a study of accessory cells in the acquired lymphoid tissue of helicobacter gastritis

JOURNAL OF PATHOLOGY, VOL. 180: 18-25 (1996)

A STUDY OF ACCESSORY CELLS IN THE ACQUIRED LYMPHOID TISSUE OF HELICOBACTER GASTRITIS

P. SARSFIELD*, D. B. JONES", A. c. WOTHERSPOON~, T. HARVARD~ AND D. H. WRIGHT*

* University Department of Pccthology, Level E, South Block, Southampton General Hospital, Tremona Road, Southampton SO16 6 YD, U. K.; ?Department of Histopathology, Royal Postgraduate Medical School, Hammersmith Hospital, Ducane Roadj

London W12 OHS, U.K.; fBUPA Chalybeate Hospital, Chalybeate Close, Tremona Road, Southampton SO16 YD, U K.

SUMMARY

This paper presents a description of the patterns of distribution of accessory cells in helicobacter gastritis and low-grade gastric MALT lymphomas. The use of gastric resection specimens afforded abundant, well-orientated lymphoid tissue. Fifteen cases were selected from patients with MALT lymphomas, three with gastritis alone, and six histologically normal controls. A panel of antibodies working in paraffin-embedded tissue, identifying differing accessory cells, was used. These comprised antibodies to HLA class I1 (WR18), acid cysteine proteinase inhibitor (ACPI), CD68 (PGMl), Factor XIIIa, S l O O protein, CD23 (BU38), CD106 (V-CAMl), CD55 (BRIC 128), and CD21 (1F8). CD68-positive macrophages in the gastritis cases were abundant in the superficial mucosa. Factor XIIla also identified dendritic cells a t deeper sites but these were absent from both the acquired and the neoplastic lymphoid tissue. Antibodies to both S l O O protein and ACPI stained dendritic cells localized to areas within and adjacent to the lymphoid tissue only. S l O O protein-positive cells were concentrated in close contact with glandular epithelium immediately above the germinal centres, while ACPI-positive dendritic cells were identified, especially around the more blastic reactive follicles, in the intervening space between the germinal centres and the overlying epithelium. Similar patterns of organization were also seen in the areas of mucosal lymphoma. The follicular dendritic markers revealed overlapping but distinct sub-populations within the germinal centres which appeared to alter depending on the activity of the germinal centres. While both ACPI and CD55 stained the germinal centre dendritic reticulum cell networks only, CD21 and CD106 also stained the mantle dendritic cells. The proportion staining with CD23, which stains dendritic reticulum cells within the centrocyte-rich areas of the germinal centres only, was greatest in the more quiescent germinal centres. Similar patterns of staining were also seen in germinal centres within the gastric MALT lymphomas. It is proposed that the sub-populations of dendritic cells staining with S l O O protein and ACPI may facilitate helicobacter antigen delivery to the germinal centres. The follicular dendritic cells then promote a sustained B-cell response to the luminal pathogen.

KEY WORDS-MALT lymphomas; accessory cells; antigen presentation; Helicobactev pyloi'i

INTRODUCTION

Infection with Helicohacter pylori is the principal cause of chronic gastritis.' The organism is ubiquitous and there is a wide variation in both the severity of inflammation and the clinical symptoms. Chronic infection with H. pylori is a predisposing factor in the development of both lymphoma and carcinoma of the

Cytotoxins of 128 kD and 86 kD produced by the organisms cause gastric mucosal i n j ~ r y . ~ There is long-term colonization of the gastric surface epithelium and although vigorous inflammation may result, the means by which a specific immune response can be directed against a non-invasive pathogen is not completely understood. 1,6 The identification of mononuclear cells and lymphoid germinal centres in the gastric mucosa is now considered to be pathognomonic of infection with helicobacter organism^.^ Significant neutrophil recruitment and activation occur in H. pylori infection, but although damage results, this response is ineffective in eliminating the p a t h ~ g e n . ~ ? ~ Autoanti- bodies reactive with H. pylori can also down-regulate cytokine-mediated neutrophil recruitment into the

Addressee for correspondence: Professor D. H. Wright, University Department of Pathology, Level E, South Block, Southampton General Hospital, Tremona Road, Southampton SO16 6YD, U.K.

