Gut 1993; 34:1452-1457

Expression ofmajor histocompatibility antigens in

human chronic pancreatitis

R P Jalleh, J A Gilbertson, R C N Williamson, S D Slater, C S Foster

Departments of SurgeryR P JallehR C N Williamson

and Histopathology,Royal PostgraduateMedical School,Hammersmith Hospital,LondonJ A GilbertsonS D SlaterC S FosterCorrespondence to:Dr C S Foster, Departmentof Histopathology, RoyalPostgraduate Medical School,Hammersmith Hospital,London W12 ONN.Accepted for publication9 February 1993

AbstractT-lymphocytic infiltration of the exocrine pan-creas and liver in patients with chronic pan-creatitis has suggested that cell mediatedimmune mechanisms may play a part in thepathogenesis of this disease. As expression ofmajor histocompatibility (MHC) antigens is aprerequisite for organ specific autoimmunity,the expression of HLA class I (P2-micro-globulin) and class II (HLA-DR) determinantshave been analysed, together with the pres-ence of T-lymphocytes, in 93 patients (64 menand 29 women, mean age 40-6 years) having anoperation for chronic pancreatitis. Ethanol (63patients), recurrent acute pancreatitis (12),congenital lesions (2), and unknown (16) weresuggested to be the causes of the disease.Immunohistochemical staining of formalinfixed and paraffin wax embedded tissue sec-tions used conventional immunohistochemicaltechniques with specific anti-serum samples.NoMHC expression was identified in 10 histo-logically normal pancreatic control specimensor in four cases of chronic pancreatitis second-ary to obstruction by neuroendocrine tumourswithin the head of the pancreas. 32-micro-globulin expression by pancreatic exocrineepithelial cells was seen in 76 chronicpancreatitis specimens (82%) while HLA-DRwas present in 61 (66%). Simultaneous expres-sion of both class I and II determinants wasseen in 53 (57%) of cases. MHC determinantexpression was not found in 10 cases (11%) ofchronic pancreatitis. In the positive speci-mens, expression was confined to ductal andductular (interlobular and intralobular)epithelium with no staining of acinar cells.Staining was not related to the suspected causeof the disease or age. T-lymphocytes weremore prominent in chronic pancreatitis mean(SEM) (131 (15) cells per high powered field)than controls (5 (1), p<0.01). Aberrant MHCexpression by exocrine pancreatic ephithelialcells occurring in the presence of anappreciable T-cell infiltration confirmedthat the appropriate cellular conditions werepresent for cell mediated cytotoxicity to con-tribute to the pathogenesis of chronic pan-creatitis.(Gut 1993; 34: 1452-1457)

Chronic pancreatitis is a progressive inflam-matory disease characterised by intractable pain,irreversible morphological change, and loss ofpancreatic exocrine and endocrine function. 'The radical operations that may be required tocontrol pain often exacerbate both exocrine andendocrine loss. While alcohol is the most fre-quently implicated cause, non-alcohol associated

(idiopathic) cases account for between nine and41 per cent of all chronic pancreatitis, the preciseincidence depending upon the populationstudied.2 Rarer causes include hypercalcaemia,hyperlipidemia, hereditary factors and, intropical countries, protein and fat malnutrition.3In individual patients, however, the precisecause and pathogenesis often remain unknown.4In this report, we explore the possible role ofautoimmune mechanisms in the cause andpathogenesis of chronic pancreatitis.

In alcoholic chronic pancreatitis, changes inpancreatic juice may lead to precipitates ofprotein and calcium, which obstruct the ducts,causing ulceration, fibrosis, and subsequentatrophy of exocrine pancreatic epithelium distalto the obstruction.5 6 This hypothesis has evolvedafter the examination of 'end stage' chronicpancreatitis in which calcium deposition iscommon,7 8 but does not identify the events thatstart the damage nor does it explain the develop-ment of the disease in non-alcoholics. Moreover,many non-alcoholics do not develop chronicpancreatitis. Chronic pancreatitis clearly com-prises more than one cause, and Sarles hasemphasised the morphological distinctionbetween the chronic calcifying form and'primary inflammatory pancreatitis.'9 Kloppeland Maillet discovered protein plugs and calci-fication only infrequently in early chronic pan-creatitis, suggesting that these are unlikely to becausal factors but rather epiphenomena occur-ring during progression of the disease.'0

