Biomedical subjects
Publications and source records attributed to A D Webster.
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.
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.
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.
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.
In most patients with common variable immunodeficiency (CVI) there is evidence for an intrinsic B cell defect, despite an apparently normal cell phenotype. There are at least five separate subgroups of CVI, based on B cell function. These groups may be variations in severity of a single defect, or distinct molecular defects. At least some patients may have an abnormality in the secretory process of the B cell. The existence of patients whose cells can secrete IgM and IgG in vitro and yet are hypogammaglobulinaemic in vivo implies that the architecture of lymphoid organs or the traffic of lymphoid cells may be involved in the pathogenesis of the disease. The data on T cell defects in CVI indicates that, with sensitive assays, many patients have some abnormality. In the face of a much more defined B cell defect it is not yet possible to assess the overall contribution of the T cell defects to the immune failure.
We have compared the proliferative responses of an enriched population of B lymphocytes from patients with acquired (common variable) hypogammaglobulinemia (CVH) with the responses of cells from normal individuals. The uptake of [3H]thymidine into DNA was measured on stimulation with a range of interleukins (IL-2, IL-4, and IL-6) and solid-phase anti-IgM. Flow cytometry using CD19 and surface IgM showed that the "non-T" preparations from the peripheral blood of CVH patients either contained B cells within the normal range (30-40% of the cells) or in a minority group no B cells (less than 3% of the cells). Overall, there were no significant differences between the proliferative responses of patients' cells (in the group where normal numbers of B cells were present) and normal cells with any combination of stimulus used. No IgG was produced by cells from any patient and in only one patient was IgM production observed. This suggests that the primary B lymphocyte defect in CVH is in the differentiation phase in B cell function rather than in the growth phase. However, the presence or absence of B cells suggests that different defects exist in subgroups of patients with this disease.
Eosinophils were found to bind radiolabelled DNA probes non-specifically during in situ hybridization. Pretreatment of cells with carbol chromotrope blocked non-specific binding without interfering with the recognition of specific nucleotide sequences.
Serum neopterin was measured in patients with acquired 'common variable' hypogammaglobulinaemia (CVH), X-linked agammaglobulinaemia (XLA) and healthy subjects. There was a highly significant increase in neopterin levels in the CVH patients as compared with that of the other groups, particularly in those CVH patients with non-A non-B or granulomatous hepatitis. There was no association between raised neopterin levels and chronic infective lung disease. Since chronic viral infections are associated with raised serum neopterin, this data add some support to a viral aetiology for CVH.
We have studied T cell defects in acquired 'common-variable' hypogammaglobulinaemia (CVH) by measuring the synthesis of DNA, RNA and protein in vitro in response to mitogens and to interleukin 2 (IL-2). We have confirmed that some patients have defective DNA synthesis in response to PHA and shown that this extends to responses to cell-derived B cell growth factor (c-BCGF) which is also mitogenic to T cells. DNA synthesis induced by IL-2 was not defective in these patients suggesting IL2-receptor induction is normal. The mitogen-related defect in DNA synthesis was not accompanied by any reduction in synthesis of RNA or of protein. Levels of the rate limiting enzyme (thymidylate synthetase EC 2.1.1.45) responsible for de novo DNA synthesis in the absence of endogenous thymidine were measured following PHA stimulation and found to be in the normal range. In the CVH patients (but not in normal individuals) the relationship between the levels of thymidylate synthetase and DNA synthesis in response to PHA approached significance, suggesting that this pathway becomes more important in CVH patients than in normal individuals perhaps because of defects in the thymidine 'salvage' pathway.
Cellular defects in patients with common variable hypogammaglobulinaemia (CVH) and X-linked agammaglobulinaemia (XLA) have been studied in vitro, using a mitogen-driven system of immunoglobulin production. We have confirmed our previous finding of impaired low-density (dendritic) accessory cell function in CVH and now show that accessory cell function is normal in XLA. We demonstrate that macrophage accessory function is normal in CVH. T cell help for IgM production is also deficient in CVH, and T cell help in XLA is also abnormal for both IgG and IgM. Some XLA patients have excessive T suppressor activity. The contribution of these defects to the clinical states is discussed.
The affinity of lymphocyte 5'-nucleotidase (5NT) for its substrate adenosine monophosphate (AMP) was studied in Epstein-Barr virus immortalized B-lymphocyte clones from healthy controls and patients with primary hypogammaglobulinaemia. Km values for AMP for 5NT in most of the patient clones were found to be significantly increased compared to B-cell clones from normal subjects, whereas Vmax values were within the normal range.
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A patient with a history of at least 10 years 'common' variable hypogammaglobulinaemia seroconverted to HIV-1 and became hypergammaglobulinaemic. The HIV isolated from his blood did not polyclonally activate B cells from normal donors. The mechanism of the hypergammaglobulinaemia is discussed.
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Although administration of rIL-2 post-T depleted allogeneic bone marrow transplantation (TD-BMT) offers the prospect of augmenting immune reconstitution and thereby reducing the risks of infection and relapse, it has been unclear what direct or indirect effects this agent would have on the regenerating myeloid system. We find that addition of 200 IU or rIL-2 to patient lymphocytes obtained within 6 wk of TD-BMT results in a substantial (2 to 3 log) increase in INF-gamma secretion and the production of TNF. Cytokines present in supernatants obtained from IL-2-stimulated patient lymphocytes have two contrasting effects on myeloid cells from normal donors and from marrow recipients. They prime granulocytes for enhanced oxidative metabolism as measured by ability to generate chemiluminescence in response to FMLP, whereas IL-2 added directly to neutrophils has no effect. However, these IL-2-induced cytokines also act to inhibit myeloid progenitor growth and reduce granulocyte macrophage (GM) colony formation by a mean of 53%. Preincubation of supernatants with anti-IFN-gamma antibody partially abrogates both enhancement of granulocyte chemiluminescence and suppression of marrow CFU-GM. Addition of IL-2 directly to recipient marrow also produces inhibition, leading to a 25% reduction of GM-colony growth. This effect is not due to direct interaction between myeloid progenitor cells and IL-2, because it is completely abrogated by removal of CD8 and Leu-7+ lymphocytes from the marrow. Although the suppressive effects on marrow growth in vitro are of particular concern after BMT, the potential of IL-2 to promote granulocyte function, immune reconstitution, and anti-leukemic activity after TD-BMT justify further consideration of IL-2 therapy in this setting.
The T4 molecule (CD4) is an important component of the human immunodeficiency virus (HIV) receptor. As yet, no other component has been demonstrated. We report here that two cell lines, a B lymphoblastoid cell line (Gupta) and a glial cell line (HEB) derived from human embryonal brain tissue, are productively infectable with two distinct isolates of HIV as judged by electron microscopy and immunological and virological studies. These two cell lines do not display detectable surface CD4 glycoprotein. However, using S1 nuclease analysis, we have found that both cell lines do express low levels of CD4 mRNA. Neither of them produced syncytia formation upon HIV infection, a recognized feature of HIV-infected cells strongly expressing the CD4 glycoprotein. It is conceivable that the CD4 mRNA is translated, resulting in meager surface expression of CD4 molecules undetectable by conventional techniques. Therefore, infection with HIV may be one of the most sensitive methods of demonstrating low levels of CD4 expression by human cells. Furthermore, HIV-infected Gupta cells have here been shown to be more susceptible to the lytic activity of natural killer (NK) cells than their uninfected counterparts. These phenomena may be important for pathogenesis of HIV-associated disorders.
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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.