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Biomedical subjects

A D Webster

Publications and source records attributed to A D Webster.

At least 73 records · Page 4Linked to original sources
PubMed1994

Cutaneous sarcoid-like granulomas in primary immunodeficiency disorders.

We report the occurrence of cutaneous sarcoid-like granulomas in one patient with common variable immunodeficiency and another with 'thymoma and hypogammaglobulinaemia'. To our knowledge, this is the first time that such skin lesions have been described in patients with primary immunodeficiency. These granulomas may be attributed to a combination of interleukin-2 deficiency and a profound CD4 lymphopenia. The lesions are similar to the non-infectious 'papular eruption' associated with human immunodeficiency virus infection, and might reflect a common pathogenic mechanism.

Adult↗
PubMed1994

Tumour necrosis factor-alpha and leukotriene E4 production in wheezy infants.

It is not clear why certain infants wheeze during viral upper respiratory tract infections (URTIs) but it is possible that they have a tendency to mount an exaggerated inflammatory response leading to production of mediators that induce airway narrowing. We studied nasal tumour necrosis factor-alpha (TNF alpha) and urinary leukotriene E4 (LTE4) production during infection and after recovery in 31 wheezy infants (median age 6.2 months). Urinary LTE4 production was not altered during wheezy episodes or URTIs. However, the concentration of TNF alpha in nasal lining fluid (NLF) was significantly increased during acute episodes of wheeze compared to recovery (median [interquartile range] of 293 [42-1753] vs 0 [0-203] pg/ml NLF). TNF alpha was detectable more often and in higher concentration when wheezing was due to respiratory syncytial virus. TNF alpha was also present in 7/30 asymptomatic wheezy infants who had recovered from infection (> 100 pg/ml NLF) and in 4/7 non-wheezy siblings during URTIs (> 200 pg/ml NLF). This suggests that upregulation of TNF alpha production is not the only factor that makes some infants wheeze.

Child, Preschool↗
PubMed1994

Failure in IgA secretion by surface IgA-positive B cells in common variable immunodeficiency (CVID).

CVID is an acquired disease with low serum immunoglobulins. Patients are classified into three groups on the ability of their B cells to secrete IgM and IgG in vitro in response to IL-2. We have now extended this patient classification to include IgA secretion and to assess whether the patients have IgA+ B cells in the circulation. B cells from almost all of the CVID patients studied were unable to secrete any IgA in vitro, with or without IL-2, although all B cells tested from normal donors showed some spontaneous IgA secretion. Thus, the defect with IgA secretion is more profound than with the secretion of IgM or IgG. Despite this failure to secrete IgA, using flow cytometry techniques all CVID patients tested were found to have IgA+ cells (expressed as a percentage of B cells) within the normal range. This suggests that CVID may involve a defect in the secretion of immunoglobulin isotypes rather than a defect in isotype switching.

B-Lymphocytes↗
PubMed1994

Effects of 17 beta-oestradiol on function of lymphocytes from normal donors and patients with common variable immunodeficiency (CVID).

Effects of oestradiol (E2) have been studied on the in vitro T cell-dependent differentiation of B cells from peripheral blood and spleen using normal donors and patients with the antibody deficiency disease CVID. We also studied whether it modifies T cell DNA synthesis. The effect of E2 was examined on cultures of B cells with T cells for IL-2-driven immunoglobulin secretion or of T cells for phytohaemagglutinin (PHA)-driven DNA synthesis. Interestingly, in control experiments without E2, the normal sex difference in immunoglobulin production is reversed in CVID. The data show that for normal individuals there is no major difference between male and female donors in the in vitro actions of E2 on blood B and T lymphocytes. With normal blood B cells, E2 failed to affect IgM production, but it did inhibit IgG. In normal splenic cells, E2 increased both IgM and IgG secretion in a similar way to the tonsillar cell data previously reported. E2 on normal blood T cell DNA synthesis was stimulatory. With blood cells from CVID patients an interesting contrast was seen. As with normal B cells, E2 had no effect on IgM secretion by those CVID blood B cells able to secrete IgM. However, a difference between patients and normals was that E2 did not inhibit the IL-2-driven IgG production by those CVID B cells able to secrete IgG. For T cell function, the stimulatory effect of E2 on CVID T cell DNA was as in normal T cells. However, E2 failed to restore CVID B and T cell function to normal levels. These data suggest that there may be subtle defects in the pathway of action of E2 in CVID lymphocytes.

Adolescent↗
PubMed1994

Failure in antigen responses by T cells from patients with common variable immunodeficiency (CVID).

