Autoimmunity, 1992, Vol. 13, pp. 165-172 Reprin’ts available directly from the publisher Photocopying permitted by license only

0 1992 Hanvood Academic Publishers GmbH Printed in the United Kingdom

UPDATE AUTOIMMUNE GASTRITIS: TOLERANCE AND AUTOIMMUNITY TO THE GASTRIC H+/K’ ATPase (PROTON PUMP) BAN-HOCK TOH, IAN R. VAN DRIEL and PAUL A. GLEESON

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Department of Pathology and Immunology, Monash University Medical School, Alfred Hospital, Commercial Road, Prahran. Victoria 3181, Australia. Fax: 61-3-529-6484 (Received January 17, 1992; in final form April 6,1992) The a and p subunits of the gastric H+/K’-ATPase (proton pump) have been identified as the major molecular targets of parietal cell autoantibodies associated with pernicious anaemia and with murine experimental autoimmune gastritis (EAG) induced by neonatal thymectomy. Recent studies with EAG suggest that the mechanisms of peripheral tolerance and autoimmunity to extrathymic autoantigens are mediated by subsets of “regulator” and “effector” CD4+ T cells, respectively. The persistence of “effector” CD4’ autoreactive T cells in the periphery may he a direct consequence of the delayed developmental expression of the target autoantigen. We hypothesize that cytokines produced by the “regulator” T cells prevent the clonal expansion of the “effector” autoreactive T cells, and that neonatal thymectomy induces organ-specific autoimmunity in genetically susceptible individuals by the reduction of the “regulator” T cell population.

INTRODUCTION

some studies, but have not been substantiated in others (for review see Ref 6).

Autoimmune gastritis or chronic atrophic gastritis (Type A) is an excellent paradigm of the organspecific autoimmune diseases involving the endocrine organs and the stomach. The lesion, typified by loss of parietal and chief cells from the gastric mucosa and submucosal lymphocytic infiltration, is the underlying basis for pernicious anaemia, the commonest cause of vitamin B12 deficiency in whites of northern European origin’,’. The acid-secreting, gastric parietal cell seems to be the main cell targeted in this disease since autoantibodies to parietal cells and to intrinsic factor (a parietal cell secretory product) are found in most patients with pernicious anaemia’ and parietal cell autoantibody titres correlate with the severity of the gastritis. Longitudinal studies suggest that pernicious anaemia is the end stage of autoimmune gastritis4, with estimated prevalences are 0.1 % and 1% respectively’. The anaemia is the result of the lack of intrinsic factor necessary for vitamin B12 absorption in the ileum. A genetic predispostion to the disease is suggested by familial occurrence of pernicious anaemia and by the presence of circulating parietal cell autoantibodies, and associated type A chronic atrophic gastritis, in 20-30% of relatives of patients with pernicious anaemia. These relatives also have a higher frequency of other organ-specific autoantibodies directed against the endocrine organs. An increased frequency of a number of MHC alleles in patients compared to control groups has been suggested in

The gastric proton pump (H’IK’ ATPase) The gastric H’/K+-ATPase (proton pump), localised to the intracellular membranes of parietal cells, is responsible for acid secretion into the stomach lumen. The H+/K’-ATPase, together with the Na+/K+-ATPase and the Ca’-ATPase, belong to a family of ion-motive “P-type” ATPases which have highly conserved catalytic a subunits that are phosphorylated during their reaction cycles7. It is now established that the gastric proton pump, along with the Na+/K+-ATPase, possesses glycoprotein p subunits8-”. Two distinct p subunit isoforms have been identified for the Na’/K’ATPase. The gene structure of the p subunit of the gastric proton pump indicates that it is more closely related to the p 2 subunit isoform of the Na+/K+ ATPase (also known as the adhesion molecule of glia, AMOG) than to that of the pl isoform’2.In the case of the Na+/K+-ATPase, the p subunit appears to be critical for correct intracellular transport and function of the a-subunit”. The same seems to be true for the gastric proton pump p - s u b ~ n i t ’ ~ .

