in 5 (12.5%), and adenocarcinoma developed in 3 (7.5%). However, dysplasia or adenocarcinoma did not develop in the patients who had polyps located outside of areas of histologically proven colitis. In addition, at least one more benign polypoid epithelial neoplasm developed in 15 of 40 patients (37.5%). Patients with probable IBD-associated polypoid dysplasia had a statistically significant (p < 0.05), longer disease duration than patients with probable sporadic adenoma. A statistically significant, higher proportion of polyps with tubullovillous or villous architecture, an admixture of normal and dysplastic epithelium at the surface of the polyps, and increased lamina propria mononuclear inflammation was noted in probable IBD-associated polypoid dysplastic lesions compared with those considered to be sporadic adenomas. Several clinical and pathologic features may be useful to help categorize a polypoid dysplastic lesion as a sporadic adenoma or an IBD-related neoplasm in a patient with IBD. This distinction is important because the natural history of these two lesions (as shown by the results of this study) and their subsequent management are quite different.

Adenoma↗

Neutrophil apoptosis is delayed in patients with inflammatory bowel disease.

Delayed neutrophil apoptosis is a feature of persistent acute inflammation. Neutrophil-mediated damage has been shown to be associated with the development of inflammatory bowel disease (IBD). Persistence of these cells both at the colonic site and circulation may further contribute to IBD. The aims of this study were to determine whether neutrophils isolated from IBD patients delay apoptosis and to investigate possible mechanisms involved in this delay. We studied 20 patients with IBD, 13 with Crohn's disease, and 7 with ulcerative colitis, all of whom were undergoing intestinal resection for symptomatic disease. Seventeen patients undergoing elective resection of colon cancer acted as operative controls. Systemic, mesenteric arterial, and mesenteric venous blood was harvested. Neutrophils isolated from patients with IBD showed decreased spontaneous apoptosis compared to cancer patients. Mesenteric venous serum of IBD patients contributed to this delay, which contained higher concentrations of interleukin-8 (IL-8). Pro-caspase 3 expression was also reduced in IBD neutrophils, which may contribute to decreased spontaneous and Fas antibody-induced apoptosis. Neutrophil apoptosis may be altered in Crohn's disease and ulcerative colitis through release of anti-apoptotic cytokines and altered caspase expression. The alterations in cell death mechanisms may lead to persistence of the inflammatory response associated with IBD.

Adolescent↗

Predictors of disease-related concerns and other aspects of health-related quality of life in outpatients with inflammatory bowel disease.

OBJECTIVE: Disease-related concerns are a major dimension of health-related quality of life in inflammatory bowel disease (IBD). The aim of this study was to assess the concerns of IBD patients in an outpatient sample, and to determine the impact of psychological and disease factors on concerns and on other variables of health-related quality of life. METHODS: Seventy-two outpatients with IBD were assessed with regard to disease-related concerns [with the Rating Form of IBD Patients' Concerns (RFIPC)], psychological symptoms and somatic complaints non-specific to IBD as dependent variables. Coping with illness, health locus of control, and disease variables were assessed as predictor variables. Multiple regression analyses determined the independent contribution of each predictor on the dependent variables. RESULTS: Women reported more intense concerns than men. No difference in concerns was found between patients with Crohn's disease and ulcerative colitis. The highest predictive value for the RFIPC total score was found for depressive coping. It explained a greater proportion of variance on the RFIPC total score (23%) than demographic (10%) and disease variables (7%), and comparably impinged on RFIPC subscores. Furthermore, depressive coping was significantly associated with psychological distress, the self-rated health status and somatic complaints non-specific to IBD. CONCLUSIONS: Our findings suggest that in IBD psychological variables, particularly depressive coping, are more predictive than medical variables for disease-related concerns and other variables of health-related quality of life. Further studies are needed to examine the effects that the way of coping with disease have on long-term outcome in IBD.

Adaptation, Psychological↗

Well-adjusted children: an alternate view of children with inflammatory bowel disease and functional gastrointestinal complaints.

