autoimmune gastritis: historical antecedents, outstanding discoveries, and unresolved problems

AUTOIMMUNE GASTRITIS: HISTORICAL ANTECEDENTS,OUTSTANDING DISCOVERIES, AND UNRESOLVEDPROBLEMS

SENGA WHITTINGHAM and IAN R. MACKAYDepartment of Biochemistry and Molecular Biology, Monash University,Clayton, Victoria, Australia

The earliest recorded history of autoimmune gastritis can be traced to 1849 in London, whenThomasAddison described ‘‘a very remarkable form of anemia’’ later called pernicious (fatal)anemia (PA). This was followed by the recognition of a gastric mucosal defect suspected tohave a nutritional basis, the discovery of the megaloblast that characterized the anemia,the insufficiency of a dietary extrinsic factor characterized as vitamin B12 (cobalamin), anda gastric-secreted intrinsic factor. Treatment with vitamin B12 proved curative. The linkbetween PA and gastritis and atrophywas first confirmed histologically after immediate fix-ation of the stomachpostmortemand later, in the 1940s, byperoral tubebiopsy.The causes ofgastritis remained enigmatic until the era of autoimmunity, when autoantibodies weredetected first to gastric intrinsic factor and then to gastric parietal cells. Hints of a dichotomyin pathogenesis of gastritis were crystallized by the description in 1973 of Type A (Auto-immune) andTypeB (later, Bacterial) gastritis. Clarificationwas enhanced by identificationin Type A gastritis of the autoantigen of the parietal cell antibody, by the a and b subunitsof gastric Hþ=Kþ ATPase, and by the highly informative experimental murine model ofpostneonatal thymectomyautoimmunegastritis, and inTypeBof thecausative roleof gastricinfectionwithHelicobacterpylori (H. pylori). A denouementwill require a full understandingof (1) the origin and pathogenetic contribution of antibody to intrinsic factor; (2) the connec-tion, if any, betweenH. pylori infection andTypeA autoimmune gastritis; and (3) the geneticcontributions to gastritis, whether due to autoimmunity or toH. pylori infection.

SOMETHING AMISS WITH THE BLOOD

The Clinical Recognition of Pernicious Anemia (PA)

A ‘‘very remarkable form of general anaemia’’ was described byThomas Addison of Guy’s Hospital in London at a South London

Address correspondence to Senga Whittingham, Department of Biochemistry andMolecular Biology, Monash University, Clayton, Victoria 3800, Australia. E-mail:[email protected]

Figure 2 in this article has previously been published in Clinical ExperimentImmunology, Volume 3, Number 4, pp. 359�366, 1968, authored by A. J. Wall, SengaWhittingham, and I. R. Mackay, and published by Blackwell Publishing, Oxford, UK.

International Reviews of Immunology, 24: 1�29, 2005

Copyright # Taylor & Francis Inc.

ISSN: 0883-0185 print/1563-5244 online

DOI: 10.1080=08830180590884413

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Medical Society meeting in 1849. Similar cases had been observed ear-lier but fell short of certain diagnosis [1,2]. Later, Anton Biermer ofZurich [3] reported what is taken to be a similar anemia as perniciosa,meaning ‘‘fatal’’. Then, other features including a sore tongue, numb-ness of the hands, and ataxia became associated with this anemia, firstas single case reports and then in larger series. Notably, the associ-ation of PA with spinal cord lesions affecting both dorsal and lateralcolumns led to the descriptive term sclerosis or, subacute combineddegeneration of the spinal cord [4]. Of the large series of 1200 casesof PA reported by Cabot [5], 40% had a sore tongue and 10% hadataxia. Interestingly, the early accounts of PA came almost exclusivelyfrom the English, European, and North American populations, indi-cating susceptibility of people of northern European origin to PA.Nowadays the advanced stages of PA are seldom if ever seen, butthe earlier prototype patient would have been a middle- to older-agedwoman of northern European extraction with pallor, mentaldepression, fatigue, a smooth sore tongue, loss of appetite and, in someinstances, peripheral numbness, muscle wasting, diminished tendonreflexes, perception of light touch and vibration, and spastic ataxia.

The Microscopic Blood Picture

The celebrated late-nineteenth-century scientist Paul Ehrlich [6]applied analine dyes, which had recently been introduced by his cou-sin Carl Weigert, to stain blood films from patients with PA, revealinglarge precursor erythroid cells which he called megaloblasts [6]. Suc-ceeding hematologists recognized the various features that charact-erized megaloblastic anemia, namely macrocytes, poikilocytes, andhypersegmented neutrophils [7] in the peripheral blood, and mega-loblasts, large metamyelocytes, and megakaryocytes with morpholo-gically abnormal nuclei in the bone marrow, indicating profounddisturbance in progenitor cells for blood formation.

