W R Thomas

Telethon Kids Institute, Western Australia, Australia

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Publications (107)511.1 Total impact

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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.
    Genes and immunity 04/2015; DOI:10.1038/gene.2015.12 · 3.79 Impact Factor
  • 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.
    Clinical & Experimental Allergy 02/2013; 43(2):152-163. DOI:10.1111/j.1365-2222.2012.04059.x · 4.32 Impact Factor
  • Journal of Allergy and Clinical Immunology 02/2012; 129(2):AB140. DOI:10.1016/j.jaci.2011.12.469 · 11.25 Impact Factor
  • W R Thomas
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    ABSTRACT: Cite this as: W. R. Thomas, Clinical & Experimental Allergy, 2011 (41) 769-772.
    Clinical & Experimental Allergy 06/2011; 41(6):769-72. DOI:10.1111/j.1365-2222.2011.03751.x · 4.32 Impact Factor
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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.
    International Archives of Allergy and Immunology 05/2011; 156(2):159-70. DOI:10.1159/000322879 · 2.43 Impact Factor
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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.
    European Respiratory Journal 09/2010; 36(3):509-16. DOI:10.1183/09031936.00184109 · 7.13 Impact Factor
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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.
    International Archives of Allergy and Immunology 09/2009; 151(3):190-8. DOI:10.1159/000242356 · 2.43 Impact Factor
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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.
    Clinical & Experimental Allergy 05/2009; 39(8):1170-8. DOI:10.1111/j.1365-2222.2009.03252.x · 4.32 Impact Factor
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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.
    Tissue Antigens 04/2009; 73(3):206-12. DOI:10.1111/j.1399-0039.2008.01185.x · 2.35 Impact Factor
  • W. R. Thomas · P. T. Cunningham · C. E. Elliot · P. G. Holt
    Journal of Allergy and Clinical Immunology 02/2009; 123(2). DOI:10.1016/j.jaci.2008.12.357 · 11.25 Impact Factor
  • 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.
    12/2008: pages 311-324;
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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.
    Thorax 03/2008; 63(3):221-7. DOI:10.1136/thx.2006.069492 · 8.56 Impact Factor
  • W. R. Thomas · P. T. Cunningham · P. G. Holt
    Journal of Allergy and Clinical Immunology 02/2008; 121(2). DOI:10.1016/j.jaci.2007.12.538 · 11.25 Impact Factor
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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.
    Clinical & Experimental Allergy 10/2007; 37(9):1357-63. DOI:10.1111/j.1365-2222.2007.02786.x · 4.32 Impact Factor
  • S. E. O'Neil · W. Smith · T. K. Heinrich · B. J. Hales · W. R. Thomas
    Journal of Allergy and Clinical Immunology 01/2007; 119(1). DOI:10.1016/j.jaci.2006.11.553 · 11.25 Impact Factor
  • Journal of Allergy and Clinical Immunology 01/2007; 119(1). DOI:10.1016/j.jaci.2006.12.384 · 11.25 Impact Factor
  • W. R. Thomas · B. J. Hales · A. C. Martin · P. N. LeSouef
    Paediatric respiratory reviews 12/2006; 7. DOI:10.1016/j.prrv.2006.04.039 · 2.22 Impact Factor
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    ABSTRACT: House dust mites Dermatophagoides pteronyssinus and Dermatophagoides farinae cause allergic disease in humans as well as in dogs. In geographical regions where the two mite species coexist, they both elicit specific immunoglobulin (Ig E) responses in humans whereas dogs preferentially react to D. farinae extracts. In dogs the main IgE binding is directed to the D. farinae chitinase allergens Der f 15 and Der f 18 and not to the groups 1 and 2 allergens as found for humans. Although the IgE response of humans to Der f 18 has been investigated there is no report on Der f 15-specific IgE in humans. This study aimed to characterize the chitinase allergens Der p 15 and Der p 18 of D. pteronyssinus and to find out whether they are important allergens for humans. cDNA was cloned by a polymerase chain reaction strategy from D. pteronyssinus libraries using primers based on conserved chitinase sequences. IgE binding to the recombinant polypeptides was measured by immunosorbent assay. Mice were immunized with the polypeptides and cross-reactivity examined. Two variants of Der p 15 were isolated, encoding mature proteins of 58.8 and 61.4 kDa. The amino acid sequences had 90% identity to Der f 15. The cDNA for Der p 18 encoded a mature protein of 49.2 kDa with 88% sequence identity to Der f 18. Der p 15-specific IgE was detected in 70% and Der p 18-specific IgE in 63% of a panel of 27 human allergic sera. The D. pteronyssinus chitinases Der p 15 and Der p 18 show a high frequency of binding to IgE in allergic human sera. They are therefore potentially important allergens for humans as well as dogs.
    Clinical & Experimental Allergy 07/2006; 36(6):831-9. DOI:10.1111/j.1365-2222.2006.02497.x · 4.32 Impact Factor
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    ABSTRACT: Polymorphic sequence substitutions in the major mite allergens can markedly affect immunoglobulin E binding and T cell responses, but there are few studies on environmental isolates from Dermatophagoides pteronyssinus and none for D. farinae. To determine the sequence variation of the group 1 and 2 allergens from environmental D. pteronyssinus and D. farinae. RNA from each species was isolated from homes in Bangkok and the sequence of Der p 1, Der p 2, Der f 1, and Der f 2 determined from cDNA produced by high fidelity polymerase chain reactions. The enlarged data set revealed preferred amino acid substitutions in residues 19, 81, and 215 of Der p 1 as well as sporadic changes. Der p 2 showed frequent variations with clusters of amino acid substitutions, but the canonical Der p 2.0101 was not found in any of 17 sequences. Der f 2 showed variants with clusters of substitutions similar to Der p 2 but in different amino acid positions and without any structural concordance. Der f 1 in contrast to the other allergens had few amino acid sequence substitutions. The sequence information on variants provides data important for the optimal design of allergen formulations and useful for the genetic engineering and structure-function analyses of the major allergens.
    Clinical & Experimental Allergy 05/2006; 36(4):510-6. DOI:10.1111/j.1365-2222.2006.02464.x · 4.32 Impact Factor
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    P G Holt · W R Thomas
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    ABSTRACT: Despite considerable advances in identifying the environmental agents that trigger allergy and the immunological mechanisms involved, progress in developing effective treatments remains frustratingly slow. Is it time to rethink some of the paradigms guiding this research?
    Nature Immunology 11/2005; 6(10):957-60. DOI:10.1038/ni1005-957 · 24.97 Impact Factor

Publication Stats

5k Citations
511.10 Total Impact Points

Institutions

  • 2015
    • Telethon Kids Institute
      Western Australia, Australia
  • 1993–2013
    • University of Western Australia
      • • Centre for Health Services Research
      • • Molecular Biotechnology Team
      Perth City, Western Australia, Australia
    • Flinders University
      • Department of Paediatrics and Child Health
      Adelaide, South Australia, Australia
    • University of Cambridge
      Cambridge, England, United Kingdom
  • 1995–2000
    • University of Melbourne
      • Department of Medicine
      Melbourne, Victoria, Australia
  • 1992–1998
    • Western Australia Health
      Perth City, Western Australia, Australia
  • 1997
    • Medical University of Vienna
      • Department of Pathophysiology and Allergy Research
      Vienna, Vienna, Austria
  • 1993–1996
    • Taipei Veterans General Hospital
      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