Previous studies of liver biopsy specimens inpatients with severe chronic pancreatitis suggestthat immunological mechanisms could play apart in its pathogenesis." 12 Even when alcoholwas the suspected cause, hepatic parenchymaldamage was minimal compared with the severityof pancreatic disease, showing that alcohol maynot be the sole injurious factor. T-lymphocyteinfiltration in the absence of hepatocyte damagewould be consistent with the transit of inflam-matory cells originating within the inflamedpancreas. Autoantibodies reactive with pan-creatic acinar cells and ductal antigens have beendescribed in patients with chronic pancreati-tis,'3 14 as have activated lymphocytes specificallysensitised to crude pancreatic antigens,"' sup-porting the participation of autoimmune mech-anisms in some types of chronic pancreatitis. 16 17During the development of organ specific

autoimmunity, initial events entail aberrantexpression of major histocompatibility complex(MHC) molecules by cells that do not expresssuch determinants. '8 Class I antigens areexpressed by most nucleated somatic cells butnot by exocrine pancreatic cells. 9 Normal acinarand ductal pancreatic epithelial cells do notexpress MHC class II determinants either,20 but

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Expression ofmajor histocompatibility antigens in human chronic pancreatitis

some expression has been reported in two smallseries of patients with chronic or 'obstructive'pancreatitis.2`22 Possible autoimmune recogni-tion of pancreatic epithelial cells occurring earlyin some types of chronic pancreatitis does notexclude alcohol from being an important cause oroppose the hypothesis that proteinaceous andcalcific deposits contribute to the general patho-genesis of the disease. Confirmation of auto-immune mechanisms, however, might helpdefine a population of patients who could benefitfrom non-surgical management of chronic pan-creatitis.

Patients and methods

PATIENTSPancreatic specimens were reviewed from apersonal series (RCNW) of 102 patients havingan operation for chronic pancreatitis from 1977to 1990 at Bristol Royal Infirmary or theHammersmith Hospital, London. Of these,biopsy samples from nine patients were con-sidered either not to contain sufficient materialto permit an accurate histological diagnosis orsufficient epithelial elements to assess immuno-staining adequately. These sections were ex-cluded from this study. The 93 patients nowreported comprised 64 men and 29 women with amean age of 40-6 years (range 20-72 years). Themain cause of the disease was ethanol (63patients). Causes in the other 28 patients in-cluded previous acute pancreatitis in 12, chole-dochal cyst in one and pancreas divisum inanother. No cause was identified in the remain-ing 16 patients.

CHRONIC PANCREATITIS SPECIMENSWherever possible, pancreatic resection speci-mens were received fresh and dissected in astandard manner before fixation. Blocks of tissuefor examination were taken transversely across

t~~~~~~ ~ ~ ~~~~~~~~.w.....

Figure 1: Section ofhuman pancreasfrom a region containing early morphological changes ofchronic pancreatitis. Intralobular ductules selectively expressMHC class I determinants.(P32-microglobulin). Original magnification X 750.

the pancreas through cellular regions inter-mediate between the resection margins and themacroscopically most fibrous and scarred partsof the specimens. These blocks were thenbisected vertically to allow examination of theparenchyma both in the regions surrounding thecentral ducts and at the periphery of the tissue.Blocks taken from densely fibrotic or heavilycalcified regions of the specimens were avoided.

CONTROL PANCREATIC SPECIMENSTen morphologically normal pancreatic speci-mens and four specimens of chronic pancreatitissecondary to obstruction by neuroendocrinetumours within the head of the pancreas wereused as control tissues. The normal tissues wereobtained from patients undergoing distal pan-creatic resections for small non-obstructingpancreatic neuroendocrine tumours, patientswith suspected chronic pancreatitis but normalpancreatic histology, or where the distal pan-creas was excised whole in a radical canceroperation. The tissue blocks were taken trans-versely across the pancreatic specimens throughthe regions immediately adjacent to, but at0 5 cm from, resection margins.