CCC 0022-3417/96/0900 18-08 0 1996 by John Wiley & Sons, Ltd.

mucosa.' Antibodies produced by gastric mucosal plasma cells, especially IgA, represent the principal arm of the targeted immune response to H. pylori, resulting in the blocking of adhesion of the bacterium to the

Sub-population of T-cells have also been reported to influence the host response to H. pylori. I

Accessory cells have important roles in both phago- cytosis and antigen presentation, but until now have been little investigated in H. pylori gastritis. We report an immunohistochemical study of accessory cell populations in chronic gastritis and mucosal lymphoma of the stomach, using a panel of antibodies active in paraffin-embedded tissues. The antibody panel was designed primarily to identify populations of macrophages and follicular dendritic cells (FDCs). We have previously demonstrated that antibodies to ACPI and S 100 protein identify accessory cells restricted to the dome areas of Peyer's patches.12 These antibodies show a similar pattern of localization in the acquired lymphoid tissue in the stomach and may facilitate antigen delivery from the gastric lumen. We describe phenotypically distinct populations which may play a role in maintaining the B-cell response to H. pylori. We also demonstrate parallel patterns of organization of accessory cells within mucosal lymphomas which may be of importance in sustaining the helicobacter drive for these neoplasms.

Received 4 July 1995 Accepted 19 February 1996

DISTRIBUTION OF ACCESSORY CELLS IN HELICOBACTER GASTRITIS 19

Table I-The panel of antibodies used

Antibody (CD group) Pretreatment Reactivity/function Source Ref.

PGMl (68) SlOO ACPI

WR18 FXIIIa IF8 (21) BU38 (23) BRIC 128 (55) V-CAM (106)

T T T

MW T

MW MW MW MW

Tissue macrophages Antigen-presenting cells Acid cysteine proteinase inhibitor ? protection

against complement damage HLA class I1 antigen presentation Tissue macrophage (associated with fibrosis) Follicle dendritic cells. Anti-apoptosis Follicle dendritic cells (subset). Anti-apoptosis. C3, C5 convertase inhibitor Adhesion molecule. Antibody affinity selector

Dako Dako A. Rinne*

Wessex Immunology Beringewerk, A. G. Marburg Dako The Binding Site D. J. Anstee? D. Haskardt

14 15 16

17 18 19 20 21

T= trypsin; MW=microwave. *A. Rinne, University of Tromso, Norway. TD. J. Anstee, South West Region Blood Transfusion Centre, Bristol. ID. Haskard, ICRF, ST Bartholomew’s Hospital, London.

Fig. 1-Reactive germinal centre in the superficial gastric mucosa of a stomach infected with Helicobacter pylori

MATERIALS AND METHODS

Eighteen cases were studied. All of the patients had undergone partial gastrectomy for the treatment of either low-grade mucosal lymphoma of the stomach (1 5 cases) or inflammatory gastritis (3 cases). The blocks selected included a strip of gastric mucosa, at least 2 cm long, and contained abundant, well-orientated, reactive

Fig. 2-CD68 (PGM1)-positive staining of tingible body macrophages and numerous dendritic macrophages in the superficial lamina propria

lymphoid follicles (Fig. 1). Although blocks were selected primarily to include areas of gastritis, six also included areas with low-grade mucosal lymphoma. Six histologically normal stomachs were used as controls. These specimens were obtained from the margins of resected stomachs from patients undergoing gastrectomy for either carcinoma of the stomach or carcinoma of the pancreas. One hundred and ten cases had to be

20 P. SARSFIELD ET AL.

Fig. 3--Factor XIIIa staining of dendritic cells throughout the gastric mucosa, extending into the deeper layers but absent from the lymphoid tissue

reviewed before six cases showing no evidence of gastritis were obtained. Sections were stained with haematoxylin and eosin and with a modified Giemsa stain for the detection of H. pylori. Control sections were stained with the macrophage antibodies only, as they did not contain lymphoid tissue, while all the gastritis cases were also stained with follicular dendritic cell markers. Specificities of all the antibodies employed are shown in Table I . Antibodies were used at dilutions previously determined by titration against control material. Sec- tions were dewaxed in xylene and passed through graded alcohols to water. Endogenous peroxidase was blocked with freshly prepared 0.5 per cent hydrogen peroxide in methanol for 10 min. Sections were rinsed in tap water before being treated in one of three ways, as appropriate for individual antibodies, as follows: (1) 0.1 per cent trypsin in 0.1 per cent calcium chloride,

pH 7.8, at 37°C for 10 min; (2) 0.01 M citric acid, adjusted to pH 6.0 with sodium

hydroxide and microwave-irradiated for 25 min (Panasonic "-6450, 800 W) using a previously published technique;' 1 per cent bovine serum albumin (BSA) in TBS for 30 min.

