Toll-like Receptor 3 L412F Polymorphism Promotes a Persistent Clinical Phenotype in Pulmonary Sarcoidosis

Authors

Gordon Cooke, Technological University DublinFollow
Ijaz Kamal, University College Dublin
Monika Strengert, University College Dublin
Emily Hams, Trinity College Dublin
Leona Mawhinney, Trinity College Dublin
Aisling Tynan, Trinity College Dublin
Ciaran O’ Reilly, Trinity College Dublin
David N. O’ Dwyer, University College Dulbin
Steven L. Kunkel, University of Michigan
Ulla G. Knaus, University College Dublin
Denis C. Shields, University College Dublin
David R. Moller, Johns Hopkins University School of Medicine
Andrew G. Bowie, Trinity College Dublin
Padraic G. Fallon, Trinity College Dublin
Cory M. Hogaboam, University of Michigan Medical School, Ann Arbor
Michelle E. Armstrong, Trinity College Dublin
Seamas C. Donnelly, Trinity Centre for Health Sciences, Tallaght Hospital

Document Type

Article

Rights

Available under a Creative Commons Attribution Non-Commercial Share Alike 4.0 International Licence

Disciplines

1.6 BIOLOGICAL SCIENCES

Publication Details

QJM,

Volume 111 Issue 4 April 2018

Abstract

Background: Sarcoidosis is a multisystemic disorder of unknown etiology, characterised by the

presence of non-caseating granulomas in target organs. In ninety percent 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.

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 412F-homozygous pulmonary sarcoidosis patients resulted in reduced IFN-â and TLR3 expression, reduced apoptosis- and dysregulated fibroproliferative-responses compared with TLR3 wild-type patients.

Conclusions: 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.

DOI

https://doi.org/10.1093/qjmed/hcx243

Recommended Citation

Cooke, C., Kamal, I, Strengert, M. et al (2018). : Toll-like receptor 3 L412F polymorphism promotes a persistent clinical phenotype in pulmonary sarcoidosis. QJM:an International Journal of Medicine 111(4), pp. 217–224. doi:10.1093/qjmed/hcx243