Early Ideas on Treatment

The idea that PA resulted from dietary deficiency developed in theearly twentieth century, following discoveries on scurvy and beriberi.The term vitamin had been coined by Funk to designate dietary com-ponents deficient in scurvy and beriberi [8], so that term would befavored were such a component found to be deficient in PA. It wasWhipple, Minot, and Murphy who recognized that a dietary compo-nent was in fact involved, and their painstaking investigations wererewarded by a Noble Prize in 1934. Initially, Whipple, Hooper, and

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Robscheit [9] found that the liver optimally restored the level of hemo-globin in dogs made anemic by venesection, so leading to testing vari-ous diets on patients with PA, including the daily ingestion of up to240 g of lightly cooked bovine liver and 120 g of muscle, as well as eggs,vegetables, and milk for up to 2 years [10]. Inducing patients with PAto persist with monotonous, unpalatable diets despite a poor appetiteand a disinclination for eating meat required much persuasiveness,but in a group of 45 patients the diet was tolerated, and clinicalimprovement was accompanied by a tell-tale rise in peripheral bloodreticulocyte counts, indicative of regeneration of the bone marrow[11]. This led to the preparation of more palatable liver extracts fororal or parental administration, although the latter sometimesinduced an immunologic hypersensitivity which negated their effect.Isolation of the active component in liver was impeded because theonly bioassay was the slow ameliorating effect the component had inpatients with PA. Eventually such assessments were replaced bymicrobiological assays [12].

The Discovery of Vitamin B12

In 1948 Lester-Smith [13] and Rickes et al. [14] independently isolatedcrystals of a red material, which was named vitamin B12. It was acyanide with one cobalt atom, hence the name cyanocobalamin.The structure of crystalline vitamin B12 was shown by X-ray crys-tallography to consist of a single cobalt in a coordination state of sixpositions, four of which comprised a tetrapyrrole or corrin ring, onea benzimidazole nitrogen, and another several ligands [15], and forthis research Dorothy Hodgkin was awarded a Nobel Prize in 1964.The next advance was the use of cobalamin-producing bacteria toreplace liver as a source of vitamin B12 and then, after years of collab-oration between various research groups, the complete synthesis ofvitamin B12 was achieved [16]. It then became possible to clarify themetabolic pathways that were impaired as a result of its deficiency.Thus, it was established that a methyl derivative of vitamin B12 wasrequired to convert homocystine to methionine [17], and a 5-deoxyade-nosyl derivative was required for the methylmalonyl-CoA mutasereaction, that is, methylmalonyl CoA to succinyl CoA [18]. Also, knowl-edge on the cobalamin-binding proteins, transcobalamin I and II,revealed how cobalamin is transported from the terminal ileum viathe blood to the liver for long-term storage [19].

The availability of radioactive isotopes of cobalt by Rosenblum’sgroup [20] greatly facilitated diagnostic assays and investigativeresearch on PA. Such assays included the development by

Historical Aspects of Autoimmune Gastritis 3

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Schilling [21] of an ingenious bioassay based on oral administration ofradiolabelled vitamin B12 and measurement of its excretion in theurine. The Schilling test measured the efficiency or otherwise ofabsorption of vitamin B12 and thus the secretion and transport of itsbinding factor, intrinsic factor. Unfortunately, this informative bioas-say has now fallen into disuse. Other assays using isotopes to measurethe level of cobalamin in serum were developed by Ross [22].

The Factors

The success of treatment of PA with a mixture of beef muscle and gas-tric juice led investigators to experiment with digests of hog gastricmucosa. Castle and colleagues [23] first attempted this but failed,possibly because intrinsic factor was inactivated by autolysis duringthe prolonged digestion of the mucosa with pepsin, but others suc-ceeded with desiccated defatted preparations. Nevertheless, it wasCastle’s experiments that demonstrated there was an active factorin gastric juice [24�27]. Castle fed 300 g of cooked ground beefsteakto young healthy men and an hour later withdrew 200 g of the semidi-gested stomach contents, which he then delivered to the stomach of atest group of patients with PA. To a control group of non-PA patientshe gave 200 g of cooked ground beefsteak without gastric juice. A briskreticulocyte response occurred in the test group. Then he gave either300 ml of gastric juice obtained from healthy subjects after stimulationwith histamine or 200 g of beefsteak thoroughly digested with pepsinto patients with PA, and in neither group a reticulocyte responsewas induced. Finally, he mixed a pepsin-digested preparation of beef-steak with gastric juice and gave that to patients with PA. The reti-culocyte response induced was similar to that in the originaltest group. Thus the fault in PA was a deficiency of a gastric intrinsicfactor that was required to react with a dietary extrinsic factor togenerate an absorbable hemopoietic complex.

With variable success many investigators, using hog gastric juiceand various purification procedures, attempted to isolate gastricintrinsic factor [28,29]. Starch gel electrophoresis of human gastricjuice revealed two vitamin B12-binding proteins, one that migratedrapidly and hence was termed rapidly moving or R-binder and anotherthat had intrinsic factor activity [30]. Thus, in assays using vitaminB12 for quantitation of gastric intrinsic factor it was necessary to sub-tract the activity due to the R-binder-vitamin B12 complex from thetotal binding [31]. Later, in the era of molecular biology, human gas-tric intrinsic factor became available as a recombinant protein [32].Intrinsic factor was characterized as a glycoprotein with a molecular


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weight of 60 kD and was shown to be produced by the gastric parietalcells [33]. It serves as a transporter of vitamin B12 to the terminalileum, and there the complex binds to its high-affinity membranereceptor, cubilin, and is absorbed [34].

