Genetic Variation in TOLLIP is Associated with Leprosy Susceptibility and Cutaneous IL-1 Receptor Antagonist Expression.

Editor's Abstract: Leprosy is a chronic disease characterized by skin and peripheral nerve pathology and immune responses that fail to control Mycobacterium leprae. Toll-Interacting Protein (TOLLIP) regulates TLR and IL-1R signaling against mycobacteria. We analyzed mRNA expression of candidate immune genes in 85 leprosy skin biopsies. TOLLIP mRNA was highly and specifically correlated with IL-1 receptor antagonist (IL-1Ra). In a case-control gene association study with 477 cases and 1021 controls in Nepal, TOLLIP SNP rs3793964 TT genotype was associated with increased susceptibility to leprosy (recessive, p=1.4 x 10(-3)) and with increased skin expression of TOLLIP and IL-1Ra. Stimulation of TOLLIP-deficient monocytes with M. leprae produced significantly less IL-1Ra (p<0.001) compared to control. These data suggest that M. leprae upregulates IL-1Ra by a TOLLIP-dependent mechanism. Inhibition of TOLLIP may decrease an individual's susceptibility to leprosy and offer a novel therapeutic target for IL-1-dependent diseases.