Antigen-driven responses by T cells from patients with CVID and normal subjects have been assessed. Low-density cells enriched for antigen-presenting dendritic cells were cultured with T cells using a 20-microliters hanging drop system. T cells from all subgroups of CVID patients showed markedly reduced responses to the recall antigens purified protein derivative (PPD) or tetanus toxoid, whereas responses by cells from patients with X-linked agammaglobulinaemia, used as a disease control, were in the normal range. However, primary allo-stimulation of CVID T cells was normal. CVID cells from two patients failed to respond to stimulation with a neoantigen, an HIV env peptide, under conditions where normal T cells did respond. These data illustrate a profound defect in antigen-stimulated T cell proliferation in vitro in all groups of CVID patients, but do not distinguish whether the defect is in the presenting cell or in the T lymphocyte. In vivo, germinal centre B cells are thought to present antigen to primed T cells to obtain essential signals (e.g. CD40 ligand and IL-2) for B cell survival and progression to immunoglobulin secretion. A failure of antigen-specific T cell function in vivo in CVID would thus not provide the primed T cells needed for B cell rescue, and could be the primary defect leading to the low immunoglobulin production in this condition.

Antigen-Presenting Cells↗
PubMed1994

Co-stimulation with anti-CD28 (Kolt-2) enhances DNA synthesis by defective T cells in common variable immunodeficiency.

In normal T cells, an anti-CD28 MoAb (Kolt-2) will synergize with the mitogenic stimuli phytohaemagglutinin (PHA), anti-CD3 (OKT3) or a combination of anti-CD2 antibodies (OKT11 and GT2) in the induction of DNA synthesis. A subgroup of patients with common variable immunodeficiency (CVID) show a defect in DNA synthesis by T cells stimulated in vitro with the above mitogens. We have now investigated whether anti-CD28 will correct the defect. This strategy partially restored DNA synthesis, providing evidence that the CD28 co-stimulatory pathway in CVID T cells is normal. Ligation of CD28 acts through co-stimulating IL-2 secretion. The natural ligand (B7) for CD28 on antigen-presenting cells from CVID patients is expressed normally. We conclude that the defect in CVID T cells lies in pathways that lead to transcription of the IL-2 gene other than that induced by ligation of CD28 with Kolt-2.

Antibodies, Monoclonal↗
PubMed1994

Mycoplasmas and ureaplasmas in patients with hypogammaglobulinaemia and their role in arthritis: microbiological observations over twenty years.

OBJECTIVES: To study the occurrence of mycoplasmas and ureaplasmas in patients with hypogammaglobulinaemia and the relationship of these micro-organisms to septic arthritis. METHODS: Over a period of about 20 years, 53 men and 38 women with hypogammaglobulinaemia, most of whom were less than 50 years old, were examined clinically and microbiologically. Mycoplasmas and ureaplasmas were sought in the throat, urogenital tract and joints by standard cultural methods, although not consistently in the three sites of all patients. RESULTS: Arginine-hydrolysing mycoplasmas and ureaplasmas occurred with similar frequency in the sputum/throat of the hypogammaglobulinaemic patients, but no more often than might be expected in immunocompetent patients. Ureaplasmas, however, dominated in the urogenital tracts of both men and women, being found in 75% of vaginal specimens. Arginine-hydrolysing mycoplasmas occurred two to six times more frequently and ureaplasmas two to three times more frequently in urine specimens from hypogammaglobulinaemic patients than they did in such specimens from sex- and age-matched non-venereal disease, hospital patients or healthy subjects; these differences were statistically significant (p < 0.05). Enhanced mucosal colonisation probably increases the chance of spread to distant sites, such as the joints. Of the 91 patients, 21 (23%) had septic arthritis involving one or more joints. Mycoplasmas and/or ureaplasmas, but not bacteria, were isolated from the joints of eight (38%) of these patients. However, dissemination to joints apparently had not occurred in some despite the opportunity by virtue of mycoplasmal or ureaplasmal colonisation at a mucosal site. Sometimes antibiotic therapy failed clinically, and microbiologically and recommendations for management are outlined. CONCLUSIONS: Hypogammaglobulinaemic patients appear to be more susceptible to colonisation of mucous membranes, especially of the urogenital tract, with mycoplasmas and ureaplasmas than are immunocompetent individuals. These micro-organisms are responsible for about two fifths of the septic arthritides occurring in these patients.

Adolescent↗
PubMed1994

Studies on the enteropathy associated with primary hypogammaglobulinaemia.

Twelve patients with primary hypogammaglobulinaemia with diarrhoea not associated with known microbial pathogens were investigated. Histological evidence of inflammation was common in the stomach and jejunum. Moreover, eight of 10 patients undergoing colonoscopy had low grade 'microscopic colitis' with raised intraepithelial lymphocytes and an intact crypt architecture. Five of 12 patients had small intestinal inflammation on 111indium leucocyte scintigrams and all had increased faecal excretion (normal < 1%) of 111indium (over four days), which varied in intensity from mild (faecal excretion of 111indium = 1-3%) to that comparable with moderately active (7-14.5%) Crohn's disease. Three patients had small intestinal strictures superficially resembling Crohn's disease. Histologically, however, these lacked characteristic diagnostic features of Crohn's disease in two and the third patient had non-steroidal anti-inflammatory drug induced diaphragm like strictures. Six of seven who were most severely symptomatic were successfully treated with an elemental diet with rapid improvement of symptoms. The faecal excretion of 111indium was repeated in five and all improved but histologically the colitis remained unchanged. These studies show that some patients with primary hypogammaglobulinaemia have intestinal inflammation unlike that found in classic inflammatory bowel disease. Elemental diet is a useful temporary measure in the treatment of these patients.

