Increased group II phospholipase A2 in colonic mucosa of patients with Crohn's disease and ulcerative colitis.

The immunochemical protein content of group II phospholipase A2 (PLA2) and PLA2 enzymatic activity were measured for colonic mucosal biopsy samples obtained from patients with either Crohn's disease of the colon or ulcerative colitis, and control patients without inflammatory bowel disease. Immunoreactive group II PLA2 (IR-PLA2 II) content and PLA2 activity in actively inflamed colonic mucosa of Crohn's disease patients were significantly higher than those in inactively inflamed mucosa of Crohn's disease patients and the colonic mucosa of controls. IR-PLA2 II content and PLA2 activity in severely inflamed mucosa of ulcerative colitis patients were significantly higher than those in the colonic mucosa of the controls. Mucosal PLA2 enzymatic activity was closely correlated with mucosal IR-PLA2 II content in patients with Crohn's disease and ulcerative colitis. These results suggest that an increase in PLA2 enzymatic activity in inflamed colonic mucosa of Crohn's disease and ulcerative colitis was mainly attributed to increased protein content of group II PLA2, and that an increase in mucosal group II PLA2 may be involved in the pathogenesis of intestinal inflammation of Crohn's disease and ulcerative colitis.     

Ectopic colonic mucosa in ulcerative colitis and in Crohn's disease of the colon

Colectomy specimens from 62 patients (22 with ulcerative colitis, 20 with Crohn's disease of the colon, and 20 with invasive adenocarcinoma [without inflammatory bowel disease]) were reviewed for the presence of ectopic colonic mucosa. One or more foci of ectopic colonic mucosa were found in 16 of the 22 specimens (72 per cent) with ulcerative colitis and in 11 of the 20 specimens (55 per cent) with Crohn's disease of the colon. None of the 20 specimens having adenocarcinoma (without chronic inflammatory bowel disease) had ectopic colonic epithelium. The presence of ectopic colonic mucosa was found to be dependent on the age of the patients (more frequent among younger patients) and on the number of sections per specimen. One adenocarcinoma in a case of long-standing ulcerative colitis had apparently originated in ectopic colonic mucosa. This study was supported by grants from the Karolinska Institute.     

Circulating antibodies against human colonic extract enriched with a 40 kDa protein in patients with ulcerative colitis.

We have previously described a 40 kDa colonic protein(s) which is specifically recognised by tissue-bound immunoglobulin G obtained from the colon of patients with ulcerative colitis. We now report the presence of circulating antibodies against this antigen using an enzyme-linked immunosorbent assay with a highly enriched preparation of the 40 kDa protein from normal colon extracts. Serum was collected from 79 patients with ulcerative colitis, 36 with Crohn's disease, 16 with specific diarrhoeal syndromes, and from 19 normal subjects. Twenty nine of 79 patients with ulcerative colitis, 21 of 36 with Crohn's disease, and all patients with diarrhoea were symptomatic during the collection of sera. The difference in optical density values between patients with symptomatic ulcerative colitis and each of the other groups, including patients with ulcerative colitis in remission, was highly significant (p less than 0.01). Seventy nine per cent of patients with symptomatic ulcerative colitis had optical density values above the means for all other groups. Fifty five per cent of sera from patients with symptomatic ulcerative colitis had optical densities beyond two SDs of the values for all other groups and only two of 71 sera from non-ulcerative colitis patients (one Crohn's disease and one normal subject) had values in this range. These results show the presence of anti-colon antibodies against the 40 kDa protein(s) in the sera of many patients with symptomatic ulcerative colitis.     

