Gut 1993; 34: 375-381 375 Early mucosal changes in Crohn's disease Gut: first published as 10.1136/gut.34.3.375 on 1 March 1993. Downloaded from E A Sankey, A P Dhillon, A Anthony, A J Wakefield, R Sim, L More, M Hudson, A M Sawyerr, R E Pounder

Abstract of Crohn's disease. We have compared areas of Aphthoid ulceration has been regarded as an bowel resected from patients with Crohn's early macroscopic feature of Crohn's disease, disease, ulcerative colitis, and controls which yetthe cause ofthis mucosal lesion is unknown. appeared normal macroscopically and showed no Examination ofareas of apparently normal and cellular inflammation histologically. Using both non-inflamed bowel in Crohn's disease has immersion and perfusion fixation of specimens, allowed the identification of mucosal changes together with immunohistochemical staining, which occur before macroscopic and micro- we have been able to visualise damage to small scopic ulceration. Thirty five resection mucosal capillaries which is not apparent after specimens from patients with Crohn's disease routine processing and staining. We have found were compared with 12 specimens from early, mucosal vascular changes in areas of patients with ulcerative colitis and 13 controls. apparently normal non-inflamed bowel. The Specimens were fixed either by immersion in areas selected for study were not ulcerated, and formalin in the routine way or by perfusion showed no morphologically discernible, or only fixation withformalin at mean arterial pressure. minimal inflammation or fibrosis. Immunostaining for macrophages, vessel wall, and blood constituents allowed identification of small mucosal capillaries which were not Methods apparent otherwise. In Crohn's disease damage Small and large bowel resection specimens from and rupture of these small capillaries occurred 35 patients with Crohn's disease, 12 patients before infiltration of the lamina propria by with ulcerative colitis, and 13 controls were inflammatory cells. Loss of the overlying either immersion fixed in 10% formalin (13 epithelium seemed to follow this vascular Crohn's disease, four ulcerative colitis, five damage. controls) or perfusion fixed with 10% normal (Gut 1993; 34: 375-381) formalin or 4% paraformaldehyde in phosphate

buffered saline at 100 mm Hg (mean arterial http://gut.bmj.com/ pressure).9 As many of the cases of ulcerative Mucosal ulceration is a common feature of many colitis were total colectomies resected for diseases of the small and large intestine. The extensive disease, fewer areas ofmacroscopically pattern ofulceration varies in different conditions normal bowel were available for study. Patients and may show characteristic appearances in forming the control group included seven under- certain diseases, so forming the basis of histo- going resection for large bowel carcinoma, one

