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

Cooke, Gordon; Kamal, I; Strengert, Monika; Hams, Emily; Mawhinney, Leona; Tynan, Aisling; O’Reilly, Ciaran; O’Dwyer, David N.; Kunkel, Steven L.; Knaus, Ulla G.; Shields, Denis C.; Möller, David R.; Bowie, Andrew; Fallon, Padraic G.; Hogaboam, Cory M.; Armstrong, Michelle E.; Donnelly, Seamas C.

doi:10.1093/qjmed/hcx243

Cited by 17 publications

(10 citation statements)

References 33 publications

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“…Sarcoidosis is an inflammatory disease characterized by granulomatosis present in multiple organs and triggered by environmental factors that interact with environmental triggers to result in the innate immune activation of macrophages and dendritic cells, which further upregulates the expression of the major histocompatibility complex (MHC) and cytokines that induce the activation of the adaptive immune response ( 3 ). Previous GWAS on the sporadic and familial aggregation of sarcoidosis patients showed that the candidate genes are strongly associated with disease severity, including HLA and non-HLA genes ( 9 , 12 ). Most of the genes were related to T-cell regulation and T-cell activation during antigen presentation by APCs (antigen-presenting cells) ( 5 ).…”

Section: Discussionmentioning

confidence: 99%

“…Previous studies suggested that class II HLA-DRB1*03:01 is associated with resolving disease more than the persistent group in Finnish, Croatia, and Czech sarcoidosis patients ( 9 – 11 ). Other non-HLA gene polymorphisms associated with clinical course, including TLR3 (L412F, rs3775291), promoted a persistent clinical phenotype in Irish and American Caucasian patients ( 12 ); also, tumor necrosis factor-β (TNF-β) alleles TNF-β1 and TNF-β3 were found to be associated with prolonged clinical course in Japan and Dutch sarcoidosis patients, respectively ( 12 , 13 ).…”

Section: Introductionmentioning

confidence: 99%

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Exome Sequencing Reveals Genetic Variability and Identifies Chronic Prognostic Loci in Chinese Sarcoidosis Patients

Zhang

Huang

Zhang³

et al. 2022

Front. Oncol.

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BackgroundSarcoidosis is an inflammatory disease characterized by non-caseating granuloma formation in various organs, with several recognized genetic and environmental risk factors. Despite substantial progress, the genetic determinants associated with its prognosis remain largely unknown.ObjectivesThis study aimed to identify the genetic changes involved in sarcoidosis and evaluate their clinical relevance.MethodsWe performed whole-exome sequencing (WES) in 116 sporadic sarcoidosis patients (acute sarcoidosis patients, n=58; chronic sarcoidosis patients, n=58). In addition, 208 healthy controls were selected from 1000 G East Asian population data. To identify genes enriched in sarcoidosis, Fisher exact tests were performed. The identified genes were included for further pathway analysis using Gene Ontology (GO) and the Kyoto Encyclopedia of Genes and Genomes (KEGG). Additionally, we used the STRING database to construct a protein network of rare variants and Cytoscape to identify hub genes of signaling pathways.ResultsWES and Fisher’s exact test identified 1,311 variants in 439 protein-coding genes. A total of 135 single nucleotide polymorphisms (SNPs) on 30 protein-coding genes involved in the immunological process based on the GO and KEGG enrichment analysis. Pathway enrichment analysis showed osteoclast differentiation and cytokine–cytokine receptor interactions. Three missense mutations (rs76740888, rs149664918, and rs78251590) in two genes (PRSS3 and CNN2) of immune-related genes showed significantly different mutation frequencies between the disease group and healthy controls. The correlation of genetic abnormalities with clinical outcomes using multivariate analysis of the clinical features and mutation loci showed that the missense variant (rs76740888, Chr9:33796673 G>A) of PRSS3 [p=0.04, odds ratio (OR) = 2.49] was significantly associated with chronic disease prognosis. Additionally, the top two hub genes were CCL4 and CXCR4 based on protein–protein interaction (PPI) network analysis.ConclusionOur study provides new insights into the molecular pathogenesis of sarcoidosis and identifies novel genetic alterations in this disease, especially PRSS3, which may be promising targets for future therapeutic strategies for chronic sarcoidosis.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Exome Sequencing Reveals Genetic Variability and Identifies Chronic Prognostic Loci in Chinese Sarcoidosis Patients

Zhang

Huang

Zhang³

et al. 2022

Front. Oncol.

