02608nas a2200373   4500000000100000008004100001260001200042653000900054653001300063653001300076653002500089653001800114653001200132653001400144653001400158653001300172653001500185653001500200653001300215100001400228700001600242700001300258700001600271700001400287700001700301700001300318700001300331245012300344856007700467300002000544490000600564050001500570520164900585       2008                            d  c2008///10aRisk10aReaction10aPatients10aMycobacterium leprae10aMycobacterium10aleprosy10aKnowledge10aInfection10aImmunity10aDisability10aDeficiency10aActivity1 aMisch E A1 aMacdonald M1 aRanjit C1 aSapkota B R1 aWells R D1 aSiddiqui M R1 aKaplan G1 aHawn T R00aHuman TLR1 deficiency is associatedwith impaired mycobacterial signaling and protection from leprosy reversal reaction  uhttp://www.ncbi.nlm.nih.gov/pmc/articles/PMC2330092/pdf/pntd.0000231.pdf  ae321,1 - e321,90 v2  aMISCH 20083 aToll-like receptors (TLRs) are important regulators of the innate immune response to pathogens, including Mycobacterium leprae, which is recognized by TLR1/2 heterodimers. We previously identified a transmembrane domain polymorphism, TLR1_T1805G, that encodes an isoleucine to serine substitution and is associated with impaired signaling. We hypothesized that this TLR1 SNP regulates the innate immune response and susceptibility to leprosy. In HEK293 cells transfected with the 1805T or 1805G variant and stimulated with extracts of M. leprae, NF-?B activity was impaired in cells with the 1805G polymorphism. We next stimulated PBMCs from individuals with different genotypes for this SNP and found that 1805GG individuals had significantly reduced cytokine responses to both whole irradiated M. leprae and cell wall extracts. To investigate whether TLR1 variation is associated with clinical presentations of leprosy or leprosy immune reactions, we examined 933 Nepalese leprosy patients, including 238 with reversal reaction (RR), an immune reaction characterized by a Th1 T cell cytokine response. We found that the 1805G allele was associated with protection from RR with an odds ratio (OR) of 0.51 (95% CI 0.29-0.87, p = 0.01). Individuals with 1805 genotypes GG or TG also had a reduced risk of RR in comparison to genotype TT with an OR of 0.55 (95% CI 0.31-0.97, p = 0.04). To our knowledge, this is the first association of TLR1 with a Th1-mediated immune response. Our findings suggest that TLR1 deficiency influences adaptive immunity during leprosy infection to affect clinical manifestations such as nerve damage and disability.