Biomedical subjects
Publications and source records attributed to D M Weir.
Mononuclear phagocyte functions are critically dependent on cell surface recognition events. This review describes a number of receptors that appear to recognize simple sugars and function in the clearance of foreign or effete material or in the stimulation of other cellular processes.
The inability to secrete the water-soluble glycoprotein form of the ABO blood group antigens is a genetic characteristic associated with susceptibility to superficial fungal infections and also insulin-dependent diabetes mellitus (IDDM). As oral carriage of Candida albicans in healthy adults is associated with non-secretion, we examined oral carriage of yeasts among 275 patients attending diabetic outpatient clinics, 137 with IDDM and 138 with non-insulin dependent diabetes mellitus (NIDDM) with reference to ABO blood group, secretor status and yeast species. Of the 166 yeast isolates, 109 (66.7%) were C. albicans, a lower proportion compared with 94% reported for healthy individuals. There was no association between ABO blood group and carriage. There was no increase in the proportion of non-secretor carriers of C. albicans among patients with IDDM; but among those with NIDDM, 44% of non-secretors were carriers compared with 21% who were non-carriers (p less than 0.01). The results are discussed in the context of host-parasite interactions influencing colonization.
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The X chromosomes of individuals with isolated steroid sulphatase deficiency (X-linked ichthyosis) from ten families were studied by flow karyotype analysis. In four of the families, a small but significant reduction in the relative fluorescence of the X chromosome was detected consistent with a deletion ranging from 1.2%-3.4% of the X and amounting to a DNA loss of 1.9-5.2 million base pairs. In the remaining six families, three of which demonstrated a molecular deletion of the DNA sequence GMGX9 (DXS237), the relative fluorescence of the X chromosomes was indistinguishable from normal. The phenotypes of those with X deletions detectable by flow cytometry were similar to those of patients without such deletions.
Lower levels of C3 and C4 components of the complement system have been reported for patients with insulin dependent diabetes mellitus (IDDM) but not among those with non-insulin dependent diabetes (NIDDM). We have found a significantly higher proportion of patients who are non-secretors of the ABO blood group antigens among patients with IDDM but not among those with NIDDM. As the gene that controls secretion of these antigens is in the same linkage group as that for the C3 complement component, we compared the levels of C3 and C4 of patients with IDDM by secretor state. The mean level of C3c for 45 non-secretors (75.2 IU/ml) was significantly lower than that found for 59 secretors (86.4 IU/ml) (p less than 0.025). The level of C4 among non-secretors (77.1 IU/ml) was also significantly lower than that of secretors (96.3 IU/ml) (p less than 0.025). The significance of these observations is discussed.
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Gram negative bacteria precipitate reactive arthritis and may be concerned in the pathogenesis of ankylosing spondylitis and other spondyloarthropathies. Susceptibility to many infectious agents is associated with ABO blood group or secretor state, or both. The distribution of the ABO blood group or secretor state, or both, was therefore determined in 87 patients with ankylosing spondylitis and 32 with other forms of spondyloarthropathy. The prevalence of non-secretors was significantly increased in the total patient group (54/114; 47%) and in the subgroup with ankylosing spondylitis (41/84; 49%) compared with local controls (89/334; 27%) (p less than 0.001). Other subgroups of patients showed a similarly increased prevalence of non-secretion (33-47%). The distribution of ABO blood groups did not differ between patients and controls. The association between non-secretor state and ankylosing spondylitis strengthens the hypothesis that ankylosing spondylitis is a form of reactive arthritis. It also suggests several pathogenic mechanisms which may be relevant to the initial hostparasite interaction in ankylosing spondylitis.
In order to investigate whether the ability of peripheral blood monocytes to bind bacteria is impaired in diabetes, we studied carbohydrate-binding ("lectin-like") receptors and the receptor for the Fc portion of immunoglobulin on monocytes from 25 male Type 1 (insulin-dependent) diabetic patients and 10 age-matched healthy control subjects. Peripheral blood monocytes from the diabetic patients expressed lower levels of "lectin-like" receptors compared to the control subjects, whereas the expression of the receptor for the Fc portion of immunoglobulin was similar in both populations. There was no correlation between the degree of "lectin-like" binding activity and plasma glucose concentration or glycaemic control. Recognition of unopsonized bacteria by the "lectin-like" receptor is impaired in Type 1 diabetes; this may affect the efficient elimination of potential pathogens.
Bactericidal activities of normal human serum for non-serogroupable strains of Neisseria meningitidis were determined. In similar experiments with isolates of Neisseria gonorrhoeae from localized infections, strains with group I lipopolysaccharide (LPS) were uniformly serum resistant and those with group II were serum sensitive. We found no similar association between serum sensitivity of the meningococcal strains and their lipopolysaccharide groups determined by the same pyocin typing system used to classify the gonococcal isolates. Immune mouse sera raised against non-serogroupable meningococci of either LPS group I or II were bactericidal for non-serogroupable strains of the same LPS group and also cross-reactive for strains of the opposite group. They were not bactericidal for the majority (13/17) of the serogroupable strains tested. These findings suggest there are antigens, in addition to the LPS and capsules, that elicit some of the "natural" bactericidal antibodies to pathogenic meningococci.
