A.D.B. Webster's research while affiliated with Diving Diseases Research Centre and other places

Publications (259)

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TNFRSF13B encodes transmembrane activator and calcium modulator and cyclophilin ligand interactor (TACI), a B cell- specific tumor necrosis factor (TNF) receptor superfamily member. Both biallelic and monoallelic TNFRSF13B mutations were identified in patients with common variable immunodeficiency disorders. The genetic complexity and variable clin...
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Soluble CD8, soluble CD4, soluble CD25 (IL-2 receptor), β2-microglobulin and the cytokine tumour necrosis factor-alpha (TNF-α) were measured in sera from patients with common variable immunodeficiency (CVI). Levels of soluble CD8, soluble CD25 and β2-microglobulin but not of soluble CD4 and TNF-α were raised significantly above levels in normal ser...
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Myeloid and plasmacytoid dendritic cells (MDCs, PDCs) play critical roles in B cell development and antibody production. Primary antibody deficiencies in humans might therefore reflect a deficit in MDCs and/or PDCs. We tested this hypothesis by measuring dendritic cell (DC) subset numbers in patients with common variable immunodeficiency (CVID), X-...
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The heterogeneity of common variable immunodeficiency (CVID) calls for a classification addressing pathogenic mechanisms as well as clinical relevance. This European multicenter trial was initiated to develop a consensus of 2 existing classification schemes based on flowcytometric B-cell phenotyping and the clinical course. The clinical evaluation...
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Adenosine deaminase (ADA) deficiency is an inherited disorder which leads to elevated cellular levels of deoxyadenosine triphosphate (dATP) and systemic accumulation of its precursor, 2-deoxyadenosine. These metabolites impair lymphocyte function, and inactivate S-adenosylhomocysteine hydrolase (SAHH) respectively, leading to severe immunodeficienc...
Chapter
Primary immunodeficiency: introductionSevere combined immunodeficiencyCombined immunodeficiencySecondary defects in cellular immunityPrimary antibody deficiencyPrimary defects in innate immunity(IL-12/IFN-g and NFkB pathways)Defects in complement components
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The phenotype of common variable immunodeficiency (CVID) is characterized by recurrent infections owing to hypogammaglobulinemia, with deficiency in immunoglobulin (Ig)G and at least one of IgA or IgM. Family studies have shown a genetic association between CVID and selective IgA deficiency (IgAD), the latter being a milder disorder compatible with...
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Common variable immunodeficiency (CVID) is an antibody deficiency syndrome that often co-occurs in families with selective IgA deficiency (IgAD). Vorechovský et al. (Am J Hum Genet 64:1096-1109, 1999; J Immunol 164:4408-4416, 2000) ascertained and genotyped 101 multiplex IgAD families and used them to identify and fine map the IGAD1 locus on chromo...
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The functional interaction of BAFF and APRIL with TNF receptor superfamily members BAFFR, TACI and BCMA is crucial for development and maintenance of humoral immunity in mice and humans. Using a candidate gene approach, we identified homozygous and heterozygous mutations in TNFRSF13B, encoding TACI, in 13 individuals with common variable immunodefi...
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Polymorphisms in exon 1 of the MBL-2 gene, resulting in reduced plasma levels of mannose binding lectin, were significantly overrepresented in 23 patients with primary antibody deficiency and culture-proven mycoplasma infections (P = 0.0038). This association persisted with the inclusion of a further nine suspected (doxycycline-responsive) cases (P...
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Primary immunodeficiency diseases result from genetic defects in the development and maturation of cells of the immune system. They lead to an increased susceptibility to infections, which are usually characteristic of the specific immune defect. They are classified into combined cellular and antibody deficiencies, predominant antibody deficiencies...
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The phenotype and function of monocyte derived dendritic cells (MdDC) were investigated in 25 patients with common variable immunodeficiency (CVID) to test for abnormalities that might help explain the failure of antibody production. Using MHC class II DR and CD86 as markers of maturation, DCs from the majority of CVID patients were normal. However...
