Immunology

The gastric autoantigens

The two autoantigens targeted by autoantibodies are components unique to the gastric parietal cell in the

Figure 1 The gastric parietal cell antibody detected by immunofluorescence and illustrated here on murine gastric mucosa reacts with the cytoplasm of gastric parietal cells. Characteristic of the Immunofluorescence reaction is the denser staining of the newly formed cells at the base of the mucosa (bottom left) and lighter staining of the mature cells towards the top of the mucosa. Experimental evidence suggests that the autoantigen in the parietal cell is the enzyme H+,K*-ATPase which is involved in production of acid secreted into the gastric juice.

body of the stomach. The autoantigen with which GPCA reacts is the enzyme H+,K+-adenosine triphosphatase (H+,K+-ATPase) which is cell-specific but not species-specific, indicating the importance of the physiologic role of the molecule in the gastric parietal cell. The second autoantigen is a secreted product of the gastric parietal cell, gastric intrinsic factor.

H+,K+-ATPase Gastric H+,K+-ATPase is the enzyme responsible for the acidification of gastric juice and is otherwise known as the proton pump. It belongs to a family of ion-motive-P-type ATPases which include Na+,K+-ATPase and Ca2+-ATPase which have highly conserved catalytic a subunits that are phosphoryl-ated during their reaction cycles. Only H*,K+-ATPase and Na+,K+-ATPase have a (3 subunit which includes a heavily glycosylated 35 kDa core protein. The gastric enzyme, which is heterodimeric, is located on intracellular and apical membranes of the gastric parietal cells. Autoantigenic determinants of H',K+-ATPase are located on both the catalytic 100 kDa (a) and the glycosylated 60-90 kDa (3) subunits.

Gastric intrinsic factor Gastric intrinsic factor, the other major autoantigen in autoimmune gastritis, is a glycoprotein with a molecular weight of 44 kDa. Each molecule has the capacity to bind to one molecule of vitamin Bu and of its two autoantigenic determinants, one is at the binding site for vitamin B12 and the other is on a part of the molecule remote from this site.

The gastric autoantibodies

The major autoantibodies implicated in autoimmune gastritis are GPCA and the two antibodies that react with gastric intrinsic factor. Since H+,K+-ATPase is unique to the gastric parietal cell and is responsible for acid production, the inhibitory effect of the immune response on anti-H+,K+-ATPase accounts for hypochlorhydria. The scenario for the effect of autoantibodies is as follows.

Upon reaching the stomach after ingestion, vitamin B12 in the acid medium of gastric juice is freed from protein to bind to intrinsic factor. When acid secretion is inhibited by anti-H+,K+-ATPase the amount of vitamin B12 free to bind to intrinsic factor is greatly reduced and if the vitamin B,2 site on intrinsic factor is blocked by antibody little, if any, will bind to intrinsic factor. The result is malabsorption of vitamin B12 and as the autoimmune gastritis progresses the stores of vitamin B12 dwindle to levels that can no longer sustain blood and nervous system metabolism. The patient becomes anemic and neurologic complications follow (Figure 2).

Figure 1 The gastric parietal cell antibody detected by immunofluorescence and illustrated here on murine gastric mucosa reacts with the cytoplasm of gastric parietal cells. Characteristic of the Immunofluorescence reaction is the denser staining of the newly formed cells at the base of the mucosa (bottom left) and lighter staining of the mature cells towards the top of the mucosa. Experimental evidence suggests that the autoantigen in the parietal cell is the enzyme H+,K*-ATPase which is involved in production of acid secreted into the gastric juice.

Histologic features

Normal gastric mucosa

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