SOMETHING AMISS WITH THE STOMACH

Gastritis

Well before Addison’s description of PA, in Paris Broussais [35] estab-lished the belief that gastritis was a common malady. However, therewas ‘‘a reaction against the Broussaic period’’ [36], such that gastritisbecame virtually disregarded after the mid 1850s in the Europeanclinics, possibly in part due to difficulties with microscopic exami-nation of the autolyzed gastric mucosa postmortem. A link with PAwas drawn by Flint [37], who speculated that glandular atrophy ofthe stomach caused deficient gastric secretion and thereby impairedthe assimilation of food, with ensuing anemia. This was substantiatedby Fenwick [38], who at postmortem scraped the mucosa from the sto-mach of patients with and without PA, diffused the mucosa with waterand hydrochloric acid for 12 h, and then tested its capacity to digestegg white by incubating it with egg white for 9 h. The egg whiteremained unchanged by the PA mucosa but was digested by thecontrol mucosa. Achlorhydria was demonstrated in PA by Cohn andvon Mering [39], and this lack of acidity was soon widely confirmedby others. By 1880 attempts were made to fix the mucosa by immedi-ate injection of preservative postmortem. Faber favored injection of500 ml of formalin into the abdominal cavity, so providing ‘‘excellentfixation.’’ Subsequent observations led him to remark, ‘‘we frequentlyobserve serious diseases such as pernicious anemia, combined sclero-sis of the spinal cord and chronic ulcer develop on the basis of protrac-ted, apparently trivial diseases of the alimentary canal’’ [36]. Faber’slimited studies were supplemented by the availability of fresh gastricmaterial from partial gastrectomy widely used after the 1920s as atreatment for gastro-duodenal ulcers.

Bacteriological colonization and histological changes in surgicalsamples were extensively studied by Konjetzny [40] whose percep-tive observations, which were reported in the German literature andneglected by the Anglo-American readership [41], included the prem-ise that gastritis was the precursor of ulceration, instead of vice versa.Moreover he reported massive presence of bacteria in areas ofgastritis, particularly in the pits of atrophic gastric glands, and aremarkable degree of lymph follicle formation and lymphocytic


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infiltration in the gastric mucosa [41]. These observations underlaidthe subsequent micromorphological classification of gastritis as acute,chronic erosive, chronic follicular, and chronic atrophic gastritis [36]that were combined with classifications based on visual appearancesof the gastric mucosa subsequent to the development of the semiflex-ible gastroscope by Schindler [42].

Faber devoted a substantial part of his 1935 monograph to theassociation between gastritis and anacidity, commenting that ‘‘therehas long been something mysterious about the aetiology of chronicgastritis. . .its commencement often lies far back in the life of thepatient.’’ His proposed causes of gastritis included exogenous agentssuch as ingested irritants and endogenous agents including a widevariety of primarily extragastric infections [36], in contrast to the intra-gastric infection described by Konjetzny [40]. Furthermore, Fabernominated—probably erroneously—a category of hyposecretion with-out gastritis as an inborn error, a deduction derived from the propen-sity that Faber noted had been widely known since 1891 forAddisonian PA and gastric hyposecretion to run in families [36]. None-theless, Faber was fully aware of the association of histologicallyevident chronic gastritis and gastric hyposecretion in PA with or with-out spinal cord degeneration, and he recognized the significance ofCastle’s observations. However, following Meulengracht [43], Faberincorrectly identified the source of Castle’s antianemic (intrinsic)factor as the pyloric part of the stomach, based on the therapeuticantianemic effect of different parts of the pig stomach, promptinghim to state that ‘‘true pernicious anaemia must be regarded as adisease of the pyloric organ (antrum).’’ It appears that the source ofintrinsic factor in the pig stomach differs from that in the humanstomach. Notable among Faber’s many illustrated photomicrographsare examples of gastric histology in PA that range from a severeinflammatory gastritis with only moderate atrophy to atrophy withtotal loss of glandular elements [36], thus forecasting the possibilitythat PA can occur by a process that does not require the complete lossof the cellular source of intrinsic factor.

A substantial advance was made by the introduction in 1949 byWood and colleagues in Melbourne [44] of the flexible gastric biopsytube, which allowed for study of multiple samples of gastric mucosafrom living patients, correlation with other indices of gastric function,and repetitive studies over time [45]. Wood and colleagues accumu-lated extensive experience in gastric histopathology, with one of theirpublications recording experience of gastric biopsy on no less than1000 individuals [46]. A monograph by Wood and Taft [45] describesthe design of the original biopsy tube, clinical and functional


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correlations in acute and chronic gastritis, and features of gastric atro-phy. The photomicrographs shown in Figure 1 are tubal biopsy speci-mens illustrating the evolution of gastritis.