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The molecular basis of common variable immunodeficiency (CVID) is undefined, and diagnosis requires exclusion of other diseases including X-linked lymphoproliferative disease (XLP). This rare disorder of immunedysregulation presents typically after Epstein-Barr virus infection and results from defects in the SAP (SLAM associated protein) gene. SAP...
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To estimate the rate of long-term poliovirus excretors in people known to have B-cell immune deficiency disorders. An active search for chronic excretors was conducted among 306 persons known to have immunoglobulin G (IgG) deficiency in the United States, Mexico, Brazil, and the United Kingdom, and 40 people with IgA deficiency in the United States...
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We investigated the expression of T helper (Th)1/Th2 regulatory cytokine receptors on lymphocytes from patients with common variable immunodeficiency (CVID), a disorder associated with raised Th1 cytokine production, comparing the results with those from healthy individuals and atopic asthmatics, the latter generally considered to have a Th2-driven...
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Selective IgA deficiency (IgAD) and common variable immunodeficiency (CVID) are the most common primary immunodeficiencies in humans. A high degree of familial clustering, marked differences in the population prevalence among ethnic groups, association of IgAD and CVID in families, and a predominant inheritance pattern in multiple-case pedigrees ha...
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Chronic enteroviral meningoencephalitis (CEMA) is a rare complication of immunodeficient individuals and may present as insidious intellectual deterioration. Diagnosis requires isolation or PCR identification of enterovirus from the CSF. Pleconaril, a novel anti-picornaviral compound is available on a compassionate release basis to treat patients w...
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We have explored the natural history of enteroviral infection in patients with primary antibody deficiency by surveying both published and unpublished case reports before the new anti-enteroviral drug, pleconaril, was available. Many different enteroviruses were involved, Echovirus 11 being the most common. The central nervous system was nearly alw...
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Fas (CD95) plays an important role in apoptosis. Patients with defects in Fas have an autoimmune lymphoproliferative syndrome (ALPS) characterized by lymphadenopathy, autoimmune cytopenias and an increased incidence of lymphomas. There are approximately 70 known cases described worldwide. The autoimmune cytopenias are difficult to treat in this gro...
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Treatment of neurological disorders with intravenous immunoglobulin (IVIg) is an increasing feature of our practice for an expanding range of indications. For some there is evidence of benefit from randomised controlled trials, whereas for others evidence is anecdotal. The relative rarity of some of the disorders means that good randomised control...
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We have identified 14 patients with diverse primary immunodeficiencies who have developed progressive neurodegeneration of unknown etiology. All patients had received immunoglobulin replacement therapy for a mean duration of 6.5 years (range of 0.5-13.5 years) at the time of first neurological symptoms. Diagnostic tests of blood and cerebrospinal f...
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We present a dense STR/linkage disequilibrium(LD)/gene map between the RING3 and HLA-B loci, reference allelic sizes on the most prevalent HLA haplotypes and their allelic frequencies in pedigree founders. This resource will facilitate LD, evolution and gene mapping studies, including comparisons of HLA and STR haplotypes and identification of HLA...
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There have been major advances in the understanding of the mechanisms of primary immunodeficiencies (PIDs) during the last decade as a result of the cloning of abnormal genes responsible for the majority of these disorders. These include rare single-gene disorders in which the mutated alleles were discovered by genetic linkage followed by mapping a...
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IgA deficiency (IgAD, MIM 137100) is the most frequent primary immunodeficiency in humans (for review see Burrows and Cooper, 1997; Hammarstrom et al., 2000). It is characterized by the absence of IgA in serum and mucosal secretions due to an as yet unidentified defect of terminal lymphocyte differentiation. Affected individuals may suffer from sus...
Article
Enteroviruses usually cause self-limited disease that, although associated with high morbidity, is rarely fatal. In certain patient populations, however, the enteroviruses may cause potentially life-threatening infections. Pleconaril is a novel compound that integrates into the capsid of picornaviruses, including enteroviruses and rhinoviruses, pre...