Agammaglobulinemia↗
PubMed1994

CD4+ lymphocytopenia due to common variable immunodeficiency mimicking AIDS.

There are an increasing number of published reports of patients with acquired immunodeficiency without evidence of HIV infection, who have been labelled as having "idiopathic CD4+ lymphocytopenia". The case is reported here of a young man who presented with Pneumocystis carinii pneumonia (PCP), CD4+ lymphopenia, and hypogammaglobulinaemia attributable to common variable immunodeficiency (CVID). The presentation of this condition, with many of the clinical and laboratory features of AIDS, highlights CVID as a diagnosis to be considered in the differential diagnosis of CD4+ lymphocytopenia.

Acquired Immunodeficiency Syndrome↗
PubMed1994

Study of B and T cell phenotypes in blood from patients with common variable immunodeficiency (CVID).

B and T cell phenotypes in peripheral blood from 71 CVID patients have been measured in a study using directly conjugated monoclonal antibodies and two colour flow cytometry. Data was compared between different patient groups (based on whether their B cells could secrete IgM or IgG in vitro) and normal donors. There was a clear correlation between abnormalities of both B and T cells and the different patient groups. There were reduced absolute numbers of circulating CD4+ T cells, particularly those of the CD4+.CD45RA+ subset, and of CD19+ B cells in those patients whose B cells failed to secrete IgM or IgG in vitro. This demonstrates an association between B cell lymphopenia, failure of B cell immunoglobulin production in vitro and T cell subset lymphopenia in CVID. It supports the view that this group of CVID patients has a disease involving T cell regulation of B cells of varying severity.

Antibodies, Monoclonal↗
PubMed1993

Diagnosis of enterovirus brain disease in hypogammaglobulinemic patients by polymerase chain reaction.

CSF samples taken from three patients with primary hypogammaglobulinemia and chronic brain disease were positive for enterovirus RNA by use of a technique based on the polymerase chain reaction (PCR) to amplify viral genomic sequences. Repeated attempts to culture viruses from the CSF from these patients were unsuccessful, possibly because the patients were treated regularly with intravenous immunoglobulin, which may have contained enough specific antibody to partially neutralize the viruses. Our data suggest that enteroviruses are responsible for diverse CNS features in patients with primary hypogammaglobulinemia and that for these patients the diagnosis should be pursued using PCR technology.

Adult↗
PubMed1993

Rheumatoid arthritis in a patient with primary hypogammaglobulinaemia.

A 44-year-old woman with primary hypogammaglobulinaemia developed classical RA and inflammatory bowel disease. She represents an example of rheumatoid disease developing in the absence of endogenous antibodies and raises interesting questions regarding the pathophysiology of the disease.

Adult↗
PubMed1993

Lymphotropic viruses in 'common variable' immunodeficiency--PCR analysis of lymphocyte DNA for HIV-1 and HHV-6.

DNA of circulating lymphocytes obtained from 17 patients with 'common variable' immunodeficiency (CVID) was tested for the presence of HIV-1 sequences, using a variety of primers complementary to conserved regions of HIV-1 genomes. None of the patients was positive. The DNA from 12 CVID patients was tested for the presence of human herpesvirus 6 (HHV-6), using appropriate primers for this virus which is known to remain latent following primary infection in the majority of people during childhood. Similar numbers of patients and normal subjects were positive (about 30%), suggesting that CVID patients are not particularly prone to reactivation of this virus. Despite previous anecdotal reports of an unexplained association between HIV-1 and CVID, we conclude that there is no evidence that this virus is implicated in the pathogenesis of CVID. A role for HHV-6 also seems unlikely.

Adult↗
PubMed1993

Nasal IgA response in wheezy infants.

It is unknown why some infants wheeze during upper respiratory tract infections. One possibility is that secretory IgA, which has a major role in mucosal defence against viral infection, might be deficient in wheezy infants. The nasal IgA response to upper respiratory tract infection in 32 wheezy infants (median age 5.8 months) was compared with nine siblings (median age 2.6 years) who had nasal symptoms only. Nasal lavage was performed during infections and on follow up when free from symptoms, using inulin as a marker of dilution to determine absolute concentrations of IgA in the nasal secretions. The two groups showed a similar increase in total IgA and total protein levels during infection, but secretory IgA concentrations were unchanged. This study shows that wheezy infants have a normal nasal IgA response to infection and that the increase in total IgA during early infection is due to plasma exudation rather than increased production of secretory IgA.

Child, Preschool↗