Identification of the 92 kDa proton pump catalytic a subunit as a molecular target The ultrastructural localisation of the parietal cell

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autoantigen to the secretory canaliculi of gastric parietal cells” and to the gastric “microsomes”’6 suggested that the autoantigen is a component of these membranes. The secretory canaliculi are channels for hydrochloric acid secretion into the gastric lumen which are present only in parietal cells stimulated by secretagogues. In the unstimulated cell, abundant tubulovesicules are present. It has been suggested that parietal cell stimulation results in translocation and fusion of the tubulovesicles to form secretory canaliculi continuous with the apical cell surface. The major proteins of parietal cell canalicular and tubulovesicular membranes are the a subunit” and the P subunit’’.’”of the gastric proton pump. Parietal cell autoantibodies specifically immunoblot and immunoprecipitate two molecules of apparent molecular mass 60-90 kDa’” and 92 kDa” from gastric membrane extracts. In addition, these autoantibodies also immunoprecipitate molecules of 120 kDa and >200 kDa”. Karlsson et al.” had suggested that the 92 kDa parietal cell autoantigen detected by immunoblotting is the catalytic a subunit of the gastric proton pump, based on the mass of this component and on autoantibody-mediated reduction of enzyme activity from detergent extracts of crude gastric membranes and of gastric tubulovesicular membranes. The 120 kDa component and the components of >200 kDa, observed in immunoprecipitates with human parietal cell autoantibodies, have been shown to be derived from the a-subunit since these components react with a rabbit antibody specific to the a subunit of the proton pump”. The heat-induced aggregation of the a-subunit appears to be typical of proteins with multiple hydrophobic transmembrane domain^'^. The a-subunit has at least 8 transmembrane domains3. The location of the antibody autoepitopes in this subunit has not yet been identified. Identification ojthe 60-90 kDa proton pump p subunit us u molecular- target The 60-90 kDa autoantigen reactive with parietal cell autoantibodies comprises a heavily N-glycosylated 35 kDa core potein. Binding of autoantibodies from a number of different patient sera to the 60-90 kDa molecule requires both the carbohydrate and protein moieties of the autoantigen since treatment with Nglycanase or reduction of disulphide bonds abolished autoantibody binding2*.The identity of the 60-90 kDa molecule as the P-subunit of the gastric proton pump was established by studies using a number of monospecific reagents to this component and by the molecular cloning of the 35 kDa core potein cDNA. We demonstrated that the 60-90 kDa glycoprotein autoantigen specifically reacted with lectins derived from tomato and potato, which bind polylactosamine carbohydrate sequences”. In addition, two murine

