The initial division o f chronic gastritis into Type A and Type B (Strickland and Mackay, 1973 and W yatt and Dixon, 1988) indicated that Type A gastritis is characterized by autoimmune genesis and accompanies pernicious anaemia, whereas Type B is nonauto immune (Strickland and Mackay 1973, Salupere 1978), predominantly H. /jy/orz-associated gastritis (Whyat and Dixon 1988,
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Strickland 1990). At present there is ample evidence that H. pylori too is responsible for induction o f autoimmune processes in the gastric mucosa (Engstrand et al. 1991,Negrini et al. 1989, 1991, 1993, 1996, Varis et al. 1993, M a e ta l. 1994, Faller et al. 1996, 1997, 1998, Appelmelk etal. 1996).
The main target o f autoimmune reactions described in the stomach is parietal cells and its secretory product intrinsic factor (Taylor 1959, Irvine et al. 1962, Markson and M oor 1962). Among pernicious anaemia patients, parietal cell antibodies (PCA) have been found in 90% o f patients with atrophic corpus gastritis (Irvine et al. 1962, Taylor et al. 1962, Strickland and Mackay 1973, Glass and Pitchumoni 1975). PCA have been found also in other gastritis forms, not associated with pernicious anaemia, which involve mainly the antrum (Schraier et al. 1983, W yatt et al. 1992). Furthermore, there have been de
monstrated immune reactions to antral mucosa (Salupere et al. 1972, Vandelli et al. 1979, Uibo et al. 1984b). Studies o f Vandelli et al. (1979) and Uibo et al.
(1984b) showed that in several antrum gastritis cases (6% o f cases in a study o f Vandelli and 16%> o f cases in a study o f Uibo) there occur antibodies to gastrin cells; both researchers suggested that antral gastritis too can be associated with immunological abnormalities, in which the role o f H. pylori has now been established (Jaskiewicz et al. 1993, Seifarth et al. 1996, Sommer et al. 1998).
Gastric H+, K+ ATPase as a major parietal cell autoantigen
The parietal cell autoantigen is located o f cell surface membrane, covering microvilli on its free surface and lining the secretory canaliculi o f the gastric parietal cells (Hoedemaeker and Ito 1970). Studies o f biochemical and mole
cular cloning identified this autoantigen as the a-and P-subunits o f gastric H+, K+ ATPase (Karlsson et al. 1988, Goldkorn et al. 1989, Toll et al. 1990).
Membrane-bound gastric H+, K+ ATPase represents a proton pump responsible for acidification o f the stomach lumen (Ganser and Forte 1973, Reuben et al.
1990). Gastric H+, K+ ATPase consists o f two subunits, the transmembrane 100 kDa catalytic a-subunit and the 60-90 kDa glycoprotein p-subunit and it is localized in the intracellular membranes o f gastric parietal cells (Karlsson et al.
1988, Toh et al. 1990, M a et al. 1994). It has also been established that gastric H+, K+ ATPase serves as the causative autoantigen in the pathogenesis o f experimental autoimmune gastritis (Scarff et al. 1997, Toh et al. 2000). Toh et al. (2000) proposed the following scenario for the genesis o f the gastric lesion initiated by the p subunit o f gastric H+, K+ ATPase: dendritic cells in the gastric mucosa become activated, capture and process gastric H+, K+ ATPase, released during the turnover o f parietal cells, and migrate then to draining lymphnode. In T-cell areas o f the lymphnode, dendritic cells present gastric H+, K+ ATPase peptide to naive CD4+ CD25- T-cells. In the presence o f nai've regulatory CD4+CD25+ T-cells, activation o f naive pathogenic CD4+ T-cells and IL-2 secretion is suppressed. In absence o f regulatory T-cells, naive pathogenic CD4+ T-cells become activated. Activated pathogenic CD4+ T-cells
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acquire adhesion molecules that allow their migration to the stomach via efferent lymphatic and blood vessels o f the gastric mucosa, where they infiltrate the mucosa in response to appropriate chemotactic stimuli. Antigen-specific CD4+ T-cells recruit other CD4+ T-cells, monocytes, CD8+ cells and B-cells through release o f cytokines (Steinman 1996). Supported by activated CD4+ T cells, B-cells produce autoantibodies to gastric H+, K+ ATPase (Toh et al.
2000). Recent data o f d ’Elios et al. (2001) showed that H+ K+ ATPase is the target autoantigen o f T hl type cytotoxic T-cells in autoimmune gastritis. Acti
vation o f proton pump-specific T h l cytotoxic/proapoptotic T-cells in the gastric mucosa can represent an effector mechanism for the target cell destruction in autoimmune gastritis.
