Genotypic analysis of Asp299Gly and Thr399Ile polymorphism of Toll-like receptor 4 in systemic autoimmune diseases of Korean population

Abstract

Dear Editor, Systemic autoimmune diseases such as rheumatoid arthritis and systemic lupus erythematosus are mainly characterized by chronic inXammation ampliWed by large quantities of proinXammatory cytokines released from immune cells including macrophages and dendritic cells. Although the pathogenesis of autoimmune diseases are largely unknown, adaptive immune responses in various systemic autoimmune diseases can be driven by innate immune system as exempliWed in pathogenic autoantibody production triggered by infectious agents in the pathogenesis of rheumatoid arthritis and systemic lupus erythematosus [1, 2]. Toll-like receptors (TLRs) are phylogenetically conserved receptors expressed on various cells, mainly on macrophages and dendritic cells that recognize pathogen-associated molecular patterns and are key players in cellular innate immunity with an emerging role as a bridge between innate and adaptive immune responses [3]. TLRs, especially TLR4, are predominantly activated by bacterial lipopolysaccharides [4] and by endogenous ligands such as heat shock proteins [5], fragments of hyaluronic acid [6] and Wbronectin [7], which are released by damaged cells. Activation of TLRs Wnally leads to activation of nuclear transcription factors such as NFB via signal transduction involving various intracellular signaling systems and to expression of various inXammatory cytokines. There are two variants of TLR4 gene, Asp299Gly and Thr399Ile; both are present in a putative coreceptor-binding region of TLR-4 and in linkage disequilibrium [8]. The polymorphisms at these two TLR4 variants appeared to be correlated with the susceptibility to gram-negative septic shock [9], the development of atherosclerosis [10] and ischemic stroke [11], and with the host susceptibility to autoimmune process in human [12, 13]. Therefore, aberrant TLR functions, especially TLR4 involved in host defense against Gram-negative bacteria, may alter the response of this receptor to stimulation with LPS and probably endogenous ligands and eventually may induce the loss of self-tolerance and triggering of autoimmune diseases. The expression and function of TLR4 in systemic autoimmune diseases have been studied by diVerent groups, but the frequencies of variant alleles and the clinical signiWcance were diVerent depending on diagnosis or on race [9–14]. The frequencies of TLR4 gene polymorphism in these two alleles among Korean population, is not known. Therefore, we report the frequencies of TLR4 Asp299Gly and Thr399Ile polymorphism in E.-S. Kang Division of Diagnostic Immunology, Department of Laboratory Medicine, Ewha Womans University Mokdong Hospital, College of Medicine, Ewha Womans University, Mokdong, Yangcheongu, Seoul 135-710, South Korea