Fusobacterium varium localized in the colonic mucosa of patients with ulcerative colitis stimulates species-specific antibody

BACKGROUND: Microbial agents are a possible cause of ulcerative colitis. We have previously reported evidence of bacteria invading the colonic mucosa of patients with ulcerative colitis. We have isolated bacteria from inflamed colonic mucosa, examined the localization of the species in the mucosa, and assayed for serum antibodies to the bacteria. METHODS: Cohorts of 31 per group were enrolled from patients with active ulcerative colitis, Crohn's disease, ischemic colitis, and colon adenomas. A group of 31 healthy controls were also studied. The presence of bacteria in biopsies of patients with ulcerative colitis was analyzed by both isolation and immunohistochemistry. Sera from patients were tested for bacterial antibodies using both Western blots and enzyme-linked immunosorbent assay (ELISA). RESULTS: Only sera from patients with ulcerative colitis gave specific reactions with Fusobacterium varium in Western blot assays. The detection rate of specific bands was higher for patients with ulcerative colitis (61%) than for subjects with either Crohn's disease (13%) or healthy controls (29%) (P < 0.001 and P = 0.021, respectively). The ELISA showed that the mean optical densities with extracts of F. varium as antigen were significantly higher for ulcerative colitis patients than for subjects with either Crohn's disease or healthy controls (P < 0.001). Immunohistochemical detection of F. varium in colonic mucosa was significantly higher in patients with ulcerative colitis (84%) than for subjects with either Crohn's disease (16%) or other controls (3-13%) (P < 0.001). CONCLUSIONS: Fusobacterium varium bacteria were present in a significant number of patients with active ulcerative colitis, and should be tested in therapeutic trials in order to confirm the causal relationship between F. varium and ulcerative colitis.     

Immunoglobulin containing cells in inflammatory bowel disease of the colon: a morphometric and immunohistochemical study.

Immunoglobulin containing cells in rectal and sigmoid colonic mucosa in endoscopically obtained biopsies from 10 patients with ulcerative colitis and 10 patients with Crohn's disease were studied, using an indirect immunoperoxidase technique. These findings were compared with the immunoglobulin containing cell number in colonic biopsies from 10 control patients with no evidence of colitis. In biopsies from the 20 patients with inflammatory bowel disease a marked increase in area of the lamina propria per millimetre mucosa length was found. In ulcerative colitis a marked increase in number of IgG containing cells was observed. In Crohn's disease the increase in IgG containing cell number is dependent on the degree of activity of inflammation. In quiescent of active Crohn's disease of the colon we found a significant increase of the IgM containing cells. The number of IgM containing cells per millimetre mucosa length will differentiate the pathology of Crohn's disease from ulcerative colitis.     

Cellular hypersensitivity to components of intestinal mucosa in ulcerative colitis and Crohn''s disease

The migration of peripheral leucocytes in vitro is examined in 36 patients with ulcerative colitis, in 34 patients with Crohn's disease, in 12 patients with ulcerative colitis or Crohn's disease, and in 31 patients with other gastrointestinal disorders. In a majority of the patients with ulcerative colitis extracts of foetal, colonic, and jejunoileal mucosa inhibit migration of leucocytes. A similar reactivity is seldom seen in Crohn's disease. Extracts of liver, kidney, and adrenal gland do not inhibit the migration. The reactivity of the ulcerative colitis group was found to be significantly different from that in controls and in the Crohn group, whereas the Crohn group did not differ significantly from the controls. The examination thus reveals a biological difference between ulcerative colitis and Crohn's disease, which are otherwise separable mainly on nosological criteria.The finding of a similar inhibition of leucocyte migration in five out of 31 patients with miscellaneous gastrointestinal disorders unrelated to ulcerative colitis and Crohn's disease was inconclusive.An antigen-induced inhibition of leucocyte migration has been shown in vitro to be a correlate of cellular hypersensitivity. The immunological mechanisms behind the present system are discussed, and it is concluded that the reactivity observed probably indicates the existence in ulcerative colitis of a state of cellular hypersensitivity to components of normal foetal, colonic, and jejunoileal mucosa.     

Increased protein tyrosine kinase activity of the colonic mucosa in ulcerative colitis.