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We report a patient with common variable immunodeficiency (CVID) who developed an axonal sensorimotor polyneuropathy, a hitherto unreported association to our knowledge. These conditions may be linked at the pathogenetic level, since some CVID patients are prone to the development of autoimmune disease.
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Absolute and relative NK cell numbers were determined in peripheral whole blood by flow cytometry in patients with common variable immunodeficiency (CVID) (n = 55) and X-linked agammaglobulinaemia (XLA) (n = 19) on regular immunoglobulin (IVIG) therapy. Absolute CD3-CD16+ NK cell numbers were significantly reduced in CVID patients (median 108/micro...
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Polyethylene glycol-conjugated adenosine deaminase (pegademase) is used for enzyme replacement therapy for patients with severe combined immunodeficiency caused by adenosine deaminase deficiency. The entrapment of pegademase within human energy-replete carrier erythrocytes using a hypo-osmotic dialysis procedure was investigated with the objective...
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To limit the region containing a mutation predisposing to selective IgA deficiency (IgAD) and common variable immunodeficiency (CVID), 554 informative members of 101 multiple-case families were haplotyped at the IGAD1 candidate locus in the MHC. Microsatellite markers were placed onto the physical map of IGAD1 to establish their order and permit ra...
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The description of X-linked agammaglobulinaemia (XLA) 48 years ago provided the catalyst for a fruitful interaction between basic immunologists and clinicians, and was the beginning of Clinical Immunology as practised in the UK today. Over the subsequent 40 years many more immunodeficiency syndromes were described and partially characterized at a f...
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To determine the prevalence of M. fermentans at different anatomical sites in healthy subjects and in patients with congenital immunodeficiency, and to determine whether haematogenous invasion occurs among the latter. A polymerase chain reaction (PCR) assay was used to detect M.fermentans in throat swabs and urine specimens from healthy students, a...
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We show that LPS-stimulated circulating CD14-positive monocytes from patients with common variable immunodeficiency (CVID) express a higher proportion of intracellular IL-12-positive cells than monocytes from patients with X-linked agammaglobulinemia or normal subjects. We used four-color flow cytometry and measured IL-12 with an Ab to the p40 subu...
Article
Although the inactivation of the BTK gene accounts for most primary immunodeficiency cases with absent B-cells and immunoglobulins, about 15-20% of such patients are estimated to lack Bruton's tyrosine kinase gene (BTK) alterations. In the remaining subset of such XLA-like phenotypes, mutations have been reported in the μ heavy chain, VpreB, λ5/14....
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Previous reports of an association between constitutional chromosome 18 abnormalities and low levels of IgA suggested that this chromosome contains a susceptibility locus for selective IgA deficiency (IgAD), the most frequent Ig deficiency in humans. IgAD is genetically related to common variable immunodeficiency (CVID), characterized by a lack of...
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We examined the effects of intravenous immunoglobulin (IVIG) on cytokine regulation in vivo using samples taken before and after replacement-dose (200-400 mg/kg) IVIG in a group of patients with common variable immunodeficiency (CVID) and X-linked agammaglobulinaemia (XLA). The intracellular cytokine content of CD4+ and CD8+ lymphocytes, and their...
Article
Immunoglobulin A (IgA) deficiency (IgAD) is characterized by a defect of terminal lymphocyte differentiation, leading to a lack of IgA in serum and mucosal secretions. Familial clustering, variable population prevalence in different ethnic groups, and a predominant inheritance pattern suggest a strong genetic predisposition to IgAD. The genetic sus...
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We review recent developments in the pathogenesis of the major immunodeficiencies, the pathogens involved, and new diagnostic and treatment options. Early diagnosis and prophylaxis are the mainstays in the current management of these immunological disorders. New advances, including the use of cytokines and growth factors, molecular diagnosis and a...
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Sera from 77 patients with common variable immunodeficiency (CVID) were tested for GB virus C (GBV-C) RNA, because they are prone to unexplained chronic hepatitis, and from 28 patients with X-linked agammaglobulinemia (XLA) who have a similar primary antibody deficiency but are not prone to hepatitis. Eight CVID and 8 XLA patients were positive; 6...