logical diagnosis. The 'aphthoid' ulcer, first with diverticular disease of the colon, one with on September 24, 2021 by guest. Protected copyright. described by Brooke in 1953,' has been polyposis coli, and one who had normal bowel recognised for many years to be an early macro- removed during excision ofan ovarian carcinoma. scopic feature ofCrohn's disease. More recently, Blocks of tissue were selected from macro- the use of fibreoptic endoscopic equipment has scopically normal areas (>5 cm from tumour) allowed the identification of subtle mucosal and paraffin processed in the routine way. changes which are present before the develop- Sections (4 [tm) were cut and stained with ment of aphthoid ulcers. These include patchy haematoxylin and eosin. Sections showing areas a non-ulcerated The Inflammatory Bowel hyperaemia and friable mucosa,2 'worm eaten' of microscopically non-inflamed, Disease Study Group, mucosal pattern,3 and pinpoint haemorrhages the bowel were selected and examined in detail by University Department of size of a single villus.4 Histological examination two independent pathologists, one of whom was Histopathology of these areas shows that inflammation and in of the diagnosis. Occasionally, E A Sankey kept ignorance A P Dhillon granulomas are present in these 'early' lesions"' in sections included in the study there was a A Anthony suggesting that the disease process is already well minimal focal surplus of lymphocytes or plasma A J Wakefield established this stage. Cellular inflammation cells, or both, which on routine histological R Sim by L More also occurs before the 'epithelial surface assessment would usually be regarded as very erosions', described as a reliable feature of early mild changes within normal limits. Sections were University Department of inflammatory bowel disease by Allison et al.' discarded from this study if there was any Medicine, The Royal Free Hospital School of Indeed, inflammation and granulomas have been ulceration, significant inflammation, or fibrosis. Medicine, London recognised in areas of macroscopically normal Our observations were therefore only concerned M Hudson bowel.23 '8 with 'preinflammatory' changes in non-ulcerated A M Sawyerr R E Pounder Early lesions, with features that have yet to be areas. characterised, must occur before established Independent opinions were noted, and Correspondence to: Dr A P Dhillon, Academic ulceration, inflammation, and granulomas in differences were resolved by consensus and by Department of a third 112 Histopathology, The Royal Crohn's disease. A search for these subtle changes arbitration by histopathologist. Free Hospital School of in 'normal' areas of bowel from patients with sections from patients with Crohn's disease (68 Medicine, Rowland Hill a 44 small 56 sections from Street, London NW3 2PF. Crohn's disease may allow chronological large bowel, bowel), to which with ulcerative colitis Accepted for publication sequence of events be postulated, patients (52 large bowel, 28 July 1992 would help the understanding ofthe pathogenesis four small bowel), and 90 sections from controls 376 Sankey, Dhillon, Anthony, Wakefield, Sim, More, Hudson, Sawyerr, Pounder

monoclonal KP1 (a macrophage marker, 1:40 dilution; DAKO Ltd), monoclonal platelet glycoprotein IlIa (PGIIIa, 1:5 dilution; DAKO Ltd), and polyclonal factor XIIIA (1:400 dilution; Behring Diagnostics, Hounslow, UK). Gut: first published as 10.1136/gut.34.3.375 on 1 March 1993. Downloaded from Standard immunohistochemical and develop- ment techniques (peroxidase-antiperoxidase, avidin-biotin complex, diaminobenzidine, and alkaline phosphatase) were used.

Results The diagnoses of Crohn's disease and ulcerative colitis were established for each of the patients using the usual clinical, radiological, and histo- logical criteria. Twenty nine of the 35 cases of Crohn's disease contained granulomas. No dif- ference in the features described below was noted Figure 1: A thick, continuous baAd oflarge eosinophilic macrophages is present in the between those specimens which had been fixed subepithelial area ofthe lamina propria (arrow)from a patient with ulcerative colitis. (Haematoxylin and eosin, original magnification x 146.) by immersion in formalin and those which had been perfused with formalin at mean arterial pressure. Those appearances which were seen before the appearance of inflammatory cells in the surrounding lamina propria (macrophage accumulation and 'pre-inflammation') have been separated from those changes which were identified in the presence of polymorphs, lym- phocytes, and plasma cells (early inflammation).

MACROPHAGE ACCUMULATION The first mucosal change identified in both Crohn's disease and ulcerative colitis, and present before a definable mucosal 'lesion' could be recognised, was the diffuse accumulation oflarge eosinophilic macrophages within the lamina http://gut.bmj.com/ Figure 2: Macrophages adherent to the endothelium ofsmall capillaries (arrows) in areas of propria. These cells were larger in size and mucosa showing no cellular inflammation. (Immunostained with KPI, original magnification number than in controls. They were seen most x365.) clearly in large bowel specimens, where they had abundant eosinophilic cytoplasm and often (58 large bowel, 32 small bowel) were examined formed a thick, continuous band, predominantly in total. Where mucosal changes were identified, beneath the surface epithelium (Fig 1). The band serial sections were cut and immunostained with occupied up to one third of the lamina propria.