(3)

Slides were washed in TBS ( 3 x 5 min) between all steps. Primary antibodies were applied overnight (1 8 h) at 4°C. Second stage antibodies were applied as follow.

Biotinylated rabbit anti-mouse immunoglobulin (Amersham, Amersham U.K.) was applied at 1:200 for 30 min and streptavidin biotin complex/HRP (Dako, High Wycombe, U.K.) at 1:200 for 30min. Diamino- benzidine (Sigma D 5637) hydrogen peroxidase sub- strate was applied for 10 min. The sections were washed in running tap water and counterstained with Harris' haematoxylin, dehydrated, and cleared and mounted in DPX (Diachem). In view of the heterogeneity of the tissues being studied and the irregular distribution of accessory cells, no formal attempt at quantitation was made, other than to categorize the number of cells as absent, scanty, moderate, or abundant. Sections were examined by two of the authors (PS and DHW) and there was good inter-observer agreement.

Fig. 4-HLA class 11 (WR18) staining of gastric mucosal lymphoid cells, with selective up-regulation in the deeper parts of the gastric glands with sparing of the surface epithelium

RESULTS

Helicobacter pylori-like organisms were detected in all the cases of lymphoma and of gastritis but in none of the control cases. Although there was an overlap in the pattern of reactivity of the different antibodies employed, each helped to identify separate accessory cell populations. Both CD68 (PG-MI) and Factor XIIIa stained small numbers of cells with dendritic mor- phology in the controls. The sub-population staining with CD68 was largely superficial (Fig. 2), whilst Factor XIIIa-positive dendritic cells were also identified in the deeper part of the lamina propria and the muscularis propria (Fig. 3) . Both populations were more numerous in the gastritis cases, although there was a patchy distribution which correlated with the alterations in intensity of local inflammation. Factor XIIIa-positive cells were almost totally absent from areas of acquired lymphoid tissue and lymphoma.

WR18 (HLA class 11, DR, DP, DQ) identified oc- casional dendritic cells in the controls but there was only minimal staining of gastric epithelium. Stomachs showing gastritis contained numerous positively stained dendritic cells, especially in the more inflamed areas. In contrast to the controls, HLA class I1 was up-regulated on the gastric epithelium in the gastritis cases (Fig. 4).


Fig. 5-S100 protein-positive dendritic cells concentrated in the dome areas above the germinal centres in close proximity to the gastric glands macrophages

Fig. bACPI-positive dendritic cells in the dome area. Positive staining of the follicular dendritic reticulum cells and tingible body

There was a gradual decrease in intensity of staining from the isthmic to the surface epithelium, which expressed little HLA, despite close proximity to abundant inflammatory cells in the superficial lamina propria. Areas of intestinal metaplasia also showed only weak HLA expression. Elsewhere, expression of HLA class I1 on the epithelium, particularly in the deeper parts of the lamina propria, correlated with the intensity of local inflammation.

Dendritic cells staining for SlOO protein were localized above the germinal centres in close contact with the epithelium (Fig. 5). Dendritic processes from these cells were frequently interposed between the epithelial cells and appeared to reach the gastric lumen. A second population of dendritic cells staining with ACPI occupied the area between crypt epithelium and germinal centres (Fig. 6). There was thus a continuous network of dendritic cells with distinctive phenotypic characteristics between the gastric lumen and the germinal centres, ACPI stained a complete follicle dendritic cell network within the germinal centres but mantle areas were negative. Tingible body macrophages also expressed ACPI. Expression of SlOO protein and ACPI was not seen in the control stomachs. Each of the FDC markers showed overlapping but distinctive patterns of reactivity. CD55 (DAF) had a pattern of reactivity identical to that of ACPI within

the follicular dendritic cell network, but did not stain dendritic cells outside the germinal centre (Fig. 7). Epithelium also stained strongly for CD55, particularly in the most inflamed areas, while ACPI showed only focal weak epithelial positivity. CD21 (lF8) positivity was restricted exclusively to the germinal centre and mantle FDC networks (Fig. 8) ACPI-positive dendritic cells were especially numerouh around the more blastic germinal centres. CD 106 (VCAM 1) similarly stained germinal centre and mantle FDCs and also identified a sub-population of weakly staining dendritic cells outside the germinal centres (Fig. 9). CD23 (BU38) stained centrocyte-rich areas of the FDC network within germinal centres (Fig. lo). Smaller germinal centres showed complete and compact positive networks staining with this antibody, but this DRC population was more dispersed in germinal centres with a prominent blast population.