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“…Also, consequences of this mutation on immune responses in primary human PUUV infection should require further studies [ 37 ]. The TLR3 p.L412F variant without enrichment in our patient population was observed in another two patients; this common variant exhibit neutral functional testing and it is not associated with any disease condition in heterozygous form [ 27 – 30 ]. All cases and their family members with the hypormophic TLR3 p.L742F variant or the common p.L412F variant were positive for HSV1 antibodies; none of them had a history of HSE.…”

Section: Discussionmentioning

confidence: 99%

“…We chose not to analyze activity of the TLR3 p.L412F variation, as this variant is not enriched in our patients and it is thoroughly analyzed by previously studies in different conditions. [27][28][29][30][31]…”

Section: The L742f Tlr3 Protein Is Severely Hypomorphic In Vitromentioning

confidence: 99%

Heterozygous TLR3 Mutation in Patients with Hantavirus Encephalitis

et al. 2020

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Puumala hantavirus (PUUV) hemorrhagic fever with renal syndrome (HFRS) is common in Northern Europe; this infection is usually self-limited and severe complications are uncommon. PUUV and other hantaviruses, however, can rarely cause encephalitis. The pathogenesis of these rare and severe events is unknown. In this study, we explored the possibility that genetic defects in innate anti-viral immunity, as analogous to Toll-like receptor 3 (TLR3) mutations seen in HSV-1 encephalitis, may explain PUUV encephalitis. We completed exome sequencing of seven adult patients with encephalitis or encephalomyelitis during acute PUUV infection. We found heterozygosity for the TLR3 p.L742F novel variant in two of the seven unrelated patients (29%, p = 0.0195). TLR3-deficient P2.1 fibrosarcoma cell line and SV40-immortalized fibroblasts (SV40-fibroblasts) from patient skin expressing mutant or wild-type TLR3 were tested functionally. The TLR3 p.L742F allele displayed low poly(I:C)-stimulated cytokine induction when expressed in P2.1 cells. SV40-fibroblasts from three healthy controls produced increasing levels of IFN-λ and IL-6 after 24 h of stimulation with increasing concentrations of poly(I:C), whereas the production of the cytokines was impaired in TLR3 L742F/WT patient SV40-fibroblasts. Heterozygous TLR3 mutation may underlie not only HSV-1 encephalitis but also PUUV hantavirus encephalitis. Such possibility should be further explored in encephalitis caused by these and other hantaviruses.

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“…Defects in the immune system, when dealing with lung microbiome, may be key drivers for ILDs development. Mutation of the innate sensor TLR3, which recognizes viral dsRNA, is associated with IPF and pulmonary sarcoidosis (30,31). Staphylococcus nepalensis released corisin, a peptide conserved in diverse staphylococci, induces apoptosis of lung epithelial cells and is upregulated in IPF patients with acute exacerbation compared to patients without disease exacerbation (32).…”

Section: Persistent Infections Are Associated With Ilds Developmentmentioning

confidence: 99%

Interrelation Between Fibroblasts and T Cells in Fibrosing Interstitial Lung Diseases

Lai

Wei

et al. 2021

Front. Immunol.

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Interstitial lung diseases (ILDs) are a heterogeneous group of diseases characterized by varying degrees of inflammation and fibrosis of the pulmonary interstitium. The interrelations between multiple immune cells and stromal cells participate in the pathogenesis of ILDs. While fibroblasts contribute to the development of ILDs through secreting extracellular matrix and proinflammatory cytokines upon activation, T cells are major mediators of adaptive immunity, as well as inflammation and autoimmune tissue destruction in the lung of ILDs patients. Fibroblasts play important roles in modulating T cell recruitment, differentiation and function and conversely, T cells can balance fibrotic sequelae with protective immunity in the lung. A more precise understanding of the interrelation between fibroblasts and T cells will enable a better future therapeutic design by targeting this interrelationship. Here we highlight recent work on the interactions between fibroblasts and T cells in ILDs, and consider the implications of these interactions in the future development of therapies for ILDs.

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

Abstract: 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.

Cited by 17 publications

References 33 publications

Exome Sequencing Reveals Genetic Variability and Identifies Chronic Prognostic Loci in Chinese Sarcoidosis Patients

Exome Sequencing Reveals Genetic Variability and Identifies Chronic Prognostic Loci in Chinese Sarcoidosis Patients

Heterozygous TLR3 Mutation in Patients with Hantavirus Encephalitis

Interrelation Between Fibroblasts and T Cells in Fibrosing Interstitial Lung Diseases

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