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Publication History View all

  • Oral Surgery, Oral Medicine, Oral Pathology, Oral Radiology, and Endodontology 01/2014; 117(5):e334–e335.
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    ABSTRACT: Professor Thomas Lehner is one of the most distinguished oral and dental researchers to have come out of the UK. Over the past 40 years, he has made an astonishing number of discoveries which have had an impact on our understanding of the pathogenesis of a variety of mucosal diseases. He has consistently practiced both basic and clinical research and built an integrated group of clinical and non-clinical researchers, which allowed him easy transition from the laboratory to the clinic. Tom Lehner was among the early scientists studying mucosal immunology, initially exploring oral diseases, with special emphasis on the immunobiology of Streptococcus mutans, leading to active and passive vaccination against dental caries. He was the first to demonstrate cellular immunity as the immunopathological basis of periodontal diseases, recurrent aphthous stomatitis, and candidiasis. Over the past 20 years, his expertise in mucosal immunobiology has been applied to the immunology of HIV/SIV infections. His seminal contributions include regional innate mucosal immunity, prevention of SIV infection in macaques by secretory IgA antibodies, up-regulation of CC chemokines, and the first demonstration of protective CCR5 antibodies. Arguably, his leadership, his students, and the establishment of immunology applied to oral mucosal diseases will be his greatest legacy. His contributions continue unabated.
    Journal of dental research 03/2013;
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    ABSTRACT: The etiology and maintenance of inflammatory bowel disease (IBD) is the subject of much speculation. Iliev et al. (2012) impose a change in our views of the gut microbiome and catapult the fungal "mycobiome" center-stage in the exploration of IBD.
    Cell host & microbe 06/2012; 11(6):551-2.
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    ABSTRACT: The fungus C. albicans uses adhesins to interact with human epithelial surfaces in the processes of colonization and pathogenesis. The C. albicans ALS (agglutinin-like sequence) gene family encodes eight large cell-surface glycoproteins (Als1-Als7 and Als9) that have adhesive function. This study utilized C. albicans Δals mutant strains to investigate the role of the Als family in oral epithelial cell adhesion and damage, cytokine induction and activation of a MAPK-based (MKP1/c-Fos) signaling pathway that discriminates between yeast and hyphae. Of the eight Δals mutants tested, only the Δals3 strain showed significant reductions in oral epithelial cell adhesion and damage, and cytokine production. High fungal:epithelial cell multiplicities of infection were able to rescue the cell damage and cytokine production phenotypes, demonstrating the importance of fungal burden in mucosal infections. Despite its adhesion, damage and cytokine induction phenotypes, the Δals3 strain induced MKP1 phosphorylation and c-Fos production to a similar extent as control cells. Our data demonstrate that Als3 is involved directly in epithelial adhesion but indirectly in cell damage and cytokine induction, and is not the factor targeted by oral epithelial cells to discriminate between the yeast and hyphal form of C. albicans.
    PLoS ONE 01/2012; 7(3):e33362.
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    ABSTRACT: Intracellular responses to external pathogens/stimuli are crucial to the host's response to infection. The methods used to analyse these responses fall into many categories. Activation of proteins as part of a signal cascade can be screened for using conventional immunoblotting techniques or immunoprecipitation to identify the presence of modified proteins or protein complexes. Transcription factor activity can be screened for by EMSA or ELISAs to identify DNA binding of these factors. Finally, expression of activated genes can be quantified using real-time PCR methods. Here, we will show how to perform these assays and discuss the relative merits of each.
    Methods in molecular biology (Clifton, N.J.) 01/2012; 845:345-60.
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    ABSTRACT: The role of human papillomaviruses (HPV) in dysplastic and malignant oral verrucous lesions is controversial since there is a wide range in the incidence of virus detection. This study used a multi-tiered method of HPV detection using DNA in-situ hybridisation (ISH) for low- and high-risk subtypes, consensus PCR, and HPV genotype analysis in archival tissue from 20 cases of dysplastic and malignant oral verrucous lesions. The biological significance of HPV DNA detection was assessed by p16 immunohistochemistry (IHC). While 1/7 carcinomas and 5/13 dysplasias contained HPV DNA by consensus PCR and genotype analysis, all specimens were negative for low- and high-risk HPV ISH and negative for p16 IHC. Results show that although high-risk HPV DNA is detectable in a subset of these lesions, the lack of p16 overexpression suggests that the oncogenic process is not driven by HPV oncoproteins.
    Journal of clinical pathology 12/2011; 65(3):283-6.