a to IV on September 24, 2021 by guest. Protected copyright. monoclonal antibody collagen (1:50 Smaller cells, with less cytoplasm, were also dilution; DAKO Ltd, High Wycombe, UK) to identify vascular basal lamina, monoclonal scattered in the remaining lamina propria and, to QBEndlO (a vascular endothelial cell marker, a lesser extent, in the submucosa. In small bowel 1:400 dilution; SEROTEC, Oxford, UK), poly- specimens the cells were mainly localised in the clonal fibrinogen (1:1000 dilution; DAKO Ltd), tips of villi. They showed immunostaining for KPl and were occasionally seen adherent to the endothelium ofvessel walls within the superficial lamina propria (Fig 2). A second cell type, a dendritic cell immunostaining for factor XIIIA, was also diffusely increased in the non-inflamed lamina propria of patients with Crohn's disease and ulcerative colitis compared with controls. These cells were found predominantly beneath Figure 3: Dendritic cells are the KP1 macrophages in the lower two thirds of diffusely increased within the the lamina propria (Fig 3) and submucosa. lower two thirds ofthe lamina propria. (Immunostained with factor XIIIA, original PRE-INFLAMMATION magnification x146.) Pre-inflammation changes were identified in areas of bowel which were macroscopically TABLE Summary ofearly microscopic mucosal changes in Crohn's disease normal. Microscopically, these areas showed No ofcases Summit Summit normal numbers of mucosal plasma cells and no No of perfused Haemorrhages Haemorrhages lesions lesions polymorphs or lymphocyte aggregates - that is, cases/slides fixed (slides) (%) (cases) (%) (slides) (%) (cases) (%) no histological inflammation. The findings are Crohn's disease 35/112 22 13 (12) 9 (26) 8 (7) 6 (17) presented in the table. The first focal lesions Ulcerative colitis 12/56 8 3 (5) 2 (17) nil nil identified were small haemorrhages at all levels Control 13/90 8 nil nil nil nil of the mucosa. These were defined as extra- Early mucosal changes in Crohn's disease 377

Figure 4: Rupture ofsmall capillaries with haemorrhage into the lamina propria. A plug is present within the tip

ofthe capillary (arrow). Gut: first published as 10.1136/gut.34.3.375 on 1 March 1993. Downloaded from (Haematoxylin and eosin, original magnification x365.) Figure 5: Immunostaining forfibrinogen shows trails of fibrillary matenral extending from damaged capillaries within the mucosa towards the surface epithelium (original magnification x146.) Figure 6: Disruption ofthe basement membrane ofa small superficial mucosal capillary shown by immunostaining with collagen IV (original magnification x365.) Figure 7: Eruptions offibrin and epithelial cellsfrom the mucosal surfaceform 'summit' lesions in Crohn's disease. There is no surrounding inflammation in the lamina propria. (Haematoxylin and eosin, Fig. 5 original magnification x 365.) http://gut.bmj.com/ on September 24, 2021 by guest. Protected copyright.

Fig. 6 Fig. 7 vasated red blood cells associated with surround- from ruptured capillaries and extending towards ing homogeneous or fibrillary material (Fig 4) the surface epithelium (Fig 5). Some capillaries which were found to be positive for fibrinogen in these areas showed discontinuous collagen IV after immunostaining. Simple extravasation of (Fig 6) or QBEndIO immunostaining, although red blood cells, occurring as a result of handling this could not be shown at every focus of or sectioning of the bowel by the pathologist and haemorrhage. identified by morphological traumatic artefact, The overlying epithelium remained intact in was not associated with similar trails of fibrin. these 'early' haemorrhagic lesions, but sometimes These small haemorrhages were present in showed necrosis of individual cells with nuclear specimens which had been fixed by either pyknosis. In a few cases ofCrohn's disease (8/112 immersion or perfusion. They were seen more (7%) of all sections examined; six patients) a commonly in patients with Crohn's disease small focus of the overlying epithelium, with a (13/112 (12%)) of all sections examined (9/35 plume of fibrin, was seen erupting into the (26%) patients), and were identified in 3/56 lumen of the bowel as a micro ulceration or (5%) of sections from patients with ulcerative 'summit' lesion (Fig 7). No similar 'summit' colitis (2/12 (17%) patients) and in none of the 90 lesions were identified in areas of normal bowel control sections. Immunostaining for fibrinogen from patients with ulcerative colitis or controls. showed trails of fibrillary material originating Loose accumulations of eosinophilic, fibrillary 378 Sankey, Dhillon, Anthony, Wakefield, Sim, More, Hudson, Sawyerr, Pounder