Wood and Taft [45] made several points in their monograph that areworthy of comment. First, the question was engaged whether PA couldbe diagnosed in the presence of normal acid secretion and a normalappearance of the gastric mucosa as was earlier believed, but no suchinstance was encountered. Second, there was confirmation of earlierobservations by Hurst [47] and Riley [48] that achlorhydria precededPA by several years; much later in history, the importance of acid inthe feedback loop of gastrin secretion would become evident from thehigh levels of serum gastrin detected in PA [49]. Third, their dis-cussions on the etiology of chronic atrophic gastritis merely reiteratedprevailing beliefs in causes such as aging, debilitating diseases, alco-holism, malnutrition, and gastric irritants, and such ideas remainedpopular [50] until evidence for autoimmunity became available.Fourth, there were ample illustrations in the monograph of denseinflammatory infiltrations in the mucosa in chronic atrophic gastritis,as the harbinger of the two major etiologies, autoimmunity andbacterial infection, that were then unsuspected but were soon to berevealed. Wood’s extensive biopsy material provided for the laterdistinction by Strickland and Mackay [51] of chronic gastritis intothe two major categories of A, Autoimmune, and B, later shown tobe Bacterial.

The ready availability of gastric biopsy material coincided with thediscovery of autoimmune responses to the gastric autoantigens, intrin-sic factor, and parietal cell cytoplasm, prompting correlation betweenhistological and serological abnormalities. It became evident thatwhile advanced atrophic gastritis or gastric atrophy aligned with PAand autoantibody responses, there were cases of asymptomatic, histo-logically evident chronic gastritis without PA and with or without apositive test for parietal cell antibody (PCA) to which the term simpleatrophic gastritis was applied [52]. A revised view in Melbourne wasthat chronic atrophic gastritis with a positive test for PCA, comprisingsome 60% of cases studied [53], aligned with the autoimmune cate-gory. Thus the term simple atrophic gastritis was reserved for theantibody-negative cases for which a pathogenic process was not at thattime discernible, and which seemed to be an antecedent to gastriculcer [54] (Figure 2) and gastric cancer [55]. These ideas were to predi-cate the Type A and Type B dichotomy.

The Type A=Type B classification was made from a perspective ofautoimmunity. Cases classifiable as Type B had no such marker butseemed to have greater predisposition to gastric ulceration and gastric


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cancer than cases of Type A. The Type A=Type B classification wasbiased towards a polarization of the two categories to emphasize thedistinctions. However, in 1975, Glass and Pitchumoni [56] modi-fied the classification to accommodate mixed forms of gastritis thatinvolved both the fundus and the antrum with or without the presenceof gastric PCA, respectively called Type ABþve and Type AB�ve gas-tritis [56]. The story came together when in 1984 in Perth, WesternAustralia, Marshall and Warren [57] again addressed the questionof infection as a cause of gastritis and fortuitously discovered themicrobiological conditions suitable for the growth of curved bacillipresent in tissue biopsied from patients with gastritis and peptic ulcer-ation. The curved bacillus was identified as the gram-negative spiralbacterium Campylobacter pylori, now termed Helicobacter pylori.Its pathogenicity was established by Marshall’s self-infection experi-ment [58], and numerous studies have since validated the causal roleof H. pylori in gastritis, not only in antral gastritis, gastroduodenalulceration, and gastric cancer, but also in the autoimmune-mediatedextension of gastritis from the antrum to the corpus, as discussed indetail by Bergman and colleagues in this issue.

The resurgence of interest in gastritis following the discovery ofHelicobacter pylori led to it being recognized as ‘‘a worldwide problemof enormous magnitude’’ [59]. Accordingly, experts from many fieldsconvened at the World Congress of Gastroenterology in Sydney,Australia in 1990 to develop a new classification published as theSydney System [59] in which autoimmune gastritis was endorsed asthe preferred term for Type A gastritis. This classification wasupdated in 1996 to include some special categories [60].

SOMETHING AMISS WITH THE IMMUNE SYSTEM

Autoantibodies to Gastric Intrinsic Factor

The idea that autoimmunity was implicated in PA arose from observa-tions in the late 1950s that the initial benefit of enhanced vitamin B12

absorption in patients who were fed hog intrinsic factor became atte-nuated [61�63]. This acquired resistance was investigated by givingpatients with PA a mixture of 50 mls of PA serum and 100 mg hogpyloric mucosa with a test dose of 60Co vitamin B12. There was noresponse to the vitamin B12 [64,65], and there was no response whenthe same experiment was performed using serum from rabbits thathad been immunized with intrinsic factor [66]. The inhibitory factorwas found to reside in the IgG fraction of PA serum which, bystarch gel electrophoresis, was shown to combine with and retard


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the electrophoretic mobility of the intrinsic factor—vitamin B12 com-plex [67]. Accordingly, the inhibitory factor was nominated as auto-antibody to gastric intrinsic factor and, following the development ofthe radioimmunoassay for their detection [31,68,69], these autoanti-bodies were demonstrated in serum, gastric juice, or both in 50�70%of patients with PA [70�72]. The incidence reached 82% in patientstested 10 years after diagnosis [73].

