Ashni Kapadia

Indirect immunofluorescence studies of blood group A, H, I, and i antigens were performed on the gastric mucosae and tumor tissues of patients with gastric carcinoma, on the mucosae of patients with chronic benign gastric ulceration, and on the mucosae of infants who had died of causes other than gastrointestinal disease. The following findings were of particular interest: (1) Normal 'secretor' type mucosae were distinguishable from 'non-secretor' type mucosae by the uniform staining of the A or H antigens at the surface and in the pits. Normal 'non-secretor' type mucosae showed little staining of the H or A antigens but, instead, there was staining with anti-I(Ma) antibody. Staining with anti-I(Step) and anti-i(Den) did not show a clear correlation with the 'secretor'/'non-secretor' status of the normal mucosae. (2) Apparently normal areas of gastric mucosae of patients with gastric carcinoma or the normal part of gastric mucosae of patients with benign gastric ulcer frequently showed focal areas of loss or gain of the blood group antigens as is often seen in gastric carcinoma tissues. (3) In the mucosae of patients with intestinal metaplasia there was marked loss of A/H antigens in 'secretors' and I(Ma) antigen in 'non-secretors'. (4) Staining characteristics of tissues from gastric carcinoma were:(a) Focal loss of the expected A/H or I antigens was observed with much variation in staining from area to area, but only a minority showed complete loss of the expected staining. (b) A majority of the carcinomas from 'secretors' showed foci of substantial staining with anti-I(Ma) in contrast to normal 'secretor' mucosae. This is probably due to incomplete biosynthesis of A/H determinants. (c) Incompatible A-like staining by a rabbit anti-A serum was observed in one out of nine adenocarcinomas from blood group B or O persons. (d) A few cases showed substantial i antigen staining. The aberrant expression of blood group A, H, I, and i antigens in neoplastic as well as in some areas of morphologically normal mucosa of patients with benign and malignant diseases of the stomach is discussed in the context of current biochemical knowledge.

Surface immunofluorescence experiments using a human anti-i and two anti-I antisera have been performed on human peripheral blood lymphocytes. These are known to contain cold-reactive monoclonal IgM antibodies against the carbohydrate sequence: (formula: see text). A high proportion of B- and T-type lymphocytes express these I and i determinants. In the presence of anti-human immunoglobulin, the cold-reactive membrane-associated complexes of I-anti-I and i-anti-i become stabilized, and redistribution (with patching and capping) can be elicited at 37 degrees C. Dual fluorescence experiments have shown striking concordant staining of I or i (fluorescein) caps and patches with concanavalin A (rhodamine) reactive sites on normal and leukemic cells, suggesting that a proportion of I and i active structures of lymphocyte membranes are structurally associated or physiologically coupled with glycoproteins carrying oligosaccharides with branched mannosyl cores.

transcription. The specific mechanism underlying this dysregulation remains unclear, but it is hypothesized to involve the formation of G-quadruplexes (G4) structures within the XDP-SVA that impede transcription. In this study, we show that ZNF91, a critical repressor of SVA retrotransposons, specifically binds to G4-forming DNA sequences. Further, we found that genetic deletion of ZNF91 exacerbates the molecular phenotype associated with the XDP-SVA insertion in patient cells, while no difference was observed when ZNF91 was deleted from isogenic control cells. Additionally, we observed a significant age-related reduction in ZNF91 expression in whole blood and brain, indicating a progressive loss of repression of the XDP-SVA in XDP. These findings indicate that ZNF91 plays a crucial role in controlling the molecular phenotype associated with XDP. Since ZNF91 binds to G4-forming DNA sequences in SVAs, this suggests that interactions between ZNF91 and G4-forming sequences in the XDP-SVA minimize the severity of the molecular phenotype. Our results showing that ZNF91 expression levels significantly decrease with age provide a potential explanation for the age-related progressive neurodegenerative character of XDP. Collectively, our study provides important insights into the protective role of ZNF91 in XDP pathogenesis and suggests that restoring ZNF91 expression, destabilization of G4s, or targeted repression of the XDP-SVA could be future therapeutic strategies to prevent or treat XDP.