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    ABSTRACT: Oral epithelial cells discriminate between the yeast and hyphal forms of Candida albicans via the mitogen-activated protein kinase (MAPK) signaling pathway. This occurs through phosphorylation of the MAPK phosphatase MKP1 and activation of the c-Fos transcription factor by the hyphal form. Given that fungal cell wall polysaccharides are critical in host recognition and immune activation in myeloid cells, we sought to determine whether β-glucan and N- or O-glycosylation was important in activating the MAPK/MKP1/c-Fos hypha-mediated response mechanism and proinflammatory cytokines in oral epithelial cells. Using a series of β-glucan and N- and O-mannan mutants, we found that N-mannosylation (via Δoch1 and Δpmr1 mutants) and O-mannosylation (via Δpmt1 and Δmnt1 Δmnt2 mutants), but not phosphomannan (via a Δmnn4 mutant) or β-1,2 mannosylation (via Δbmt1 to Δbmt6 mutants), were required for MKP1/c-Fos activation, proinflammatory cytokine production, and cell damage induction. However, the N- and O-mannan mutants showed reduced adhesion or lack of initial hypha formation at 2 h, resulting in little MKP1/c-Fos activation, or restricted hypha formation/pseudohyphal formation at 24 h, resulting in minimal proinflammatory cytokine production and cell damage. Further, the α-1,6-mannose backbone of the N-linked outer chain (corresponding to a Δmnn9 mutant) may be required for epithelial adhesion, while the α-1,2-mannose component of phospholipomannan (corresponding to a Δmit1 mutant) may contribute to epithelial cell damage. β-Glucan appeared to play no role in adhesion, epithelial activation, or cell damage. In summary, N- and O-mannosylation defects affect the ability of C. albicans to induce proinflammatory cytokines and damage in oral epithelial cells, but this may be due to indirect effects on fungal pathogenicity rather than mannose residues being direct activators of the MAPK/MKP1/c-Fos hypha-mediated immune response.
    Infection and immunity 09/2011; 79(12):4902-11.
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    ABSTRACT: Development of novel diagnostics for tuberculosis has so far been governed by the clinical requirement of improving the detection of patients with paucibacillary forms of the disease. For this aim, serological assays have been evaluated using several antigens, but were found insufficiently sensitive, because antibody production associates with the bacterial load of the disease. Consequently, detection of antibodies against a relatively small number of selected well-defined antigens has a much higher sensitivity for sputum smear-positive pulmonary disease in adult HIV-negative patients. They are the most active in generating and spreading aerosols containing live tubercle bacilli, but their detection is often delayed, thus perpetuating the transmission of the infection and disease in the population. High volume throughput serological screening of clinical suspects with mild clinical symptoms may help to achieve diagnosis earlier, than currently used procedures. Such expanded testing could be done more efficiently in laboratories, than at 'points-of-care' and at a lower cost than other tests. The feasibility of this approach towards reducing the delayed diagnosis of the most infectious cases of pulmonary tuberculosis needs to be ascertained in prospective diagnostic trials, in populations at a high risk. Reducing the transmission of tuberculosis is of key importance for achieving its continued decline and therefore it is proposed, that the aims of serological screening should shift from clinical to public health priorities.
    Tuberculosis (Edinburgh, Scotland) 09/2011; 92(1):31-7.
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    ABSTRACT: Oral epithelial cells detect the human pathogenic fungus Candida albicans via NF-κB and a bi-phasic mitogen-activated protein kinase (MAPK) signaling response. However, discrimination between C. albicans yeast and hyphal forms is mediated only by the MAPK pathway, which constitutes activation of the MAPK phosphatase MKP1 and the c-Fos transcription factor and is targeted against the hyphal form. Given that C. albicans is not the only Candida species capable of filamentation or causing mucosal infections, we sought to determine whether this MAPK/MKP1/c-Fos mediated response mechanism was activated by other pathogenic Candida species, including C. dubliniensis, C. tropicalis, C. parapsilosis, C. glabrata and C. krusei. Although all Candida species activated the NF-κB signaling pathway, only C. albicans and C. dubliniensis were capable of inducing MKP1 and c-Fos activation, which directly correlated with hypha formation. However, only C. albicans strongly induced cytokine production (G-CSF, GM-CSF, IL-6 and IL-1α) and cell damage. Candida dubliniensis, C. tropicalis and C. parapsilosis were also capable of inducing IL-1α and this correlated with mild cell damage and was dependent upon fungal burdens. Our data demonstrate that activation of the MAPK/MKP1/c-Fos pathway in oral epithelial cells is specific to C. dubliniensis and C. albicans hyphae.
    Medical Microbiology and Immunology 06/2011; 201(1):93-101.
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    ABSTRACT:  Oral potentially malignant disorders (OPMD) are known to precede the development of oral cancer. Detection of OPMD allows delivery of interventions that may reduce the evolution of these disorders to malignancy. Following oral examinations, the accuracy of detection of OPMD by chemiluminescence was evaluated using a commercially available detection kit - ViziLite. Data derived were compared in relation to conventional oral examination and surgical biopsy. A total of 126 patients, 70 men and 56 women (mean age 58.5 ± 11.9 years) attending Oral Medicine Clinics at King's and Guy's Hospitals, London, with oral white, red, and mixed white and red patches were enrolled. Sixty-one patients were current smokers, 28 were ex-smokers, while 92 were alcohol users. In a detailed investigation, these patients underwent ViziLite examination followed by surgical biopsy.  Based on the clinical diagnosis, 70 patients had oral leukoplakia/erythroplakia, 32 had oral lichen planus, nine had chronic hyperplastic candidiasis, and rest had frictional keratosis (13) or oral submucous fibrosis (2). Of 126 lesions, 95 (75.4%) showed aceto-whitening. Most oral leukoplakias had enhanced visibility and sharpness of the lesion when viewed with the ViziLite system. Following biopsy, 44 had oral epithelial dysplasia (29 mild, eight moderate, and seven severe). The sensitivity (se) and specificity (sp) of chemiluminescence for the detection of a dysplastic lesion were 77.3% and 27.8%, respectively. While ViziLite has the ability to detect OPMD, it does not accurately delineate dysplastic lesions. The device can be used as a general oral mucosal examination system and may in particular improve the visualization of leukoplakias.
    Journal of Oral Pathology and Medicine 05/2011; 40(7):541-4.
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