In serum, intrinsic factor antibodies were mainly IgG and to a lesserextent IgA, and in gastric juice there was a slight predominance of IgAover IgG [74]. Two epitopes were identified on the intrinsic factormolecule, one within the 251�265 amino acid sequence at the vitaminB12�binding site [75], and the other at the site of binding of intrinsicfactor to its receptor in the ileum. ‘‘Binding’’ antibodies to the formersite prevented vitamin B12 from binding to intrinsic factor, and‘‘blocking’’ antibodies to the latter site prevented absorption of thevitamin B12 complex in the ileum [76�78]. Thus, either type ofantibody could contribute to the malabsorption of vitamin B12. Sinceantibody is linked closely to overt PA or its preclinical state of deficitof vitamin B12 storage, it is surmised that such antibody in serum,or secreted into gastric juice, can make an important contribution tovitamin B12 deficiency in addition to the destruction of its cellularsource, the gastric parietal cell.

Autoantibodies to Gastric Parietal Cells (PCA)

The early 1960s was the period when complement-fixing antibodies tosaline extracts of human gastric mucosa were demonstrated in sera ofpatients with PA [79�80], and these antibodies were shown by Tayloret al. [81] to react specifically with the cytoplasm of gastric parietalcells by immunofluorescence (Figure 3). Immunofluorescence provedto be a simpler assay than complement fixation because rat or mousegastric mucosa could be conveniently used as a substrate and, sinceover 90% of patients with PA were found to be positive for PCA[73], the test became widely accepted for diagnosis. Two groups,Karlsson et al. [82] and Toh et al. [83,84] identified the autoantigen asHþ=Kþ -adenosine triphosphatase (ATP-ase), which is a hydrogen-transporting enzyme or proton pump present in gastric parietal cellcanaliculi responsible for the secretion of hydrogen ions into gastricjuice. The antigenic moiety of the molecule is the a and b subunits ofthe gastric Hþ=Kþ ATPase; the autoepitope of the b subunit has beenlocated in the luminal domain of the molecule, and the integrity of thesugar moiety is required for antibody binding [85].


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Serum PCA played a key role in the definition of Type A gastritis[51], its topography, and progression to atrophy. Type A gastritiswas shown to be associated with hypochlorhydria progressing to ach-lorhydria, impaired absorption of vitamin B12, and increased levelsof serum gastrin. The progress of destruction of the gastric mucosa(Figure 1b) was slow with the absorption of vitamin B12, remainingadequate for many years. Typically, gastric atrophy that marked theend stage was recognized macroscopically by gross thinning of the wallof the fundus and corpus, and microscopically by replacement of theparietal and zymogenic cells with mucous-secreting cells and a sparsecollection of mononuclear cells (Figure 1c).

Autoantibodies to Autoimmune Diseases in theThyrogastric Cluster

As diagnostic tests for autoantibodies became more readily availableand the sensitivity of the assays improved, autoantibodies to the gas-tric autoantigens and to the autoantigens in autoimmune diseasesassociated with autoimmune gastritis became recognized genetic mar-kers of predisposition to these diseases. Such was the closeness of theassociation of autoimmune gastritis with autoimmune thyroid diseasethat Mackay [86] coined the term thyrogastric cluster of autoimmunediseases.

Cell-Mediated Immunity

The early immunological studies that were designed before the T andB cell paradigm were entirely concerned with autoantibodies in bloodand gastric juice. However, following the discovery of T and B lym-phocyte subsets, immunologists became interested in the role of cell-dependent immunity to gastric antigens in the immune response,whether as initiators in the induction of gastritis or as effectors of gas-tritis. As early as 1969, Tai and McGuigan [87] showed that peripheralblood lymphocytes from patients with PA proliferated in the presenceof human gastric intrinsic factor, gastric juice, or a homogenate ofgastric mucosa. Subsequently, Finlayson et al. [88], Fixa et al. [89],Goldstone et al. [90] and Chanarin and James [91] reported positiveresults for release of migration inhibition factor (MIF) from, presum-ably, T cells among peripheral blood leucocytes from patients withPA when the cells were exposed to gastric juice intrinsic factor in vitro.Interestingly, in the study by Chanarin and James [91], four patientswith PA who showed release of MIF in the presence of intrinsic factorhad hypogammaglobulinemia. The performance of these studies was


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fraught with technical difficulties and the results were not alwaysreadily interpretable or repeatable, so these assays lost favor.

