Linkage between Toll-like receptor (TLR) 2 promotor and intron polymorphisms: functional effects and relevance to sarcoidosis

Abstract

SummaryThe intracellular pathogens Propionibacterium acnes and Mycobacterium tuberculosis have been leading suspects as the cause of sarcoidosis, a systemic disorder characterized by the formation of non-caseating granulomas. Tolllike receptor (TLR) 2 is important in the innate immune response against both pathogens, and is therefore of interest in sarcoidosis research. In the present study, three single nucleotide polymorphisms and one dinucleotide repeat polymorphism in the TLR-2 gene were genotyped in 419 sarcoidosis patients, divided into a study cohort and a validation cohort, and 196 healthy controls. In the study cohort we found a significant increase in prevalence of the AA-genotype at promotor location -16934 in patients with chronic disease compared to patients with acute/self-remitting sarcoidosis (34·5% versus 15·9%, respectively, P = 0·006, Pc = 0·019). These results could not be confirmed in our validation cohort, implicating a possible role for TLR-2 genetics in only a small percentage of sarcoidosis patients. Furthermore, linkage was found between the promotor polymorphism -16934 A/T and the number of GT repeats in intron 1 (P < 0·0001). After in vitro stimulation of peripheral blood mononuclear cells (PMBCs) with different TLR-2 agonists, a correlation between induction of TNF-a (P = 0·008), interleukin (IL)-12 (P = 0·008) as well as IL-6 (P = 0·02), and the number of GT repeats was observed. In conclusion, the data show that polymorphisms in TLR-2 might be important in a small group of sarcoidosis patients and that their functional consequences explain partly some of the variance in cytokine pattern observed in different clinical phenotypes of this disease.

Dysregulation of p38 and MKP-1 in Response to NOD1/TLR4 Stimulation in Sarcoid Bronchoalveolar Cells

“…The NOD1-RIP2 complex then recruits TAK1, whose activation is required for the activation of MAP kinase and NF-kB (37,38). Although genetic variations in NOD1 and TLRs (e.g., TLR2) have been implicated in sarcoidosis (12,39), abnormalities in MAP kinase signaling have not been reported in this disease. We have observed the active form of p38 (phosphorylated) in BAL cells of most patients with sarcoidosis even under unstimulated conditions and increased and sustained p38 activation after NOD1 or TLR4 stimulation (Figure 3).…”

Serum Amyloid A Regulates Granulomatous Inflammation in Sarcoidosis through Toll-like Receptor-2

“…Given that RAGE is also expressed in sarcoidosis granulomas (48), SAA could also regulate granulomatous inflammation through RAGE (49). Both RAGE and TLR2 polymorphisms have been associated with sarcoidosis, suggesting that SAA or its receptors may play a role in the genetic basis of sarcoidosis (44,48). Future studies using TLR2-and RAGE-deficient mice are likely to further elucidate the mechanistic pathways by which these receptors mediate the effects of soluble and aggregated SAA on granulomatous inflammation in sarcoidosis.…”

“…Importantly, these findings were translated to patients with sarcoidosis by the demonstration that SAA regulates cytokine production from lung macrophages through TLR2 signaling, suggesting a role for this innate receptor in this disease. Prior studies have shown that TLR2 agonists such as Staphylococcus aureus peptidoglycan or synthetic TLR2 ligands stimulate cytokine production in BAL cells from patients with sarcoidosis, but these ligands have not been shown to have in vivo relevance (44,45). Our finding that both tissue SAA and soluble SAA are present at sites of inflammation in sarcoidosis provides for a known repository of TLR2 ligands that can enhance Th1 responses (46) and up-regulate IFN-g, TNF, and IL-10 release (47) to regulate chronic granulomatous inflammation.…”

Genetics of Sarcoidosis

“…[62] Several studies in German and Dutch cohorts have investigated the potential association of polymorphisms in the TLR4, TLR2 and TLR9 genes with sarcoidosis but found no association with the risk of sarcoidosis. [63][64][65][66][67] One study in a German cohort suggested an association with chronic sarcoidosis. [63] In a Dutch cohort, SNPs rs1109695 and rs7658893 in the TLR-10 gene and rs57436004 and rs5743594 in the TLR-1 gene were associated with the risk of sarcoidosis.…”