IMMUNOHISTOCHEMISTRYClass I MHC expression was determined byidentification of 132-microglobulin, the non-poly-morphic light chain component ofhuman class Iantigens, using polyclonal rabbit antibody(Dako Ltd, High Wycombe, UK) diluted to1:1000 in 120 mmol/l sodium phosphatebuffered saline (PBS, pH 7.4). Monoclonalmouse anti-human HLA-DR (Dako Ltd), whichreacts with the 13-chain of all products of theHLA gene subregions DP, DQ, and DR, wasdiluted to 1:150 in PBS to identify class II MHCexpression. Monoclonal antibody UCHL1 (anti-human T cell) was obtained as a gift from DrPeter Beverley, University College Hospital,London and used at a 1:10 dilution. Humantonsillar tissue was used as the positive controlfor the three antibodies used.Formalin fixed and paraffin wax embedded

tissue sections (2 [tm thickness) were dewaxed inTCF 30 (Infrakem Ltd, Wigan, UK), brought towater through graded ethanols and digested withtrypsin (0. 1% wt/vol in aqueous 0-1% CaCl2 forfive minutes at 37°C). Endogenous peroxidasewas blocked with 0 3% hydrogen peroxide(H202 in distilled water for 30 minutes at roomtemperature). A peroxidase anti-peroxidasetechnique was used to detect bound P2-micro-globulin. HLA-DR staining was performed bythe avidin-biotin-peroxidase complex methodusing the Vectastain ABC kit (Vector Labora-tories, Burlingame, USA).23 A conventionalindirect immunoperoxidase technique was usedfor detection of bound HCHL1. In all cases,sections were incubated with primary antibodiesovernight at 4°C. The resultant immuneperoxidase complexes were developed in 0.5%(vol/vol) 3,3'-diaminobenzidine hydrochloride(DAB, Aldrich, Gillingham, Dorset, UK) inPBS containing 0.03% (vol/vol) H202. Sectionswere counterstained with haematoxylin and

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14alleh, Gilbertson, Williamson, Slater, Foster

TABLE II MHC expression according to age group

Age group r2m HLA-DR(y) No positive* positive

<40 39 3 1 2540-55 44 37 29>55 10 8 7Total 93 76 61

*p>0 5 v no in each age group of population studied.

?, ,.... .i..Zs ...... ,,' *,-

ti

Figure 2: Section ofhuman pancreas containing an interlobular duct with adjacentchronic inflammatory infiltrate. There isfocal and selective expression ofclass IIMCHdeterminants (HLA-DR) by ductal epithelial cells and adjacent lymphocytes. Originalmagnification x600.

mounted in Pertex (Histolab, Hemel Hemp-stead, UK). Expression of P2-microglobulin andHLA-DR were assessed as either being positiveor negative in the epithelial elements (acinar,ductular, or ductal), mononuclear cells, andislets. Lymphocyte morphometry was per-formed using a lOx 10 mm graticule within themicroscope ocular at x400 magnification. Foreach specimen, the number of T-lymphocytesper high power field (hpf) in three areas ofmaximal infiltration was counted and a meanvalue calculated.

STATISTICSStatistical analyses were performed using X2 andunpaired Student's t tests.

Results

HISTOPATHOLOGICAL ASSESSMENTTissues from the 93 patients included in thisstudy contained the characteristic features ofchronic pancreatitis. In all cases, the disease wasfocal in distribution. Lobulo-acinar destructionwas severe in some foci while many adjacentlobules were morphologically unaffected. Isletsof Langerhans seemed to be spared during thisprocess and were prominent, particularly inthose regions where exocrine epithelial structureshad been destroyed. Tissue sections were chosento show the early rather than later stages of

TABLE I Comparison ofmajor histocompatibility antigen expression and causes ofchronicpancreatitts (n= 93)

Previous acuteEthanol pancreatitis Congenital IdiopathicNo % No % No % No % Total

No of patients 63 12 2 16 93[32-microglobulin positive 50 (79)* 10 (83)* 1 (50)* 15 (94)** 76 (82)HLA-DR positive 29 (61)* 6 (50)* 2 (100)t 14 (88)t 61(66)

Statistical analysis; *p>0.5 v total, **p>0. 1 v total, tno analysis, :tO 10>p>005 v total.

chronic pancreatitis. In these, neither proteinplugging of major ducts nor calcification ofminute ducts were identified in the specimensincluded in this study. Sections of endstagechronic pancreatitis comprising only a fewresidual epithelial elements together with nervesand vascular structures in dense fibrous connec-tive tissue, together with focal calcification, wereavoided in the assessment of MHC expression.

