01582nas a2200205   4500000000100000008004100001260002100042100001200063700001800075700001100093700001200104700001600116700001400132700001300146700001200159700001200171245012500183520105400308022001401362       2015                            d  bOxford Journals 1 aShah JA1 aBerrington WR1 aVary J1 aWells R1 aPeterson GJ1 aKunwar CB1 aKhadge S1 aHagge D1 aHawn TR00aGenetic Variation in TOLLIP is Associated with Leprosy Susceptibility and Cutaneous IL-1 Receptor Antagonist Expression.3 a<p>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&lt;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.</p>
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