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The ATM gene deficient in ataxia-telangiectasia, a recessive multisystem disease associated with a high risk of lymphomas and leukemias, was found previously to be inactivated in a rare sporadic malignancy, T-cell prolymphocytic leukemia (T-PLL), which is often associated with cytogenetic aberrations of chromosome 14. The ATM gene was shown to sust...
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Hyper-IgM (HIM) syndrome is a rare primary immunodeficiency disorder. Approximately 120 cases have been described in the literature world-wide. Features of HIM include low serum IgG, a very low IgA with normal or high IgM levels. Autoimmune phenomena are recognized associations but connective tissue disorders have so far not been described in HIM p...
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We have measured by flow cytometry the ability of subsets of CD8+CD3+ lymphocytes within mononuclear cell preparations to make intracellular cytokines (IL-2, tumour necrosis factor-alpha (TNF-alpha) and IFN-gamma) on stimulation in vitro with phorbol myristate acetate (PMA) and ionomycin for 16 h. These CD8+ subsets were defined by the presence or...
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Various methods have been reported for measuring intracellular cytokines in peripheral blood mononuclear cells isolated by density-gradient centrifugation. In this report, we describe a whole-blood method for the determination of intracellular cytokines (IFN-gamma, TNF-alpha and IL-2) that uses small-volume (500 microl) blood samples. Directly conj...
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Ataxia-telangiectasia (A-T) is a recessive multi-system disorder caused by mutations in the ATM gene at 11q22-q23 (ref. 3). The risk of cancer, especially lymphoid neoplasias, is substantially elevated in A-T patients and has long been associated with chromosomal instability. By analysing tumour DNA from patients with sporadic T-cell prolymphocytic...
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Common variable immunodeficiency (CVID) is a major antibody-deficiency syndrome, leading to a significantly increased risk of bacterial infection, as well as autoimmune and granulomatous diseases. The clinical and immunological features are heterogeneous. Four decades have passed since it was first described and, despite considerable research, the...
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A survey of 358 patients with primary antibody deficiency shows that mycoplasmal infection is the commonest cause of severe chronic erosive arthritis. We review our experience with 18 patients with confirmed or probable mycoplasmal arthritis. There was a broad spectrum of severity from a monoarthritis rapidly responding to tetracyclines to severe d...
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Several T cell defects have been described in the antibody deficiency disease, CVID, but there have been few data on the generation of responses of specific T cell populations to primary neoantigens. We have now used immunization with the neoantigens, keyhole limpet haemocyanin (KLH) and DNP-Ficoll, to evaluate immune responses in CVID patients and...
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Mutation pattern was characterized in the Bruton's tyrosine kinase gene (BTK) in 26 patients with X-linked agammaglobulinemia, the first described immunoglobulin deficiency, and was related to BTK expression. A total of 24 different mutations were identified. Most BTK mutations were found to result in premature termination of the translation produc...
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A case is reported of common variable immunodeficiency (CVID) presenting as an acute septic arthritis due to Mycoplasma hominis. The diagnosis was not considered until the hypogammaglobulinaemia was discovered and the synovial fluid cultured specifically for mycoplasmas. The importance of diagnosing immunodeficiency states and searching for mycopla...
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Using three-colour flow cytometry, we have measured intracellular IL-2, interferon-gamma (IFN-gamma) and tumour necrosis factor-alpha (TNF-alpha) induced in human CD4+ and CD8+ T cells from normal donors and patients with common variable immunodeficiency (CVID). Since a new range of directly FITC-conjugated anti-cytokine antibodies was used, condit...
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Ataxia-telangiectasia (A-T) is a multisystem recessive disease characterized clinically by cerebellar ataxia, oculocutaneous telangiectasias, immunodeficiency, sensitivity to radiomimetic agents, and cancer predisposition. This pleiotropic disorder is caused by mutations in the ATM (mutated in A-T) gene, which is located in the human chromosomal re...
