title: Genetic Variation in Toll-Interacting Protein Is Associated With Leprosy Susceptibility and Cutaneous Expression of Interleukin 1 Receptor Antagonist.
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 Toll-like receptor (TLR) and interleukin 1 receptor (IL-1R) signaling against mycobacteria. We analyzed messenger RNA (mRNA) expression of candidate immune genes in skin biopsy specimens from 85 individuals with leprosy. TOLLIP mRNA was highly and specifically correlated with IL-1R antagonist (IL-1Ra). In a case-control gene-association study with 477 cases and 1021 controls in Nepal, TOLLIP single-nucleotide polymorphism rs3793964 TT genotype was associated with increased susceptibility to leprosy (recessive, P = 1.4 × 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 < .001), compared with 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.
authors.affiliation: University of Washington School of Medicine, Seattle, Washington.
authors.forename: Javeed A
authors.initials: JA
authors.lastname: Shah
authors.affiliation: University of Washington School of Medicine, Seattle, Washington.
authors.forename: William R
authors.initials: WR
authors.lastname: Berrington
authors.affiliation: University of Washington School of Medicine, Seattle, Washington Puget Sound VA Health Care System, Seattle, Washington.
authors.forename: James C
authors.initials: JC
authors.lastname: Vary
authors.affiliation: University of Washington School of Medicine, Seattle, Washington.
authors.forename: Richard D
authors.initials: RD
authors.lastname: Wells
authors.affiliation: University of Washington School of Medicine, Seattle, Washington.
authors.forename: Glenna J
authors.initials: GJ
authors.lastname: Peterson
authors.affiliation: Mycobacterial Research Laboratories, Anandaban Hospital, Kathmandu, Nepal.
authors.forename: Chhatra B
authors.initials: CB
authors.lastname: Kunwar
authors.affiliation: Mycobacterial Research Laboratories, Anandaban Hospital, Kathmandu, Nepal.
authors.forename: Saraswoti
authors.initials: S
authors.lastname: Khadge
authors.affiliation: Mycobacterial Research Laboratories, Anandaban Hospital, Kathmandu, Nepal.
authors.forename: Deanna A
authors.initials: DA
authors.lastname: Hagge
authors.affiliation: University of Washington School of Medicine, Seattle, Washington.
authors.forename: Thomas R
authors.initials: TR
authors.lastname: Hawn
mesh_terms: D000328:Adult; D016022:Case-Control Studies; D015964:Gene Expression Regulation, Bacterial / Q000502:physiology*; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D053590:Interleukin 1 Receptor Antagonist Protein / Q000235:genetics / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins / Q000235:genetics / Q000378:metabolism*; D007918:Leprosy / Q000453:epidemiology / Q000235:genetics*; D009390:Nepal; D020641:Polymorphism, Single Nucleotide; D011446:Prospective Studies; D012867:Skin / Q000378:metabolism
chemical_list: D053590:Interleukin 1 Receptor Antagonist Protein; D047908:Intracellular Signaling Peptides and Proteins; C410602:TOLLIP protein, human
keywords: IL-1; IL-1 receptor; IL-1Ra; Mycobacterium leprae; Skin immunity; TLR regulation; TOLLIP; genetics; immune evasion; leprosy