Crohn's Intestine Research Articles

IL-23–responsive innate lymphoid cells are increased in inflammatory bowel disease

Results of experimental and genetic studies have highlighted the role of the IL-23/IL-17 axis in the pathogenesis of inflammatory bowel disease (IBD). IL-23-driven inflammation has been primarily linked to Th17 cells; however, we have recently identified a novel population of innate lymphoid cells (ILCs) in mice that produces IL-17, IL-22, and IFN-γ in response to IL-23 and mediates innate colitis. The relevance of ILC populations in human health and disease is currently poorly understood. In this study, we have analyzed the role of IL-23-responsive ILCs in the human intestine in control and IBD patients. Our results show increased expression of the Th17-associated cytokine genes IL17A and IL17F among intestinal CD3⁻ cells in IBD. IL17A and IL17F expression is restricted to CD56⁻ ILCs, whereas IL-23 induces IL22 and IL26 in the CD56⁺ ILC compartment. Furthermore, we observed a significant and selective increase in CD127⁺CD56⁻ ILCs in the inflamed intestine in Crohn's disease (CD) patients but not in ulcerative colitis patients. These results indicate that IL-23-responsive ILCs are present in the human intestine and that intestinal inflammation in CD is associated with the selective accumulation of a phenotypically distinct ILC population characterized by inflammatory cytokine expression. ILCs may contribute to intestinal inflammation through cytokine production, lymphocyte recruitment, and organization of the inflammatory tissue and may represent a novel tissue-specific target for subtypes of IBD.

Altered ENaC Expression Leads to Impaired Sodium Absorption in the Noninflamed Intestine in Crohn's Disease

Crohn's disease (CD) is a chronic inflammatory bowel disease. In this study, we have investigated sodium absorption via epithelial sodium channels (ENaC) in the macroscopically noninflamed colon in active CD. Sodium transport via ENaC was investigated in Ussing chambers using biopsy specimens of sigmoid colon from controls and active CD limited to the small intestine. ENaC messenger RNA expression and subcellular localization were studied by real-time polymerase chain reaction and confocal microscopy. Effects of proinflammatory cytokines on ENaC and signaling via mitogen-activated protein kinases were investigated in rat distal colon. Therapeutic inhibition of mitogen-activated protein kinases was studied in CD biopsy specimens. Electrogenic sodium absorption via ENaC was strongly impaired in the macroscopically noninflamed CD colon because of reduced gamma-ENaC transcription, whereas subcellular localization of ENaC was not changed. In contrast to impaired epithelial sodium transport, epithelial barrier function was not altered in noninflamed CD colon, indicating that paracellular leak flux of ions did not contribute to decreased sodium absorption. Exposure of rat distal colon to tumor necrosis factor alpha led to reduced electrogenic sodium absorption because of impaired transcriptional gamma-ENaC induction, which resembled the changes found in CD. Tumor necrosis factor alpha effects were dependent on extracellular signal-regulated kinase 1/2 but not p38 or c-Jun-N-terminal kinase because inhibition of mitogen-activated protein kinase/extracellular regulated kinase (MEK)1/2 but not inhibition of p38 or c-Jun-N-terminal kinase prevented suppression of ENaC. Finally, therapeutic inhibition of MEK1/2 restored electrogenic sodium absorption in CD. In CD, macroscopically noninflamed colon contributes to diarrhea via impaired ENaC-mediated sodium absorption. Inhibition of extracellular signal-regulated kinase might serve as a potential therapeutic strategy for CD diarrhea.

Stenosis of the proximal intestine in Crohn's disease – a case report

A 34 year old male patient was referred to our department with heartburn, progressive sickness, vomiting, intermittent upper abdominal pain, feeling of early saturation and weight loss of 10kg within 4 months. An ultrasound scan 4 weeks before had been considered normal and a gastroscopy had revealed signs of gastritis with no effect of a proton pump inhibitor therapy. The ultrasound scan focussed on the upper GI-tract. There was a far stretching stenosis of the proximal jejunum with widening of the mucosal layer, multiple paraintestinal lymph nodes and an accelerated flow of the mesenteric superior artery. These findings were confirmed by CT-Scan. The following endoscopy revealed fissural ulcerations starting in the duodenum and prominent stenosis of the proximal jejunum. Histological examination showed an active inflammation of the mucosa without demonstration of granuloma. A coloscopy was normal. Parenteral steroid treatment was started with improvement of symptoms within 3 days and was continued with cortisone and azathioprin orally. On follow-up ultrasound scans the stenosis and mucosal widening in the proximal jejunum were regressing. In summary we present a rare case of Crohn's disease onset with isolated involvement of the proximal jejunum in an adult patient. Symptoms are mostly due to proximal GI-tract stenosis, while fistulas do not develop frequently and diarrhoea does not occur. First choice treatment is a conservative approach with steroids and azathioprin in the longterm. The ultrasound scan guided the way to the correct diagnosis in this case and was useful for follow-up examinations.

