Differential production of interleukin‐10 and interleukin‐12 in mononuclear cells from leprosy patients with a Toll‐like receptor 2 mutation

Abstract

SUMMARYToll-like receptor 2 (TLR2) is a key mediator of the immune response to mycobacterial infections, and mutations in TLR2 have been shown to confer susceptibility to infection with mycobacteria. This study investigated the profiles of cytokines, such as interferon (IFN)-c, interleukin (IL)-10, IL-12 and tumour necrosis factor (TNF)-a in response to Mycobacterium leprae in peripheral blood mononuclear cells (PBMC) with the TLR2 mutation Arg677Trp, a recently reported polymorphism that is associated with lepromatous leprosy. In leprosy patients with the TLR2 mutation, production of IL-2, IL-12, IFN-c, and TNF-a by M. leprae-stimulated PBMC were significantly decreased compared with that in groups with wild-type TLR2. However, the cells from patients with the TLR2 mutation showed significantly increased production of IL-10. There was no significant difference in IL-4 production between the mutant and wild-type during stimulation. Thus, these results suggest that the TLR2 signal pathway plays a critical role in the alteration of cytokine profiles in PBMC from leprosy patients and the TLR2 mutation Arg677Trp provides a mechanism for the poor cellular immune response associated with lepromatous leprosy.

Clinical, immunological, and genetic aspects in leprosy

“…Studies of leprosy patient cells indicate that TLR2 controls the production of cytokines that act in cell signaling and other aspects of resistance to M. leprae [Bochud et al, 2003]. A TLR2 mutation, Arg677Trp, has been associated with signicantly lower IL-12 and TNF-a production, but higher IL-10, in comparison with PBMC from those with the TLR2 wild-type gene, suggesting that this TLR2 gene mutation can provide a molecular mechanism for the poor cellular immune response associated with lepromatous leprosy [Kang et al, 2004].…”

The Continuing Challenges of Leprosy

“…Kang and Chae (193) first noted the correlation of a C-to-T substitution at nucleotide 2029 of TLR2, which resulted in the change of Arg to Trp at amino acid residue 667, with the lepromatous form of leprosy. Subsequently, upon stimulation of cells expressing this mutation with M. leprae or M. leprae antigens, this mutation was shown to be associated with a defective activation of NF-B (35) and decreased production of IL-12, IL-2, IFN-␥, and TNF-␣ but increased generation of 196) compared to wild-type cells.…”

“…Evidence from studies of leprosy patients indicates that TLR2 controls the production of cytokines, cell signaling, and other aspects of resistance to M. leprae (35,195,196,223).…”

Imunologia da hanseníase

“…79 Evidências de vários estudos em pacientes com hanseníase indicam que o receptor TLR2 controla a produção de citocinas, a sinalização celular e outros aspectos que conferem resistência ao M. leprae. 37,40,41,80 A mutação no gene do receptor TLR2 é mais comum nos pacientes portadores da forma VV em comparação com pacientes portadores de outras formas da doença, na Coréia, sugerindo que o mesmo contribui para a susceptibilidade. 81 Polimorfismos no gene da proteína 1 do macrófago associado à resistên-cia natural (Nramp1) estão associados com a hanseníase MB em pacientes africanos, 82 e esse gene também tem sido relacionado com a resposta imune celular ao M. leprae.…”