Previous studies have suggested impaired psychosocial adjustment in children and adolescents with inflammatory bowel disease (IBD). We examined 62 subjects referred to a regional Pediatric Gastroenterology Clinic with IBD or functional gastrointestinal (FGI) complaints. Characteristics of the clinic include a unified team approach, regularly scheduled appointments at 3-month intervals, proactive medical care emphasizing maintenance of full functioning, and close medical-surgical interaction (joint clinics). A research assistant administered a questionnaire regarding children's perceptions of their illness, as well as the Child Depression Inventory (CDI), the Piers-Harris (PH) test of self-concept, and the Child Behaviour Checklist (CBCL). The 36 children with IBD (25 Crohn's disease, 11 ulcerative colitis, mean age 13.3 +/- 3.0 years) were compared with 26 patients with FGI complaints (16 recurrent abdominal pain, 10 functional megacolon, mean age 11.4 +/- 2.8 years). The scores on the standardized tests were not clinically significant for either group. In comparison, however, children with IBD were less depressed and had fewer behaviour problems than the FGI group. Surprisingly, only 19% (7 of 36) of children with IBD described their illness as a problem to them, compared with 65% (17 of 26) of children with FGI symptoms. The latter children also considered themselves significantly sicker than did those with IBD. We conclude that normal psychosocial adjustment is possible in pediatric patients with IBD. We speculate that this group benefitted from the professional supports that our clinic specifically provides to patients with IBD. The FGI group may have suffered from a lack of such professional supports, as well as from the absence of a specific diagnosis.

Abdominal Pain↗

Meeting summary: Signal transduction pathways in immune and inflammatory cells. November 30-December 3, 2000, Amelia Island, Florida, U.S.A.

Throughout this symposium, recurrent themes were highlighted that may provide important clues to the pathogenesis of mucosal inflammation and IBD. First, the mucosal immune system is unique: Studies describing signaling paradigms in peripheral immunocytes should be re-explored in the gut where the rules that govern cell signaling may not be the same. Paradigms are a point of departure to characterize similarities and differences in mucosal immunity. A good example is a differential requirement for costimulation through CD2 in lamina propria T cells compared with peripheral T cells. Furthermore, a new definition of T-cell "costimulation" is beginning to emerge. Costimulatory molecules may function to overcome physical barriers by allowing cognate interactions between other molecules or by targeting signaling complexes to membrane microdomains. This concept also relates to another recurrent theme: Interactions between signaling pathways and the cytoskeleton are functionally important. Finally, we were introduced to the novel concept of metabolic parameters as a readout for signal transduction in the immune system. In the recent past, cell signaling has been viewed as a linear exercise, connecting a cell surface receptor to a series of intermediate molecules to a program of gene expression. However, signal transduction is in fact a three-dimensional exercise in cell biology. The future challenge, as pointed out in the keynote address, is to integrate reductionist models into reality and describe networks of signal transduction pathways in complex biosystems. "Threshold" responses were emphasized, with a small incremental increase or decrease in enzymatic activity leading to an on-off phenomenon referred to as a "molecular switch." In IBD, minute genetically determined differences in enzymatic activity may be critical. This point emphasizes the power of a genetic approach in IBD. Without strong genetic evidence, it is unlikely that fuctional assays will clarify the importance of small differences in enzymatic activity that may have dramatic biologic consequences. This symposium identified recently described signal transduction molecules that may be attractive therapeutic targets in IBD. Characterization of signaling molecules such as SLP-76, SLAM, SAP, and Fyb in the mucosal immune system will be an important area of future research. Ultimately, well-developed scientific hypotheses need to be tested in human beings. This paradigm was perhaps best illustrated by PPARgamma, where reductionist models and mouse experiments have recently lead to small trials suggesting proof of concept in human IBD. This meeting also emphasized a renewed interest in innate immunity in IBD and inflammation research. The role of enteric flora in initiating and perpetuating inflammation in animal models of IBD suggests at some level the importance of the innate immune response. The role of TLRs and bacterial interactions were discussed, as was NF-kappaB as the prominent transcription factor target of innate immune activation. Numerous bridges between innate and adaptive immunity were highlighted, including IL-10, IL-12, IL-18, and IFN-gamma. Their production during an innate immune response can profoundly affect functional T-cell responses in humans. In conclusion, the challenge of understanding signal transduction in IBD is one of integrating well-characterized inflammatory pathways into a complex biologic system that is inhabited by diverse cell types that communicate, and is characterized by interactions with a complex microbial environment. Making sense of this complexity is a daunting task that will require a multifactorial approach utilizing reductionist systems, mouse models, genetic studies, and ultimately human clinical trials.

