HLA antigens in pernicious anaemia.

The increased frequency of HLA-B7 alone and HLA-A3/B7 together, in the same patient, has been confirmed in pernicious anaemia. There is no increase prevalence of HLA-A3 alone. No association has been found between the presence of serum intrinsic factor type 1 antibody and HLA-A3 or HLA-B7.     

Molecular targets in pernicious anaemia.

Autoimmune gastritis, leading to pernicious anaemia, is an organ-specific autoimmune disease characterized by chronic atrophic gastritis and circulating gastric parietal cell autoantibodies. The parietal cell autoantigens have recently been identified as the alpha and beta subunit of the gastric proton pump (H+, K+ ATPase). Here Paul Gleeson and Ban-Hock Toh discuss how the identification of these gastric parietal cell autoantigens and the development of a mouse model of autoimmune gastritis have paved the way for an understanding of the pathogenesis of the gastric lesion.     

Agammaglobulinaemia and co-existent pernicious anaemia

Immunological studies were performed on a woman with agammaglobulinaemia and coexistent pernicious anaemia, on her two daughters who had recurrent sinusitis, and on her husband. Serum levels of IgG, IgA and IgM were markedly reduced in the patient, whereas both daughters had a marked selective deficiency of IgA. Autoantibodies to intrinsic factor and to the gastric parietal cell were absent in these subjects, but the serum of one daughter contained thyroid autoantibodies. Assessment of the in vitro response of lymphocytes to four phytomitogens (phytohaemagglutinin, pokeweed, wax-bean and Concanavalin A) showed an altered response to Concanavalin A and an essentially normal response profile to the other mitogens. These responses differed significantly from those of eight agammaglobulinaemic patients without coexistent autoimmune disease, suggesting that subtle immune differences may exist between these two groups of patients. The findings suggest that at least three immunological aberrations in this family were under genetic control; these included abnormalities in serum immunoglobulin levels, altered in vitro lymphocyte response to Concanavalin A and an autoimmune concomitant of pernicious anaemia.     

Nitrate- and nitrite-reducing bacteria in the achlorhydric stomach

The microbial composition of samples of gastric juice from eight achlorhydric patients was determined by aerobic and rigorously anaerobic culture techniques. Bacteria from 16 genera were commonly isolated, but representatives of only three genera, (streptococci, neisseriae and haemophili) were isolated from every patient. Nitrate and nitrite were both reduced by veillonellae, haemophili, staphylococci, corynebacteria, lactobacilli, flavobacteria and fusobacteria, but the potential rate of nitrate reduction by suspensions of veillonellae, Haemophilus parainfluenzae and members of the Enterobacteriaceae were up to ten times more rapid than the rate of nitrite reduction. Conversely, although all Neisseria spp. reduced nitrite only some strains reduced nitrate. Streptococci did not reduce nitrate. Streptococcus sanguis reduced nitrite when grown with haematin; other streptococci did not reduce nitrite. Bacterial nitrate and nitrite reduction were active over the pH range 6-8, similar to the pH range of the achlorhydric stomach. From a knowledge of the composition of the bacterial flora and their potential rates of nitrate and nitrite reduction under prevailing conditions, predictions were made about the tendency of nitrite to accumulate during nitrate reduction. Studies of the transient accumulation of nitrite by mixed cultures of H. parainfluenzae and N. subflava were consistent with these predictions. Haemophili and veillonellae could be responsible for the accumulation of nitrite in the gastric juice of some patients, whereas streptococci and neisseriae would tend to remove nitrite from the stomach as rapidly as it formed.     

Longitudinal study of circulating gastric antibodies in pernicious anaemia.

Temporal changes in gastric antibody response were investigated in 113 (51 men, 62 women) patients with confirmed pernicious anaemia. Their ages ranged from 31-92 years (mean (SD 13.2) 66). At diagnosis, parietal cell antibody and intrinsic factor antibody were detected in 90.9% and 39.1% of all patients, respectively. When the tests were repeated after a mean follow up of 70 months (range 14-137), parietal cell antibody and intrinsic factor antibody were positive in 82.8% and 58.7%, respectively. There was a definite but not significant trend for the organ specific parietal cell antibody to disappear; intrinsic factor antibody became more positive. These results may indicate that with progressive parietal cell destruction, the antigen is no longer available to sustain an immunological response. On the other hand, this hypothesis does not explain the increased prevalence of intrinsic factor antibody which is also a product of parietal cells.     

High incidence of type II autoantibodies in pernicious anaemia.

