Conflicting findings about the association between leprosy and TLR1 variants N248S and I602S have been reported. Here, we performed case-control and family based studies, followed by replication in 2 case-control populations from Brazil, involving 3162 individuals. Results indicated an association between TLR1 248S and leprosy in the case-control study (SS genotype odds ratio [OR], 1.81; P = .004) and the family based study (z = 2.02; P = .05). This association was consistently replicated in other populations (combined OR, 1.51; P < .001), corroborating the finding that 248S is a susceptibility factor for leprosy. Additionally, we demonstrated that peripheral blood mononuclear cells (PBMCs) carrying 248S produce a lower tumor necrosis factor/interleukin-10 ratio when stimulated with Mycobacterium leprae but not with lipopolysaccharide or PAM3cysK4. The same effect was observed after infection of PBMCs with the Moreau strain of bacillus Calmette-Guerin but not after infection with other strains. Finally, molecular dynamics simulations indicated that the Toll-like receptor 1 structure containing 248S amino acid is different from the structure containing 248N. Our results suggest that TLR1 248S is associated with an increased risk for leprosy, consistent with its hypoimmune regulatory function.
SBRT for previously irradiated, locally recurrent NSCHN provides promising local control, especially for tumors <25 mL, with minimal toxicity. The optimal dose for larger tumors remains to be defined.
Dendritic cells (DCs) play a pivotal role in the connection of innate and adaptive
immunity of hosts to mycobacterial infection. Studies on the interaction of
monocyte-derived DCs (MO-DCs) using Mycobacterium leprae in leprosy
patients are rare. The present study demonstrated that the differentiation of MOs to
DCs was similar in all forms of leprosy compared to normal healthy individuals. In
vitro stimulation of immature MO-DCs with sonicated M. leprae
induced variable degrees of DC maturation as determined by the increased expression
of HLA-DR, CD40, CD80 and CD86, but not CD83, in all studied groups. The production
of different cytokines by the MO-DCs appeared similar in all of the studied groups
under similar conditions. However, the production of interleukin (IL)-12p70 by MO-DCs
from lepromatous (LL) leprosy patients after in vitro stimulation with M.
leprae was lower than tuberculoid leprosy patients and healthy
individuals, even after CD40 ligation with CD40 ligand-transfected cells. The present
cumulative findings suggest that the MO-DCs of LL patients are generally a weak
producer of IL-12p70 despite the moderate activating properties ofM.
leprae. These results may explain the poor M.
leprae-specific cell-mediated immunity in the LL type of leprosy.
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