Animals↗

Familial occurrence of inflammatory bowel disease in celiac disease.

BACKGROUND: The authors have previously reported a possible increased risk of the familial occurrence of Crohn's disease in patients with celiac disease. AIM: The aim of the current study was to evaluate in a case-control study the familial occurrence of inflammatory bowel disease (IBD) in first-degree relatives of patients with celiac disease. METHODS: One hundred eleven consecutive patients with biopsy-proven celiac disease were interviewed to ascertain whether IBD was present in first-degree relatives. The number of relatives, their ages, and possible IBD status were collected in a questionnaire. When a diagnosis of familial IBD was reported, the diagnosis was checked in the hospital records. Two hundred twenty-two controls matched for age and sex (111 from the general population and 111 from orthopedic wards) were also interviewed regarding the possible occurrence of IBD in first-degree relatives. The chi2 test was used to evaluate the difference in proportion of familial occurrence of IBD among individuals with celiac disease and controls. RESULTS: Among 600 first-degree relatives of patients with celiac disease, 10 cases of IBD were identified among first-degree relatives (7 cases of ulcerative colitis and 3 cases of Crohn's disease), whereas only 1 case of IBD was identified among the 1,196 first-degree relatives of control patients (p < 0.01). When ulcerative colitis and Crohn's disease were analyzed separately, only the prevalence of ulcerative colitis was statistically significant (p </= 0.02). CONCLUSIONS: This case-control study shows that there is a significantly increased prevalence of familial ulcerative colitis in patients with celiac disease. There was no significant increase in the prevalence of Crohn's disease in patients with celiac disease. The possible role of this association is discussed.

Adult↗

Fecal S100A12: a novel noninvasive marker in children with Crohn's disease.

BACKGROUND: The calcium-binding protein S100A12 is related to calprotectin, a protein shown to be a useful marker of gut inflammation. S100A12 levels are elevated in serum and mucosa of children with inflammatory bowel disease (IBD) and may be implicated in the pathogenesis of IBD. The aims of this study were to validate an immunoassay for the detection of fecal S100A12, to assess its value as a new noninvasive marker of gut inflammation, and to investigate S100A12 levels in feces of children with IBD at diagnosis and during treatment. MATERIALS AND METHODS: Feces were collected from children with active IBD at diagnosis and during treatment for IBD and from normal healthy control subjects. Fecal and serum levels of S100A12 were measured by immunoassay. RESULTS: A sensitivity of 96% and a specificity of 92% were observed when 10 mg/kg fecal S100A12 was used as a cutoff. S100A12 levels were evenly distributed throughout fecal samples and were stable for 7 days when stored at room temperature. Fecal S100A12 was elevated in children with IBD compared with healthy control subjects, with levels closely correlated to disease activity and other serum inflammatory markers, particularly lower gut involvement. Fecal S100A12 levels fell during therapy in children entering remission with normal C-reactive protein levels. CONCLUSIONS: Fecal S100A12 is a novel noninvasive marker that distinguishes children with active IBD from healthy control subjects with high sensitivity and specificity. Fecal S100A12 possesses characteristics that are desirable for a noninvasive disease marker and therefore is a suitable candidate marker for IBD. Further evaluation is required to examine this marker in additional contexts.

Adolescent↗