Toll-like receptor 3 L412F polymorphism promotes a persistent clinical phenotype in pulmonary sarcoidosis

G. Cooke, I. Kamal, M. Strengert, E. Hams, L. Mawhinney, A. Tynan, C. O'Reilly, D. N. O'Dwyer, S. L. Kunkel, U. G. Knaus, D. C. Shields, David Moller, A. G. Bowie, P. G. Fallon, C. M. Hogaboam, M. E. Armstrong, S. C. Donnelly

Research output: Contribution to journalArticle

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 Fhomozygous 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.

Original languageEnglish (US)
Pages (from-to)217-224
Number of pages8
JournalQJM
Volume111
Issue number4
DOIs
StatePublished - Apr 1 2018

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Toll-Like Receptor 3
Pulmonary Sarcoidosis
Phenotype
Sarcoidosis
Fibroblasts
Lung
Single Nucleotide Polymorphism
Interferon Type I
Granuloma
Thorax
Biomarkers
Apoptosis
Cytokines

ASJC Scopus subject areas

  • Medicine(all)

Cite this

Cooke, G., Kamal, I., Strengert, M., Hams, E., Mawhinney, L., Tynan, A., ... Donnelly, S. C. (2018). Toll-like receptor 3 L412F polymorphism promotes a persistent clinical phenotype in pulmonary sarcoidosis. QJM, 111(4), 217-224. https://doi.org/10.1093/qjmed/hcx243

Toll-like receptor 3 L412F polymorphism promotes a persistent clinical phenotype in pulmonary sarcoidosis. / Cooke, G.; Kamal, I.; Strengert, M.; Hams, E.; Mawhinney, L.; Tynan, A.; O'Reilly, C.; O'Dwyer, D. N.; Kunkel, S. L.; Knaus, U. G.; Shields, D. C.; Moller, David; Bowie, A. G.; Fallon, P. G.; Hogaboam, C. M.; Armstrong, M. E.; Donnelly, S. C.

In: QJM, Vol. 111, No. 4, 01.04.2018, p. 217-224.

Research output: Contribution to journalArticle

Cooke, G, Kamal, I, Strengert, M, Hams, E, Mawhinney, L, Tynan, A, O'Reilly, C, O'Dwyer, DN, Kunkel, SL, Knaus, UG, Shields, DC, Moller, D, Bowie, AG, Fallon, PG, Hogaboam, CM, Armstrong, ME & Donnelly, SC 2018, 'Toll-like receptor 3 L412F polymorphism promotes a persistent clinical phenotype in pulmonary sarcoidosis', QJM, vol. 111, no. 4, pp. 217-224. https://doi.org/10.1093/qjmed/hcx243
Cooke G, Kamal I, Strengert M, Hams E, Mawhinney L, Tynan A et al. Toll-like receptor 3 L412F polymorphism promotes a persistent clinical phenotype in pulmonary sarcoidosis. QJM. 2018 Apr 1;111(4):217-224. https://doi.org/10.1093/qjmed/hcx243
Cooke, G. ; Kamal, I. ; Strengert, M. ; Hams, E. ; Mawhinney, L. ; Tynan, A. ; O'Reilly, C. ; O'Dwyer, D. N. ; Kunkel, S. L. ; Knaus, U. G. ; Shields, D. C. ; Moller, David ; Bowie, A. G. ; Fallon, P. G. ; Hogaboam, C. M. ; Armstrong, M. E. ; Donnelly, S. C. / Toll-like receptor 3 L412F polymorphism promotes a persistent clinical phenotype in pulmonary sarcoidosis. In: QJM. 2018 ; Vol. 111, No. 4. pp. 217-224.
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AU - Cooke, G.

AU - Kamal, I.

AU - Strengert, M.

AU - Hams, E.

AU - Mawhinney, L.

AU - Tynan, A.

AU - O'Reilly, C.

AU - O'Dwyer, D. N.

AU - Kunkel, S. L.

AU - Knaus, U. G.

AU - Shields, D. C.

AU - Moller, David

AU - Bowie, A. G.

AU - Fallon, P. G.

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AU - Donnelly, S. C.

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N2 - 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 Fhomozygous 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.

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