Peyer’s patches (PPs), a major component of the gut-associated lymphoid tissue, serve as important antigen entry sites in mucosal immunity. PPs may play a role in the extension of ulcerative colitis (UC) into the terminal ileum. We sought to clarify the magnified endoscopic findings of the PPs in the terminal ileum of UC patients. Eighteen UC patients underwent magnifying chromoendoscopy before initial treatment to evaluate the follicle-associated epithelium (FAE) on the PPs domes and the surrounding villi. In 8 UC patients, as in healthy controls, the PPs’ domes were slightly elevated, covered with the regular FAE lining, and surrounded by dense and bulky villi; however, in 10 UC patients, the PPs’ domes were irregular, and the surrounding villi were sparse and atrophic. These abnormal findings within the PPs were associated with minimal mucosal lesions but not with backwash ileitis; both electron microscopy and magnifying endoscopy confirmed that these lesions were reversible following remission with prednisolone-mesalazine therapy. Similar to Crohn’s disease patients, UC patients commonly had abnormalities in the FAE on PPs’ domes and the surrounding villi on magnifying endoscopy.
Keywords: Peyer’s patches, ulcerative colitis, magnifying endoscopy, follicle associated epithelium, M cells
Gut-associated lymphoid tissue (GALT) is the largest lymphoid organ in the body [1 ]. GALT has to recognize and allow the transfer of beneficial antigens while concurrently dealing with and successfully removing putative and overtly harmful antigens. This distinctive biological feature of GALT is crucial to good health, whereas the deregulation or dysfunction of GALT is thought to predispose to inflammatory bowel disease, ulcerative colitis (UC) and Crohn’s disease (CD) [1 –3 ].
Peyer’s patches (PPs) are central to mucosal immunity as they play a major role in GALT; they modulate intestinal immune and inflammatory responses or tolerance [1. 3 ]. PPs are widely distributed along the small intestine but their highest density is in the human ileum [4 ]. PPs are concentrated in the distal 25 cm of the ileum [4 ]; there they serve as important antigen entry sites for the immune system. PPs consist of 10–1000 individual follicles organized into discrete lymphoid structures that are overlaid by follicle-associated epithelium (FAE) [4. 5 ].
In patients with CD, involvement of the terminal ileum is most common, and the initial mucosal lesions of CD often appear over PPs [2 ]. More recently, using magnifying chromoendoscopy, we identified aphthous erosions in the FAE on the domes of PPs [6 ]. In addition, most CD patients examined had irregularly even PPs domes surrounded by sparse villi. Of note, non-caseous epithelioid granuloma were frequently identified in the biopsies taken from PPs [6 ]; this supports the concept that CD lesions may originate from PPs [3. 7 ].
However, scant attention has been paid to the association of PPs with the pathogenesis of UC. In this regard, there is no information dealing with detailed macroscopic observations of the terminal ileum of UC patients with special reference to PPs. UC is a chronic inflammatory condition that invariably involves the rectum and over time often extends proximally in a continuous manner [2 ]. UC does not typically involve other areas of the gastrointestinal tract, but further extension of the inflammatory process into the terminal ileum is common [8. 9 ]. It is possible that PPs play a role in the development of the ileal lesions seen in UC patients. In the present study, the magnified endoscopic findings of PPs in the terminal ileum of UC patients were clarified.
Patients and Methods
Between 1998 and 2005, 18 UC patients without any prior treatment were enrolled. The diagnosis of UC was made on the basis of the endoscopic, radiological, histological, and clinical criteria provided by the WHO Council for International Organizations of Medical Sciences and the International Organization for the Study of Inflammatory Bowel Disease [10. 11 ]. Patients with Crohn’s disease,
indeterminate colitis, and autoimmune diseases, such as RA, multiple sclerosis, and systemic lupus erythematosus, were excluded from the study. The patients were classified into subgroups according to the extent of their lesions (proctitis, left-sided colitis, or pancolitis), disease severity (mild, moderate, or severe), and activity (active or inactive) [12 ].
After usual premedication, colonoscopic examination was performed using a magnifying videocolonoscope with an image processor (Olympus CF-240ZI). After routine conventional observation, chromoendoscopic observation was performed using 0.1% indigo carmine, which was sprayed directly onto the mucosal surface of the terminal ileum to identify the PPs. The FAE on the PPs’ domes and the surrounding villi was examined by magnifying endoscopy. According to the classification that we previously proposed, the macroscopic appearance of PPs was divided into two categories: type E, consisting of a nodular or convoluted elevation pattern; and type F, consisting of a flat pattern [6 ]. During endoscopy, biopsy specimens were taken from the PPs’ domes; one of the specimens was fixed in formalin, embedded in paraffin wax, and stained with hematoxylin and eosin for histopathological examination.
The following histologic features were evaluated in accordance with previous report [9 ]: 1) presence, type, and degree of ulceration; 2) severity and extent of active (neutrophilic) inflammation. Inflammation was noted as to whether it was limited to the lamina propria, infiltrating crypts (cryptitis), forming crypt abscesses or whether it was associated with ulceration. 3) Degree of mononuclear inflammation in lamina propria, graded as normal, or increased. 4) Extent of villous atrophy was graded as none, subtotal, or total.
In certain cases, the biopsy sample was prepared for electron microscopy; each specimen was rinsed with physiological saline solution, fixed in 2.5% glutaraldehyde at 4°C, and then fixed in phosphate buffered 1% osmium peroxide (pH 7.4) and in 1% tannic acid overnight, followed by 1% osmium tetroxide and dehydration through a graded ethanol series. After drying in a critical point dryer, the specimens were coated with platinum palladium and observed with a Hitachi S-570 scanning electron microscope [6. 13 ].
The Statistical significance of differences in patients’ characteristics and clinicopathological features was determined using Fisher’s exact test, the χ 2 test, the Mann-Whitney U test, or Student’s t test, as appropriate. p values less than 0.05 were considered statistically significant.
All examinations were conducted according to Good Clinical Practice and the Declaration of Helsinki, and were approved by the university ethics committee. All samples were obtained after written informed consent was obtained from the patients prior to their inclusion in the study.
The characteristics of the 18 UC patients are summarized in Table 1. There were 11 men; the patients’ mean age was 36 years (range, 16 to 72 years). Twelve patients had pancolitis, two had left-sided colitis, and four had proctitis. All of the patients but one had active UC. On chromoendoscopy, 9 UC patients had type E PPs (Fig. 1 A), and 9 had type F PPs (Fig. 1 B). The type E PPs were associated with definite lymphoid follicles, as well as abundant lymphoid hyperplasia (Fig. 1 C), whereas the type F PPs were associated with aggregated lymphocytes without distinct follicle formation (Fig. 1 D). During the same time period, 140 subjects without any gastrointestinal disorders underwent chromocolonoscopy to evaluate PPs in the terminal ileum (Table 2 ). There was no difference in the age distribution of the type E and type F PPs between the 140 controls and the 18 UC patients; in both groups, type E PPs were exclusively observed in individuals younger than 30 years, while type F PPs were predominantly observed in individuals older than 30 years. Ileal lesions were present within the PPs in 6 UC patients, 4 of whom had pancolitis and 2 of whom had proctitis; of the 6 UC patients, disease activity was mild in 3 and moderate in 3.