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Biomedical subjects

A D Webster

Publications and source records attributed to A D Webster.

At least 19 recordsLinked to original sources
PubMed1992

Growth retardation and immunodeficiency in a patient with mutations in the DNA ligase I gene.

DNA ligases are required for the replication, repair, and recombination of DNA. A cell line derived from a young woman with growth retardation, sun sensitivity, and immunodeficiencies, who died aged 19 with lymphoma, showed two different miscoding mutations at the DNA ligase I locus on chromosome 19, one in each allele. One of the mutations was inherited from the mother and has also been detected in two healthy brothers. The patient had features similar to those of Bloom's syndrome (BS), but cell lines from BS patients do not have mutations in the DNA ligase I gene. This patient seems to represent a distinct genetic entity.

Cell Line↗
PubMed1992

Mutations in the DNA ligase I gene of an individual with immunodeficiencies and cellular hypersensitivity to DNA-damaging agents.

Two missense mutations occurring in different alleles of the DNA ligase I gene, encoding the major DNA ligase in proliferating mammalian cells, were detected in a human fibroblast strain (46BR). These cells exhibit retarded joining of Okazaki fragments during DNA replication and hypersensitivity to a variety of DNA-damaging agents. 46BR was derived from a patient who displayed symptoms of immunodeficiency, stunted growth, and sun sensitivity. A strongly reduced ability of DNA ligase I to form a labeled enzyme-adenylate intermediate correlated with the genetic defect in 46BR cells. The data indicate that human DNA ligase I is required for joining of Okazaki fragments during lagging-strand DNA synthesis and the completion of DNA excision repair.

Alleles↗
PubMed1992

An association between homozygous C3 deficiency and low levels of anti-pneumococcal capsular polysaccharide antibodies.

Inherited deficiencies of complement components are associated with an increased risk of infection by encapsulated, high grade bacterial pathogens such as Streptococcus pneumoniae, Haemophilus influenzae type b and Neisseria meningitidis. Hence, the levels of antibodies to bacterial capsular polysaccharide antigens were measured using ELISA in 65 patients with inherited deficiencies covering the classical, alternative and terminal components of the complement cascade. Three of the four C3-deficient individuals studied were found to be almost totally deficient in specific anti-pneumococcal capsular polysaccharide (PCP) antibodies. These individuals had a history of recurrent pneumococcal sepsis. While single individuals with C1r, C2 and C1Inh deficiency were found to have low anti-PCP antibody levels, no other group of complement deficiency had significantly reduced anti-PCP antibody levels compared with 100 controls. Antibody levels to the other two polysaccharides were not significantly lower in the patient groups. These findings suggest that C3 may be able to provide a stimulatory signal to promote the production of anti-PCP antibodies.

Adolescent↗
PubMed1992

Effect of 12,13-phorbol dibutyrate and ionomycin on defective B cells in common variable immunodeficiency.

Secretion of IgM and IgG in vitro by B cells from patients with common variable immunodeficiency (CVI) has been used to classify the disease into three groups. On stimulation with anti-IgM and IL-2, group A patients' cells fail to secrete IgM or IgG, group B patients' cells secrete no IgG and significantly lower levels of IgM than normal cells, and group C patients' cells produce normal levels of both isotypes. Direct activation of protein kinase C using 12,13-phorbol dibutyrate and ionomycin followed by IL-2 or IL-4 has been reported to induce immunoglobulin secretion by normal human B cells. We therefore attempted to induce B cells from group A and group B CVI patients to secrete IgM and IgG after direct activation of protein kinase C together with IL-2 or IL-4. The data show that the failure of secretion of immunoglobulin by B cells from CVI patients could not be reversed using this approach. This finding suggests that the activation channel involving protein kinase C in B cells from CVI patients is not involved in the defect in cell differentiation.

B-Lymphocytes↗
PubMed1992

LFA-1-dependent OKT3-driven T cell clusters in common variable immunodeficiency.