CONTROL IMMUNOHISTOCHEMICAL STUDIESNo class I or class II MHC expression byexocrine epithelial cells of any of the 10 normalcontrol specimens, or by the four cases ofobstructive chronic pancreatitis, was identified.Only a few scattered foci of T-lymphocytes wereseen in the interlobular stroma of these speci-mens.

CLASS I MHC (,32-MICROGLOBULIN) EXPRESSIONOf the 93 cases of chronic pancreatitis studied,class I MHC expression was seen in the epithelialelements of 76 (82%) specimens. Expression wasfocal and varied. Positive staining was confinedto intralobular and interlobular ductules (Fig 1)and interlobular ducts; there was no stainingidentified in acinar cells. In 27 biopsies; thisexpression affected both ductular and ductalepithelium, while in another 44 cases ,32-micro-globulin staining was limited to either ductules(28 specimens) or ducts (16 specimens). Thispattern of distribution was not assessed in theremaining five biopsies because of the absence ofeither of these structures. We could not identifya predominance of either a ductular or ductalpattern of 32-microglobulin expression in thisseries (x2= 3*01, 0 10>p>0.05).

Class I MHC expression was not related to thesites of maximal lymphocytic infiltration,although concurrent P2-microglobulin expres-sion by epithelial cells and adjacent lymphocyteswas identified in 10 specimens. In 79 cases(85%), mononuclear cells expressing 12-micro-globulin were present, contrasting with only twocases (20%) among controls (p<0i001). In allspecimens, both of controls and chronic pan-creatitis, islet cells exhibited positive staining forP2-microglobulin. This provided a convenientinternal positive control within each tissue sectionfor this antibody.

Analysis of the data for alcohol intake showed50 of 63 patients (79%) with a possible alcoholiccause of the disease to express 132-microglobulinwhile in the non-alcohol group, 26 of 30 patientswith chronic pancreatitis (87%) expressed thisdeterminant. The differences between the groupswere not significant (p>05).

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Expression ofmajor histocompatibility antigens in human chronic pancreatitis

CLASS II MHC (HLA-DR) EXPRESSIONHLA-DR expression was identified in 61 (66%)specimens. This followed a similar pattern ofdistribution to ,2-microglobulin. No expressionwas seen in any acinar cell, positive stainingbeing confined to ductular and ductalepithelium. In 40 cases, HLA-DR was identifiedin both these structures while expression wasrestricted to ductules in 12 cases and to ducts inseven cases. Absence of either structure pre-cluded analysis of distribution in the remainingtwo cases. There was also no relation betweenareas of HLA-DR expression and foci oflymphocyte infiltration. Concurrent staining ofboth epithelial elements and adjacent lympho-cytes was seen in eight biopsy specimens (Fig 2).Mononuclear cells expressed HLA-DR in 88(95%) cases compared with five (50%) in controls(p<0 001). In five cases, a population of

A-.

a,,.

*,' d

1M~~~~~~~~~~~~1

Figure 3: Different patterns of T-lymphocyte distribution identified in chronicpancreatitis by immunostaining with UCHL 1. Original magnification x 125. (A)focalperiductal infiltration. The adjacent acinar structures do not contain an inflammatoryinfiltrate; (B) perilobular infiltrate. T-cells are loosely scattered around individuallobules although few inflammatory cells are present within acini; (C)focal lymphoidaggregate. These structures are identified, not infrequently, in late stage chronicpancreatitis; (D) diffuse inflammation. Sheets ofmixed chronic inflammatory cellseffacing the underlying pancreatic architecture.

islet epithelial cells and adjacent intra-isletendothelial cells were HLA-DR positive. Inthese tissues, however, not all the islets con-tained positive cells.