ACPI and SlOO protein-positive dendritic cells were abundant in areas of mucosal lymphoma, with a similar distribution to that seen in reactive lymphoid tissue (Fig. 11). The SlOO protein-positive cells maintained their epitheliotropism (Fig. 12). Staining with each of the FDC markers revealed colonized germinal centres within the tumour areas. CD106 also showed an abun- dance of dendritic cells immediately circumferential to the germinal centres within areas of tumour.

22 P. SARSFIELD ET At,.

Fig. 7-CD55 (BRlC 128) staining of dendritic reticulum cell networks in the germinal centre only. There is also evidence of up-regulation on the gastric epithelium (top left)

DISCUSSION

The use of antibodies active in paraffin-embedded tissue has allowed detailed analysis of accessory cell populations in chronic follicular gastritis. A diagram- matic illustration of these cells is shown in Fig. 13. An elaborate network of accessory cells is apparent inside and outside germinal centres both in acquired lymphoid tissue and in areas of mucosal lymphoma. SlOO protein- and ACPI-positive dendritic cells were largely restricted to presumed sites of antigen challenge, immediately above and around germinal centres. Factor XIIla- positive dendritic cells were abundant throughout the lamina propria, while CD68-positive cells had a more superficial distribution. CD21 and CD106 both stained germinal centre and mantle FDC networks, while ACPI and CD55 demonstrated a more restricted pattern of staining. Centrocyte-rich germinal centres contained complete CD23-positive FDC networks, which were absent from centroblast-rich areas of more active germinal centres. HLA class I1 showed a distinctive zonation in expression which was largely centred on the deeper part of the niucosa.

The host response to H. pylori contains, rather than eliminates, the organism and the beneficial and deleteri- ous components of the inflammatory process cannot be clearly distinguished.6 The principal arm of the response

Fig. 8-CD21 (1F8) staining of both germinal centre and mantle dendritic reticulum cell networks

is effected by germinal centre B-cells, but there is also neutrophil and inacrophage recruitment in response to infection with H. p . y l o ~ i . ~ ~ - ~ ~ In addition, H. pylori derived lipopolysaccharide can augment the inflammatory response to the organism through induction of c y t o k i n e ~ . ~ ~ These observations suggest that macrophage recruitment has a role in the immune response to H. p y 1 0 r i . ~ ~ Our study shows that phenotypically distinct sub-populations of accessory cells are a significant com- ponent of cellular response to H. pylori. The pattern of distribution of these accessory cell populations closely resembles the patterns which we have already established for normal lymphoid tissue in the gastrointestinal tract.” S100 protein- and ACPI-positive populations, in particular, are localized in areas of presumed intense antigen challenge and transfer and these dendritic cells are in a position to facilitate the delivery of antigens to the adjacent germinal centres. l2

Although the number of cases studied which included areas of mucosal lymphoma is small, it was noted that these tumours also contained significant populations of S100 protein- and ACPT-positive dendritic cells, with a distribution similar to those seen in normal intestinal and acquired gastric lymphoid tissue. It has been suggested that low-grade mucosal lymphomas of the stomach are antigen-driven by H. pylori. 3,25 It is possible that the specialized sub-populations of accessory cells identified within the tumours may have a role


Fig. 9-Positive staining of both germinal centre and mantle dendritic reticulum cell networks with antibody to V-CAM1

in sustaining the antigen delivery to the neoplastic lymphoid cells.

Our study represents the first detailed analysis of the organization of FDC networks in acquired lymphoid tissue in the gastrointestinal tract, although they have been previously described in low-grade MALT lymphomas.26 These networks have a critical role in capturing immune complexes and through delivery of antigen and interaction with germinal centre B-lymph~cytes ,~~ they permit a sustained and specific synthesis of immuno- globulins directed against H. pylori. The antibodies employed identified distinctive but overlapping patterns of reactivity within the DRC networks.

