Biomedical subjects
Publications and source records attributed to A D Webster.
Erythrocyte CR1 receptors were measured in 16 patients with primary hypogammaglobulinaemia and compared with those in 14 normal controls. There was no significant difference in the number of receptors in the two populations. One patient with hypogammaglobulinaemia had a very low number of receptors and subsequently developed red cell aplasia.
Viral infections that occur in patients with primary immunodeficiencies are summarized. These viral infections include: Echovirus, poliovirus, varicella zoster, non-A non-B hepatitis and hepatitis B. Cases of X-linked lymphoproliferative syndrome associated with Epstein-Barr virus infection and congenital rubella syndrome are also reviewed. In the second part of the paper, retrovirus (HIV) isolations from blood mononuclear cells of 3 out of 31 patients with common variable hypogammaglobulinemia are reported. This supports the concept that some of the non-familial "primary" immunodeficiencies may be due to retrovirus infections.
Mononuclear cells were obtained from 42 patients with 'common variable' hypogammaglobulinaemia (CVH) and co-cultured with various cell lines in an attempt to isolate retroviruses. Cultures from only two patients showed evidence of a viral infection, although the virus could not be isolated and characterized in either. Despite the previous isolation of HIV's from two other CVH patients, this data suggests that similar viruses are not etiologically involved in the majority of patients.
Dipeptidyl peptidase IV (DPIV), a T cell enzyme, has been implicated in the regulation of lymphocyte proliferation in response to lectins and allogeneic cells. A sensitive fluorimetric assay has been established for the enzyme and used to investigate DPIV activity, kinetics and the subcellular localization in lymphocytes from control subjects, cord blood and patients with common variable hypogammaglobulinaemia (CVH) and chronic lymphatic leukaemia (CLL). Using sucrose density gradient centrifugation and organelle marker enzyme assays, in conjunction with digitonin as a selective plasma membrane perturbant and diazotized sulphanilic acid as a non-permeant enzyme inhibitor, DPIV was shown to be a plasma membrane ecto-enzyme. A significant decrease in lymphocyte DPIV activity was observed in cord blood and in patients with CVH and CLL compared to controls. Kinetic analysis showed a marked decrease in the Vmax of lymphocyte DPIV from cord blood and patients with CVH and CLL compared to controls. The apparent Km for the substrate was unaffected in cord blood and patients with CLL. However, in patients with CVH the Km was significantly reduced. Various enzyme inhibitors showed no differences between control subjects and CVH lymphocyte activities. The decreased Km for DPIV provides further evidence for a stem cell defect rather than cell immaturity in CVH.
The adenine nucleotide profiles (AMP, ATP, NAD and NADH2) of peripheral blood lymphocytes isolated from patients with common variable hypogammaglobulinaemia (CVH) were similar to those in control cells. AMP and ATP levels were also similar in the lymphocytes of patients with chronic lymphatic leukaemia (CLL). Since CVH and CLL patients have reduced activity of plasma membrane ecto-5'-nucleotidase, our data suggests that this enzyme does not regulate the levels of intracellular adenine nucleotides, at least in "resting" cells.
We have shown that mycoplasmas bind spontaneously to neutrophils, as well as directly activating the first component of complement with probable subsequent binding through neutrophil complement receptors. Thus, antibody is not required to opsonize mycoplasmas for neutrophil phagocytosis. Furthermore, mycoplasmas remain viable when phagocytosed in the absence of antibody and may be carried inside neutrophils to various parts of the body to cause infection (e.g. joints). We found that antibody alone inhibits the growth of mycoplasmas in vitro. These observations suggest that the role of antibodies is to control the growth of mycoplasmas on mucosal surfaces; neutrophils play no part in defence and may even aid dissemination of the infection. This helps to explain why patients with hypogammaglobulinaemia are prone to systemic mycoplasma infections.
Three hypogammaglobulinaemic patients with non-A, non-B hepatitis transmitted by gammaglobulin replacement therapy were treated with lymphoblastoid alpha-interferon. All showed a striking improvement in serum aminotransferases after the start of each course of treatment.