However, over the succeeding 30�35 years there have been majoradvances in immunology, including the development of reliablereagents for identifying subsets of T lymphocytes and their secretedproducts, i.e., cytokines, and sensitive assays for studying T lympho-cyte function in autoimmunity. Even so, until recently there has beenscant evidence of any modern interpretation of the early studies in PAon cell-mediated immunity to intrinsic factor nor, in fact, much effortto reproduce the earlier studies in the context of gastric autoimmun-ity. Nevertheless, attention had been directed to the study of subpopu-lations of CD4þ and CD8þ T lymphocytes in the gastric mucosa [92].Then, eventually, when Hþ=Kþ -ATPase was identified as the autoan-tigen for gastric PCA and the spotlight turned to the study of murinemodels of autoimmune gastritis, the human T lymphocyte response toHþ=Kþ -ATPase was examined in a modern context. Epitopes on boththe a and b chains of Hþ=Kþ -ATPase have been shown to be recog-nized by Th 1 T lymphocyte clones derived from the gastritis mucosa[93]. These studies, reviewed by D’Elios and colleagues in this issue,indicate that such lymphocytes provide help for B lymphocytes,produce Th 1 cytokines, and mediate direct cytotoxicity and Fas-dependent apoptosis crucial for the evolution of chronic gastritisto gastric atrophy. However, we are not aware of similarly detailedstudies on T lymphocyte responses to gastric intrinsic factor.

Response to Corticosteroid Drugs

The megaloblastic anemia of PA was reported to respond to predniso-lone [94] with improvement of absorption of vitamin B12 [95,96], a fallin the serum level of antibodies to gastric intrinsic factor and parietalcells, a return of intrinsic factor in gastric juice [97], and regenerationof gastric parietal and zymogenic cells in the gastric mucosa [98�102].These findings are consistent with the view that stem cells presentin the mucosa are capable of regeneration when the autoimmuneresponse is suppressed (Figure 4).

Experimental Models of Autoimmune Gastritis

Limitations to research on human autoimmune gastritis, especiallythat relating to the causal role of autoimmunity and an analysis ofthe autoimmune response, led to attempts to develop animal modelsof autoimmune gastritis by injection of extracts of gastric mucosa orgastric juice with adjuvants [89,103�105]. These early attempts met


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with mixed success, and the gastritis was transient in nature. Noneproved as informative as the experimental BALB=c murine modelsof chronic gastritis elicited by neonatal thymectomy. These murinemodels were based on a model described by Ansar Ahmed and Penhale[106], who observed gastritis three weeks after thymectomy and irra-diation. Although Ansar Ahmed and Penhale [106] found that thymec-tomy alone or irradiation alone were insufficient for the induction ofautoimmune gastritis, Sakaguchi et al. [107] showed that thymectomywas not necessary when total lymphoid irradiation was used. Equallyeffective in neonates was cyclosporine [108] or cyclophosphamide[109], although in adult mice these drugs, without thymectomy, wereinsufficient as inducers of gastritis [109].

Gastritis appeared within 4 weeks of thymectomy in the 2�4 dayBALB=c neonate. It manifested itself as an infiltrate of inflammatorycells within a gastric mucosa that initially was grossly hypertrophiedin contrast to the human counterpart and in which the normal devel-opmental pathways of mucosal cells were disrupted, such that therewas a rapid expansion of immature glandular cells followed by deathby apoptosis [110�112]. Analysis of the infiltrating cells in themucosal lesion revealed a predominance of lymphoid elements, Blymphocytes, and CD4þ Th1 cells, together with macrophages. In cell-transfer experiments from affected mice to syngeneic, immunocompro-mised host mice, the cell responsible for the autoimmune attack wasthe CD4 Th1 cell and the target of that attack was the gastric Hþ=Kþ

ATPase, as in human autoimmune gastritis [113,114]. Mice rendereddeficient in the b subunit of Hþ=Kþ ATPase did not develop gastritis[112]. Homing of attacking CD4þ Th1 cells to the target autoantigendepended on intact adhesion molecules [111�112], and the mechanismof destruction involved interaction between the Fas ligand on the par-ietal cells and Fas on the CD4þ Th1 cell [115]. A mixture of Th1, andTh2-associated cytokines participated in the lesion [111], but a majorrole of interferon-c (IFN-c) was notable because a single injection ofantibody to IFN- c prevented development of gastritis [116]. The pres-ence of serum antibody to parietal cells, and specifically toHþ=KþATPase, was a constant finding, but antibody failed to transfergastritis. Mechanisms to explain how immunologic tolerance toHþ=KþATPase failed were examined by generating transgenic micethat expressed in the thymus the b subunit of Hþ=KþATPase underthe control of an MHC class II promoter. Such mice failed to developgastritis, whether after thymectomy as neonates or after immuni-zation and thymectomy combined with cyclophosphamide as adults[117]. Notably, similar protocols using the a subunit did not protectagainst development of gastritis [118].