Generation of regulatory gut-homing human T lymphocytes using ex vivo interleukin 10 gene transfer

Background & Aims: Systemic treatment of Crohn's disease patients using recombinant interleukin (rIL)-10 has not resulted in significant therapeutic benefit presumably because of limited bioavailability and unexpected proinflammatory effects of high-dose rIL-10. Ex vivo gene transfer of the interleukin (IL)-10 gene to gut-homing CD4+ cells may lead to improved long-term management. Methods: Peripheral blood mononuclear cells (PBMCs) were transduced with a retroviral vector containing the IL-10 and green fluorescent protein (GFP) gene or a control vector containing GFP only. Transduced CD4+ cells were sorted and maintained in culture for phenotypic and functional analysis. Results: Stimulated IL-10–GFP CD4+ cells produced significantly higher levels of IL-10 than control cells for at least 4 months. The IL-10 transgene was biologically active and decreased proliferation of IL-10–GFP CD4+ cells as well as expression of major histocompatibility class (MHC) class II, proliferation of autologous responder cells, and IL-12 production by dendritic cells (DCs). The majority of transduced CD4+ cells had a gut-homing potential because they expressed the mucosal integrin α4β7, and displayed efficient binding to MAdCAM-1–expressing cells in vitro. Conclusions: Transduction of peripheral blood CD4+ lymphocytes with IL-10 results in a regulatory phenotype. The use of regulatory gut-homing human CD4+ cells may provide a novel approach to local delivery of immunomodulatory signals to the intestine in Crohn's disease.GASTROENTEROLOGY 2002;123:1877-1888

Spontaneous free perforation of the small intestine in Crohn's disease.

Spontaneous free perforation of the small intestine is a rare but often dramatic event in the clinical course of Crohn's disease. Fifteen new cases of spontaneous free perforation of the small intestine--nine female patients and six male patients--were discovered in a series of 1000 consecutively evaluated patients with Crohn's disease seen during a period spanning 20 years, for an estimated frequency of 1.5%. Spontaneous free perforation was the presenting clinical feature of Crohn's disease in nine (60%) of the newly discovered cases. Most perforations were located in the ileum rather than in the jejunum, and there were no duodenal free perforations. One patient with extensive intestinal disease presented with concomitant free perforations of the jejunum and ileum, while a second patient had two free ileal perforations that developed independently, separated by about six years. No perforations were the result of a superimposed malignant process, ie, adenocarcinoma or lymphoma. There have been no mortalities, and the subsequent clinical course of these patients has been limited to a minority requiring corticosteroid or immunosuppressive medications, or further surgical resections.

7122 Can endoscopic retrograde ileography alone assess the disease activity in crohn's disease ?

Background: The ileum is frequently affected site of the small intestine in Crohn's disease (CD). However, precise evaluation of disease activity is sometimes difficult by small bowel enteroclysis (SBE) because of multiple overlapping loops. We have reported the usefulness of balloon occluded endoscopic retrograde ileography (ERIG) that is a combination of colonoscopic and radiological ileal examination for the evaluation of the disease activity not only in the colon but also in the distal ileum at one procedure (Taruishi M. et al. Radiology; in press). Aim: To evaluate weather ERIG alone can represent the disease activity of the whole small intestine without SBE information. Patients and Methods: Between May 1990 and May 1999, 50 times of both ERIG and SBE were performed within two weeks in 33 cases of known CD. Three cases were colitis, 12 were ileocolitis and 18 were ileitis type of CD. Written informed consent was obtained. Briefly, ERIG procedures were as follows. Total colonoscopy was performed, followed by intubation to the ileum. After a guide wire was introduced through the forceps channel into the ileum, only colonoscope was removed. Silicon balloon tube was inserted into the terminal ileum and fixed by the expanded balloon. After barium surfate and air was injected followed by several turning of position, double contrasted radiography was obtained. Disease activity was diagnosed independently on ERIG and SBE.We compared the disease activity assessed by ERIG with that by SBE. Results: Of 50 procedures, both ERIG and SBE revealed identical CD activity; active disease in 25 procedures and remission in 9. On the other hand, in 10 procedures ERIG showed active disease but SBE did not, and SBE showed active disease but ERIG did not in 6 procedures. ERIG could represent and evaluate the disease activity of whole small bowel in 44 (88%) of 50 procedures. The reasons to fail in evaluating the disease activity by ERIG alone were visualization of only short part of the distal ileum (less than about 100 cm) in 4 procedures, severe stricture in 1 procedure and active disease affected only in the jejunum and remission in the ileum in 1 procedure. Conclusion: Because most CD affected distal ileum, ERIG could represent the disease activity of CD not only in the colon but also in the whole small bowel, and assess it at one procedure without SBE.

