W R Thomas

Telethon Kids Institute, Western Australia, Australia

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Publications (104)498.22 Total impact

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    ABSTRACT: Background and objectiveThe allergenicity of several German cockroach (Bla-g) antigens at the level of IgE responses is well established. However, less is known about the specificity of CD4(+) T-H responses, and whether differences exist in associated magnitude or cytokine profiles as a function of disease severity. Methods Proteomic and transcriptomic techniques were used to identify novel antigens recognized by allergen-specific T cells. To characterize different T-H functionalities of allergen-specific T cells, ELISPOT assays with sets of overlapping peptides covering the sequences of known allergens and novel antigens were employed to measure release of IL-5, IFN, IL-10, IL-17 and IL-21. ResultsUsing these techniques, we characterized T-H responses in a cohort of adult Bla-g-sensitized subjects, either with (n=55) or without (n=17) asthma, and nonsensitized controls (n=20). T cell responses were detected for ten known Bla-g allergens and an additional ten novel Bla-g antigens, representing in total a 5-fold increase in the number of antigens demonstrated to be targeted by allergen-specific T cells. Responses of sensitized individuals regardless of asthma status were predominantly T(H)2, but higher in patients with diagnosed asthma. In asthmatic subjects, Bla-g 5, 9 and 11 were immunodominant, while, in contrast, nonasthmatic-sensitized subjects responded mostly to Bla-g 5 and 4 and the novel antigen NBGA5. Conclusions Asthmatic and nonasthmatic cockroach-sensitized individuals exhibit similar T(H)2-polarized responses. Compared with nonasthmatics, however, asthmatic individuals have responses of higher magnitude and different allergen specificity.
    No preview · Article · Nov 2015 · Clinical & Experimental Allergy
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    ABSTRACT: Streptococcus pneumoniae causes invasive pneumococcal disease. Delayed development of antibodies to S. pneumoniae in infancy is associated with the development of atopy and asthma. Pneumococcal surface protein C (PspC) is a vaccine candidate and variation in its choline-binding region is associated with invasive disease. This study examined 523 060 single-nucleotide polymorphisms in The Western Australian Pregnancy Cohort (Raine) Study to find loci influencing immunoglobulin G1 (IgG1) responses to PspC measured at age 14 years (n=1152). Genome-wide significance (top SNP rs9275596; P=3.1 × 10(-14)) was only observed at human leucocyte antigen (HLA). Imputed HLA amino-acid polymorphisms showed the strongest associations at positions DRB1 47 (P=3.2 × 10(-11)), 13SRG (P=9.8 × 10(-10)) and 11SP (P=9.8 × 10(-10)), and at DQA1 34 (P=6.4 × 10(-10)), DQB1 167R (P=9.3 × 10(-6)) and HLA-B 95 W (P=1.2 × 10(-9)). Conditional analyses showed independent contributions from DRB1 47 and DQB1 167R to the signal at rs9275596, supported by an omnibus test showing a strong signal for the haplotype DRB1_47_DQB1_167 (P=9.02 × 10(-15)). In silico analysis showed that DRB1 four-digit allele groups defined by DRB1 47F bind to a greater complexity of core 9-mer epitopes compared with DRB1 47Y, especially across repeats in the C-term choline-binding region. Consequent differences in CD4 T-cell help for IgG1 to PspC could have implications for vaccine design. Further analysis in other cohorts is merited.Genes and Immunity advance online publication, 30 April 2015; doi:10.1038/gene.2015.12.
    Full-text · Article · Apr 2015 · Genes and immunity
  • W.R. Thomas
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    ABSTRACT: Activation of receptors of the innate immune system is a critical step in the initiation of immune responses. It has been shown that dominant allergens have properties that could allow them to interact with toll-like and C-type lectin receptors to favour Th2-biased responses and many bind lipids and glycans that could associate with ligands to mimic pathogen-associated microbial patterns. In accord with the proposed allergen-specific innate interactions it has been shown that the immune responses to different allergens and antigens from the same source are not necessarily coordinately regulated.
    No preview · Article · Feb 2013 · Clinical & Experimental Allergy