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The neonatal thymectomy model of autoimmune gastritis inevitablyled to questions about the role of the thymus in the disease and arevival of interest in the regulatory effects of suppressor T cells in Tlymphocyte-dependent autoimmune responses. The availability of amurine marker for the IL2 receptor a chain (CD25) led to the identifi-cation of a subset of T cells, CD4þCD25þ cells that behaved as immu-noregulatory cells [119,120] and originate in the thymus [121]. Whilethese cells constitute only 10% of the peripheral CD4þ Th1 subset,they exhibit unique properties including the capacity to downregulateautoimmune responses and prevent autoimmunity in both mouse andman [122,123]. Finally, it is of note that there is a spontaneouslyoccurring model of autoimmune gastritis reported in the C3H=Hemouse [124].

Historians must await the ultimate contribution that the variousmurine models will make to the complete understanding of the humandisease, with progress up until 2004 reviewed by Field and colleaguesin this issue. Particular questions on murine autoimmune gastritisinclude the following: Does the gastric lesion evolve to total atrophy?Is there antibody to gastric intrinsic factor? Do vitamin B12 deficiencyand PA eventually supervene in aging gastritic mice?

SOMETHING AMISS WITH THE GENES

A Family Affair

Since 1891 various authors have commented on the occurrence of PAin families [36]. One study of 3000 relatives of 234 patients with PAestimated that PA occurred 20 times more frequently in those subjectsthan in controls with no history of PA in their family [125]. However, itwas not until the era of autoimmunity, when reliable diagnostic testsfor PA and serological markers of autoimmune gastritis had becomeavailable, that informative studies could be reported on familial aggre-gation, with disease in some families spanning several generations[126�135]. Other genetic pointers included concordance of PA inmonozygotic twins [136,137] and other autoimmune diseases, parti-cularly the autoimmune thyroid diseases [79,130,138�140]. As well asthyroid autoimmune disease, various disorders, mainly endocrinopa-thies including type 1 diabetes [141�142], primary Addison’s disease[143], hypoparathyroidism [144], vitiligo [145], and Lambert-Eatonsyndrome [146] were seen to be associated with PA. As an aside, thereis no suggestion that George Minot himself had autoimmune gastritis,but the history of PA may have taken a very different course hadBanting and Best not isolated insulin in 1922 because, in the autumn


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of 1921, Minot developed the then fatal type 1 diabetes, but fortu-nately was rescued by insulin [147] and survived to undertake hisground-breaking studies on the treatment of PA.

The PA phenotype includes blue eyes and blood group A [126], andsome predisposition is conferred by major histocompatibility complex(MHC) genes that encode human leukocyte antigens (HLA). Ungaret al. [148,149] found that HLA-B12 was associated with severe vit-amin B12 malabsorption and neuromyelopathy, and an increasedfrequency of Dw2 was associated with antibodies to gastric intrinsicfactor. HLA-B7, B12, DR2, and DR2=4 heterozygosity was increasedin PA as a single disease, and HLA-B8, B18, Bw15, DR3, and DR3=4heterozygosity in PA was associated with autoimmune endocrinopa-thies. However, the relatively weak HLA associations are insufficientto explain the strong familial aggregations in PA; moreover,HLA alleles provide only a partial explanation for the clear racialdifferences, including the rarity of PA among Asians [150,151],Latin-Americans, and Africans, as well as the atypical expressions ofPA among the latter group [152]. Thus there are genes involved insusceptibility to human autoimmune gastritis that are currentlyunknown, and clearly there is a need for genome-wide screening amongfamilial cases to clarify the nature of the inheritance and to identifythose genes exclusive to gastritis and those common to other auto-immune diseases. We note the progress made in identifying geneticdeterminants of autoimmune thyroid disease [153] and, given the clini-cal overlap, we can assume that some of these would predispose to auto-immune gastritis. Also, clues may lie in the murine models. Thus, inthis issue Baxter and colleagues report on the identity of four loci thatconfer susceptibility to autoimmune gastritis in the murine model, withthree showing colocalization with genes for murine Type 1 diabetes.This is of historical as well as of contemporary interest because theearliest clues to the autoimmune basis of Type 1 diabetes were providedby its clear association with thyrogastric autoimmunity [142,154].

SOMETHING AMISS IN THE COMMUNITY

Epidemiological Studies

A history of gastritis would be incomplete without reference to the out-standing epidemiological studies in Finland and Estonia over the past40 years. Initially these studies were conducted without reference tothe presently known causes, autoimmunity and H. pylori, but later,they did accommodate these causes [155]. The studies from Finlandrelating to the prevalence of gastritis in the Finnish population,