The triggering of the TCR/CD3 complex by anti-CD3 (OKT3) antibody leads to the formation of T cell clusters. In cultures of T lymphocytes from most normal individuals, the peak of cluster formation occurs at 24 h, but with cells from patients with common variable immunodeficiency (CVI) it was seen earlier at 4-9 h; in addition, the clusters were larger than normal, particularly at 9 h. Cluster formation by CVI and normal cells was dependent on temperature and divalent cations, but did not require Fc receptors. Since OKT3 clustering is known to be dependent on the LFA-1/ICAM-1 adhesion system, the effect of monoclonal antibodies directed against these molecules was tested. A potent inhibitor was the antibody against the common beta chain of the integrin family (CD18), but of four MoAbs against the alpha chains (CD11), three inhibited and one stimulated T cell aggregate formation. Increased expression of LFA-1 or ICAM-1 on CVI patients' T cells could not be demonstrated. The accelerated clustering was therefore probably due to an increase in the proportion of cells carrying the activated form of LFA-1. The formation of large numbers of homotypic lymphocyte clusters might reduce the effective interaction between B and T cells, thus contributing to the depression of immunoglobulin synthesis observed in this disease.

Adolescent↗
PubMed1991

Bronchiectasis in hypogammaglobulinaemia--a computed tomography assessment.

To determine the pattern of bronchiectasis in hypogammaglobulinaemia we reviewed the CT scans of 38 hypogammaglobulinaemic patients. Twenty-two had bronchiectasis, seven had bronchial wall thickening without bronchiectasis and the remaining nine were normal. The middle lobe was the most common site of bronchiectatic involvement, followed by the lower lobes and the lingula. There were no cases of isolated upper lobe involvement. In patients who had bronchial wall thickening without bronchiectasis the middle lobe and lower lobes were again most commonly affected. It is postulated that in these hypogammaglobulinaemic patients bronchial wall thickening represents a stage of bronchial inflammation prior to the development of bronchiectasis. Patients with X-linked agammaglobulinaemia (XLA) develop bronchiectasis at a significantly earlier age than those with 'common variable' hypogammaglobulinaemia (CVH) (P = 0.02). No correlation was found between the serum levels of immunoglobulin classes at diagnosis and the subsequent development of bronchiectasis.

Adolescent↗
PubMed1991

Antiidiotypic responses to immunization with anti-Leu 3a in human immunodeficiency virus-seropositive individuals.

Anti-idiotypic antibodies to anti-CD4 monoclonal antibodies (MAbs) have been reported to bind to the human immunodeficiency virus (HIV) envelope glycoprotein gp120. To establish whether HIV-infected patients can mount an anti-idiotypic response to murine MAb, four individuals with symptoms of AIDS-related complex (ARC) were immunized over 10 weeks with six intramuscular injections of anti-Leu 3a (1 mg). Despite their immunocompromised state, all patients made anti-constant region and anti-idiotypic antibodies, although the amplitude of the responses varied between individuals. No significant toxic or allergic reactions were seen, and there were no changes in clinical status during the 6 months after immunization. No increase in serum HIV-neutralization titers was seen, and purified anti-idiotypic antibodies did not bind gp120.

Adult↗
PubMed1991

Role of leucocyte integrins in phagocyte responses to granulocyte-macrophage colony stimulating factor (GM-CSF): in vitro and in vivo studies on leucocyte adhesion deficiency neutrophils.

The role of leucocyte integrins in phagocyte function has been studied by comparing normal neutrophils with those from a patient with partial leucocyte adhesion deficiency (LAD), in whom the levels of CD11b and CD11c were 10% of controls, whereas CD11a levels were normal. Unstimulated LAD neutrophils exhibited defective adhesion to plastic (4.4 +/- 1.5% cf. 14.4 +/- 3.8% in controls), but not to human umbilical vein endothelial cells (HUVECs). The adhesion to HUVECs could be further upregulated by granulocyte-macrophage colony stimulating factor (GM-CSF), but not by 12-O-tetradecanoylphorbol 13-acetate (TPA) which, in normal cells, is a more potent 'pro-adhesive agonist'. The normal neutrophil-endothelial interaction induced by GM-CSF in LAD neutrophils was confirmed in vivo when administration of GM-CSF resulted in rapid phagocyte margination. Neutrophil migration and phagocytosis/killing were defective in LAD neutrophils, and some improvement in phagocytosis/killing was seen following in vivo administration of GM-CSF. These studies illustrate that the degree to which the leucocyte integrins mediate adherence-related phagocyte functions varies not only with the particular function, but also with the conditions of stimulation. High levels of CD11b and CD11c expression appear not to be required for unstimulated or GM-CSF-stimulated neutrophil-endothelial interactions, either in vitro or in vivo. Other neutrophil functions, on the other hand, such as migration and phagocytosis/killing are much more dependent on the leucocyte integrins.