The protein tyrosine kinase (PTK) activity was measured in the inflamed colonic mucosa of 12 patients with ulcerative colitis and in the normal colonic mucosa of 12 control patients with colon cancer. The specific PTK activity in the particulate fraction obtained from ulcerative colitis mucosa was significantly increased compared with that of normal mucosa (5.10 +/- 0.60 pmol/min/mg versus 2.12 +/- 0.44 pmol/min/mg protein; p less than 0.05). Inflamed ulcerative colitis mucosa also showed a significantly higher total PTK activity in the particulate fraction than normal mucosa (2.60 +/- 0.42 pmol/min/g versus 0.91 +/- 0.16 pmol/min/g tissue; p less than 0.05). Mucosal samples from ulcerative colitis patients were divided into those with mild and those with severe inflammation on histologic examination (n = 6 each). The particulate PTK activity of severely inflamed mucosa was significantly higher than that of mildly inflamed mucosa (p less than 0.05). These results suggest that colonic inflammation in ulcerative colitis is associated with alterations in cellular PTK activity.     

Immunoglobulin G (IgG), IgG1, and IgG2 determinations from endoscopic biopsy specimens in control, Crohn's disease, and ulcerative colitis subjects.

Acute exacerbations of chronic inflammatory bowel disease (ulcerative colitis and Crohn's disease) are characterised by an increase in immunoglobulin G (IgG) positive cells in the mucosa, whereas uninflamed mucosa of inflammatory bowel disease patients displays only moderately increased or normal numbers of these cells. Previous data suggest that acute exacerbations of ulcerative colitis and Crohn's disease can be distinguished by different IgG subclass expression of mucosal immunocytes and a different IgG subclass production pattern of lamina propria lymphocytes. A procedure to obtain enough intestinal mononuclear cells from biopsy specimens to measure in vitro IgG and IgG1 production in control subjects and various patient groups has been established. IgG2 could be measured in Crohn's disease and ulcerative colitis only, as the concentrations in control subjects were below the sensitivity of the ELISA method. We found that IgG and IgG1 production correlated with the degree of local inflammation in both diseases, even in slightly inflamed mucosa, compared with control subjects. The proportion of IgG1 subclass was significantly increased in severely inflamed mucosa of both ulcerative colitis and Crohn's disease patients. A major difference between Crohn's disease and ulcerative colitis mucosa is apparent in mild or no inflammation. In Crohn's disease mucosa in remission, the IgG1/IgG ratio is comparable with that in controls, yet ulcerative colitis mucosa still displays significantly increased proportions of IgG1. In addition, the IgG2/IgG ratio is 0.12 in ulcerative colitis and 0.19 in Crohn's disease patients. The results show the dependence of local IgG and IgG1 production on the degree of inflammation and that an increase in subclass IgG1 in ulcerative colitis is present at all stages, including remission. These findings support the hypothesis that different immunoregulatory mechanisms are involved in Crohn's disease and ulcerative colitis. Environmental stimuli or genetic background may be responsible for the observed differences.     

Mr 40,000 human colonic epithelial protein expression in colonic mucosa and presence of circulating anti-Mr 40,000 antibodies in cotton top tamarins with spontaneous colitis.

Saguinus oedipus, Callithrix jacchus, and Saguinus fuscicollis are three species of New World monkeys which develop a form of colitis that is similar to human ulcerative colitis. Only S oedipus, however, develop colon cancer. We examined intestinal tissues from these animals for the presence of an antigen cross reacting to the Mr 40,000 human colonic epithelial protein that acts as an autoantigen in ulcerative colitis. Using an anti-Mr 40,000 monoclonal antibody (7E12H12, IgM isotype), by an immunoperoxidase assay we showed that all colon specimens from S oedipus reacted with 7E12H12; however, the colonic tissue from C jacchus and S fuscicollis did not. In immunotransblot analysis eluted IgG antibody bound to human ulcerative colitis colon (CCA-IgG) reacted with Mr 40,000 protein(s) present in the extracts of colon from S oedipus animals and humans. Small intestinal tissue reacted neither with 7E12H12 nor with CCA-IgG. In S oedipus, the Mr 40,000 protein was localised exclusively to colonic epithelial cells. Preincubation of seven S oedipus colon specimens with eight of 10 sera from animals with acute or chronic colitis and 0 of four sera from animals without colitis almost completely inhibited the binding of 7E12H12 to the colonic epithelium. Four of these 10 sera inhibited the binding of 7E12H12 to the autologous colon. These results show the presence of circulating autoantibodies in S oedipus with colitis against an epitope(s) on Mr 40,000 protein shared by human and S oedipus colon.     

