title: Disordered Toll-like receptor 2 responses in the pathogenesis of pulmonary sarcoidosis.
abstract: In this study, we hypothesized that the granulomatous disorder sarcoidosis is not caused by a single pathogen, but rather results from abnormal responses of Toll-like receptors (TLRs) to conserved bacterial elements. Unsorted bronchoalveolar lavage (BAL) cells from patients with suspected pulmonary sarcoidosis and healthy non-smoking control subjects were stimulated with representative ligands of TLR-2 (in both TLR-2/1 and TLR-2/6 heterodimers) and TLR-4. Responses were determined by assessing resulting production of tumour necrosis factor (TNF)-α and interleukin (IL)-6. BAL cells from patients in whom sarcoidosis was confirmed displayed increased cytokine responses to the TLR-2/1 ligand 19-kDa lipoprotein of Mycobacterium tuberculosis (LpqH) and decreased responses to the TLR-2/6 agonist fibroblast stimulating ligand-1 (FSL)-1. Subsequently, we evaluated the impact of TLR-2 gene deletion in a recently described murine model of T helper type 1 (Th1)-associated lung disease induced by heat-killed Propionibacterium acnes. As quantified by blinded scoring of lung pathology, P. acnes-induced granulomatous pulmonary inflammation was markedly attenuated in TLR-2(-/-) mice compared to wild-type C57BL/6 animals. The findings support a potential role for disordered TLR-2 responses in the pathogenesis of pulmonary sarcoidosis.
authors.affiliation: Division of Pulmonary, Critical Care and Sleep Medicine, Case Western Reserve University School of Medicine, Cleveland, OH 44106-4941, USA.
authors.forename: M I
authors.initials: MI
authors.lastname: Gabrilovich
authors.forename: J
authors.initials: J
authors.lastname: Walrath
authors.forename: J
authors.initials: J
authors.lastname: van Lunteren
authors.forename: D
authors.initials: D
authors.lastname: Nethery
authors.forename: M
authors.initials: M
authors.lastname: Seifu
authors.forename: J A
authors.initials: JA
authors.lastname: Kern
authors.forename: C V
authors.initials: CV
authors.lastname: Harding
authors.forename: L
authors.initials: L
authors.lastname: Tuscano
authors.forename: H
authors.initials: H
authors.lastname: Lee
authors.forename: S D
authors.initials: SD
authors.lastname: Williams
authors.forename: W
authors.initials: W
authors.lastname: Mackay
authors.forename: J F
authors.initials: JF
authors.lastname: Tomashefski
authors.forename: R F
authors.initials: RF
authors.lastname: Silver
mesh_terms: D000293:Adolescent; D000328:Adult; D000368:Aged; D000818:Animals; D001992:Bronchoalveolar Lavage Fluid / Q000166:cytology / Q000276:immunology; D016022:Case-Control Studies; D016207:Cytokines / Q000096:biosynthesis; D004195:Disease Models, Animal; D005260:Female; D015870:Gene Expression; D006801:Humans; D008024:Ligands; D008297:Male; D051379:Mice; D018345:Mice, Knockout; D008875:Middle Aged; D011014:Pneumonia / Q000235:genetics / Q000276:immunology; D011425:Propionibacterium acnes / Q000276:immunology; D055503:Protein Multimerization; D017565:Sarcoidosis, Pulmonary / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051195:Toll-Like Receptor 2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051197:Toll-Like Receptor 4 / Q000819:agonists / Q000378:metabolism; D051193:Toll-Like Receptors / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D055815:Young Adult
chemical_list: D016207:Cytokines; D008024:Ligands; D051195:Toll-Like Receptor 2; D051197:Toll-Like Receptor 4; D051193:Toll-Like Receptors
keywords: Toll-like receptors; bronchoalveolar lavage (BAL); sarcoidosis