G Cooke1, I Kamal2,3, M Strengert2, E Hams4,5, L Mawhinney4, A Tynan4, C O'Reilly4, D N O'Dwyer2,3, S L Kunkel6, U G Knaus2, D C Shields7, D R Moller8, A G Bowie9, P G Fallon4,5, C M Hogaboam6, M E Armstrong4, S C Donnelly4,10. 1. Department of Applied Sciences, Institute of Technology Tallaght, Tallaght, Dublin 24, Ireland. 2. School of Medicine and Medical Science, College of Life Sciences, UCD Conway Institute of Biomolecular and Biomedical Research, University College Dublin, Belfield, Dublin 4, Ireland. 3. National Pulmonary Fibrosis Referral Centre at St. Vincent's University Hospital, Elm Park, Dublin 4, Ireland. 4. School of Medicine, Trinity Biomedical Sciences Institute, Trinity College, Dublin 2, Ireland. 5. National Children's Research Centre, Our Lady's Children's Hospital Crumlin, Dublin 12, Ireland. 6. Department of Pathology, University of Michigan Medical School, Ann Arbor, MI 48109, USA. 7. UCD Complex and Adaptive Systems Laboratory, University College Dublin, Belfield, Dublin 4, Ireland. 8. Division of Pulmonary and Critical Care Medicine, Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21224, USA. 9. School of Biochemistry and Immunology, Trinity Biomedical Sciences Institute, Trinity College, Dublin 2, Ireland. 10. Department of Clinical Medicine, Trinity Centre for Health Sciences, Tallaght Hospital, Tallaght, Dublin 24, Ireland.
Abstract
BACKGROUND/ INTRODUCTION: Sarcoidosis is a multi-systemic disorder of unknown etiology, characterized by the presence of non-caseating granulomas in target organs. In 90% of cases, there is thoracic involvement. Fifty to seventy percent of pulmonary sarcoidosis patients will experience acute, self-limiting disease. For the subgroup of patients who develop persistent disease, no targeted therapy is currently available. AIM: To investigate the potential of the single nucleotide polymorphism (SNP), Toll-like receptor 3 Leu412Phe (TLR3 L412F; rs3775291), as a causative factor in the development of and in disease persistence in pulmonary sarcoidosis. To investigate the functionality of TLR3 L412F in vitro in primary human lung fibroblasts from pulmonary sarcoidosis patients. DESIGN: SNP-genotyping and cellular assays, respectively, were used to investigate the role of TLR3 L412F in the development of persistent pulmonary sarcoidosis. METHODS: Cohorts of Irish sarcoidosis patients (n = 228), healthy Irish controls (n = 263) and a secondary cohort of American sarcoidosis patients (n = 123) were genotyped for TLR3 L412F. Additionally, the effect of TLR3 L412F in primary lung fibroblasts from pulmonary sarcoidosis patients was quantitated following TLR3 activation in the context of cytokine and type I interferon production, TLR3 expression and apoptotic- and fibroproliferative-responses. RESULTS: We report a significant association between TLR3 L412F and persistent clinical disease in two cohorts of Irish and American Caucasians with pulmonary sarcoidosis. Furthermore, activation of TLR3 in primary lung fibroblasts from 412 F-homozygous pulmonary sarcoidosis patients resulted in reduced IFN-β and TLR3 expression, reduced apoptosis- and dysregulated fibroproliferative-responses compared with TLR3 wild-type patients. DISCUSSION/ CONCLUSION: This study identifies defective TLR3 function as a previously unidentified factor in persistent clinical disease in pulmonary sarcoidosis and reveals TLR3 L412F as a candidate biomarker.
BACKGROUND/ INTRODUCTION: Sarcoidosis is a multi-systemic disorder of unknown etiology, characterized by the presence of non-caseating granulomas in target organs. In 90% of cases, there is thoracic involvement. Fifty to seventy percent of pulmonary sarcoidosis patients will experience acute, self-limiting disease. For the subgroup of patients who develop persistent disease, no targeted therapy is currently available. AIM: To investigate the potential of the single nucleotide polymorphism (SNP), Toll-like receptor 3 Leu412Phe (TLR3 L412F; rs3775291), as a causative factor in the development of and in disease persistence in pulmonary sarcoidosis. To investigate the functionality of TLR3 L412F in vitro in primary human lung fibroblasts from pulmonary sarcoidosis patients. DESIGN: SNP-genotyping and cellular assays, respectively, were used to investigate the role of TLR3 L412F in the development of persistent pulmonary sarcoidosis. METHODS: Cohorts of Irish sarcoidosis patients (n = 228), healthy Irish controls (n = 263) and a secondary cohort of American sarcoidosis patients (n = 123) were genotyped for TLR3 L412F. Additionally, the effect of TLR3 L412F in primary lung fibroblasts from pulmonary sarcoidosis patients was quantitated following TLR3 activation in the context of cytokine and type I interferon production, TLR3 expression and apoptotic- and fibroproliferative-responses. RESULTS: We report a significant association between TLR3 L412F and persistent clinical disease in two cohorts of Irish and American Caucasians with pulmonary sarcoidosis. Furthermore, activation of TLR3 in primary lung fibroblasts from 412 F-homozygous pulmonary sarcoidosis patients resulted in reduced IFN-β and TLR3 expression, reduced apoptosis- and dysregulated fibroproliferative-responses compared with TLR3 wild-type patients. DISCUSSION/ CONCLUSION: This study identifies defective TLR3 function as a previously unidentified factor in persistent clinical disease in pulmonary sarcoidosis and reveals TLR3 L412F as a candidate biomarker.
Authors: Manuela Sironi; Mara Biasin; Rachele Cagliani; Diego Forni; Mariacristina De Luca; Irma Saulle; Sergio Lo Caputo; Francesco Mazzotta; Juan Macías; Juan A Pineda; Antonio Caruz; Mario Clerici Journal: J Immunol Date: 2011-12-14 Impact factor: 5.422
Authors: L Di Alberti; A Piattelli; L Artese; G Favia; S Patel; N Saunders; S R Porter; C M Scully; S L Ngui; C G Teo Journal: Lancet Date: 1997-12-06 Impact factor: 79.321
Authors: Magdalena J Laska; Bettina Hansen; Anne Troldborg; Tove Lorenzen; Kristian Stengaard-Pedersen; Peter Junker; Bjørn A Nexø; Hanne M Lindegaard Journal: BMC Res Notes Date: 2014-10-10