gut - associated lymphoid tissue ( galt ) is the largest lymphoid organ in the body .
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 ) [ 13 ] . 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 .
pps are concentrated in the distal 25  cm of the ileum ; there they serve as important antigen entry sites for the immune system .
pps consist of 101000 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 . more recently , using magnifying chromoendoscopy , we identified aphthous erosions in the fae on the domes of pps .
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 ; 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 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 .
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 ) .
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 . 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 : 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 4c , 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  test , the mann - whitney u test , or student s t test , as appropriate .
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 .
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 .
the type e pps were associated with definite lymphoid follicles , as well as abundant lymphoid hyperplasia ( fig . 
1c ) , whereas the type f pps were associated with aggregated lymphocytes without distinct follicle formation ( fig . 
1d ) . 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 .
on magnifying chromoscopy , the pps domes rose into a little mound and were surrounded by dense villi ( fig . 
2a ) in 8 uc patients , whereas 10 uc patients had abnormal domes that were unevenly flat with irregular sizes and shapes and surrounded by atrophic villi that were sparse ( fig . 
the endoscopic findings of these 6 uc patients were mild , with few erosions and redness within the pps ( fig . 
although the appendix was involved in 2 of the uc patients , the macroscopic appearance was mild , with redness and edema , and there were no associated ileal lesions .
post - treatment magnifying endoscopy done 3 to 10 months ( mean 8 months ) later in 13 uc patients after remission with oral treatment ( prednisolone plus mesalazine in 10 patients or mesalazine alone in 3 patients ) . in the 3 patients treated with mesalazine alone
, there was no change in the magnified endoscopic appearance of pps with treatment ( fig . 
4a and b ) . on the other hand , in 6 of 10 of the patients treated with dual therapy , the irregularity of the pps domes ( fig . 
2b ) , had improved , and they were surrounded by more dense and bulky villi ( fig . 
4c ) ; however , the endoscopic category of the pps remained unchanged after treatment .
active inflammation in association with cryptitis , abscess or ulceration was not seen in any cases .
increased mononuclear cell infiltration was identified in 7 cases , and was associated with the presence of villous atrophy .
in fact , 6 of the 7 cases with the increased mononuclear cell infiltration exhibited villous atrophy , while none ( 0/11 ) lacking mononuclear cell infiltration had villous atrophy ( p<0.01 ) . among the 7 patients with the increased mononuclear infiltration ,
biopsies under endoscopy were performed in 6 ones , who had achieved remission with prednisolne plus mesalazine or mesalazine monotherapy .
mesalazine alone ( n  =  2 ) did not alter the histological findings including the increased mononuclear cell infiltration and villous atrophy . on the other hand , in 4 patients who had achieved remission with the dual therapy
, the histological abnormalities were disappeared in 2 , whereas the increased mononuclear cell infiltration and villous atrophy were still present in 2 and 1 , respectively .
electron microscopic observation using the biopsy specimens taken from the pps showed the presence of m cells in the fae ( fig . 
of note , the surrounding villi were found to be longer and thicker after treatment with prednisolone plus mesalazine ( fig . 
this is the first study to document the detailed macroscopic appearance of pps in the terminal ileum of uc patients using magnified endoscopy . prior to initial treatment , in 8 of the 18 uc patients ,
the pps domes were slightly elevated , covered with the regular fae lining , and surrounded by dense and bulky villi , as previously observed in healthy controls . however , in 10 uc patients , the pps domes were irregular and surrounded by atrophic villi that were sparse .
the pps domes irregularity improved in more than half of the patients who achieved remission with prednisolone plus mesalazine therapy , which has also been seen with treatment in cd patients .
the scattered atrophic villi seen prior to treatment became more bulky and were more densely distributed around pps domes after successful treatment with prednisolone plus mesalazine , which was confirmed by not only magnified endoscopic but also electron microscopic examination .
although it is of clinical usefulness to observe the pps with magnified endoscope before and after treatment for inflammatory bowel diseases , endoscopists require training to gain early proficiency in this technique and to overcome flat learning curves .