In this study we tested the hypothesis that the increased susceptibility of non-secretors of blood group antigens to recurrent urinary tract infections might be due, in part, to lower levels of IgA reported for non-secretor Caucasian women. Total serum IgA and IgG levels of 200 women in a retrospective study group monitored by the local pyelonephritis unit for 20 yr was compared with those of 100 women from a prospective group recently referred to the clinic. Immunoglobulin levels of the retrospective group were analyzed with reference to the secretor state of the patient, improvement over the 20 yr and presence or absence of renal scars. Total IgA and IgG levels were significantly higher in the sera of non-secretors with or without renal scars and also among patients who had clinically improved over the 20-yr period. Most women appeared to improve regardless of age of onset of infections or treatment prescribed. It was suggested that improvement might be associated with a self-immunization phenomenon. The significantly higher levels of IgA and IgG found among the women in the retrospective study compared with the levels found in the sera of age-matched women in the prospective study is evidence for this hypothesis. The implications of these findings for further investigations of the pathogenesis of urinary tract infections are discussed.
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The effect of clindamycin on Fc receptor expression has been investigated with mouse peritoneal macrophages and human peripheral blood monocytes. When monolayers of these cells were treated with therapeutic concentrations of clindamycin for periods up to 1 hr at 37 degrees C binding of IgG2b coated sheep erythrocytes (EAG) was inhibited. No effect was observed at 4 degrees C or 22 degrees C. An independent effect of the antibiotic on the sheep erythrocytes was noted when they were pretreated with clindamycin that resulted in enhanced binding to the mouse but not the human phagocytes. These findings are discussed in relation to possible in vivo actions of the antibiotic.
Macrophage lectin receptors that recognize bacterial cell wall sugars are reduced in alloxan diabetic mice. This is in contrast to the expression of macrophage Fc (IgG2b) receptors which remains unaltered. Peritoneal macrophages, from diabetic and normal mice, were used as a source of accessory cells in an antigen dependent T cell proliferation assay with unopsonized Staph. epidermidis as the antigen. Uptake of this antigen in the absence of serum is via the macrophage lectin receptors. We have shown that diabetic macrophages induce a level of antigen dependent T cell proliferation to Staph. epidermidis. However the T cell response to Con A was similar with both normal and diabetic macrophages. We suggest that the observed defect in antigen presentation by diabetic macrophages is at the level of uptake of antigen. High glucose levels, such as those found in diabetes, down-regulate the lectin receptor, reduce phagocytosis of Staph. epidermidis and affect antigen presentation. This has important consequences in terms of the ability of diabetics to mount an effective immune response.
Alginate obtained from a mucoid strain of Pseudomonas aeruginosa was shown to inhibit the phagocytosis of an isogenic non-mucoid revertant by rat alveolar macrophages. Phagocytosis of Staphylococcus albus, binding of sensitized sheep erythrocytes to Fc receptors and uptake of latex particles were also inhibited. These results suggest that the alginate acts as a barrier, surrounding the macrophage preventing the attachment of bacteria or other particles to the plasma membrane. This conclusion was supported by showing that alginic acid, a polysaccharide from seaweed structurally similar to alginate also inhibited the phagocytosis of non-mucoid Ps. aeruginosa. The alginate also inhibited opsonisation of the non-mucoid revertant by a non-agglutinating hyperimmune serum. It is proposed that alginate confers a selective advantage on mucoid producing forms of Ps. aeruginosa by impairing the host immune response by its action on alveolar macrophages and opsonization of bacteria.
Host-parasite interactions influencing the development of the protective humoral immune response to Neisseria meningitidis are briefly reviewed. Possible consequences of the observed decreased titres of bactericidal activity specific for meningococcal serogroups A, B and C among patients with gonorrhoea are discussed with reference to: the epidemiology of the two diseases, the protective role of "natural" antibodies to the Neisseria species and the carriage rate of serogroupable strains of N. meningitidis among patients with gonorrhoea and a control population.
The effects of 3 antibiotics, azlocillin, ticarcillin and tobramycin, on rat alveolar macrophage function has been examined. These antibiotics are used in the treatment of Pseudomonas aeruginosa lung infections in cystic fibrosis patients. In this study low concentrations of the antibiotics were used, similar to the low levels found in the lungs of these patients. Tobramycin, a highly active aminoglycoside, inhibited the phagocytosis of opsonized Pseudomonas aeruginosa and enhanced the binding of sheep erythrocytes sensitized with IgG2b, when pre-incubated with macrophage monolayers for 30 min. Inhibition of both phagocytosis and binding of sensitized sheep erythrocytes was observed when tobramycin was co-incubated with the macrophage monolayers and indicator cells. Azlocillin, a semi-synthetic penicillin, caused inhibition of phagocytosis of opsonized bacteria and binding of sensitized sheep erythrocytes when added with the indicator cells. However, no effect was found if the macrophages were pre-incubated with azlocillin for 30 min. Ticarcillin, a semi-synthetic penicillin which is less active in vitro as an antimicrobial agent than azlocillin, had no effect on alveolar macrophages at the concentrations used in these assays. It is postulated that if these in vitro findings with rat alveolar macrophages are reflected in the in vivo situation in humans, the effect of antibiotics on host defence may be of clinical importance.
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