Toll-like receptor 3 L412F polymorphism promotes a persistent clinical phenotype in pulmonary sarcoidosis
QJM: An International Journal of Medicine, 2018•academic.oup.com
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 …
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 …
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.
Oxford University Press