Figure 8: Fibrinoid plugs are occasionally seen occluding small capillaries. This material does not stain withfibrinogen but immunostains withfactor Gut: first published as 10.1136/gut.34.3.375 on 1 March 1993. Downloaded from XIIIA and PGPIIIa (arrow). (Immunostained with PGPIIIa, original magnification x365.) Figure 9: Macrophages and lymphocytes collect in the lamina propria giving the mucosa a patchy appearance. The base of some glands subsequently shows invasion by lymphocytes. (Haematoxylin and eosin, original magnification x365.)

Fig. 8 Fig. 9 material were seen in the superficial lamina with Crohn's disease the first mucosal inflam- propria. In places this material formed 'fibrinoid' matory change was macrophage and lymphocyte plugs partly occluding the lumen of damaged collections within the lamina propria. These were capillaries particularly at the point of rupture present loosely within the interstitium, around (Fig 4). This material did not immunostain with areas of capillary damage in some cases or at the fibrinogen, but did immunostain with factor base of otherwise normal glands. These aggre- XIIIA and PGIIIa (Fig 8). In these areas of gates occurred at any level within the mucosa, haemorrhage there were no focal increases in giving the lamina propria a patchy appearance. KP1 positive macrophages or dendritic cells The overlying epithelium was generally intact, immunostaining for factor XIIIA, either within particularly if the collections of macrophages the lamina propria or the underlying submucosa. were deep. Remaining microscopic evidence of haemorrhagewas notalways present in these deep lesions; however, more superficial collections

EARLY INFLAMMATION were occasionally associated with trails of http://gut.bmj.com/ Histological evidence of cellular inflammation fibrinogen, extravasated red blood cells or was uncommon in normal areas of bowel from 'summit' lesions. With increasing numbers of patients with ulcerative colitis and controls. In a inflammatory cells the infiltrate showed some small number of sections from patients with organisation and early invasion of gland epithe- ulcerative colitis (8/56) there were small scattered lium at the base of glands, particularly by collections ofchronic inflammatory cells, mainly lymphocytes and macrophages (Fig 9). Intra-

lymphocytes and plasma cells, within the lamina on September 24, 2021 by guest. Protected copyright. propria. Three sections from the controls showed single, isolated, dilated glands with minimal cryptitis in otherwise normal mucosa. In patients

Fig. IOA Figure JOA and IOB. Occasionally lesions can be identified close to, or overlying, lymphoid aggregates (A) or Peyer's patches (B). (Haematoxylin and eosin, original magnification x146.) Fig. IOB Early mucosal changes in Crohn's disease 379

