ORIGINAL ARTICLESAUTOANTIBODY-CONTAINING CELLS IN THE GASTRIC MUCOSA IN PERNICIOUS ANÆMIA
Abstract
In gastric biopsies taken from patients with pernicious anæmia, mononuclear inflammatory cells have been shown to contain antibodies against two constituents of human gastric parietal cells—namely, a microsomal component, and Castle's intrinsic factor.
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2 Immunological aspects of gastritis and pernicious anaemia
1987, Bailliere's Clinical GastroenterologyPernicious anaemia (PA) and chronic atrophic gastritis (CAG) aggregate in families, occur more often in women, and are associated with various heritable traits such as fair skin and blue eyes. They are linked to certain HLA types. Linkages are relatively weak for A and B antigens, but somewhat stronger in the case of DR antigens. There are strong associations between PA and other organ-specific autoimmune diseases, particularly those affecting the thyroid. Discordance for PA in monozygotic twins has been reported, and it may well be that expression of the disease requires, in a genetically susceptible individual, initial injury to the gastric mucosa by some environmental agent such as a virus or some physical irritant, with perpetuation of injury then depending upon autoimmune mechanisms.
Numbers of T cells are substantially increased in the gastric mucosa of patients with PA, but the ratio of T suppressor to T helper cells is normal. There is a relatively greater increase in numbers of cells not of T lineage, presumably B-cells. Gastric autoantibodies, both to different components of the parietal cell and to two sites on the IF molecule, are present in a majority of patients with PA. There is evidence that these autoantibodies, especially PCA, may be cytotoxic to parietal cells, and may also inhibit their maturation and proliferation. Antibodies to chief cells have not been described, and the parallel disappearance of these cells in atrophic gastritis is unexplained. The peripheral blood lymphocytes of some patients with autoimmune gastritis transform, or produce lymphokines, when exposed to gastric antigens, and patients with PA have been shown to have delayed type cutaneous hypersensitivity to gastric antigens. The relevance of these observations to the pathogenesis of their gastric mucosal lesion is unclear. There is a growing body of evidence to support the operation of humoral immune mechanisms in autoimmune gastritis, but this clearly does not preclude the coexistent involvement of cellular mechanisms. For example, impaired suppressor T cell function has been strongly implicated in certain other autoimmune disorders, but has received scant attention in PA.
By generally accepted criteria, PA is an excellent example of an organspecific autoimmune disease. As yet, there is no acceptable single unifying hypothesis which will account for all of the phenomena which have been described in the disease. Since the population of patients with classical PA is not fully homogeneous in respect to any single abnormality which might be implicated in pathogenesis, and since a disease which is very similar to PA occurs in patients both with hypogammaglobinaemia and with chronic mucocutaneous candidiasis (disorders which in some respects are at opposite ends of the immunological spectrum), one must leave open the possibility of pathogenetic heterogeneity.
Anti-gastric antibodies
1971, Revue Francaise d'AllergologieLes anticorps anti-cellules pariétales (ou bordantes) sont essentiellement décelés par immunofluorescence indirecte en utilisant des coupes (non fixées) de qumuquse gastrique (d'homme, de singe et de rat). Ils s'observent dans le sérum chez :
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75 à 90 p. cent des cas d'anémie pernicieuse,
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50 p. cent des gastrites atrophiques chez la femme,
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30 p. cent des thyroïdites ou thyrotoxicose et 16 p. cent des normaux âgés de plus de 60 ans.
Les anticorps sont aussi produits localement dans la muqueuse gastrique et excrétés dans le liquide gastrique.
Les anticorps anti-facteur intrinsèque sont : soit capables de bloquer la combinaison de IF avec B 12, soit aptes à se fixer sur le complexe IF-B 12.
Ils s'observent dans le sérum de 40 à 60 p. cent des biermériens mais sont parfois présents dans le liquide gastrique et absents dans le sérum.
L'expérimentation animale nous a confirmé l'apparition possible d'auto-anticorps anti-cellules pariétales, anti-facteur intrinsèque et anti-pepsinogène, notamment après une immunisation réalisée avec des antigènes d'origine hétéro-spécifique.
The anti-parietal (or border) cell antibodies are mainly found by means of indirect immunofluorescence using (unfixed) sections of the gastric mucosa (of humans, monkeys and rats). They can be seen in the serum in 75 to 90 per cent of cases of pernicious anaemia, in 50 per cent of atrophic gastritis in women, in 30 per cent of thyroidites or thyrotoxicoses and in 16 per cent of normal subjects over sixty.
The antibodies are also produced locally in the gastric mucosa and excreted in the gastric juice.
The anti-intrinsic factor antibodies are able either to block the combination of the intrinsic factor with B 12 or to fasten on to the intrinsic factor-B 12 complex.