Alterations in serum immunoglobulin G subclasses in patients with ulcerative colitis and Crohn's disease

We have examined the concentration of immunoglobulin G (IgG) subclass antibodies in the sera of 27 patients with ulcerative colitis and 21 patients with Crohn's disease as well as in 11 normal controls and 11 patients with systemic lupus erythematosus. In comparison with a control mean serum IgG1 concentration of 5173 micrograms/ml, patients with ulcerative colitis exhibited a significantly increased mean serum concentration of 7924 micrograms/ml (p less than 0.05), whereas patients with Crohn's disease had a near normal mean serum IgG1 level of 5898 micrograms/ml. In contrast, control sera had a mean IgG2 level of 2477 micrograms/ml and ulcerative colitis sera had a similar IgG2 level of 2269 micrograms/ml, whereas Crohn's disease sera had a significantly increased mean IgG2 level of 5111 micrograms/ml (p less than 0.05). Patients with systemic lupus erythematosus, like those with ulcerative colitis, had a markedly elevated serum IgG1 level of 15,594 micrograms/ml (p less than 0.001) without a significantly increased IgG2 serum level (3271 micrograms/ml). Neither ulcerative colitis nor Crohn's disease sera exhibited altered levels of IgG3 or IgG4. These data show that alterations in IgG subclass concentrations occur in the sera of patients with active, untreated inflammatory bowel disease, similar to the previously noted changes in the IgG subclasses secreted by lymphocytes from involved inflammatory bowel disease intestinal specimens.     

Enhanced colonic nitric oxide generation and nitric oxide synthase activity in ulcerative colitis and Crohn's disease.

Recent studies have suggested that nitric oxide (NO.), the product of nitric oxide synthase in inflammatory cells, may play a part in tissue injury and inflammation through its oxidative metabolism. In this study the colonic generation of oxides of nitrogen (NOx) and nitric oxide synthase activity was determined in ulcerative colitis and Crohn's disease. Colonic biopsy specimens were obtained from inflammatory bowel disease patients and from normal controls. Mucosal explants were cultured in vitro for 24 hours and NOx generation was determined. Nitric oxide synthase activity was monitored by the conversion of [3H]-L-arginine to citrulline. Median NOx generation by inflamed colonic mucosa of patients with active ulcerative colitis and Crohn's colitis was 4.2- and 8.1-fold respectively higher than that by normal human colonic mucosa. In ulcerative colitis and Crohn's colitis nitric oxide synthase activity was 10.0- and 3.8-fold respectively higher than in normal subjects. Colonic NOx generation is significantly decreased by methylprednisolone and ketotifen. The decrease in NOx generation by cultured colonic mucosa induced by methylprednisolone suggests that NO synthase activity is induced during the culture and the steroid effect may contribute to its therapeutic effect. Enhanced colonic NOx generation by stimulated nitric oxide synthase activity in ulcerative colitis and Crohn's disease may contribute to tissue injury.     

Thickness of adherent mucus gel on colonic mucosa in humans and its relevance to colitis.