monoclonal antibodies, generated using dog tubulovesicules as antigen, reacted with the 35 kDa core protein of a 60-90 kDa gastric membrane glycoprotein. Further, both monoclonal antibodies reacted with the core potein of the 60-90 kDa autoantigen purified by either tomato lectin chromatography or by “reverse immunoaffinity chromatography””. As the monoclonal antibodies recognize the polypeptide backbone, and as they bind all the 60-90 kDa autoantigen, the polypeptide of the antigen must be a single molecular species. The strategy of “reverse immunoaffinity chromatography”, involved initial purification of parietal cell autoantibodies on a column of crude gastric autoantigen followed by the generation of an immunoaffinity support, for the isolation of the 60-90 kDa autoantigen”. Tomato lectin chromatography provided a rapid purification procedure on the 60-90 kDa autoantigen from pig stomach in high yield”. The autoantigen was purified, together with the H’/K’ ATPase a-subunit, as an active enzyme complex’”. Tryptic peptide sequences obtained from the lectin-purified 60-90 kDa glycoprotein and from the 35 kDa core protein, allowed the cloning of the cDNA’” and genomic sequences”. The deduced full length amino acid sequence from cDNA clones encoding the autoantigen showed a 38% identity with the P2 subunit of the pig kidney Na+/K+-ATPase“’,a 55 kDa glycoprotein with a 35 kDa core protein. Furthermore, exon placements relative to amino acid sequence was identical for both these genes, indicating a very close evolutionary relationship. The 35 kDa core proteins has 6 potential N-linked glycosylation sites and 6 conserved cysteine residues on the luminal carboxyl-terminal domain of the molecule”’ (Figure 1). The autoepitopes recognised by parietal cell autoantibodies are probably on this luminal domain since the autoantibodies only react with the non-reduced, glycosylated molecule. A physical association between the 60-90 kDa autoantigen and the a-subunit of the proton pump was directly demonstrated by immunoprecipitation of both components with either the monoclonal antibodies to the 60-90 kDa autoantigen or with a rabbit antibody to the ct subunit of the proton pump“’.’3. Furthermore, affinity chromatography using either one of the monoclonal antibodies to the 60-90 kDa autoantigen, or tomato lectin, showed that the majority of the a subunit co-purified with the 60-90 kDa glycoprotein from detergent extracts of gastric membranes”,2’. The 60-90 kDa autoantigens was therefore identified as the P subunit of the gastric proton pump. The role of autoantibodies to the proton pump subunits in the immunopathogenesis of the human disease remains in question. Since the intact proton pump is not expressed on the basolateral surface of parietal cells, circulating autoantibodies are unlikely to mediate any direct cytopathic effects. On the other

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hand, autoantibodies to the proton pump in gastric secretions could have direct access to the apical surface of parietal cells, although the acidic gastric environment will probably inhibit effective antibodyantigen interactions. Parietal cell positive-autoantibodies have been detected in gastric secretions of patients with pernicious anaemia. However, the speci-

ficity of these autoantibodies have not been characterised and their potential pathogenic role has not been assessed. Furthermore, the role of human autoreactive T cells directed against the proton pump or to any other gastric component has not, as yet, been addressed. Another unresolved issue is the basis for the concomittant loss of chief cells from the gastric

EXTRA

IN T R A

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TM

0 Figure 1 The p-subunil of the H'K'-ATPase, displaying the short amino-terminal cytoplasmic tail, transmembrane domain and the luminal carboxy-terminal domain. The 6 luminal potential N-linked glycosylation sites at positions 99, 130, 146, 161, 193 and 221 are indicated ( f i ; most if not all of these sites probably contain carbohydrate since at least 4-5 intermediate products have been observed with N-glycanase digestion". The proposed disulphide (S-S) bonds linking thc 6 conserved cysteins at 13'C-'s'C, '6'C-'76C and 20'C-262Care based on the location of the 3 disulphide bonds in the related p subunit of the Na'/K'-ATPase'", The autoantibody epitopcs are located in the luminal domain of the molecule since the autoantibody reacts only with the non-reduced, glycosylated molecule. TM, transmembrane domain; INTRA, intra-cytoplasmic (amino-terminal) domain; EXTRA, extra-luminal (carboxyl-terminal) domain.

neonatal BALB/c

1

/ sera

1 au toanti bodies to a - and p - subunits of gastric proton pump

neonatal thymectorny

au toimrnune gastritis auto-reactive T cells

1 specificity ??

Figure 2 Induction of experimental autoimmune gastritis in BALB/c mice by neonatal thymectomy carried out at days 2 4 after birth. About 50% of these mice develop autoimmune gastritis after 3-6 months. Sera from diseased mice contain parietal cell autoantibodies which are directed against thc a and p subunits of the gastric H+/K' ATPdse (proton pump). The specificity of the autoreactive effector T cells is currently nor known.