Gene expression of group II phospholipase A 2 in intestine in Crohn’s disease

OBJECTIVE: Phospholipase A 2 (PLA 2) has been suggested to play an important role in the pathogenesis of inflammatory bowel diseases. Our aim was to identify cells that express group II phospholipase A 2 (PLA 2-II) at the mRNA and enzyme protein levels in the intestine in Crohn’s disease. METHODS: Tissue samples were obtained from the intestine of 20 patients with Crohn’s disease (seven operated and 13 colonoscopied) and from eight control patients without inflammatory diseases. The samples were studied by immunohistochemistry for PLA 2-II enzyme protein and in situ hybridization for PLA 2-II mRNA. RESULTS: PLA 2-II protein and mRNA were detected in the Paneth cells of the small intestinal mucosa in all patients and controls. PLA 2-II protein and mRNA were found in the columnar epithelial cells of the small intestinal mucosa in six of eight and eight of eight patients with Crohn’s ileitis, respectively. In the eight control patients PLA 2-II protein and mRNA were not found in these cells ( p = 0.007 and p < 0.001, respectively). Metaplastic Paneth cells, which consistently contained PLA 2-II mRNA, were found in the colonic mucosa in five of six patients with Crohn’s colitis and of one of eight control patients ( p = 0.026). The columnar epithelial cells of the colonic mucosa contained PLA 2-II protein in three of six and PLA 2-II mRNA in six of six patients with Crohn’s colitis, whereas the protein was found in these cells in none of eight of the controls ( p = 0.055) and the mRNA in only one of eight ( p = 0.005) controls. CONCLUSIONS: In Crohn’s disease, Paneth cells and columnar epithelial cells of the small and large intestinal mucosa synthesize PLA 2-II at the site of active inflammation.

Gene expression of group II phospholipase A2 in intestine in Crohn's disease.

Phospholipase A2 (PLA2) has been suggested to play an important role in the pathogenesis of inflammatory bowel diseases. Our aim was to identify cells that express group II phospholipase A2 (PLA2-II) at the mRNA and enzyme protein levels in the intestine in Crohn's disease. Tissue samples were obtained from the intestine of 20 patients with Crohn's disease (seven operated and 13 colonoscopied) and from eight control patients without inflammatory diseases. The samples were studied by immunohistochemistry for PLA2-II enzyme protein and in situ hybridization for PLA2-II mRNA. PLA2-II protein and mRNA were detected in the Paneth cells of the small intestinal mucosa in all patients and controls. PLA2-II protein and mRNA were found in the columnar epithelial cells of the small intestinal mucosa in six of eight and eight of eight patients with Crohn's ileitis, respectively. In the eight control patients PLA2-II protein and mRNA were not found in these cells (p = 0.007 and p < 0.001, respectively). Metaplastic Paneth cells, which consistently contained PLA2-II mRNA, were found in the colonic mucosa in five of six patients with Crohn's colitis and of one of eight control patients (p = 0.026). The columnar epithelial cells of the colonic mucosa contained PLA2-II protein in three of six and PLA2-II mRNA in six of six patients with Crohn's colitis, whereas the protein was found in these cells in none of eight of the controls (p = 0.055) and the mRNA in only one of eight (p = 0.005) controls. In Crohn's disease, Paneth cells and columnar epithelial cells of the small and large intestinal mucosa synthesize PLA2-II at the site of active inflammation.

Distribution and colocalization of nitric oxide synthase and calretinin in myenteric neurons of developing, aging, and Crohn's disease human small intestine.