The thickness of adherent mucus gel on the surface of colonic mucosa was measured in surgically resected specimens from 46 'control' patients most of whom had carcinoma of the colon; 12 were from right colon, 17 left colon, and 21 from rectum. In addition specimens were examined from 17 patients with ulcerative colitis and 15 patients with Crohn's disease. In controls a continuous layer of mucus was readily seen on specially prepared sections viewed by phase contrast illumination. Mean values for right and left colon and rectum were 107 (48), 134 (68), and 155 (54) microns respectively with a significant difference between right colon and rectum (p = 0.015). Values in ulcerative colitis showed greater variation and in those areas with acute inflammation mucosa was denuded of the mucus layer. In contrast, values for Crohn's disease were normal or greater than normal in thickness--right colon 190 (83) microns compared with 107 48 microns, p = 0.0093. A series of validation experiments are described for the method used to measure mucus thickness. The possible role of mucus in the pathogenesis of inflammatory bowel disease is discussed.     

Ulcerative colitis--a disease characterised by the abnormal colonic epithelial cell?

The leakiness of the cell membranes of colonic epithelial cells isolated by the collagenase/Dispase technique from normal or diseased colons was assessed in a 4 h 51Cr release assay. Cells from normal, adenoma bearing or cancer bearing colons showed 51Cr release of 8% or less in almost all of 46 cell populations tested. In contrast, cells from mucosa affected by ulcerative colitis [11.9 (4.3%) n = 23] or Crohn's disease [8.4 (2.7%) n = 18] released significantly more 51Cr than the non-inflamed groups. Values are expressed as mean (SD). Overall, release values were greater in ulcerative colitis than Crohn's disease (p less than 0.01). In Crohn's disease, cells obtained from histologically inflamed mucosa released significantly more 51Cr [9.7 (2.5%) n = 11] than those from non-inflamed mucosa [6.4 (1.5%) n = 7, p less than 0.02] whereas, in ulcerative colitis, abnormal release values were found in 8 of 13 cell populations isolated from mucosa showing no histological evidence of active disease. In five patients with distal ulcerative colitis, cells from mucosa not apparently involved demonstrated normal 51Cr release in four of five studies despite abnormal release from cells from involved mucosa suggesting that a diffuse abnormality of the colonic epithelial cell is not usually present. These data indicate that chronic mucosal inflammation per se is associated with abnormalities of the colonic epithelial cell but that, in ulcerative colitis, the abnormality remains in many patients with quiescent disease. Identification of the local factors responsible for such an abnormality may contribute to an understanding of the pathogenesis of ulcerative colitis.     

IgG subclass-containing cells in the human large bowel of normal controls, non-IBD colitis, and ulcerative colitis

IgG subclass-containing cells in colonic mucosa were examined in three groups; 1) normal controls 2) cases of ulcerative colitis (UC) 3) cases of colitis excluding UC and Crohn's disease (non-IBD colitis) by indirect immunoperoxidase staining method using mouse anti-IgG subclass monoclonal antibodies. The numbers (and proportions) of IgG1, IgG2, IgG3, and IgG4-containing cells in normal colonic mucosa was 80 +/- 29/mm2 (44.6%), 44 +/- 21 (24.1%), 44 +/- 24 (23.7%), 13 +/- 10 (7.7%), respectively. The proportion of IgG subclass-containing cells in normal colonic mucosa was different from the known proportion of IgG subclass in serum. In UC, the numbers of all IgG subclasses-containing cells were significantly increased compared to controls and non-IBD colitis. However, only IgG1-containing cells were increased in proportion (50.3%) compared to normal controls. In non-IBD colitis, the numbers of IgG1- and IgG2-containing cells were increased compared to the controls, but the increases were less than UC, and there was no difference in the proportion of IgG subclass compared to normal controls. The differences in the numbers and in the proportions of IgG subclass-containing cells between UC and non-IBD colitis may reflect differences in the underlying disease process.     

Protein kinase C activity of colonic mucosa in ulcerative colitis.