vascular polymorphs were present in a few areas; lamina propria. The location of these cells, some were present in the lamina propria admixed adherent to the endothelium ofcapillaries within with the other inflammatory cells. In places these the superficial lamina propria, suggested that lesions occurred over lymphoid aggregates (Fig they had migrated actively to this site. Similar Gut: first published as 10.1136/gut.34.3.375 on 1 March 1993. Downloaded from IOA) or near to Peyer's patches (Fig 10B). cells have been described in areas of inflamed Dendritic cells immunostaining for factor XIIIA, mucosa from patients with inflammatory bowel and usually scattered in the mid zone ofthe lamina disease.'7"'9 Gionchetti et al20 examined macro- propria, were increased in number around these phages in biopsy specimens from patients with areas of inflammation. Crohn's disease which were taken from areas with minimal abnormality (recognised only with a magnifying colonoscope); they compared them Discussion with biopsy specimens from areas of apparently Attempts to define a chronological order of normal bowel from the same patients, reporting events fromhistologicalmaterial is always fraught an increase in macrophages staining for RFD9 with difficulties. It is only possible to infer a (an epithelioid macrophage marker) in the sequence by examination of many sections and diseased areas. Microscopically, however, these multiple levels, and then to imagine spatial and areas were already histologically inflamed. They temporal dimensions. These interpretations, did not compare their normal Crohn's disease therefore, must be regarded as subjective. With biopsy specimens with control (non-Crohn's these reservations inmind, wepropose a sequence disease) material. Donnellan suggested that of superficial mucosal changes which occur in these cells were increased in patients with either Crohn's disease before the development of ulcerative colitis who had been receiving steroid 'aphthoid ulceration' of the overlying mucosa. It treatment2' or in patients with obstruction.22 All is uncertain whether the lesions described are an of our patients with ulcerative colitis and nearly essential precursor of overt Crohn's disease or a all those with Crohn's disease were taking, or had parallel feature ofit. been treated with, steroids before their bowel The term 'aphthoid' ulceration has been used resections. The seven patients with Crohn's by pathologists to describe varying degrees of disease who had not taken steroids showed a mucosal ulceration associated with a lymphocytic slight decrease in eosinophilic macrophages infiltrate.'0' Brooke' first used this term for the compared with the remaining Crohn's disease earliest macroscopic appearance over Crohn's cases, butthenumbers were stillhighercompared disease but the first description of mucosal with controls (unpublished data). In each of ulceration as an early microscopic change in these cases, resection had been performed for Crohn's disease was by Lockhart-Mummery and strictures or symptoms or pseudo-obstruction. Morson'2 who reported ulceration of lymphoid The single control patient who presented with http://gut.bmj.com/ follicles and Peyer's patches in the terminal obstruction showed no increase in these cells. It ileum. Later, these focal microscopic lesions remains possible that steroid treatment directly were also given the name 'aphthoid' ulcers'3"16 increased the numbers of eosinophilic macro- and the term expanded to include ulceration over- phages in the lamina propria and was responsible lying focal accumulations of lymphocytes in the for the generalised increase which we found. basal part of the mucous membrane. This paper Alternatively, the increase may reflect a seeks to examine the mucosal changes which generalised, systemic effect of inflammation on September 24, 2021 by guest. Protected copyright. occur before the presence of'aphthoid' ulceration elsewhere or a reaction to morphologically incon- For this study, we use 'aphthoid' ulcer to mean a spicuous mucosal damage. microscopic ulcer with associated active inflam- Small intramucosal haemorrhages were the mation, overlying an area of chronic first focal changes within the mucosa. These inflammation, lymphoid aggregate or Peyer's often occurred in areas of intact epithelium and patch. were more common in patients with Crohn's By examining macroscopically normal, non- disease (26%) than ulcerative colitis (17%) or inflamed areas of bowel in patients with known controls (0%). Further evidence of vascular Crohn's disease we have identified subtle damage in the form of 'summit' lesions, with mucosal changes which would normally have plumes of fibrin and loss of superficial epithelial been obscured by active inflammation. Using a cells were only identified in patients with Crohn's combination ofperfusion fixation at mean arterial disease (17%). Early vascular damage was shown pressure and immunohistochemical techniques clearly by disruption ofthe collagen IV basement we have been able to examine small mucosal membrane of capillaries, and extravasation of capillaries in detail. Focal, early mucosal red blood cells and fibrinogen into the changes seem to be associated with damage to surrounding lamina propria. This microvascular small capillaries. This was shown in our tissues damage occurred before (that is, was present by disruption of the capillary basement without) inflammation or epithelial erosion. It is membranes (collagen IV immunostaining) or the therefore unlikely to be a secondary consequence vascular endothelium (QBEndIO) with haemor- of either mucosal inflammation or ulceration. rhage and trails of fibrinogen in the surrounding The mechanism of this vascular damage is lamina propria. This damage was seen in the unclear: adhesion, migration, and accumulation absence of local accumulation of inflammatory of eosinophilic macrophages in a diffuse, sub- cells and necrosis of the overlying epithelium. epithelial distribution usually occurred before One of the earliest features identified in this damage, while focal accumulation of similar Crohn's disease and ulcerative colitis was an macrophages and lymphocytes within the lamina increase in the numbers of eosinophilic macro- propria seemed to follow it. These features were phages beneath the surface epithelium of the not seen in all cases of Crohn's disease, and this 380 Sankey, Dhillon, Anthony, Wakefield, Sim, More, Hudson, Sawyerr, Pounder