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disease, there is compensatory mucous cell hyperplasia. These mice also have parietal cell autoantibodies in their sera which also react by immunoblotting and by immunoprecipitation with the a and Murine experimental autoimmune gastritis (EAG) subunits of the proton pump".". Two monoclonal induced by neonatal thymectomy autoantibodies derived from these mice, representaNeonatal thymectomy carried out in the narrow win- tive of two different autoantibody sets, also react with dow of 2-4 days after birth in mice induces organ- the a or p subunit of the proton pump". Therefore, specific autoimmune diseases of the endocrine organs this murine disease appears to be an ideal model for and also of the s t o m a ~ h ~ (Figure ~ ~ ~ ' .2). ~ ~These auto- the study of the human disease. Organ-specific autoimmune diseases are ideal experimental models since immunity can also be induced by cyclosporine A they display the cardinal features of human organ- given in the first week of neonatal life32. The parietal specific autoimmunity with selective destruction of cell autoantibodies associated with EAG in this model target cells coupled with immunocytic infiltration of also react with the proton pump subunits (Martinelli et the affected organ and circulating organ-specific auto- al., unpublished observations). antibodies. These diseases appear to be antigen driven The murine disease appears to be cell mediated, as removal of the ovaries prior to thymectomy inhibits since EAG can be transferred by spleen cells but not the development of the ovarian autoimmune disease29. a u t ~ a n t i b o d i e s ~The ~ . precursors of the effector autoThe frequency of the particulr organ-specific auto- reactive T cells that cause EAG by adoptive transfer immune disease depends on the genetic background, have a CD4'CD5'OW phen~type''.'~ (Figure 2) which with BALB/c and AJ strains showing the highest fre- are thought to subsequently mature to a CD4+CD5h'gh quency of autoimmune gastritis26.The murine gastric T cell subset35, indicating a central role of CD4' T lesions are similar to those of human autoimmune gas- cells in disease induction. On the other hand, CD8' T tritis in that there is selective parietal and chief cell cells do not seem to have a role in this disease since loss from the gastric mucosa coupled with submucosal depletion of this T cell population do not reduce the lymphocytic infiltration. However, unlike the human capacity of the remaining T cells to transfer disease to

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mucosa in the human as well as in the murine model of this disease (see below).

CII

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Figure 3 Induction of murine experimental autoimmune gastritis by adoptive transfer of CD4TDS'""T cells from normal adult splenocytes or CD4'CDK T cells from normal adult thymus to BALB/c nude recipients. The CD4tCD5h'ghT cell population from normal splenocytes can prevent the development of experimental autoimmune gastritis.

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T cell deficient mice34.The antigen specificity of the pathogenic, autoreactive T cells is not known, however a T cell delayed hypersensitivity response to an enriched parietal cell population has been demonstratedZ7.In addition, we have shown by in vitro proliferation assays that autoreactive T cells specific- for the gastric proton pump are present in mice with EAG (Martinelli et al., unpubished observations). The pathogenic potential of these anti-pump T cells has not, as yet, been assessed. A strength of this murine model is that disease induction does not rely upon manipulation of endogenous target antigens or tissues, or upon active immunisation with autoantigens in adjuvant. Further-

NEONATE DOc

0 oo C

stem

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more, as discussed below, this model suggests that the major mechanism for peripheral tolerance to autoantigens targeted in organ-specific immunity is clonal regulation and not clonal deletion or clonal anergy. The break in immunological tolerance induced by

neonatal thymectomy The induction of EAG by neonatal thymectomy suggests that the “effector” autoreactive T cells have not been deleted from the T repertoire during intrathymic development but have seeded to the periphery prior to thymectomy at days 2-4. This suggestion is supported by the capacity of thymocytes from neonatal as well

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4/ Figure 4 Suggested model for the

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induction of experimental autoimmune gastritis by neonatal thymectomy. In this model, self-reactive “effector” T cells leave the thymus to populate the periphery before day 2 after birth. Removal of the thymus between day 2 and day 4 after birth results in an imbalance between the “effectors” and the “regulators” in the periphery in favour of the former. The model is based on the observation that organspecific autoimmunity can only be induced in susceptible mouse strains by neonatal thymectomy carried out in the narrow window of day 2 to day 4 after birth.

