Relationship Between TLR2 Polymorphism and Pulmonary Tuberculosis

Infection with Mycobacterium tuberculosis (TB) remains at epidemic levels globally. One third of the word's population is infected with this organism, making tuberculosis the most prevalent infectious disease. Annually, 8 million people contract the disease, and there are 2 million deaths worldwide each year, with increasing prevalence predicted over the next several decades.(1) In Taiwan, there are 24,161 reporting cases registered in the national tuberculosis database, and 17,660 were diagnosed as confirmed TB cases in 2004. The annual incidence rate of newly TB cases is 74.11 per 100,000 people.

Immunity Against Mycobacteria M. tuberculosis is a unique pathogen in that once infection occurs, even in the face of in intact host immune system it is not eradicated but establishes a chronically persistent, or latent, state. Viable organisms remain sequestered by the host's immune system, though they fail to progressively replicate. Subsequently, in approximately 15 % of those latently infected, the infection may reactivate with the development of overt, progressive, pulmonary disease. Impairments in the immune system may linked to reactivation, but much remains to be discovered about control of infection by M. tuberculosis.

Innate and adaptive immune responses evolve as protective mechanisms against infectious organisms in humans. Phagocytosis of relatively small numbers of organisms initiated the host response in the alveolar cells.CD14 and toll-like receptors (TLRs) are examples of pattern recognition receptors that detect antigenic molecules on the surface of bacteria and mycobacteria.(2) The family of TLRs is capable of recognizing conserved microbial patterns including components of bacterial cell wall, microbial nucleic acids, and bacterial motility. TLRs are the first defense system to detect potential pathogens, initiate immune responses and form the crucial link between innate and adaptive immune systems. TLRs also play an import role in the pathophysiology of infectious diseases, inflammatory diseases such as Crohn's disease and atherosclerosis, possibly play a role in autoimmune disease.( 3) TLRs are transmembrane proteins characterized by an extracellular leucine-rich domain that participates in ligand recognition and an intracellular tail that contains a conserved region called the Toll interleukin 1 receptor (IL-1R) homology domain.(4) Stimulation of TLR initiates a signaling cascade that involves a number of proteins, such as MyD88 and IL-1 receptor-associated kinase.(5) This signal cascade leads to NF-κB activation, which induce the secretion of pro-inflammatory cytokines. TLR2 has been reported to be the principle mediator of macrophage activation in response to mycobacteria. TLR2 expression is found primarily on alveolar macrophages and epithelial cells type Ⅱwithin tuberculous granulomas. Due to its ability to recognize Mycobacterium tuberculosis and its components, the expression of TLR2 at the site of disease is critical. (6, 7)

Single nucleotide polymorphisms of Toll-like receptors and susceptibility to pulmonary tuberculosis Growing amounts of data suggest that the ability of certain individuals to respond properly to TLR ligands may be impaired by single nucleotide polymorphisms (SNPs) within TLR genes, resulting in an altered susceptibility to, or course of, infectious disease.TLR2 is a member of the TLR family.(8) Animal studies have shown that TLR2-knockout mice are more susceptible to septicemia due to Staphylococcus and Listeria monocytogenes, meningitis due to Streptococcus pneumoniae, and infection with Mycobacterium tuberculosis, suggesting the functional TLR2 polymorphisms may impair host response to a certain spectrum of microbial pathogens.(9) Mycobacterium tuberculosis infects 2 billion people globally, yet only 10 % develop clinical disease. The identification of factors that predispose to disease could aid the development of new therapies and vaccines.

The genetic polymorphism of TLR2 (arginine to glutamine substitution at residue 753 (Arg753Gln)) has been associated with a negative influence on TLR2 function, which may, in turn, determine the innate host response to mycobacteria. In a recent cohort study, this polymorphism was demonstrated to influence the risk of developing tuberculosis in Turkey patients.(10) In addition, another polymorphism (Arg677Trp) of the TLR2 was reported to be associated with susceptibility to tuberculosis in Tunisian patients (11), as well as lepromatous leprosy(12). More recently, polymorphisms in CD 14 and TLR2 are demonstrated to be associated with increased prevalence of infection in critical ill adults (13). TLR2 gene Arg753Lin polymorphism is also strongly associated with rheumatic fever in children. Moreover, this polymorphism is a risk factor for coronary restenosis.(14)