The biological significance of TLR3 variant, L412F, in conferring susceptibility to cutaneous candidiasis, CMV and autoimmunity

Objective: Toll-like receptors, a major component of the innate immune system, play an important role in the initial response against pathogens. Genetic abnormalities in some receptors like TLR2, TLR3 and TLR4 have been associated with susceptibility to fungal and viral infections while other aberrations in TLR genes such as TLR3, TLR7 and TLR9 may predispose to autoimmunity. Recently we have shown an association of a TLR3 receptor variant, L412F, to susceptibility to chronic candidiasis, recurrent viral and bacterial infections and autoimmunity. We investigated here the biological implications of this TLR3 mutant. Methods: To study the functional impact of the L412F variant of TLR3 we tested patients' peripheral blood mononuclear cells (PBMCs) as well as fibroblasts for secretion of cytokines in response to TLR3 ligand, candida or cytomegalovirus (CMV). In addition, the P2.1 cell line was used as a model for the TLR3 WT and L412F variant receptors function. Results: Patient's cells carrying the L412F variant showed reduced IFN gamma as well as TNF alpha secretion in response to stimulation with the TLR3 ligand, CMV or Candida albicans. Fibroblasts with the L412F variant showed decreased secretion of IFN lambda in response to stimulation with both polyinosine ploycytidylic acid (Poly I:C) and CMV and P2.1 cells transfected with the L412F variant showed reduced secretion of IFN-beta in comparison to cells transfected with the wild type receptor. Conclusion: We have shown here aberrant biological responses mediated by the TLR3 variant receptor. L412F, which may explain in part susceptibility of patients to chronic candidiasis, viral infections and autoimmunity. (C) 2011 Elsevier B.V. All rights reserved.