AIMS: To investigate the incidence of type II autoantibodies to intrinsic factor in pernicious anaemia. METHODS: Three hundred and forty four serum samples submitted for intrinsic factor antibody (IFAB) analysis on clinical or laboratory grounds were tested by an established radioassay and a new enzyme linked immunosorbent assay (ELISA) method for type I and total IFAB, respectively. Sixty of these were found to be positive by ELISA; this method was used to test further, 40 samples of adequate volume for types I and II antibodies. RESULTS: Type II antibodies were detected in 39 of the 40 sera tested. A comparative analysis indicated that seven samples contained pure type II antibody, being positive for total and type II by ELISA, but negative for type I by both the ELISA and radioassay technique. CONCLUSIONS: The occurrence of type II antibody, both alone and in combination with type I, seems to be more common than has previously been recognised, and emphasises the advantage of using a technique which will detect both types of antibody.     

Coexistence of pernicious anaemia and acute erythraemic myelosis

A patient with the apparently unique combination of pernicious anaemia and acute erythraemic myelosis is described. The implications of some of the unusual features together with the difficulties encountered in diagnosis and treatment are discussed.     

Pernicious anaemia, hypogammaglobulinaemia, and altered lymphocyte reactivity: a family study

A mother and her identical twin daughters were found to have pernicious anaemia and achlorhydria. The twins lacked detectable serum IgA and had low to absent serum IgG. Both girls also demonstrated a marked impairment of antibody response to a variety of antigens. Evidence for lymphocyte sensitization to intrinsic factor was demonstrated in these patients by the increased incorporation of tritiated thymidine into DNA and by the production of migration inhibition factor.     

HL-A3 and HL-A7 in pernicious anaemia and autoimmune atrophic gastritis.

Increased frequencies of HL-A7 and the HL-A3,7 haplotype have been demonstrated in pernicious anaemia. There was no significant increase in any HL-A specificity in autoimmune atrophic gastritis. In the whole series of patients with either pernicious anaemia or atrophic gastritis there was a significant increase in the frequency of HL-A3. No association has been found between any HL-A specificity and an increased incidence of either serum gastric parietal cell or intrinsic factor antibody compared with the overall incidence in pernicious anaemia, atrophic gastritis or in the whole series.     

Mucosal argyrophil endocrine cells in pernicious anaemia and upper gastrointestinal carcinoid tumours.

The number and density of argyrophil endocrine cells were morphometrically calculated in gastric fundal mucosal biopsy specimens taken from 64 patients with pernicious anaemia (five with gastric carcinoids, 15 with nodular argyrophil cell hyperplasia, 44 with diffuse argyrophil cell hyperplasia) and from 14 healthy controls. Similar calculations were also made on the ileal mucosa away from the tumour of 10 patients with ileal carcinoids and 10 controls. In the stomach, the argyrophil cell counts were twice as high in the patients with pernicious anaemia than in controls and the densities in the whole mucosa or in the epithelial structures were similarly three to five times higher. The cell counts in the patients showed positive correlation with the serum gastrin concentration. The patients with nodular argyrophil cell hyperplasia and gastric carcinoids formed a uniform group with the highest cell counts and serum gastrin concentrations; the difference between the groups was in the longer duration of pernicious anaemia in the patients with carcinoid tumours. On the other hand, no endocrine cell hyperplasia was seen in those with ileal carcinoids. It is concluded that fundal mucosal endocrine cells show an increase in patients with pernicious anaemia that is related to the gastrin concentration. This phenomenon may favour the development of hyperplastic endocrine cell nodules and, eventually, carcinoid tumours.     

Parietal cell surface reactive autoantibody in pernicious anaemia demonstrated by indirect membrane immunofluorescence.

We examined, in a 'double blind' study, 60 sera from patients with pernicious anaemia for immunofluorescence reactivity with the surface membranes of viable parietal cells isolated from dog stomachs. Fifty-three sera (88%) gave an IgG autoantibody reaction with the surface membranes of parietal cells. Surface staining was also seen with parietal cells from monkey, pig, rat and mouse. The parietal cell surface reactive autoantibody was not found in any of 14 sera from patients with chronic active hepatitis, 10 from patients with systemic lupus erythematosus and 50 from healthy persons. The surface reactivity autoantibody was present in 13 of 14 sera without parietal cell microsomal antibody, 28 of 31 sera without intrinsic factor antibody and in four of four sera without microsomal and intrinsic factor antibodies. Absorption with parietal cell enriched gastric mucosal cells neutralized the activity of the surface reactive but not the microsomal antibody and cross absorption with gastric microsomes neutralized the activity of the microsomal but not the surface reactive antibody. Surface staining of parietal cells was not abolished by absorption with dog or rat hepatocytes, dog or rat kidney cells, human fibroblasts or human AB red blood cells. The results suggest that the parietal cell surface reactive antibody is probably different from the microsomal antibody. Immune reactions of the cell surface reactive antibody with parietal cell surface antigens may play a role in the pathogenesis of the gastric lesion in pernicious anaemia.