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B.H. TOH, I.R. VAN DRlEL AND P.A. CLEESON

as from adult mice, and a subset of splenic CD5’”” T cells to transfer d i ~ e a s e ’ ~ . (Figure ~‘ 3). Studies of recombinant inbred mouse strains showed that EAG susceptibility is not associated with the H-2 haplotype but with a minor histocompatibility locus”. Recent studies implicate two or more genes in the induction mechanism of EAG, and a possible association between MIS- I and disease susceptibility has been propo~ed’~.However, whether there is skewed usage of particular T cell receptor a and p genes by the “effector” T cells in EAG is currently not known’. The “effector” T cells which have left the thymus before days 2-4 are probably “silenced” in the normal periphery by a “regulator” T cell population (Figure 4). This suggestion is supported by the observations that ( I ) spleen cells from thymectomized mice can transfer EAG only to nude, or to immunocompromised mice but not to normal mice3* and that (2) non-fractionated spleen cells or T cell enriched (Thy-1’) spleen cells from adult mice can prevent EAG in cyclosporin A-treated animals3’. Further, thymocytes from normal adult mice can prevent the development of oophoritis, a related ovarian autoimmune disease in neonatally thymectomized mice3’. This study also suggested that the “regulator” T cells may not be autoantigen-specific since splenocytes from male mice have the same capacity as those from female mice in suppression of oophoritis in neonatally thymectomised mice3”. The phenotype of the “regulator” T cell population in both EAG and autoimmune oophoritis induced by neonatal thymectomy, is CD4’CDShIgh(Refs 34, 39). In a related rat model of organ-specific autoimmunity, the “effector” T cells were reported to be CD4SRCh”” while the phenotype of the “regulator” T cells were CD4SRC’””““ . The CD45 status of the T cells involved in the induction and immunoregulation of EAG induced by neonatal thymectomy is currently unknown. The importance of “regulator” T cells in the maintenance of peripheral tolerance to extra-thymic organspecific autoantigens is further supported by the observations that autoimmune thyroiditis can be induced in rats and in mice by a combination of early thymectomy (3-5 weeks of age) and sublethal irradiation (TX-X)”?‘~,and that the spontaneous thyroiditis in the obese strain of chickens can be aggravated by neonatal thymectomyJ4.Furthermore. the disease induced by Tx-X can also be abrogated by normal lymphoid cells and there are marked rat strain differences in disease susceptibility which do not have an MHC association“. The Tx-X studies suggest that the “regulator” T cell population is radiationsensitive. Organ-specific autoimmunity has also been observed in transgenic mice expressing rearranged TCR a-chain genes (S. Sakaguchi, personal communication). The particular autoimmune diseases

Table I Possible mechanisms of iinmunoregulation of CD4’ auloreactive “Effector” T cells by CD4’ “Regulator” T cells.

( 1 ) Antigen specific Idiotypic recognition of autoantigen-specific TCR Cytokine mediated: Th2 “regulators” versus Th I “effectors” (2) Antigen non-specific Cytokine mediated: Th2 “regulators” versus Th I “effectors”