may reflect the patchy nature of the initial features are similar to the observations in this disease process and shows one of the difficulties paper. ofidentifying such early changes. Pseudomembranous colitis is thought by some

Dourmashkin et al reported 'patchy epithelial to have an ischaemic pathogenesis.37 The foci of Gut: first published as 10.1136/gut.34.3.375 on 1 March 1993. Downloaded from necrosis in the absence of acute inflammation' as micro-ulceration or epithelial loss seen in our an early feature ofCrohn's disease in two ofseven lesions closely resembled the 'summit' lesions rectal biopsy specimens,23 and this is supported described by Price and Davies in their type I by our findings. They also noted extravasated lesions of pseudomembranous colitis.38 They red blood cells in the lamina propria and also described one case of Crohn's disease in epithelium, and interpreted this feature as an which similar lesions were seen, but significant artefact of the biopsy technique. Our sections differences in the degree of surrounding inflam- .were obtained from carefully handled resection mation led them to believe that these lesions were specimens and are unlikely to have suffered not identical. In our cases, however, vascular similar direct trauma. Our control specimens did changes without inflammation were identified as not show these features, and so they cannot be well as lesions where vessel damage and inflam- attributed to trauma alone. mation coincided. Some mucosal capillaries were associated with The mucosal changes identified here occurred intraluminal plugs of factor XIIIA positive at all levels of the mucosa, both in areas close to, material, usually close to the point of rupture. and distant from Peyer's patches. The relation Similar material was sometimes present just between these mucosal changes and the classic beneath the surface epithelium in areas of aphthoid ulcers occurring over Peyer's patches is capillary damage. Factor XIII is a protein found in plasma and platelets which is activated by thrombin to form factor XIIIA.24 This is a transamidase enzyme which, in the presence of calcium, catalyses the covalent cross linking between the y and a chains of fibrin to form stabilised fibrin - that is, the final event in the coagulation of blood. The presence of factor XIIIA immunostaining of the intravascular eosinophilic plugs in our sections suggests that this material represents either platelet thrombi or cross linked fibrin. It is only possible to speculate if these plugs represent true micro- vascular thrombi, or an attempt at haemostasis http://gut.bmj.com/ and coagulation following capillary haemor- rhage. Intravascular microthrombi have been identified before in Crohn's disease,825 although they are not widely recognised as a feature of this disease.2627 Microthrombi have been described in association with ischaemic bowel conditions, both in experimental animal models and human on September 24, 2021 by guest. Protected copyright. disease.2829 Comparison with the histological changes seen in other conditions known, or thought to have, an ischaemic cause shows some similarities. McGovern and Goulston30 described the main criteria for the diagnosis of ischaemic entero- colitis: mucosal haemorrhage, necrosis, and ulceration (all shown in our study); thrombosis and a moderate infiltrate of polymorphs were also notable features. Microthrombi have been identified in association with mucosal necrosis and ulceration in diverse ischaemic conditions where large vessel occlusion is not present. These include other reports of ischaemic entero- colitis,3' pseudomembranous colitis,32 and haemolytic-uraemic syndrome,3334 paroxysmal nocturnal haemoglobinuria,35 and anorectal ulceration associated with ergotamine suppositories.36 Models of experimental ischaemia offer the chance to examine the earliest features of ischaemia, something rarely possible in the human situation. Whitehead described early Figure I1: Proposed early mucosal changes in Crohn's features: dilatation and disruption of superficial disease. Small mucosal capillary close to base ofcrypt. capillaries, haemorrhage, oedema with fibrin (A) (?) Endothelial insult and capillary disruption: haemorrhageintolaminapropria. (B)Fibrinoidplugoccluding exudation, and eosinophilic necrosis of the damaged capillary: macrophages attracted to area ofrelative epithelium.37 A polymorphonuclear leucocyte ischaemia. (C) Lymphocytes attracted to damaged area: response did not appear until 12-24 h. These invasion ofbase ofcrypt by lymphocytes (crvptitis). Early mucosalchanges in Crohn's disease 381