Antigens, CD↗
PubMed1991

Common variable immunodeficiency is associated with polymorphic markers in the human major histocompatibility complex.

Common variable immunodeficiency (CVI) is a heterogeneous condition characterized by arrest in B cell differentiation. A high frequency of null alleles of the C4 gene has been reported in patients with this disorder. We investigated the restriction fragment length polymorphisms (RFLP) of the MHC class II genes HLA-DRB, DQA, and DQB, the class III gene C4 and the tumour necrosis factor-alpha) (TNF-alpha) gene in 40 Caucasian patients. The results showed an increase in HLA-DR3 in patients (40% vs 30.5%), but, more significantly, there was a striking increase in the number of CVI patients who carried a deletion of the C4A gene (46% vs 25%). In both patients and controls there was strong allelic association between HLA-DR3 and C4A deletion, and HLA-DR3 and TNF-alpha. Our results suggest that genes present on an extended haplotype containing these three polymorphisms contribute to genetic susceptibility to CVI.

Adolescent↗
PubMed1991

Defects in proliferative responses of T cells from patients with common variable immunodeficiency on direct activation of protein kinase C.

DNA synthesis in response to mitogens has been studied in T cells from nine patients with common variable immunodeficiency (CVI) and seven normal individuals. Five out of the nine patients had cells with subnormal responses to the mitogen phytohaemagglutinin (PHA). As PHA-induced responses are largely mediated through activation of Ca(2+)-dependent protein kinase C, we studied whether the defective response was still present on direct activation of protein kinase C. This was done using combinations of concentrations of phorbol 12,13,-dibutyrate and the calcium ionophore ionomycin which induced proliferation in normal T cells. We found that in CVI patients with T cells which had normal responses to PHA, responses to phorbol ester and ionomycin were at the same level as in normal T cells. However, with this treatment, in which the linkage between the membrane receptor and protein kinase C is bypassed, the level of DNA synthesis was still depressed in the patient group whose T cells had subnormal responses to PHA. IL-2 failed to restore the DNA synthesis to normal levels when added with the phorbol ester and ionomycin to T cells from one patient in this group. These data suggest that in a group of CVI patients there are defects in T cell activation pathways at or down-stream of protein kinase C.

Cells, Cultured↗
PubMed1991

Raised serum levels of CD8, CD25 and beta 2-microglobulin in common variable immunodeficiency.

Soluble CD8, soluble CD4, soluble CD25 (IL-2 receptor), beta 2-microglobulin and the cytokine tumour necrosis factor-alpha (TNF-alpha) were measured in sera from patients with common variable immunodeficiency (CVI). Levels of soluble CD8, soluble CD25 and beta 2-microglobulin but not of soluble CD4 and TNF-alpha were raised significantly above levels in normal sera. Sera from patients with X-linked agammaglobulinaemia, who are also antibody deficient, did not show this marked elevation. The raised levels of soluble CD8, soluble CD25 and beta 2-microglobulin in CVI, correlated with the extent of the defects in the B lymphocytes assessed in vitro, as well as with the clinical severity of the disease. The selective release of these molecules into sera may indicate that abnormal cellular activation occurs in most CVI patients. It is also possible that the raised levels of these soluble molecules play a part in the immunodeficiency.

Acquired Immunodeficiency Syndrome↗
PubMed1991

Alopecia totalis and vitiligo in common variable immunodeficiency.