The pattern of distribution and colocalization of nitric oxide synthase and the calcium-binding protein calretinin in myenteric neurons and nerve fibers were examined in the human small intestine from preterm fetuses (14-17 weeks of gestation), normal adults (mean age 50 years old), old age (mean age 80 years old), and Crohn's disease patients (mean age 30 years old) using NADPH-diaphorase histochemistry and immunohistochemical techniques. In all age groups investigated, NADPH-diaphorase-reactive and calretinin-immunoreactive neurons and nerve fibers were seen throughout the myenteric plexus. The highest proportion of NADPH-diaphorase-reactive neurons was found in the myenteric ganglia of old age intestines (56% of protein gene product-immunoreactive neurons) followed by fetal intestines (41%) and Crohn's intestine (30%) compared with intestines of control adults (20%). A similar trend was observed for calretinin-immunoreactive neurons where the highest proportion of immunoreactive neurons was found in the myenteric ganglia of old age intestines (28% of protein gene product-immunoreactive neurons), followed by fetal intestines (22%), and Crohn's intestines (18%) compared with intestines of control adults (9%). A colocalization of NADPH-diaphorase activity and calretinin immunoreactivity was only seen in the myenteric neurons of fetal intestines (2% of NADPH-diaphorase-reactive neurons were also calretinin-immunoreactive). The pattern of distribution of NADPH-reactive and calretinin-immunoreactive neurons in the myenteric ganglia of fetal intestine differs from that of the other age groups. In the fetal intestine, the myenteric neurons containing either calretinin or NADPH-diaphorase are distributed through out the myenteric ganglia with no specific orientation to one another. In the intestines of control adult, Crohn's, and old age patients, single large calretinin-immunoreactive neurons are surrounded by a number of small NADPH-diaphorase-positive neurons, with this feature being more prominent in intestines of old-age and Crohn's disease patients. In summary, a high number of both NADPH-diaphorase-reactive and calretinin-immunoreactive neurons were seen in the myenteric ganglia of fetal, old age, and Crohn's intestines; we discuss that there may be a role for nitric oxide and calretinin in the process of development, aging, and pathological changes in the human intestine associated with alteration in the calcium homeostasis in the myenteric neurons.

Assessment of blood flow in the small intestine by laser Doppler flowmetry: Comparison of healthy small intestine and small intestine in Crohn's disease

Blood flow and blood distribution were investigated in 40 patients with normal small intestine and the relation between blood flow and the morphological features of Crohn's disease was examined in 11 patients with Crohn's disease by laser Doppler flowmetry from the serosal side during surgery. In normal small intestine, blood flow was measured at six points: upper, middle, and lower small intestine, each of the mesenteric borders, and the antimesenteric surface. In Crohn's disease, macroscopically normal tissue and affected lesions were observed in detail by intraoperative endoscopy after blood flow measurement. The blood flow values in the normal small intestine gradually decreased from the upper to the lower small intestine. As the level of inflammation progressed in Crohn's disease the blood flow values gradually decreased; the exudative stage of Crohn's disease (aphthoid ulcer) showed blood flow values that were slightly below those in macroscopically normal tissue. These results are the first to demonstrate decreased blood flow in affected lesions in Crohn's disease and changes in blood flow according to the degree of inflammation in vivo.

103 DISTRIBUTION OF DIVIDING T CELLS THROUGHOUT THE BOWEL WALL IN INFLAMMATORY BOWEL DISEASE

The transmural distribution of dividing T cells was examined in ileum and colon of children with inflammatory bowel disease (Crohn's n=19, ulcerative colitis n=7, controls n=6) by double-immunohistochemistry using Ki67 to identify proliferating cells and CD3 to identify T cells. In ileal lamina propria, virtually no Ki67+, CD3+ cells were seen in control tissue or Crohn's disease tissue. Likewise in colonic lamina propria, there were very few Ki67+, CD3+ cells in control tissue, ulcerative colitis tissue or Crohn's tissue. In contrast, there were significantly more (p<0.005) Ki67+, CD3+ cells within the lymphoid follicles of ileal and colonic Crohn's disease than in the follicles in ulcerative colitis and control tissue (colon: Cr median 1.2% (range 0.6-3); UC 0.15% (0-0.5); control 0% (0-0), ileum: Cr 0.8% (0.1-1.8); control 0.2% (0-0.5)). Increased numbers of Ki67+, CD3+ cells were present in the submucosa, muscle layers (M) and serosa in Crohn's ileitis and colitis compared to the lamina propria (LP), although only in the muscle of the colon was the difference statistically significant (LP: 0.4% (0-1); M: 1.6% (0-5.2) p=0.03). Pooling data from ileal and colonic Crohn's disease however did show significantly increased Ki67+, CD3+ cells in deeper layers of the intestine compared to the lamina propria. The demonstration of dividing T cells in the deeper layers of the intestine in Crohn's disease suggests that chronic cell-mediated inflammation may be responsible for the transmural nature of this disease.