unclear. The centres of lymphoid follicles are (regional enteritis) of the large intestine and its distinction from ulcerative colitis. Gut 1960; 1: 87-105. supplied by end arterioles and it has been 13 Morson BC. The earliest histological lesion of Crohn's disease. suggested that, as a consequence, they are Proc R Soc Med 1972; 65: 71-2. prone to ischaemia;39-4' thus, Peyer's 14 Morson BC. Pathology of Crohn's disease. In: Brooke BB, ed. particularly Clinics in gastroenterology 1 (2). Crohn's disease. London: W B Gut: first published as 10.1136/gut.34.3.375 on 1 March 1993. Downloaded from patches may provide a preferred site for this kind Saunders, 1972: 265-77. 15 Morson BC, Dawson IMP. Inflammatory disorders. In: of ulceration. Alternatively, many aphthoid Morson BC, Dawson IMP, eds. Gastrointestinal pathology. ulcers overlie lymphoid aggregates rather than 2nd ed. London: Blackwell Scientific 1979: 307. 16 Morson BC. In: Curran RC, ed. Colour atlas ofgastrointestinal true follicles and such 'advanced' inflammatory pathology. Oxford: Harvey Miller Publishers and Oxford lesions were not present in the areas of 'normal' University Press, 1988: 125-6. 17 Mahida YR, Patel 5, Gionchetti P, Vaux D, Jewell DP. bowel examined in this study. Progression and Macrophage subpopulations in lamina propria ofnormal and extension, however, ofthe early features we have inflamed colon and terminal ileum. Gut 1989; 30: 826-34. 18 Seldenrijk CA, Drexhage HA, Meuwissen SGM, Pals ST, described in this paper would be compatible with Meijer CJLM. Dendritic cells and scavenger macrophages in the ultimate development of an aphthoid ulcer. chronic inflammatory bowel disease. Gut 1989; 30: 484-91. 19 Allison MC, Cornwall S, Poulter LW, Dhillon AP, Pounder The cause of mucosal changes and aphthoid RE. Macrophage heterogeneity in normal colonic mucosa ulcers in Crohn's disease has been debated for and in inflammatory bowel disease. Gut 1988; 29: 1531-8. 20 Gionchetti P, Mahida YR, Patel S, Jewell DP. Macrophage many years with some authors suggesting that and lymphocyte subpopulations in magnifying endoscopic their early presence lends support to a luminal lesions of Crohn's disease. Clin Exp Immunol 1988; 72: 373-6. cause for Crohn's disease.31314 Others believe 21 Donnellan WL. Early histological changes in ulcerative colitis. ulceration is a later feature of the A light and electron microscopic study. Gastroenterology that mucosal 1966; 50: 519-40. disease and is a consequence of the thickening, 22 Donnellan WL. The structure of the colonic mucosa. The fibrosis, and inflammation of the sub- epithelium and subepithelial reticulohistiocytic complex. Gastroenterology 1965; 49: 496-514. mucosa.67942 Our results suggest that capillary 23 Dourmashkin RR, Davies H, Wells C, Shah D, Price A, a role in the mucosal changes O'Morain C, et al. Epithelial patchy necrosis in Crohn's damage may play disease. 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