mild ileal changes , such as a few erosions and redness within the pps , were seen in 33% ( 6/18 ) of uc patients who had chromoendoscopy in the terminal ileum .
of note , all 6 of these patients had abnormal features within the pps on magnified endoscopy ; this suggests an association between pps and the occurrence of ileal lesions in uc patients . also , there was a significant association of mononuclear cell infiltration with villous atrophy of pps in uc patients , suggesting that immune and inflammatory processes may cause villous cell components , linking to villous atrophy of the terminal ileum , in particular pps , as seen in other sites of the gastrointestinal tract
nevertheless , during the study period , no association with the development of overt ileitis was noted .
most patients with uc - associated ileitis have severe / fulminant activity that involves the entire colon [ 8 , 9 ] .
it is commonly thought that severe , continuous colonic disease may lead to incompetence of the inflamed ileocecal valve , which may result in retrograde flow of colonic contents into the distal ileum , resulting in inflammation [ 8 , 9 ] .
indeed , among our patients , minimal lesions within pps were frequently related to pancolitis . however , some patients with proctitis had ileal changes without cecal involvement .
in addition , disease severity in uc patients with ileal lesions was mild to moderate .
although in many reported cases the pattern of uc - associated ileitis is consistent with a backwash etiology [ 8 , 9 ] , our data suggest that other pathogenetic factors should be considered in the pathogenesis of ileal involvement by uc . in a long - term follow - up study of 29 patients who had isolated mucosal erosions in the terminal ileum ,
goldstein found that 29% of patients developed ileocolonic cd , and that 14% were taking nonsteroidal anti - inflammatory drugs .
the etiology of ileitis was undetermined in the remaining 16 patients . in the present study
, none of the uc patients had regularly taken nonsteroidal anti - inflammatory drugs , and there was no histopathological evidence of non - caseous epithelioid granuloma , which is frequently seen in biopsies taken from the pps of cd patients .
treatment with mesalazine alone failed to improve the irregularity of the pps domes and the surrounding villous atrophy despite the colonic disease achieving remission .
clearly , larger prospective studies are warranted to determine the etiology of the abnormalities within the pps in uc patients and to clarify their implications for long - term clinical outcomes , including the occurrence of backwash ileitis .
it is unknown whether variations in the macroscopic appearance of pps have any relationship to patients susceptibility to disease or to the presence of disease .
the age distribution of the two endoscopic categories did not differ between uc patients and controls .
irrespective of the presence of disease , type e was more common in patients younger than 30 years of age , while type f was more common in patients older than 30 years of age .
in line with this , ileal lesions were also observed only in patients older than 30 years of age .
this may be consistent with the findings of cornes that the numbers of pps peaks at ages 1525 years and then declines with age .
the fae located over the pps domes that were surrounded by scattered , atrophic villi is likely to be more exposed to luminal antigens and infectious agents , for which m cells function as a portal of entry [ 3 , 4 ] .
m cells are located in the fae , but only 10% of the fae consists of m cells .
our experience indicates that target biopsy under magnifying endoscopy and chromoendoscopy is beneficial for accurate biopsy sampling to obtain m cells , because this allows us to clearly recognize the fae located on the pps domes .
in fact , on electron microscopy , m cells were detected exclusively in the fae .
m cells are characterized by the presence of irregular cell - surface microvilli [ 3 , 16 ] , as clearly shown by transition electron microscopy in fig . 
, magnifying chromoendoscopy revealed that pps dome irregularity and surrounding villous atrophy are common even in uc patients .
minimal mucosal lesions were seen within the pps that had abnormal features despite the lack of an association with backwash ileitis .
in addition , m cells could be detected in the fae located on the pps domes using electron microscopic examination of targeted biopsy samples targeted .
long - term follow - up studies of a larger cohort of patients may help determine the pathogenesis of ileal involvement in uc .
 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 . 
Introduction
Patients and Methods
Results
Discussion
Conflicts of interest