Distribution of the matrix metalloproteinases stromelysin, gelatinases A and B, and collagenase in Crohn's disease and normal intestine.

To investigate the role of the matrix metalloproteinases (MMPs) in the connective tissue changes seen in the intestine in Crohn's disease. Indirect immunofluorescence microscopy using specific antibodies to the MMPs (collagenase, gelatinase A and B, and stromelysin) were used to assess the distribution of these enzymes in normal and diseased intestine. In normal intestine the matrix metalloproteinases were confined to a few isolated inflammatory cells, but in Crohn's disease, the inflammatory infiltrate was associated with increased numbers of polymorphonuclear leucocytes which stained positive for gelatinase B. Stromelysin was also detected extracellularly on the connective tissue matrix in regions of smooth muscle cell proliferation and mucosal degradation. Interestingly, in ulcerative colitis, another inflammatory bowel disease, stromelysin was localised in the lamina propria in regions of mucosal loss. The increased numbers of inflammatory cells containing gelatinase B, and the localisation of extracellular stromelysin in regions of fibrosis and mucosal degradation, suggest that these enzymes have a role in the pathological changes seen in Crohn's disease. In cases of ulcerative colitis stromelysin was also detected on the lamina propria in regions of mucosal loss, and seems to be associated with the connective tissue changes that precede mucosal loss.

Accumulation and pepsin solubility of collagens in the bowel of patients with Crohn's disease

The collagen content of resected strictured intestine, with and without fistulas, from patients with Crohn's disease has been compared with that in macroscopically normal intestine removed from the same patients and from others without inflammatory bowel disease. Collagen content per unit wet or dry weight of tissue was significantly increased in all grossly diseased tissue whether fistulated or not. Although there was a significant increase in collagen types I, III, and V in diseased tissue, the relative proportions of major collagen types extracted by limited pepsin digestion were similar for both Crohn's and non-Crohn's intestine (type I, 65 to 70 percent; type III, 25 to 30 percent; type IV, 2 to 3 percent; and type V, 2.5 to 3 percent). CNBr digestion of pepsin insoluble material showed a similar relative abundance of types I and III, indicating no major change in collagen type distribution between older (insoluble) and more newly synthesized collagen. There was no evidence of the presence of type I trimer collagen. Type VI collagen, although not quantitated, was observed in 70 percent of intestinal specimens. The proportion of total collagen solubilized by pepsin treatment was significantly greater in both grossly diseased and macroscopically normal Crohn's bowel compared with non-inflammatory bowel disease bowel. These findings suggest that there are disturbances of collagen metabolism in Crohn's intestine, which account for the stricturing process and which may predate gross pathologic changes.

Intestinal permeability to polyethyleneglycol 600 in Crohn's disease. Peroperative determination in a defined segment of the small intestine.

Ileal permeability to different sized polyethyleneglycols (590-942 dalton PEG) was investigated peroperatively in 11 patients with Crohn's disease and seven with colonic carcinoma. A 15 cm ileal segment was converted into a tied loop, in which the PEG's were deposited. Absorption from the ileal segment was then measured as six-hour urinary recovery of the PEg dose. Polyethyleneglycol absorption in Crohn's disease was greater than in cancer patients and similar throughout the weight range, but in the cancer patients it was inversely proportional to molecular weight. Thus there was significantly greater absorption of the higher weights (greater than or equal to 678 dalton) in the Crohn's, than in the cancer patients. The apparently increased permeability of the small intestine in Crohn's disease may be an important factor in its pathogenesis.

INCREASED TYPE V COLLAGEN IN THE STRICTURES OF CROHN'S DISEASE

Histologic studies of strictured intestine in Crohn's disease have revealed an accumulation of collagen and a proliferation of smooth smooth muscle cells. In order to determine if these changes were associated with changes in collagen types, collagen was isolated (acetic acid extraction, limited pepsinisation and salt precipatation) from control intestine, inflamed intestine, and strictured intestine resected from patients with Crohn's disease and collagen types separated by slab gel electropheresis, and quantitated by densitometry. The major collagen type in control intestine was Type I followed by Types III and V. In strictured intestine the relative amount of Type V collagen was significantly increased. Quantitation of hydroxyproline content of the specimens by acid hydrolysis and HPLC demonstrated a significant (p<0.05) increase in collagen per unit area of mucosa in strictured (2308±269 nM) vs. control (1706±122 nM) intestine. Intestinal strictures in Crohn's disease contain increased Type V collagen. These data, in conjunction with the histologic data, suggest a significant role for smooth muscle cells in intestinal fibrosis. Supported by NIH grant AM34151 and the NFIC.