They can be seen in the serum in 40 to 60 per cent of pernicious anaemia cases but they are sometimes present in the gastric juice and absent from the serum.
Experiments on animals have confirmed the possible appearance of antiparietal cell, anti-intrinsic factor and anti-pepsinogenous auto-antibodies, notably after immunization carried out with antigens of hetero-specific origin.
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Eleven out of twenty-three patients with thyroid disease and intrinsic-factor (I.F.) antibodies in serum had an atrophic gastritis which did not progress to pernicious anæmia over a period of 3-7 years. In these patients the absorption of vitamin B12 remained normal, and the amount of acid and I.F. in the gastric secretion remained unchanged. Ten out of these eleven patients had thyrotoxicosis and nine had a family history of other autoimmune disorders. The other twelve patients with I.F. antibodies had early pernicious anæmia. Six had thyrotoxicosis and six had Hashimoto's thyroiditis or primary myxœdema. Four of these patients had a family history of thyroid disease or pernicious anæmia. It is concluded that the patients with I.F. antibody and a non-progressive atrophic gastritis differ from patients with pernicious anæmia in that the I.F. antibody appears in serum at a relatively early phase in the evolution of gastritis when adequate amounts of I.F. are still being produced. They also differ from patients with pernicious anæmia in the absence (with one exception) of I.F. antibody in gastric juice. The leucocyte-migration test, done to assess cellular immunity to I.F., was positive in 40% of pernicious-anæmia cases but in only one patient followed for 5 years without progression to pernicious anæmia in spite of I.F. antibodies in serum and gastric juice.
Current concepts of pernicious anemia
1970, The American Journal of MedicineThe “idiopathic” anemia described by Addison and later called “pernicious” is the result of a particular immediate cause of vitamin B12 deficiency, namely, lack of the socalled intrinsic factor of the normal human gastric secretion. In the normal stomach this insignificant glycoprotein is secreted by the parietal cells and avidly binds to itself the small amounts of vitamin B12 found in most foods of animal origin and released during peptic digestion. Once so bound, the vitamin is then conveyed to the distal ileum where the intrinsic factor-vitamin B12 complex is specifically adsorbed to the microvilli of the intestinal cell, whereas the vitamin is released to the cell interior and subsequently reaches the blood stream.
In rare instances “juvenile” pernicious anemia is the congenital result of an isolated lack of intrinsic factor in an otherwise normal gastric secretion, perhaps as the expression of the homozygous state of recessive genetic defects. The usual adult disease affects persons of middle age or older, probably as a consequence of a dominant genetic background of variable expression depending upon somatic influences. Recognizable among these is the incidence of chronic gastritis that increases with age in the general population. This process is associated with progressive glandular atrophy preceded or accompanied by local infiltration with mononuclear cells and by serum antibodies directed against the cytoplasm of the gastric parietal cell. Clinical pernicious anemia with a low serum vitamin B12 level develops as a result of failure to secrete intrinsic factor. The serum of many of these patients, as well as their blood lymphocytes and the mononuclear cells infiltrating the atrophic gastric mucosa, also contain antibodies directed against intrinsic factor. These serum antiintrinsic factor antibodies perhaps become detectable only at this stage because in the atrophic gastric mucosa there is no longer sufficient antigen to absorb them. It is uncertain whether the serum antibodies or local immunocytes are a cause or an effect of the gastritis. As a cause, the immunocytes would seem more likely than the serum antibodies. What is clear is that, unless anti-intrinsic factor antibodies leak into or are secreted into the gastrointestinal tract, they have no immediately adverse affect upon the assimilation of vitamin B12.
Effect of Prolonged Administration of Parietal Cell Antibodies from Patients with Atrophic Gastritis and Pernicious Anemia on the Parietal Cell Mass and Hydrochloric Acid Output in Rats
1970, GastroenterologyMild atrophic lesions were produced in gastric mucosa of rats injected for 6 to 8 weeks with immunoglobulin G processed from sera of patients with atrophic gastritis and pernicious anemia, containing circulating parietal cell antibody. These changes consisted of thinning of the mucosa, decrease of the mucosal volume, and significant reduction of parietal cell mass, but without signs of inflammation and delayed hypersensitivity reaction. No similar lesions were observed in control animals. The parallel between the reduction of the parietal cell mass and decrease of the mucosal volume, as well as decrease in the intrinsic factor activity of the gastric juice of rats treated for 8 weeks with parietal cell antibodies containing immunoglobulin G, suggests concomitant reduction of peptic cell mass under these circumstances. Rats treated with parietal cell antibodies also demonstrated a profound decrease of the hydrochloric acid output, which was more pronounced than was warranted by the coexisting reduction of the parietal cell mass. This was not seen in control animals. The possible implications and limitations of this study in regard to the problem of gastric atrophy and gastric anacidity in man are discussed.