Article
Heterozygosity for ataxia-telangiectasia (A-T), a cancer-prone recessive syndrome, has been associated with an increased risk of breast cancer. The gene for A-T (ATM) is located at chromosomal region 11q22-q23, a region of frequent loss of constitutional heterozygosity in breast and other tumors. Loss of constitutional heterozygosity at 1lq22-q23 w...
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The molecular basis of hereditary complement factor I deficiency is described in two pedigrees. In one pedigree, there were two factor I-deficient siblings, one of whom was asymptomatic and the other suffered from recurrent pyogenic infections. Their factor I mRNA was analyzed by reverse transcription of fibroblast RNA followed by amplification usi...
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The neurological features of 13 patients with primary hypogammaglobulinaemia are described. Seven patients had X-linked agammaglobulinaemia (XLA) and six had common variable immunodeficiency (CVID). Three clinical pictures emerged: (i) a progressive myelopathy (one case); (ii) a myelopathy progressing to an encephalopathy (four cases); (iii) a pure...
Article
Concern over sporadic hepatitis C virus (HCV) infection from treatment with contaminated immunoglobulin in patients with immunodeficiency prompted use to screen serum from 44 patients for HCV RNA. We found no evidence of either horizontal or iatrogenic infection in our Clinic, except in two patients known to have received contaminated batches, and...
Article
Using a polymerase chain reaction single strand conformation polymorphism (PCR-SSCP) assay, which amplifies individually all coding exons of the ATM gene deficient ataxia-telangiectasia (A-T), we have analyzed 10 patients with A-T for ATM mutations. Mutation were detected in 9 patients. We describe the first ATM mutation in the splice junction foun...
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Screening of close relatives of Swedish patients with selective immunoglobulin A deficiency (IgAD) and common variable immunodeficiency (CVID) for serum immunoglobulin levels has identified the positive family history of IgAD/CVID as the most significant risk factor for developing the disease. The relative risk for siblings of patients with IgAD wa...
Article
It has been suggested that tryptophan 563 is sandwiched between residues R562 and A582 in Bruton's agammaglobulinemia tyrosine kinase (Btk). Mutations of the surrounding residues have been shown to cause X-linked agammaglobulinemia. Substitutions R562P and A582V were noticed to have impaired kinase activity. However, based on Western blot analysis,...
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T cells from patients with CVID have defects that may relate to the failure in vivo of B cell production of antibodies. Antigen-driven responses of T cells from CVID patients and normal subjects have been assessed by measuring DNA synthesis in vitro. Low density cells enriched for antigen-presenting dendritic cells were pulsed with purified protein...
Article
The computed tomography (CT) scans of 37 patients with primary hypogammaglobulinaemia were reviewed to determine the frequency of enlarged mediastinal lymph nodes and splenomegaly in this group. None of the 10 X-linked Agammaglobulinaemia (XLA) patients had enlarged nodes and only one had splenomegaly. Eleven of the 27 Common Variable Immunodeficie...
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X-linked agammaglobulinaemia (XLA) is an inherited immunodeficiency resulting from mutations in the gene for a cytoplasmic protein tyrosine kinase ( Btk ). We have utilised reverse-transcription-based PCR in combination with the chemical cleavage and mis match technique (CCM) to screen for Btk mutations in 42 unrelated patients having classical XLA...
Article
Two patients with common variable immunodeficiency underwent orthotopic liver transplantation for chronic hepatitis, unequivocally caused by hepatitis C virus in one case. Although one patient had pneumonia 8 days after surgery and the other developed hepatic venular stenosis in the transplanted liver, both had a reasonably good quality of life for...
Article
Twenty-one patients with primary immunoglobulin deficiency were enrolled in a crossover study to test the efficacy and safety of Alphaglobin in comparison with the licensed preparations Sandoglobulin and Gamimune. There was no statistical difference in these parameters between Alphaglobin and Sandoglobulin/Gamimune. The level of total serum IgG and...