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assessed by gastric biopsy [135,156], were based on two sets of famil-ies, one a random set of family members over 15 years of age con-sidered to be representative of the Finnish population, and the otherof 183 relatives and 68 proband cases of PA. The gastric mucosa wasgraded as normal, superficial gastritis, and slight, moderate, or severeatrophic gastritis based on the degree of glandular loss. From thiscomplex analysis it was concluded that the overall frequency of gas-tritis in the random set was 68%. Overall, the dichotomy of Type Aand Type B gastritis was validated, although individuals with TypeAB gastritis [56], some of whom were PCA positive, were representedin both the random and PA family groups. This indicated that therewas a different dynamic evolution of gastritis within the two sets.For both sets the process began as a superficial gastritis [135], whichcontinued into middle age but thereafter evolved into Type A, Type B,or Type AB. For the set of PA families there was evidence for a majorfactor, Factor A, that contributed a dominant mode of inheritance ofan autoimmune phenotype, whereas for the set of random familiesthere was evidence for a recessive inheritance of an antral gastritisphenotype that predisposed to peptic ulcer and to gastric cancer.The strong association with gastric=duodenal ulcer (GU=DU) in theType B gastritis phenotype was corroborated by Sipponen et al.[157] in a histological study of 571 cases of GU=DU and 1074 controls.There was an association between gastric carcinoma and gastritis thatwas predominantly antral and presumably Type B, as was previouslyshown in histological studies in the Japanese population [158] amongwhom PA is relatively rare and gastric carcinoma frequent.

In 1991 the Finnish group [159] reviewed their overall experienceon gastritis in the context of infection with H. pylori, engaging issuessuch as prevalence, age-specific risk, and distribution of lesions rela-tive to findings in populations in other countries. In some so-calleddeveloping countries endoscopically and histologically proven gastri-tis and antibodies to H. pylori approaches 100%. Data collected inEstonia supports the Finnish epidemiological findings, and in thisissue Uibo discusses the highly topical question of the epidemiologicalrelationship of H. pylori infection to autoimmune gastritis, andwhether it is the primary event with host factors conditioning thesubsequent outcome.

SOMETHING AMISS WITH OUR KNOWLEDGE

It is 150 years since Addison described his ‘‘remarkable form ofanemia,’’ 100 years since atrophic gastritis was described histologi-cally, and 50 years since Castle said of pernicious anemia, ‘‘this


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disease would not develop if the patient could effect daily the transfer ofa millionth of a gram of vitamin B12 the distance of a small fraction of amillimetre across the intestinal mucosa and into the blood stream’’ [23].Over the last 50 years there has been an understanding of the essentialnature of vitamin B12 as a dietary component for cellular metabolism,particularly for cells of the blood and nervous systems, and how it istransported via the gastrointestinal system for storage in the liver.Other discoveries have included autoimmunity as a cause of the gas-tritis, the identity of the culprit autoantigens, the distinction betweenautoimmune gastritis and bacterial gastritis, and the connectionbetween gastritis, peptic ulcer, gastric cancer, and colonization of thestomach with H. pylori. Despite these advances there are still gaps inour knowledge, three of which are singled out for concluding comments.

First, why and how is gastric intrinsic factor selected by the imm-une system as a critical autoantigen in addition to Hþ=KþATPase,and how important is this immune response for the progression ofautoimmune gastritis to PA? Explanations for an autoimmuneresponse to intrinsic factor are not readily explained by cellular break-down, epitope mimicry, or by epitope spreading from a primary reac-tivity to parietal cell Hþ=Kþ ATPase, and this remains one of thecritical gaps in our knowledge. Earlier we commented on examplesof incomplete gastric atrophy with residual parietal cells in the faceof overt vitamin B12 deficiency, implying that in these cases PA coulddepend more on mucosally produced antibody to intrinsic factor thantotal destruction of parietal cells.

Second, what is the role, if any, of infection with H. pylori in theinitiation and perpetuation of autoimmune gastritis? While H. pylorican be present in the earlier stages of autoimmune gastritis accordingto epidemiologic data, it is not demonstrable in late-stage atrophicgastritis, possibly because the nonacidic gastric milieu is unfavorable.Autoimmune gastritis could be initiated by mimicking epitopes ofH. pylori with those of Hþ=KþATPase [160], an idea strengthenedby the recent demonstration that CD4þ T cells from patients withautoimmune gastritis recognized epitopes common to H. pylori andHþ=KþATPase [161]. An alternative—although by no means a mutu-ally exclusive explanation—is that H. pylori contributes by providingongoing cellular damage with ensuing exposure to the immune systemof antigenic fragments from degraded parietal cells. However, asjudged by the murine neonatal thymectomy models, infection withH. pylori is neither a necessary nor sufficient cause of autoimmunegastritis. In fact, if genetic risk for gastric autoimmunity exists,release of antigenic material from any cause, or even in the courseof tissue remodelling, may be sufficient to initiate the process.


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Third, what genes are responsible for inherited predisposition tohuman gastritis? As autoimmune gastritis is now considered a clini-cally bland disease with a remedial outcome, it is seen as not worthyof the new technologies of genome wide scans and positional cloningof susceptibility loci that have been employed in higher profile auto-immune diseases. Yet PA is ideal for informative studies on large fam-ily clusters, and the ensuing genetic data could be applicable toautoimmunity in general, particularly in identifying genes that aretarget-specific for autoimmunity and in distinguishing genes that pre-dispose to defects in immunological tolerance from those with down-stream effects such as tissue inflammation.

The recorded history of gastritis, while rich in discoveries relevantto our understanding of autoimmunity, still awaits the concludingchapters.

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autoimmune gastritis: historical antecedents, outstanding discoveries, and unresolved problems

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