Dysplasia and malignancy in inflammatory bowel disease.

Ulcerative colitis is a highly premalignant condition, particularly when there is total colonic involvement with a disease duration of 10 or more years. Screening of appropriately selected individuals at risk for colon cancer by periodic surveillance for colonic dysplasia appears to be useful in detecting those lesions at an early treatable stage. The histology of dysplasia, a term reserved for epithelial changes that are unequivocally neoplastic, is still not completely defined, and requires a pathologist familiar with the lesion for its proper interpretation. There is a mildly increased risk of cancer of the colon and intestine in Crohn's disease, but screening of these patients does not appear to be clinically warranted.

Pseudopolyps of the small intestine in Crohn's disease

The morphologic features of two types of pseudopolyps of the terminal ileum in a patient with Crohn's disease are described. One form of pseudopolyp is indistinguishable from that observed in the large intestine in Crohn's colitis, while the second, nodular lymphangiectasia, seems to be unique to the small bowel.

Risks of intestinal cancer in Crohn's disease.

This review describes the principal features of the three studies that have established clearly that patients in the U.S.A. or the U.K. who have long-standing (greater than 7 years) Crohn's colitis are at increased risk (up to 20-fold) of developing large bowel cancer. In addition, it emphasizes that there are no data on the extent of this risk in patients in other countries, and also that the magnitude of the risk of cancer of the small intestine in Crohn's disease is unknown. Despite the increased incidence of large bowel cancer in long-standing Crohn's colitis in the U.S.A. or the U.K., the total number of such patients is small, as is the number in which the colonic carcinoma will occur. However, careful supervision is advised for the small group at risk, despite the limitations of current methods for the early detection of cancer of the large intestine.

Intestinal fine structure in Crohn's disease. Lysosomal inclusions in epithelial cells and macrophages.

Resected intestines from eight patients with Crohn's disease and three control cases were investigated by transmission electron microscopy. Characteristic changes were observed in the mucosa of all Crohn's disease specimens, most typically an infiltration of numerous macrophages into the propria. These cells displayed large lysosomes with inclusions which were mainly dense, irregularly shaped and composed of aggregated particles and bizarre-shaped, myelin-like figures. Similar inclusions were also found in the lysosomes of the surface epithelial cells and the macrophages in the submucosa. This latter layer otherwise consisted of an oedematous, collagenous connective tissue. The muscularis appeared structurally unaffected. Qualitatively, the findings were almost identical in all patients with Crohn's disease, but varied quantitatively without any clear correlation with the clinical histories. Moreover, in all cases typical alterations were found not only in the macroscopically most clearly affected parts of the intestines, but also in grossly normal regions, close to the margins of resection. The analogy of the fine structural findings with those of granulomas produced by injection of bacteria into experimental animals suggests that a microbial invasion of the intestinal wall may have initiated the disease. It therefore seems reasonable to assume that the lysosomal inclusions we observed represent partly degraded bacteria. More occasionally, virus-like particles were found within the lysosomes of the epithelial cells and the macrophages in the underlying propria. In view of the diffuse spread of the alterations it seems possible that there exists a generalized defect in the barrier function of the intestine in Crohn's disease. This could lead to passage of bacteria and/or other agents into the mucosa, followed by an influx of inflammatory cells from the blood. Storage of non-degradable microbial components in macrophages could then be responsible for the initiation and propagation of a chronic inflammatory process, similar to that of other granulomatous disorders.

Immunofluorescence Studies of Gastric Heterotopia of the Small Intestine in Crohn's Disease

A patient with long-standing Crohn's disease of the large and small intestine was found to have extensive gastric metaplasia of the ileum. Most metaplastic glands were of the pyloric type, but numerous oxyntic glands with parietal and chief cells were also seen. By immunofluorescence the chief cells contained both the group I and group II pepsinogens, while the pyloric gland cells contained only the group II pepsinogens. Gastric-containing or other endocrine cells were not detected in the metaplastic pyloric and oxyntic glands. The latter findings are consistent with the concept expressed by Pearse that the endocrine and exocrine cells of the gastrointestinal mucosa may originate from different precursor elements during embryogenesis.