Decay accelerating factor (DAF) is a C3, C5 convertase inhibitor, previously reported as being largely restricted to dendritic cells in centrocyte-rich areas and postulated to have a role in protecting DRC networks from complement-mediated damage.28 There is up-regulation of CD55 on inflamed gastric epithelium and this may serve to protect the mucosa, particularly in view of the capacity of H. pylori to activate complement directly.29 In our study, both ACPI and CD55 showed similar patterns of reactivity, staining the complete germinal centre DRC networks. Although the precise role of ACPI has not yet been established, it may also have a function in protecting DRC networks from complement-mediated damage.30 CD23 identifies a protein with functions which include the promotion of

Fig. 1 C C D 2 3 (BU38) identifies the follicular dendritic network only in the centrocyte-rich areas of a reactive germinal centre

Fig. 1 I-Low-grade gastric MALT lymphoma stained with antibody to ACPI. Colonized germinal centres show numerous stained dendritic cells above and lateral to them

germinal centre cell survival3' and is normally expressed on DRC networks, mainly restricted to the centrocyte- rich zone of the germinal centre.l8>l9 Our study shows that the smallest centrocyte-rich quiescent germinal centres contain complete CD23-positive DRC networks. It is possible that the anti-apoptotic effect of CD23 is important in sustaining these less active germinal centres. This protective role is superceded in response to a new antigen challenge with blast cell proliferation and

24 P. SARSFIELD ET AL.

Fig. 12-Low-grade gastric MALT lymphoma showing SlOO protein- positive dendritic cells in and around gastric glands. Epithelial cells involved in lymphoepithelial lesions also show positive staining for SlOO protein

consequent dispersal of the CD23 network, which is ultimately restricted to the light zone of centrocyte-rich areas only. CD106 and CD21 both showed similar patterns of reactivity in the lymphoid tissue, staining both the mantle and the germinal centre DRC networks completely. CD106 functions as a germinal centre adhesion molecule and has a role in antibody affinity selection.21 CD21 appears to have a role in inhibiting apoptosis in germinal centre cells.’* DRC networks present within the low-grade MALT lymphomas may

Gastric Accessory Cells

also exert tropic effects on the adjacent neoplastic B-cells.

The pattern of zonation of HLA class I1 expression on the gastric mucosal epithelium, with preferential staining of the isthmic areas and sparing of the surface epithelium, is of interest. Expression of HLA class I1 has previously been reported to be mainly ~ r y p t a l , ~ ~ isthmic and f ~ v e o l a r , ~ ~ or generali~ed.~~.’~ The differing antibodies employed to detect HLA class I1 and variations in the severity of the gastritis may explain these discrep- ancies. Expression of HLA class I1 on epithelium is strongly influenced by ~ y t o k i n e s . ~ ~ It is therefore para- doxical that in the gastric mucosa there is almost no expression on the surface epithelium, despite the abun- dance of mononuclear cells immediately deep to it. It may be that upward migration of maturing epithelial cells from the isthmic proliferating area is associated with diminished sensitivity to cytokine induction of HLA class 11 expression. The diminished expression of HLA class I1 in areas of intestinal metaplasia has been previously reported.32

It is apparent that there is compartmentalization of the different accessory cell populations in and around acquired lymphoid tissue in the stomach. The populations may have a potential role in the delivery of antigens to the germinal centres. FDCs present in the tissue show overlapping but distinctive patterns of network staining within the acquired lymphoid tissue. The extent of CD23 staining alters in response to the activity of the germinal centres. Although the numbers examined

s100

X ACPI A PG-MI

0 FACTOR Xllla

A A A A

0 A O A A A A A

0

0 0 ACPI+

BRlC 128+ BU 3 8 +

x 0

A

0 0

x 0

GASTRIC GLANDS

A

GERMINAL CENTRE

Fig. 13-Schematic diagram showing the distributions of accessory cells in and around acquired reactive lymphoid tissue in the stomach in helicobacter gastritis


are small, the observation that similar networks of accessory cells also occur within the mucosal lymphomas suggests a potential role for these cells in sustaining these tumours.

ACKNOWLEDGEMENTS

We wish to thank the Wessex Medical Trust for a grant which supported this work; Professor A. Rinne for the gift of the antibody to acid cysteine proteinase inhibitor (ACPI); Mrs P. Johnson for invaluable tech- nical assistance; and Miss J. Foster for typing the manuscript.

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a study of accessory cells in the acquired lymphoid tissue of helicobacter gastritis

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