Protein kinase C (PKC) activity was measured in the inflamed colonic mucosa of 24 patients with ulcerative colitis and in the normal colonic mucosa of 10 patients with other benign diseases. The particulate fraction activity in ulcerative colitis mucosa was significantly increased compared with that of normal mucosa (320 +/- 47 versus 200 +/- 30 pmol/min/mg protein; p less than 0.05). Inflamed ulcerative colitis mucosa also showed significantly increased total PKC activity in the particulate fractions compared with normal mucosa (147 +/- 26 versus 37 +/- 8 pmol/min/mg tissue; p less than 0.05). Mucosal samples from ulcerative colitis patients were divided into 12 with mild and 12 with severe inflammation by histologic examination. The particulate PKC activity of severely inflamed mucosa was significantly lower than that of mildly inflamed mucosa (p less than 0.05). These results indicate that colonic inflammation in ulcerative colitis may be associated with altered cellular PKC activity.     

Reduced mucosal antimicrobial activity in Crohn's disease of the colon

OBJECTIVES: In order to maintain the mucosal barrier against luminal microorganisms the intestinal epithelial cells synthesise various broad-spectrum antimicrobial peptides including defensins and cathelicidins. Recent studies indicate that both may be deficient in Crohn's disease. To elucidate the possible functional consequences of this deficiency antimicrobial activity in colonic mucosa from patients with inflammatory bowel disease and healthy controls was investigated. METHODS: A flow cytometric assay was established to quantitate bacterial killing and test the antibacterial activity of cationic peptide extracts from colonic biopsies taken from patients with active or inactive ileocolonic or colonic Crohn's disease (n = 22), ulcerative colitis (n = 29) and controls (n = 13) against clinical isolates of Bacteroides vulgatus and Enterococcus faecalis or the reference strains Escherichia coli American Type Culture Collection (ATCC) 25922 and Staphylococcus aureus ATCC 25923. RESULTS: Compared with controls and ulcerative colitis there was a reduced antimicrobial effect in Crohn's disease extracts that was most evident against B. vulgatus. The antimicrobial effect against E. coli and E. faecalis was significantly lower in Crohn's disease compared with ulcerative colitis. Activity against S. aureus disclosed a similar pattern, but was less pronounced. The differences were independent of the inflammation status or concurrent steroid treatment. Bacteria incubated with biopsy extracts from ulcerative colitis patients frequently showed a characteristic change in cell size and granularity, compatible with more extensive membrane disintegration, compared with bacteria incubated with extracts from controls or Crohn's disease. CONCLUSION: Crohn's disease of the colon is characterized by a diminished functional antimicrobial activity that is consistent with the reported low antibacterial peptide expression.     

Demonstration of Crohn's disease tissue-specific proteins by enzyme-linked immunosorbent assay (ELISA)

Theories on the etiology of Crohn's disease have included extrinsic agents and intrinsic bowel wall defects. We sought to determine the presence of immunoreactive antigens specific to Crohn's disease tissue by modifying the enzyme-linked immunosorbent assay. Tissue proteins were extracted from four patients with Crohn's disease and from four normal segments of colon from patients with colonic cancer. These tissue extracts were further purified on Con A Sepharose 4B affinity column. The glycoproteins eluted from this column were adsorbed by polystyrene plates as antigen and tested against 85 sera from patients with Crohn's disease, ulcerative colitis, other diarrheal diseases, and normal subjects. Sera from 48 patients with Crohn's disease showed significantly greater recognition of Crohn's disease tissue glycoproteins than sera from 27 disease controls (P less than 0.0125) and 10 normal subjects. These Crohn's disease sera also showed preferential recognition of glycoproteins extracted from Crohn's disease tissue compared to glycoproteins from normal colonic tissue (P less than 0.0005). The nature of these immunoreactive proteins, whether extrinsic or intrinsic, is not yet known. The ELISA may help in further characterization of Crohn's disease tissue-specific glycoprotein(s) and to develop a clinically useful serological test.     

In vitro mucus glycoprotein production by colonic tissue from patients with ulcerative colitis.