  • No preview · Article · Feb 2012 · Journal of Allergy and Clinical Immunology
  • W R Thomas
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    ABSTRACT: Cite this as: W. R. Thomas, Clinical & Experimental Allergy, 2011 (41) 769-772.
    No preview · Article · Jun 2011 · Clinical & Experimental Allergy
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    ABSTRACT: Characterization of the complete IgE binding spectrum of cat allergens is important for the development of improved diagnosis and effective immunotherapeutics. While Fel d 1 remains unchallenged as the major cat allergen, we now report the isolation of two new allergens capable of binding similar concentrations of IgE in the allergic sera of some individuals. Cat tongue and submandibular salivary gland cDNA libraries were screened by DNA hybridisation and IgE immunoassay. The isolated DNA fragments were sub-cloned into an E. coli expression system and the IgE reactivity was examined with human cat-allergic sera using a DELFIA IgE quantitation assay. Fel d 7, an 18 kDa von Ebner gland protein Can f 1 homologue, was isolated from the tongue library. Fel d 8, a 24-kDa latherin-like protein with homology to Equ c 5, was isolated from the submandibular library. The frequency of IgE binding of cat-allergic sera to recombinant Fel d 1, 7 and 8 was 60.5, 37.6 and 19.3%, respectively. Inhibition studies indicated some IgE binding cross-reactivity between Fel d 7 and dog dander extracts. The study reports the isolation and characterization of two new cat allergens. The isolation of these allergens provides the opportunity to determine the role that IgE binding proteins other than Fel d 1 play in cat-allergic disease. For cat-allergic individuals with moderate to mild rhinoconjunctivitis these allergens may play a more important role in the manifestation of their allergic disease.
    Full-text · Article · May 2011 · International Archives of Allergy and Immunology
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    ABSTRACT: Bacterial colonisation of the airways is associated with increased risk of childhood asthma. Immunoglobulin (Ig)E against bacterial antigens has been reported in some asthmatics, suggesting a role for bacterial-specific type-2 immunity in disease pathogenesis. We aimed to investigate relationships between bacterial-specific IgE amongst teenagers and asthma susceptibility. We measured titres of IgE against Haemophilus influenzae, Streptococcus pneumoniae and Staphylococcus aureus in 1,380 teenagers, and related these to asthma symptomatology and immunophenotypes. IgE titres against S. aureus-derived enterotoxins were highest amongst atopics and were associated with asthma risk. Surprisingly, IgE titres against H. influenzae and S. pneumoniae surface antigens were higher, not stratified by atopy and independently associated with decreased asthma risk. The positive association between type-2 immunity to S. aureus and asthma phenotypes probably reflects IgE-mediated effector cell activation via enterotoxin super antigens which are secreted in soluble form. The contrasting benign nature of type-2 immunity to H. influenzae and S. pneumoniae antigens may reflect their lower availability in soluble forms that can crosslink IgE receptors. We theorise that instead they may be processed by antigen presenting cells and presented to type-2 memory cells leading to mucosal secretion of interleukin (IL)-4/IL-13, a mechanism widely recognised in other tissues to attenuate T-helper-1 associated bacterial-induced inflammation.
    Full-text · Article · Sep 2010 · European Respiratory Journal
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    ABSTRACT: The house dust mite allergen Der p 2 is one of the most important indoor allergens associated with allergic disease. Recombinant Der (rDer) p 2 with high IgE binding activity can be readily produced in Escherichia coli and Pichia pastoris, but the structure and IgE binding of the different methods of preparation have not been compared. Secondary structure was assessed by circular dichroism (CD). Intrinsic fluorescence and hydrophobic probe (1-anilinonaphthalene 8-sulphonic acid, ANS) were used to study the Der p 2 hydrophobic cavity. IgE binding was assessed by ELISA inhibition. CD analysis showed the expected secondary structure for both nDer p 2 and refolded Der p 2 prepared from E. coli inclusion bodies but primarily random structure for Der p 2 secreted from P. pastoris. The secreted product, however, had disulphide bonding and could be refolded to a similar structure to natural Der (nDer) p 2 after precipitation with trichloro-acetic or ammonium sulphate. ANS binding and intrinsic Trp92 fluorescence showed that all recombinant proteins were different to nDer p 2 and that the allergen secreted from P. pastoris did not form a hydrophobic cavity. Despite the marked structural changes, all preparations of Der p 2 had similar IgE binding to nDer p 2. Despite almost identical IgE binding, rDer p 2 prepared from both E. coli and P. pastoris showed structural differences to nDer p 2. Der p 2 secreted from P. pastoris lacked most of the natural structure, but refolding could induce the natural structure.
    Full-text · Article · Sep 2009 · International Archives of Allergy and Immunology
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    ABSTRACT: Atopic sensitization to the house dust mite (HDM) is associated with altered antibody responses to the nasopharyngeal colonizing bacterium Haemophilus influenzae and children admitted to the emergency department for asthma exacerbation have reduced IgG responses to HDM allergens. To investigate anti-bacterial and anti-allergen antibody responses during convalescence from asthma exacerbation and differences found in exacerbations associated with and without viral infection. IgE antibodies to the P6 bacterial antigen increased in 60% of sera during convalescence and for many children achieved titres as high as IgE titres to allergens. In contrast IgE anti-HDM titres declined during convalescence. The anti-bacterial IgE titres were the same in subjects with and without virus infection while the anti-HDM IgE declined more rapidly in virus-infected subjects. IgG titres to the major HDM allergens showed no consistent increase and the overall IgG anti-HDM titres even declined in subjects without a virus infection. Anti-bacterial IgG antibodies in contrast to IgE did not change. Patients with frequent episodic or persistent asthma had similar IgE anti-bacterial titres to patients with infrequent asthma during the acute phase, although they had reduced IgG titres to both the bacteria and the HDM. During the period following an acute exacerbation of asthma there was a marked and specific increase in anti-bacterial IgE compared with a reduced IgE response to HDM. This provides further support for the concept of T-helper type 2 responses to bacterial antigens playing a role in asthma pathogenesis.
    Full-text · Article · May 2009 · Clinical & Experimental Allergy
  • W R Thomas