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Thirty-two patients, including 29 children, presenting with acute unexplained encephalopathies were studied prospectively for evidence of virus infection, immunodeficiency, and immunologic involvement in the pathogenesis of their illnesses. Twenty-five of these patients had a clinical diagnosis of encephalitis. Twenty-two of these 25 had laboratory evidence of active virus infection, the majority with viruses usually associated with self-limiting illness outside the central nervous system. In patients with encephalitis, immune competence, as reflected by T-cell numbers and subsets in peripheral blood, in vitro interferon production, natural killer activity, and specific antiviral antibody production, was normal. Transudation of albumin into the cerebrospinal fluid (CSF), a measure of blood-brain barrier breakdown, was seen in 40% of patients. Intrathecal antibody synthesis was suggested by an elevated IgG index in 9/20 CSF/serum pairs but was confirmed by an elevated specific IgG ratio in only 3. The serum IgG1 and IgG3 subclass levels were significantly elevated at the time of the illness and remained elevated 8 months later; IgG2 and IgG4 levels were normal. IgE levels were elevated in 50% of patients. Serum levels of IgM antibodies against Escherichia coli measured 8 months after the neurological illness were also significantly higher in encephalitis patients than in age-matched healthy controls. Human myelin basic protein did not induce proliferation in peripheral blood lymphocytes in any patient. We conclude that most encephalopathies associated with viral infections are not due to an underlying generalized immunodeficiency, and probably result from an inappropriately vigorous immune response.
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Propylene glycol (PG) in a concentration of 0.5-1.0% inhibits natural cytotoxicity and neutrophil chemiluminescence. This is the first reported effect of PG on defence mechanisms in man. PG is frequently used as a vehicle in high concentrations by the pharmaceutical industry and it would be wise to consider its potential immunosuppressive effects in the evaluation of drug formulations.
In the light of the recognition of Toxic Shock Syndrome occurring in burned children in our Unit, IgG subclass levels were monitored during the first week post burn in a group of 16 children. There were marked differences between some of the subclasses.
Studies were performed on the binding of tritiated adenosine and its analogues, 5'-N-ethylcarboxamide adenosine (NECA) and N6-phenylisopropyladenosine (PIA), to human peripheral blood lymphocytes. These revealed binding only of adenosine (Kd, 1-10 microM, 14,000 binding sites/cell), which was abolished by dipyridamole, a specific adenosine transport inhibitor, suggesting that the binding is to the nucleoside transporter. The absence of high affinity (Kd less than or equal to 1 microM) binding of adenosine or of the two analogues. NECA and PIA suggests that the previously reported effects of adenosine on cAMP formation are not mediated by cell surface specific nucleoside receptors. Binding of adenosine to the carrier in lymphocytes from patients with common variable immunodeficiency was similar to those from control subjects.
The half-life of total IgG and antibodies to cytomegalovirus and pneumococcal polysaccharide type III was consistently prolonged after a 9 month course of intravenous gammaglobulin treatment in three patients with 'primary' hypogammaglobulinaemia. The half-life of antibody to tetanus toxoid showed no consistent pattern. These data are at variance with the traditional dogma that IgG half-life is inversely related to serum IgG concentration. They suggest that patients on intravenous gammaglobulin therapy are likely to need less, rather than more, infusions when their serum IgG has risen to within the physiological range.
The lymphokine-activated killer (LAK) cell activity in the peripheral blood of 23 patients with rheumatoid arthritis has been studied. Two control groups comprised (a) nine patients with another chronic inflammatory disease (sarcoidosis) and (b) 19 normal healthy volunteers. The LAK activity induced by human recombinant IL-2 was very similar in controls and patients with rheumatoid arthritis but was significantly decreased in patients with sarcoidosis, although the frequency of LAK-cell precursors measured using a limiting dilution assay was comparable in all three groups. The DNA synthetic response of peripheral blood mononuclear (PBM) cells to IL-2 was slightly decreased in patients with both rheumatoid arthritis and sarcoidosis as compared to controls, but this decrease was not statistically significant. Spontaneous DNA synthesis in PBM cells cultured in the absence of IL-2 was essentially identical in all three groups. We conclude on the basis of these results that the higher risk of non-Hodgkin's lymphomas in patients with rheumatoid arthritis cannot be attributed to an impairment of LAK activity. Furthermore, the doses of gamma-irradiation, which abolished the 'background' cytotoxicity of PBM cells cultured without IL-2 and also blocked effectively both spontaneous and exogenous IL-2-dependent DNA synthesis, had little effect on the generation of LAK activity. These observations are discussed in regard to the role of non-specific cytotoxic cells and the therapeutic efficacy of antiproliferative drugs in rheumatoid arthritis.
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29 children and 3 adults with acute depression of conscious level or acute onset of focal neurological signs were studied prospectively. 3 were found to have a non-infectious cause for their illness. The presence of interferon or specific antibodies in the serum and/or cerebrospinal fluid provided evidence of active virus infection in 25 of the remaining 29 patients. There was laboratory evidence that a virus had invaded the central nervous system in 11 patients. Early investigation gave the highest diagnostic yield. Since several common viruses were identified, it appears that the nature of the illness is due more to the host response than to the nature of the infective agent.