Colonic mucus production was measured in vitro by means of incorporation of tritiated glucosamine using biopsy material from patients with ulcerative colitis and compared with data from patients with Crohn's disease, colonic carcinoma, colonic polyps and patients with apparently normal colonic mucosae. Mucus production was significantly decreased (p less than 0.03) in all patients with ulcerative colitis, and in particular in patients with inactive disease when compared with normal subjects. In patients with active disease mucus production was not significantly different from normal subjects. The radiolabelled material was characterised by gel filtration and ion exchange liquid chromatography as mainly high molecular weight glycoproteins. These results indicate that the quantitative character of colonic mucus is abnormal in inactive ulcerative colitis.     

Characterization of antigen-presenting dendritic cells in the peripheral blood and colonic mucosa of patients with ulcerative colitis

OBJECTIVE: Increased lymphocyte activation and production of inflammatory cytokines are implicated in the pathogenesis of ulcerative colitis. Because antigen-presenting dendritic cells play a cardinal role in the activation and survival of activated lymphocytes, the aim of the present study was to characterize dendritic cells in ulcerative colitis. DESIGN: This study was designed to compare the phenotypes and functions of peripheral blood dendritic cells among healthy normal volunteers and patients with ulcerative colitis or Crohn's disease. Activated dendritic cells were also localized at the colonic mucosa. METHODS: Peripheral blood dendritic cells were generated from 15 patients with ulcerative colitis, 10 patients with Crohn's disease and 15 healthy control volunteers. The stimulatory capacities of dendritic cells were analysed in an allogenic mixed lymphocyte reaction. Nitric oxide was detected by the Griess method. Single- and dual-colour flow cytometry was employed to study the levels of maturation of dendritic cells. Activated dendritic cells were localized immunohistochemically in the colonic mucosa. RESULTS: In comparison to normal controls, peripheral blood dendritic cells from patients with ulcerative colitis showed significantly increased stimulatory capacities (P < 0.05) and produced significantly higher levels of nitric oxide (P < 0.05). The numbers of activated dendritic cells were also significantly higher in ulcerative colitis (P < 0.05). Mature and activated dendritic cells expressing the CD83 antigen were detected at the inflamed colonic mucosa in patients with ulcerative colitis and Crohn's disease. CONCLUSIONS: Activated and mature dendritic cells may have a role in the induction of an exacerbated immune response in ulcerative colitis. This study provides the scientific and logical basis for blocking the maturation and activation of dendritic cells in ulcerative colitis as a new therapeutic intervention.     

Microsatellite instability in non-neoplastic mucosa of patients with ulcerative colitis: effect of folate supplementation

Objective: Microsatellite instability (MSI) detected in non-neoplastic mucosa of patients with ulcerative colitis has been ascribed to an excess of DNA damage associated with chronic inflammation. Folate deficiency, commonly found in patients with long-standing disease, could further contribute to this defect because folate is essential for DNA replication and repair. We evaluated MSI in the colonic mucosa of 26 patients with ulcerative colitis for  >10 yr  and 10 patients with Crohn's colitis and correlated MSI with folate status.
Methods: DNA was amplified using primers directed at nine different loci. Folate concentrations in serum, whole blood, and colonic mucosa were determined using the Lactobacillus casei assay.
Results: MSI was found in 3/23 patients (13%) with ulcerative colitis and in none of the patients with Crohn's colitis. All three patients with MSI had inactive histological disease, whereas all patients with active disease were negative for MSI (   p = 0.08  ). Serum, whole blood, and colonic concentrations of folate were 30–50% lower in patients with MSI (   p > 0.05  ), and folate supplements had been administered less frequently during the past 5-yr (   p = 0.06  ). One of the patients with MSI was randomized to receive folate 5 mg/d for 6 months, and a clear change in MSI pattern was observed in three of six markers.
Conclusions: A defect in DNA repair associated with a low folate status may be one additional cause for patients with ulcerative colitis exhibiting MSI in non-neoplastic mucosa.