Three cases of severe and irreversible alopecia occurring in patients with common variable immunodeficiency are described. In all three cases, hair loss developed after the diagnosis of immune deficiency; one of the patients also had extensive vitiligo. A fourth patient had vitiligo in the absence of alopecia. No change in the alopecia or vitiligo was noted in any patient as a result of immunoglobulin replacement therapy.

Adult↗
PubMed1990

Phenotypic features and proliferative activity of B cell progenitors in X-linked agammaglobulinemia.

In this study, we applied mAb and heterologous antisera in double marker combinations to investigate the phenotype and the proliferative activity of immature B lineage cells in XLA. Bone marrow (BM) samples from eight male adult patients with no circulating B lymphocytes were studied. The proportions and the phenotype of the earliest identifiable B cell progenitors, expressing nuclear terminal deoxynucleotidyl transferase (TdT), cytoplasmic CD22, and membrane CD19 and CD10 were identical to those observed in normal BM. In XLA these cells represented 1.2% to 22% of BM mononuclear cells; 5% to 42% and 1% to 45% of such cells weakly expressed CD20 and CD37, respectively, and invariably lacked CD13 and CD33. Cytoplasmic mu+ sIg- pre-B cells were seen in low numbers (0.1% to 0.3%) in four samples and were undetectable in the remaining four. Consequently, the ratio TdT+/c mu+ was greater than 100 in five out of eight samples studied in contrast to the less than 10 values seen in normal individuals. The proliferative activity of B lineage progenitor cells was studied by using Ki67 and anti-bromodeoxyuridine mAb. Although the proliferation of TdT+ cells in XLA was comparable with that seen in normal BM samples (24% to 59% of TdT+ were Ki67+ and 11% to 27% incorporated bromodeoxyuridine), this was dramatically reduced in the c mu+ cells (no c mu+, Ki67+ seen in three samples where pre-B cells were observed). Thus, the abnormalities of B cell differentiation in XLA are first seen at the c mu+ pre-B stage and suggest a maturation block in the transition between TdT+, c mu- pre-pre-B cells and c mu+ pre-B cells. The severity of this block may be variable, allowing the generation of a near normal number of pre-B cells in some patients, which nevertheless have a defective proliferative activity. Finally, our study further supports the concept that the effects of the "XLA gene" are confined within the B lineage by demonstrating that the proportions of T cells bearing TCR-alpha beta and TCR-gamma delta in XLA are similar to those seen in normal individuals.

Agammaglobulinemia↗
PubMed1990

Classification of patients with common variable immunodeficiency by B cell secretion of IgM and IgG in response to anti-IgM and interleukin-2.

We have classified patients with common variable immunodeficiency (CVI) on the basis of the ability of their B cells to respond to anti-IgM and interleukin (IL)-2 in vitro. Group A had cells unable to secrete IgM or IgG, Group B secreted IgM alone, and Group C secreted both IgM and IgG. A separate small group of patients lacked peripheral B cells. Where Ig secretion was present with anti-IgM and IL-2, EBV increased it, but where it was absent, EBV only induced IgM secretion in two out of eight Group A patients and IgG in one out of five Group B patients. These classifications are related to the sex of the patient and may represent different loci of the block in B-cell differentiation in CVI.

Antibodies, Anti-Idiotypic↗
PubMed1990

Role of interleukin-2 and interleukin-6 in the mitogen responsiveness of T cells from patients with 'common-variable' hypogammaglobulinaemia.

We have assessed the ability of interleukin-2 (IL-2) and interleukin-6 (IL-6) to augment the proliferative response of T lymphocytes from 'common-variable' hypogammaglobulinaemia (CVH) patients and from normal controls, to the mitogens phytohaemagglutinin (PHA) and OKT3. We show that with cells from the control group and from those patients whose T cells respond to PHA within the control range, both IL-2 and IL-6 will significantly augment the response to OKT3. However, in those patients with a T cell defect in which the PHA response is below the control range, neither IL-2 nor IL-6 could restore the PHA or OKT3 response to normal. Responses to IL-2 or IL-6 alone were always in or above the control range.

Agammaglobulinemia↗