Analysis of the data for alcohol intake showed29 of 63 patients (61%) with a possible alcoholiccause of the disease to express class II MHCdeterminants while in the non-alcohol group, 22of 30 patients with chronic pancreatitis (73%) ex-pressed this determinant. The differences weremarginally significant (005>p>002).

COMBINATION OF CLASS I AND II DETERMINANTSSimultaneous expression of both class I and IIMHC determinants was seen in 53 (57%) cases.Twenty two specimens showed only 02-micro-globulin staining while eight cases were onlyHLA-DR positive. There was no relationbetween either j32-microglobulin or HLA-DRexpression and the underlying cause (Table I).MHC expression was also not age related (TableII).

CHARACTERISATION OF T-LYMPHOCYTEST-lymphocytes were identified in all tissuesections studied. These cells were more pro-minent in chronic pancreatitis specimens, how-ever, with an estimated density mean (SEM) of131 (15) cells per hpf compared with controls (5(1), p<001). The density oflymphocyte infiltra-tion varied among specimens. A wide variety ofmorphological patterns of T-lymphocyte distri-bution was identified (Fig 3). The proportion ofT-lymphocytes to total mononuclear cells perhpf ranged from 19% to 78%. No direct correla-tion was seen between T-lymphocyte densities in38 pancreatic specimens and the periportalregions of corresponding liver biopsy specimenstaken at the same operation."

DiscussionAbnormal expression of class I or class II MHCdeterminants, or both by exocrine epithelial cellshas been found in 89% of cases of chronicpancreatitis. In addition, all cases of chronicpancreatitis contained significantly increasednumbers of T-lymphocytes compared with con-trols. Although no 032-microglobulin expressionwas identified in control exocrine tissues despitepositive staining of islet cells, 63% of chronicpancreatitis specimens showed positive inter-lobular and intralobular ductular staining, notpreviously described.'920 Class I determinantsare present on all nucleated cells,24 their expres-sion is variable,25 but a detailed analysis of thesedeterminants failed to detect class I HLA-ABCheavy chain antigens in the exocrine pancreas.`Thus, expression of 02-microglobulin in chronicpancreatitis was abnormal and sufficientlyenhanced to suggest a state of hyperexpressionanalogous to that proposed for type I insulindependent diabetes mellitus.26

In agreement with earlier reports,'9-21 thisstudy found that normal pancreatic epithelialcells did not express HLA-DR antigens, yet suchexpression was seen in two thirds of the chronicpancreatitis specimens. There was simultaneous

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expression of class I and II antigens in 53specimens (57%), while HLA-DR expressionalone was rare (9%). We also found a substantialincrease in MHC expression by mononuclearcells in chronic pancreatitis specimens and suchexpression by T-lymphocytes is necessary for theantigen recognition process.27 Confirmation thatthese modules are expressed at readily detectablevalues by pancreatic exocrine ductular epithelialcells, in association with a considerableT-lymphocyte infiltration, establishes thepresence ofknown cellular components requiredfor the start of an autoimmune reaction in a

large proportion of patients with chronic pan-creatitis.

Participation of immune mechanisms in thecause and pathogenesis of chronic pancreatitishas been suspected as increased serum concen-

trations of immunoglobulins (IgA, IgM) andchanges in concentrations of circulatingT-lymphocytes were reported in 1974.28 Later,Nerenberg et al detected raised values of acirculating antibody monospecific for a pan-

creatic acinar antigen.29 Initial events duringdevelopment of organ specific autoimmunityentail aberrant expression of MHC class IIantigens,'8 thus allowing presentation of cellspecific antigens to potentially autoreactive T-lymphocytes. These cells recognise protein frag-ments and synthetic peptides in association withclass I and II molecules. Antigens synthesisedendogenously by target cells preferentially yieldcomplexes with class I molecules. By contrast,antigens acquired exogenously and taken intotarget cells by endocytosis preferentially yieldclass II complexes.0 While class I antigensparticipate in antigenic presentation to cytotoxicT-lymphocytes, class II MHC is necessary forsimilar presentation to helper T-cells. De novo

expression of class II MHC (HLA-DR) has beenshown in diseases such as primary biliarycirrhosis3' and type I insulin dependent diabetesmellitus,26 conditions now considered to beimmune mediated.Our data add to the current understanding of