    No preview · Article · May 2009 · Clinical & Experimental Allergy
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    ABSTRACT: The ST2 gene is a member of the interleukin-1 receptor family and is located on chromosome 2q12, an area of the genome that has been associated with asthma. The soluble product of the ST2 gene, serum ST2 (sST2), has previously been shown to be elevated in adult asthmatic patients. This study investigated the potential role of ST2 in children with acute asthma. Children aged 2-16 years (n = 186) were recruited on presentation with acute asthma in the emergency department. Blood was obtained on presentation and during convalescence. Variables assessed included sST2 levels, a comprehensive assembly of clinical parameters and two polymorphisms in the ST2 gene, -26999G/A, located in the distal promoter region, and ala78glu polymorphism, on exon 3. The A allele of the -26999G/A polymorphism occurred more frequently in asthmatics compared with an unselected control group (P = 0.031). Serum ST2 levels were substantially higher during acute asthma compared with levels after the attack: 0.29 ng/ml (95% confidence interval: 0.23-0.36) and 0.14 ng/ml (0.12-0.17), respectively (P = 0.001) and were inversely related to eosinophil counts during an acute asthma attack (P = 0.002). The -26999AA genotype, as well as the AC haplotype, was associated with asthma severity scores (P = 0.05 and 0.02) compared with the -26999GA and GG genotypes. Serum ST2 levels were not associated with any of the studied genotypes or haplotypes. The observed associations of ST2 genotypes and haplotypes with acute asthma and asthma severity scores as well as the phenotypic differences associated with ST2 polymorphisms suggest that ST2 may play a role in the pathophysiology of asthma.
    Full-text · Article · Apr 2009 · Tissue Antigens
  • W.R. Thomas · B.J. Hales
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    ABSTRACT: This chapter describes and compares the immune responses induced by the common allergens of pollen, house-dust mites, cockroaches, and cats along with the common food allergens of milk, eggs, and peanut and the venom allergens of the honeybee. The IgE, IgG, IgA, and T-cell effector and regulatory responses are described with express reference to responses measured to major allergens and knowledge of the responses produced to the different specificities of each allergen source. IgE binding is usually directed to one or two major allergens. Good examples of this are birch, olive and grass pollen, house-dust mite, milk and cat. Major allergens of cockroach, ragweed, peanut, bee venom, and egg have also been defined but are less dominant or universally recognized. Sera typically contain an average of around 50 ng/mL of IgE antibody to major allergens, with Fel d 1 being an exception with many patients showing low titers. For all allergens, however, many asthmatics only produce a few nanograms per milliliter of antibody. IgG antibody responses to pollen, food, and mite allergens are restricted to allergic subjects. For house-dust mite it has been shown that the IgG binding activity of individual allergens correlates with their allergenicity. As well as IgG4, the Th1-type IgG1 subclass is produced in titers similar to those to bacterial antigens. The IgG responses to pollens are low. IgG binding to individual cockroach allergens has less concordance with IgE, and cat and mouse allergens induce IgG antibody in the absence of IgE. This has been associated with the high levels of cat allergen in homes but comparable exposure levels are not found for the mouse allergen. The precursor frequency of allergen-specific T cells is higher in allergic than nonallergic subjects, but even nonallergic subjects show a sizeable T-cell expansion in response to allergic exposure. T cells from allergic subjects produce Th2 cytokines, and when stimulated directly ex vivo a similar Th1 response to cells from nonallergic subjects, and in similar amounts to that induced by bacterial antigens. The expression of T-cell chemokines and chemokine receptors shows the same pattern. The regulatory cytokine IL-10 and CD4+CD25+ T cells have both been shown to be able to inhibit responses of T cells to allergens in in vitro cultures. However, their relative levels in allergic and nonallergic people have been the subject of conflicting reports and they appear to have a regulatory role in the responses of both healthy and allergic subjects.
    No preview · Article · Feb 2009
  • W. R. Thomas · P. T. Cunningham · C. E. Elliot · P. G. Holt