induced also depended on the mouse strain harbouring the transgene. However, the pathogenic CD4’ T cells showed little or no expression of the transgene, indicating that the disease is mediated by T cells expressing endogenous TCR a-chain genes that have escaped allelic exclusion. Autoimmune disease was not observed in TCR p chain transgenic mice, which may be the result of more complete allelic exclusion at the p chain locus relative to the a locus. These results suggest that perturbation of the normal development of the T cell repertoire by the expression of the transgene TCR shift T cells in favour of the pathogenic T cells. The mechanism of immunoregulation of the “effector” autoreactive T cells by the “regulator” T cells is not known. Possible mechanisms are summarized in Table 1. “Suppressor” T cells are traditionally considered to be T cells which recognize T cell receptor idiotypes. Alternatively, suppression by “regulator” T cells may be mediated by cytokines. Significantly, there has been considerable interest in the mutual suppressor activities of cytokines secreted by Th 1 and Th2 subsets of CD4’ T cells“. For example, y IFN secreted by T h l cells suppress the activation of Th2 and, conversely, interleukin (1L)- 10 secreted by Th2 cells is a potent suppressor of T h l cells. The cytokines secreted by T h l cells are effective mediators of the inflammatory r e ~ p o n s e ‘ and ~ therefore likely to be responsible for the induction of EAG. A role for cytokines in mediating the suppressor activity of CD4’ regulatory T cells has recently been reported in experimental autoimmune encephalomyelitisJX.An imbalance in the ratio of “regulator” Th2 and “effector” T h l cells could shift the balance from regulation to disease. Otitogcriy o j ‘ o t . g u t i - . ~ ~ ~ cturgi’t i ~ ~ t i cuiitoutiti,qors ~ utirl p e t ~ i p h e t tnlctutii~e ~~l

The late embryonic and neonatal period is ;I crucial period for the establishment of immunological tolerance probably because immature lymphocytes are more susceptible to tolerance induction than mature lymphocytes. Clearly, tolerance induction requires engagement of the TCRs of self-reactive T cells with self-peptides presented by self-MHC molecules. Therefore, an important consideration is the presence

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AUTOIMMUNE GASTRITIS

and level of expression of the target autoantigens during the sensitive embryonic and neonatal period. Significantly, we have recently shown that there is minimal expression of the a and p subunits of the gastric proton pump during this neonatal period". Indeed, protein levels of both the a and the p subunits of the gastric proton pump are only a few percent of adult levels before 15 days after birth, and then increased to adult levels only by day 30. We further hypothesize that the restriction of the autoimmune targets to the other endocrine organs in neonatal thymectomyinduced autoimmunity may also be explained by the delayed developmental expression of the endocrine autoimmune targets. The hypothesis is further supported by the observation that the early developmental expression in the nuclei of pancreatic islets of transgenic SV40 T antigen driven by the rat insulin promoter resulted in tolerance whereas delayed developmental expression of this component in the islets resulted in anti-pancreatic islet autoimmunity manifest as inflammatory infiltrates around the islets and anti-islet autoantibodies'".

CONCLUSIONS The Q and p subunits of the proton pump are the major molecular targets recognized by parietal cell autoantibodies in autoimmune gastritis and pernicious anaemia. Using the murine model of EAG, we can now examine ( I ) the mechanisms of peripheral tolerance to the extrathymic proton pump, and in particular, the mechanisms of immunoregulation of the "effector" autoreactive CD4' T cell population by the "regulator" CD4' T cell population, (2) the trimolecular complex of T cell autoepitopes, MHC molecules and TCRs utilized in the induction of the proton pump-specific autoimmune response, and (3) the role of the proton pump-driven autoreactive T cells in the immunopathogenesis of autoimmune gastritis.

This work was supported by grants from the National Health and Medical Research Council 0 1 Australia and the William Buckland Foundation. We thank our graduate students lsabella Goldkorn, Clarewen Jones, and Teresa Martinelli, our senior research assistant Judy Callaghan and our colleagues Tohru Masuda, Kenneth Tung, George Sachs and Shimon Sakaguchi for stimulating discussions on autoimmune gastritis.

Rej'ei-cnces I. Strickland R. Gastritis. Sprin,ger. Semin Immunoputhol 1990;

12: 203-2 I7 2. Strickland R , Mackay IR. A reappraisal of the nature and sig-

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K+ ATPase (proton pump).

The alpha and beta subunits of the gastric H+/K(+)-ATPase (proton pump) have been identified as the major molecular targets of parietal cell autoantib...
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