the cause and pathogenesis of chronic pan-creatitis. Sarles et al suggested that in the earlieststages, before any cellular damage is detected,there is luminal precipitation ofcalcium salts anda special pancreatic stone protein.3 Themolecular basis for this process is unknown butcould include direct ethanolic toxicity,32 cellularadaptation to ethanol,3 or cytotoxic damage tothe cell membrane.33 Each mechanism implieschange at a cellular level before the lithogenicprocess. In a recent histopathological and im-munohistochemical study, Suda et al concludedthat protein plug obstruction of the ductalsystem is not the main cause in the genesis ofethanolic pancreatitis,34 and our morphologicalfindings support this conclusion. Any dis-crepancies between these findings and thosepreviously reported could reflect a spectrum ofdifferent causal factors or studies conducted atdifferent stages in disease progression. In our

series, absence of calcification from tissues con-

taining early changes of chronic pancreatitisagrees with the recent findings of Kloppel andMaillet.'0

We have not yet defined the characteristics of

those patients who showed abnormal pancreaticexpression of MHC antigens, nor have we yetascertained whether expression is restricted to aspecific subpopulation of patients. There was norelation between abnormal MCH expression andeither age or the currently accepted causes of thedisease, and our findings do not support a cleardifferentiation between ethanolic and non-ethanolic pancreatitis.35 Indeed, the classifica-tion of chronic pancreatitis based on the causesand morphological patterns may have to bereviewed in the light of the present and furtherimmunological studies. Our findings suggestthat a cell mediated immune reaction representsone stage in a 'multistep' pathogenetic processand could act as a common pathway in differenttypes of chronic pancreatitis. In some cases ofchronic pancreatitis, different causes mightinduce abnormal MHC expression and allow anautoimmune reaction to develop. This processseems to begin in the ductal epithelium and theinterlobular and intralobular ductules. Alterna-tively, MHC expression is secondary to lympho-cyte infiltration and activity. While a andinterferons are produced by fibroblasts, the morepotent y interferon is a T-cell derived lympho-kine. All three classes of interferons can enhanceboth class I and II MHC expression,3637 and invitro studies have shown interferon induced classI expression in class I negative cell lines.38 Whatis less certain, however, is the ability of inter-feron to induce de novo synthesis ofMHC geneproducts that are not spontaneously expressed invivo." Whether aberrant MHC determinantexpression represents a primary epithelial orlymphocyte dysfunction, its presence implicatesa cell mediated cytotoxic reaction in the patho-genesis of chronic pancreatitis.

This study has identified the expression ofcellular components that may contribute to anautoimmune mechanism in the pathogenesis ofchronic pancreatitis. It is not suggested thatautoimmunity is either the primary or even themain cause in this disease. Elucidation of themechanisms by which primary injury is sus-tained by pancreatic exocrine epithelial cells willrequire a separate study specifically designed toanswer that question. 'Aberrant' expression ofMHC determinants by epithelial cells requirescautious interpretation,39 because it might justarise in the vicinity of an inflammatory focus.Similarly, spontaneous ('normal') expression ofHLA-DR antigens does not point to a predis-position to autoimmune disease.-I Nevertheless,we have not seen calcific obstruction of pan-creatic ducts early in the disease process. Expres-sion ofHLA class I and class II determinants byexocrine epithelial cells occurred in a regional,sublobular manner and its distribution was in-compatible with a purely obstructive cause.Furthermore, such expression was found onepithelial cells in morphologically normallobules without either a significant inflammatorycomponent or evidence of epithelial destruction.Additional studies are now required to elucidatethe nature and timing of this cell mediatedimmune reaction. If subsequently proved, itholds exciting treatment prospects for chang-ing the clinical management of this difficultdisease.

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Expression ofmajor histocompatibility antigens in human chronic pancreatitis 1457

We are grateful for the assistance of Professor J W B Bradfield,Department of Histopathology, University of Bristol, in permit-ting unreserved access to the archived specimens at the BristolRoyal Infirmary. Dr S D Slater acknowledges support of theBritish Digestive Foundation during these studies.

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