Pneumologie 2005; 59 - A9
DOI: 10.1055/s-2005-925493

Toll-like receptor (TLR) 4 Asp299Gly and Thr399Ile polymorphisms are associated with a chronic progressive course of pulmonary sarcoidosis

S Pabst 1, G Baumgarten 2, A Stremmel 1, M Lennarz 1, P Knuefermann 2, A Gillissen 3, H Vetter 1, C Grohé 1
  • 1Medizinische Universitäts-Poliklinik, Rheinische-Friedrich-Wilhelms-Universität Bonn, Germany
  • 2Klinik und Poliklinik für Anästhesiologie und operative Intensivmedizin, Rheinische-Friedrich-Wilhelms-Universität Bonn, Germany
  • 3Städtisches Klinikum St. Georg, Leipzig, Germany

Background: The aetiology of sarcoidosis, an inflammatory granulomatous multisystem disorder, is unclear. It is supposed to be the product of an unknown exogenous antigenic stimulus and an endogenous genetic susceptibility.

Toll-like receptors (TLR) are signal molecules essential for the cellular response to bacterial cell wall components. Lipopolysaccharide (LPS), for example, binds to TLR 4. Two different polymorphisms for the TLR4 gene (Asp299Gly and Thr399Ile) have recently been described. This leads to a change in extracellular matrix function of TLR4 and to impaired LPS signal transduction.

Methods: We genotyped a total of 141 Caucasian patients with sarcoidosis and 141 healthy unrelated controls for the Asp299Gly and Thr399Ile polymorphisms in the TLR4 gene. The mutations were identified with polymerase chain reaction followed by restriction fragment length polymorphism (RFLP) analysis.

Results: Among sarcoidosis patients the prevalence for each Asp299Gly and Thr399Ile mutant allele was 15.6% (22/141). In the control group the prevalence was 5.67% (8/141) (P=0.07). In the subgroup of patients with acute sarcoidosis there was no difference to the control group (P=0.93), but there was a highly significant association between patients with a chronic course of sarcoidosis and TLR4 gene polymorphisms (P=0.01).

Conclusion: In conclusion, the functional effective mutations Asp299Gly and Thr399Ile of the Toll-like receptor 4 gene are much more prevalent in the sarcoidosis group than in the healthy control subjects. In fact, among patients with acute Sarcoidosis/Löfgren's syndrome the TLR4-mutations are found equally to healthy control subjects. But there is a significant association between a chronic course of sarcoidosis and TLR4-mutations. So we propose that PAMP-signalling, i.e. bacterial lipopolysaccharide may be involved in pathogenesis of chronic sarcoidosis.