Biomedical subjects
A D Webster
Publications and source records attributed to A D Webster.
Evaluation of test immunisation in the assessment of antibody deficiency syndromes.
Antibody responses after immunisation with pneumococcal polysaccharide did not correlate with the severity and frequency of infections in 22 patients with severe hypogammaglobulinaemia, when these were measured by a Farr radioimmunoassay. Five "healthy" patients with severe hypogammaglobulinaemia not only failed to make antipneumococcal polysaccharide antibody, when measured by radioimmunoassay, but also had very low or unrecordable antibody responses to Escherichia coli and failed to produce antibody when immunised with tetanus toxoid. Some of these subjects, however, did make small amounts of IgM antipneumococcal polysaccharide antibody when this was measured by an enzyme linked immunosorbent assay, while others retained some ability to produce IgM or IgA or both in their saliva. These findings show that the measurement of serum antibody responses after immunisation, with the possible exception of IgM antibodies to polysaccharides, is unlikely to be helpful in assessing the requirement for gammaglobulin replacement therapy in patients with hypogammaglobulinaemia.
Production of leucocyte interferon in vitro in children with recurrent respiratory infections.
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Chronic campylobacter colitis and uveitis in patient with hypogammaglobulinaemia.
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The role of B cell differentiation factors and specific T cell help in the pathogenesis of primary hypogammaglobulinemia.
We have examined the function of T and B cells from patients with late onset primary acquired hypogammaglobulinemia (PHG). T cells from these patients give effective help to normal B cells for antigen-dependent antibody synthesis. PHG mononuclear cells also synthesize normal quantities of B cell differentiation factors, which enhance IgG, IgM and antigen-dependent antibody synthesis by normal lymphocytes. While patient T cells appear to behave appropriately, the responsiveness of patient B cells is abnormal. Although they respond to differentiation factors with increased synthesis of IgM, overall levels are 10-50-fold lower than normal B cells, and they produce little or no IgG. This pattern of response is not altered if normal T cells are the source of help. The poor response of the B cell appears to represent immaturity rather than an inherent defect, as IgG-secreting clones can be obtained after Epstein-Barr virus transformation of lymphocytes from certain patients, and some of these clones respond to differentiation factors with increased IgG production. The lack of any functional defect in the T population, and the apparent immaturity rather than abnormality of the B cells, may implicate accessory cells in the pathogenesis of the disease.
Lymphocyte ecto 5'-nucleotidase in immunodeficiency and leukaemia.
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Cutaneous basophil hypersensitivity to inhalant allergens in atopic dermatitis patients: elicitation of delayed responses containing basophils following local transfer of immune serum but not IgE antibody.
Inhalant allergens applied to the skin of sensitive atopic dermatitis patients by means of a modified patch test technique, induce acute eczematous lesions. These lesions contain basophils, eosinophils, mononuclear cells, and neutrophils and represent an example of human cutaneous basophil hypersensitivity. The role of IgE antibody in this eczematous reaction was studied by systemic and local passive transfer experiments. Plasma with high IgE antibody when infused into patients with hypogammaglobulinemia as part of their replacement treatment resulted, post infusion, in cutaneous mast cell and blood basophil sensitization as measured by quantitative skin testing and leukocyte histamine release. Subsequent patch tests on these patients using the house dust mite antigen, antigen P1, produced macroscopic erythematous responses containing mononuclear cells, and eosinophils but not basophils. Local transfer of atopic dermatitis serum with high IgE antibody produced weak macroscopic responses and in these lesions mononuclear cells and both basophils and eosinophils were present. The serum activity which allowed transfer of basophil and eosinophil recruitment was heat labile. Specifically purified antibody to the mite antigen P1 (containing IgE and IgG antibody), when transferred, allowed eosinophil but not basophil recruitment to patch test sites. These results suggest that while the allergen-induced patch test response may involve IgE antibodies, as well as the cells normally involved in delayed responses, another serum activity is also involved.
Serum immunoglobulin concentrations in febrile convulsions.
The mean, age adjusted, serum IgA values of 47 children with febrile convulsions were almost identical to those of controls. Five children had serum IgA values less than 0.1 g/l by nephelometry, suggesting that in some cases at least there may be an association between a low serum IgA concentration and febrile convulsions.
Hypogammaglobulinaemia associated with gold therapy.
Two patients with seronegative arthropathy were noted to be hypogammaglobulinaemic after receiving gold. The clinical course and features suggest that gold is a cause of immunodeficiency.
Endocarditis with rare parvobacillus: host response and difficulty in diagnosis.
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Kinetic properties of 5' nucleotidase in blood lymphocytes from healthy subjects, immunodeficient patients and cord blood.
