It is therefore tempting to speculate that a dysregulated Th17 response due to insufficient IL-23 production upon stimulation with eitherP. conclusion, we did not find genetic differences in the TLR-9 gene between sarcoidosis patients and controls. Sarcoidosis patients produce less IFN- regardless of the stimulating agent, probably reflecting the anergic state often seen in their peripheral blood T lymphocytes. The differences in TLR-9-induced IL-23 production could indicate that functional defects in the TLR-9 pathway of sarcoidosis patients play a role in disease susceptibility or evolution. Keywords:cytokine production, polymorphisms, sarcoidosis, Toll-like receptor-9 == Introduction == Sarcoidosis is a systemic disorder IKK 16 hydrochloride of unknown aetiology leading to the formation of non-caseating granulomas in variable organs such as lungs, lymph nodes and skin. The disease is usually characterized by a strong cell-mediated immune reaction, making microbial pathogens such as viruses or intracellular bacteria leading candidates as causative brokers. In particular, the intracellular bacteriaMycobacterium tuberculosisandPropionibacterium acneshave been studied extensively and may well play a role in disease pathogenesis [15]. In recent years, many genetic association studies have been performed with an emphasis on innate immunity [612]. An important category of innate immunity receptors are the Toll-like receptors (TLR), a family of related transmembrane or endosomal molecules each recognizing a distinct, but limited, repertoire of microbial encoded molecules. Two of the TLR genes, IKK 16 hydrochloride TLR-4 and TLR-9, are located in the close vicinity of chromosomal positions that have shown linkage in a previous study on predisposing gene loci in sarcoidosis [13]. TLR-4 is an essential receptor for the recognition of lipopolysaccharide (LPS), unique to the cell wall of Gram-negative bacteria. Further studies on a genetic role of TLR-4 in sarcoidosis provide conflicting results. In a recent study, all 10 known TLR genes on seven different chromosomal loci were tested for linkage with sarcoidosis [8]. Once again, a significant linkage between a locus on chromosome 9 (near TLR-4) and sarcoidosis was found. These results could partly explain the association found by Pabst and colleagues between a functional TLR-4 polymorphism and a chronic course of sarcoidosis [7]. However, in subsequent casecontrol analysis, no association was found with this functional TLR-4 polymorphism Asp299Gly and sarcoidosis, a result in concordance with other studies showing no genetic association [6,10]. The endosomal localized receptor TLR-9, capable of recognizing unmethylated nucleic acid motifs, is one of the most important receptors in the initiation of protective immunity against intracellular pathogens and necessary for an adequate immune response against bothM. tuberculosisandP. acnes[14,15]. TLR-9 is usually expressed primarily in B cells, plasmacytoid dendritic cells (pDC) and monocytes/macrophages [16]. Regarding the genetic role of TLR-9 in sarcoidosis, both linkage studies also reach conflicting results. In the most recent study by Schurmann and colleagues [8], a subanalysis regarding sib-pair families (families with two or more siblings with sarcoidosis) showed significant transmission distortion for a marker located near the TLR-9 gene on chromosome 3p. A significant linkage of a TLR-9 locus with sarcoidosis, however, was not found. In our opinion, the above results do not rule out a genetic role for TLR-9 in the pathogenesis of sarcoidosis and warrants further study. Taken together, when considering a causative role for intracellular pathogens in the pathogenesis of sarcoidosis, the innate immunity receptor TLR-9, based on its involvement in the immune response against intracellular pathogens and its genomic location, seems an attractive candidate for genetic and functional analysis in sarcoidosis research. We hypothesize that alterations in TLR-9 function are involved in the aberrant immune response characterizing sarcoidosis and therefore are more prevalent in sarcoidosis patients. To address IKK 16 hydrochloride this hypothesis, we performed both a genetic and functional analysis of TLR-9 in sarcoidosis patients and healthy controls. == Materials MDNCF and methods == == Study subjects for genetic analysis == A total of 150 unrelated and randomly selected Dutch Caucasian patients presenting with sarcoidosis.