    No preview · Article · Feb 2009 · Journal of Allergy and Clinical Immunology
  • W. R. Thomas · W. Smith · T. K. Heinrich · B. J. Hales
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    ABSTRACT: The most widely distributed sources of allergens are the pyroglyphid Dermato phagoides pteronyssinus and Dermatophagoides farinae mites [1], temperate grass pollens [2] and cats [3]. Other important allergens with less global distributions are birch [4], olive [5], ragweed and mugwort pollens [6]. Cockroach allergy is important for inner-city dwellers in America [7]. Dog allergy has been more evident in regions with low exposure to other allergens but is also a frequent source of sensitisation elsewhere [8]. The glycyphagid mite Blomia tropicalis is important in highly populated tropical and subtropical regions [9]. The conifers Japanese cedar in Japan and mountain cedar in USA and to a lesser degree cypress are regionally important [10]. Allergens from Aspergillus, Alternaria, Cladosporium and Penicillium moulds sensitise 5–10% of most populations and are associated with severe asthma [11]. Emerging sources of sensitisation are domestic exposure to mice in inner city environments, and pollens from the weeds Salsola kali (Russian thistle or tumble weed) and Chenopodium album (lambs quarter or goosefoot) [5]. The pollens occur worldwide but have attracted interest in areas of desertification.
    No preview · Chapter · Dec 2008
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    B J Hales · L J Pearce · M M H Kusel · P G Holt · P D Sly · W R Thomas
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    ABSTRACT: The immune response to bacterial antigens on mucosal surfaces may be modified in individuals allergic to aeroallergens due to a maturational or genetic difference or from the interaction between inhaled allergens and bacteria at the mucosa. Plasma from children and adults allergic (n = 97) and non-allergic (n = 54) to aeroallergens were initially tested for IgG1 (Th1) and IgG4 (Th2) reactivity to P6, a conserved outer membrane protein of Haemophilus influenzae. IgE binding was measured for some allergic donors. The development of the antibody responses to P6 was subsequently examined in the plasma from 35 children aged 1, 2 and 5 years taken from a prospective birth cohort. IgG4 antibodies to P6 were more readily detected in allergic subjects than in non-allergic subjects (p<0.001), with a strong bias to the male gender. Some allergic subjects (35%) also had IgE antibody (1-10 ng/ml) that was not associated with IgG4 or gender. In the cohort study of infants, subjects who developed skin prick test positivity to mite allergens by 5 years of age had an 85% reduction in the IgG1 anti-P6 antibody at year 2 (p<0.05) and, unlike skin test negative infants, this group had IgG4 anti-P6 antibodies at 5 years of age. The antibodies of subjects allergic to a bacterial antigen included IgE and IgG4 (particularly for males) compared with the almost exclusive IgG1 response of non-allergic subjects. The IgG1 responses of 2-year-old children who became skin test positive was markedly reduced and P6-specific IgG4 became detectable at 5 years of age.
    Full-text · Article · Mar 2008 · Thorax
  • W. R. Thomas · P. T. Cunningham · P. G. Holt

