Absence of KIR2DS3, a receptor implicated in NK cell activation is associated with pulmonary sarcoidosis (136.23)

Abstract

Abstract By interacting with certain HLA class I molecules, the killer cell immunoglobulin-like receptors (KIR) control the function of NK cells that trigger early immune response against infection and tumors. To determine whether certain KIR and HLA genes are associated with pulmonary sarcoidosis (PS), a chronic inflammatory disease characterized with pulmonary granuloma, we have characterized KIR and HLA genes in 149 PS patients and 186 healthy controls. There was a significant decrease in the frequencies of KIR2DL2 (56.4% vs. 71.5%, P = 0.0041; 95% CI, 0.33-0.81, OR = 0.52), 2DL5 (61.7% vs. 76.3%, P = 0.0041; 95% CI, 0.31-0.80, OR = 0.50) and 2DS3 (28.2% vs. 45.2%, P = 0.0015; 95% CI, 0.30-0.75, OR = 0.48) in PS compared to controls. Interestingly, these three KIR genes 2DL2, 2DL5 and 2DS3 are closely linked together in the cetromeric half of the KIR gene complex, and thus any of these KIRs or other linked loci may contribute to the risk for PS. Particularly, the decrease in activating receptor KIR2DS3 in PS is consistent with the clinical anergy and diminished cellular immunity evidenced in PS. The individuals missing KIR2DS3 may fail triggering early NK cell response to clear antigenic stimuli, which may contribute granulomas formation. This study offers new insights into the molecular mechanisms of granuloma formation in sarcoidosis and provides a framework for developing new therapeutic strategies. This work was supported by UCLA Department of Pathology and Laboratory Medicine to RR.