It was shown in many studies that infection with H. pylori induces auto
antibodies reactive with gastric parietal cell canaliculi and that autoantibodies to H+, K+ ATPase indicate a link between bacterial and classical autoimmune gastritis (Negrini et al. 1991, 1996, Ma et al. 1994, Faller et al. 1996, 1997, Appelmelk et al. 1996, 1998). Faller et al. (1997) showed a good correlation between H. pylori infection, antiluminar antibodies binding to the foveolar epithelium as well as anticanalicular autoantibodies and corpus mucosa atrophy with increased fasting gastrin levels (Faller et al. 1997). This relationship was supported by a significant reduction o f anticanalicular autoantibodies after H.
pylori eradication (Faller et al. 1997). Recently, it was shown that antigastric autoantibodies, reacting against canaliculi o f human parietal cells, are not only detectable in the serum but are produced locally in the gastric mucosa o f H.
pylori infected patients (predominantly IgA type) (Faller et al. 2000).
Antigastric autoimmunity and molecular mimicry
Because most H. pylori strains contain human blood group antigens Lewis X and Lewis Y, which are expressed also on epithelial cells in the gastric mucosa (Sherburne and Taylor 1995, Aspinall et al. 1996, Simoons-Smit, 1996 et al.), it has been proposed that such molecular mimicry is responsible for formation o f antigastric autoantibodies, particularly in animal models (Negrini et al. 1996, Aspinall et al. 1996, Appelmelk et al. 1996, 1997). In a study o f Guruge et al.
(1998) it was shown that if the host is colonized by a H. pylori strain that ex
presses adhesins, promoting attachment to epithelial receptors, and if that strain expresses also Lewis X surface antigens, mimicking host parietal cell structure then the course o f infection leads to development o f autoantibodies to parietal cells and, as a consequence, a tendency for atrophic gastritis with loss o f parietal cells.
However, Faller et al. (1998) showed that human autoantibodies against the canaliculi o f parietal cells could not be absorbed by Lewis X or Lewis Y posi
tive H. pylori strains. Additionally, Clayes et al. (1998) demonstrated that 50%
o f anticanalicular autoantibodies react with the peptide part o f the a or p subunit o f gastric H+, K+, ATPase but not with a carbohydrate structure such as
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the blood group antigen. These authors suggest that there exist some other pathogenic mechanisms leading to formation o f antigastric autoantibodies.
Furthermore, heat shock proteins have been considered as the cause o f anti
genic mimicry between H pylori and host structures, which gives evidence o f a high degree o f homology (Macchia et al. 1993). Engstrand et al. (1991) demonstrated that monoclonal antibodies, raised against HSP60 (GroEL) o f M ycobacterium, cross-reacted exclusively with the HSP60 protein o f H. pylori as well as with gastric epithelial cells in all H. pylori positive specimens.
Engstrand et al. (1991) suggested that intraepithelial y/5 T-cells may play a role in host defence against H. pylori, and that H. pylori may trigger autoimmune response to stress proteins expressed by gastric epithelial cells.
Negrini et al. (1996) reported an additional autoimmune target — the mucosal neck and chief cells o f the gastric mucosa. The cross reaction between H. pylori and epithelial cells, observed by Negrini, was directed to the glandular epithelium o f the stomach, in particular, to the regenerative mucosal neck cells.
Also, a significant correlation o f anticanalicular autoantibodies was found with presence o f intraepithelial lymphocytes within the glandular epithelium, with periglandular lymphocytes and with corpus atrophy. In the concept o f molecular mimicry introduced by Negrini, H. pylori presents common epitopes to the host which react with antibody response, recognizing the gastric mucosal epithelium and, together with other host and environmental factors, influences the tendency o f chronic gastritis to progress into atrophic gastritis and gastric cancer (Negrini e ta l. 1996).
Invasion o f human gastric mucosa by H. pylori
Considering the interaction between H. pylori and host immune response and gastric tissue damage, there arises the question about the possible entry o f H.
pylori to the human gastric epithelium. H. pylori has been considered to colonize the gastric mucosa exclusively extracellularly (Blaser 1997). However, there are data confirming an intracellular location o f H. pylori (Bode et al.
1988, Andersen and Hoick 1990, Evans and Graham 1992, Noach et al. 1994, Engstrand et al. 1997, Ko et al. 1999, Su et al. 1999, Björkholm et al. 2000, Petersen et al. 2000). Björkholm et al. (2000) show that H. pylori can invade epithelial cells actively in culture, while production o f vacuolating cytotoxin increases the ability to invade Hep-2 cells. The authors suppose that invasion o f the gastric epithelium contributes to the bacterium ’s ability to establish persis
tent infection that evades mucosal defence and sometimes also antimicrobial therapy in case antibiotics with extracellular activity are used. Su et al. (1999) found that invasion o f cultured cells by H. pylori occurs via an integrin- mediated pathway and entry is higher for type I (cytotoxin) strains.
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H. pylori and induction o f apoptosis and proliferation