    No preview · Article · Feb 2008 · Journal of Allergy and Clinical Immunology
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    ABSTRACT: There is evidence that the specificity of the IgE binding in allergy tests can vary for different populations. We aimed to examine the allergenic specificity of IgE binding in sera from house dust mite (HDM)-atopic subjects in a tropical Australian Aboriginal community. Sera shown to contain IgE antibodies to an HDM extract of Dermatophagoides pteronyssinus were examined for IgE binding to a panel of nine purified HDM allergens from this mite species by quantitative microtitre assays. IgG antibody binding (IgG1 and IgG4) was also measured. The IgE-binding activity in the sera from the Aboriginal community was not directed to the expected major groups 1 and 2 HDM allergens but instead to the group 4 amylase allergen. There was also little IgE binding to the potentially cross-reactive tropomyosin (Der p 10) or arginine kinase (Der p 20) allergens. The IgG4 antibody was rarely detected and limited to the Der p 4 allergen. IgG1 antibody binding was frequently measured to all the allergens regardless of an individual's atopic status, whereas in urban communities it is restricted to the major allergens and to atopic subjects. The high IgE anti-HDM response of Australian Aboriginals predominantly bound Der p 4 and not the Der p 1 and 2 allergens, showing a distinctive allergy that could affect the disease outcome and diagnosis.
    Full-text · Article · Oct 2007 · Clinical & Experimental Allergy
  • S. E. O'Neil · W. Smith · T. K. Heinrich · B. J. Hales · W. R. Thomas

    No preview · Article · Jan 2007 · Journal of Allergy and Clinical Immunology

  • No preview · Article · Jan 2007 · Journal of Allergy and Clinical Immunology
  • W. R. Thomas · B. J. Hales · A. C. Martin · P. N. LeSouef

    No preview · Article · Dec 2006 · Paediatric respiratory reviews

Publication Stats

4k Citations
498.22 Total Impact Points

Institutions

  • 2015
    • Telethon Kids Institute
      Western Australia, Australia
  • 1995-2015
    • University of Western Australia
      • • Centre for Health Services Research
      • • Molecular Biotechnology Team
      Perth City, Western Australia, Australia
  • 2001
    • Centro Nacional De Investigaciones En Salud Materno Infantil (Cenismi)
      Santo Domingo Pueblo, New Mexico, United States
  • 2000
    • Royal Melbourne Hospital
      Melbourne, Victoria, Australia
  • 1995-1999
    • University of Melbourne
      • Department of Medicine
      Melbourne, Victoria, Australia
  • 1993-1998
    • Western Australia Health
      Perth City, Western Australia, Australia
    • University of Cambridge
      • Department of Pathology
      Cambridge, England, United Kingdom
    • Flinders University
      • Department of Paediatrics and Child Health
      Adelaide, South Australia, Australia
  • 1997
    • Medical University of Vienna
      • Department of Pathophysiology and Allergy Research
      Vienna, Vienna, Austria
  • 1993-1996
    • Taipei Veterans General Hospital
      • Department of Medical Research and Education
      T’ai-pei, Taipei, Taiwan
  • 1989-1994
    • The Princess Margaret Hospital
      Toronto, Ontario, Canada
  • 1991-1992
    • Institute for Child Health Policy (ICHP)
      Alabama, United States