The Km for AMP for 5' nucleotidase was increased in lymphocytes from patients with common variable (CVH) and sex linked (XLH) hypogammaglobulinaemia and from patients with chronic lymphatic leukaemia (CLL): the Vmax of the latter was low. The kinetic constants for cord blood lymphocytes are similar to adults and the Km does not change with age in lymphocytes from healthy adults. alpha-beta-Methylene adenosine diphosphate competitively inhibited 5' nucleotidase in lymphocytes from both healthy subjects and patients with CVH: the inhibitor constant (Ki) was higher for lymphocytes from patients with CVH than from control subjects. The concentration of zinc, an activator and modulator of 5' nucleotidase, was similar in control and CVH lymphocytes. It is concluded that lymphocyte 5' nucleotidase is functionally, abnormal in both primary hypogammaglobulinaemia and CLL and is deficient in the latter. These results provide support for the concept that CVH is a stem cell disease.
Immunoglobulin levels and function in pre-school children with recurrent respiratory infections.
Thirty pre-school children with recurrent respiratory infections had a higher age adjusted mean serum IgG level than their siblings or a reference group. One index child had persistently low serum IgA, but mean serum IgA and IgM levels for the index children were normal. All of the 23 index children and 17 siblings studied had a four-fold or greater rise in virus neutralizing antibody titre. There was no correlation between serum immunoglobulin levels and frequency of infections. There was, however, a significant inverse correlation between salivary IgA levels when healthy and the number of infections experienced by each child in the study year. Salivary IgA levels rose considerably during acute infections.
Bacterial colonization and nitrite concentration in the achlorhydric stomachs of patients with primary hypogammaglobulinaemia or classical pernicious anaemia.
The degree and type of bacterial colonization was similar in achlorhydric patients with either severe primary hypogammaglobulinaemia or classical pernicious anaemia. This suggests that antibodies do not play a significant part in controlling the gastric flora in achlorhydric patients. The nitrite concentration in gastric juice was higher in the hypogammaglobulinaemia patients, raising the possibility that these patients may have very high levels of nitrite-derived mutagenic compounds in their gastric juice. This may account for the high incidence of gastric cancer in these patients.
Inflammatory disorders of muscle. Echovirus disease in hypogammaglobulinaemic patients.
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Arthritis caused by Mycoplasma salivarium in hypogammaglobulinaemia.
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Enzyme analysis and subcellular fractionation of human peripheral blood lymphocytes with special reference to the localization of putative plasma membrane enzymes.
Human lymphocytes were isolated from defibrinated blood by Ficoll-Hypaque centrifugation with erythrocyte hypotonic lysis. Homogenates of mixed lymphocytes were subjected to analytical subcellular fractionation by sucrose gradient centrifugation in a Beaufay automatic zonal rotor. The principal organelles were characterized by their marker enzymes: cytosol (lactate dehydrogenase), plasma membrane (5'-nucleotidase), endoplasmic reticulum (neutral alpha-glucosidase), mitochondria (malate dehydrogenase), lysosomes (N-acetyl-beta-glucosaminidase), peroxisomes (catalase). gamma-Glutamyl transferase was exclusively localized to the plasma membrane. Leucine amino-peptidase, especially when assayed in the presence of Co2+, was also partially localized to the plasma membrane. Experiments with diazotized sulphanilic acid, a non-permeant enzyme inhibitor, showed that these plasma membrane enzymes are present on the cell surface. No detectable alkaline phosphatase was found in the lymphocytes. Acid phosphatase and beta-glucuronidase were localized to lysosomes and there was some evidence for lysosomal heterogeneity. Leucine amino peptidase, optimal at pH 8.0, showed a partial localization to intracellular vesicles, possibly lysosomes, especially when assayed in the presence of EDTA. These studies provide a technique for determining the intracellular distribution of hitherto unassigned lymphocyte constituents and serve as a basis for investigating the cell pathology of lymphocytic disorders.
Viruses and immunodeficiency diseases.
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Acquired basophil and eosinophil deficiency in a patient with hypogammaglobulinaemia associated with thymoma.
A 55-year-old male with a history of recurrent bacterial and viral infection was found to have hypogammaglobulinaemia in association with a benign thymoma. The patient lacked eosinophils and was deficient in basophils in both the peripheral blood and bone marrow. The absence of eosinophils in a skin challenge known to recruit these cells, and below normal total peripheral blood leucocyte histamine content further suggests a deficiency of eosinophils and basophils respectively. Abnormal suppressor T cell function was documented both phenotypically, using OKT monoclonal antisera, and functionally in pokeweed mitogen stimulated cultures. This patient is the first reported with a deficiency of both eosinophils and basophils occurring in the presence of hypogammaglobulinaemia and thymoma; these abnormalities may be related to the abnormal suppressor T cell function that is present.