TLRs play an important role in both innate and adaptive immune responses [19]. In innate immunity, TLRs directly trigger the intracellular bactericidal mechanism or induce the production of immune inflammatory factors based on the recognition of pathogenic microorganisms to expand the non-specific defense [20]. In adaptive immune response, TLRs can induce dendritic cells to mature, activate them to secrete cytokines and chemokines, and induce their expression of costimulatory molecules [21]. In addition, TLRs could activate naive B cells, affect the intensity and quality of the memory T cell response, and initiate the CD8+T cell response against soluble protein antigen [22]. Thus, TLRs are widely involved in various pathways of specific immune response and in the occurrence and development of chronic immune inflammatory diseases. Furthermore, increased expression of TLRs was found in peripheral blood mononuclear cells, synovial tissues, synovial fluid, synovial macrophages and synovial fibroblasts in RA patients. And, TLR-2, -3, -4, -5, -7, -8 and − 9 were also demonstrated to involve in the development of RA [23–24].
As a member of an important pattern recognition receptor, TLR2 can not only bind with exogenous ligands such as lipoproteins, peptidoglycan, lipophosubic acid, lipophosubic mannose, glycosyl, yeast polysaccharides, and glycolipids, but also recognize endogenous danger associated molecular patterns (DAMPs) such as hyaluronic acid (HA), heat shock proteins (HSP), and high-mobility group protein 1 (HMGB1) [25]. Studies have shown that HSP72 can be actively or passively released to the outside of the cell, and can bind to TLR2 on the surface of immune cells to participate in immune response [26]. Additionally, TLR2 is involved in the recognition of HMGB1. HMGB1 is highly expressed in active RA, which can be used as an important indicator to evaluate the disease activity of RA [27]. There was a positive correlation between the expression of HMGB1 and TLR2 in active RA patients [28]. Furthermore, Li et al. showed that the expression of TLR2 in peripheral blood mononuclear cells increased in active RA patients, and the expression of TLR2 was closely related to disease activity indicators such as disease activity score (DAS), serum c-reactive protein, and blood sedimentation [29]. Blocking TLR2 can prevent the spontaneous release of cytokines in vitro synovial graft cultures of RA, suggesting that targeting TLR2 may play an important role in the treatment of RA [30]. However, little is known about the relation of TLR2 gene polymorphisms and the susceptibility of RA. In the present study, we found no association between the TLR2 rs5743708 and RA risk, as well as the RF and anti-CCP status, which was similar with the results reported by Sa’nchez et al. in a Spanish population [17]. Although, no significant association was found between TLR2 rs5743708 and RA in the present study, we could not rule out that the impact of TLR2 gene in the pathogenesis of RA. This SNP may be linked to other SNPs, which could regulate the expression or function of TLR. Further studies with larger number of subjects are needed to investigate the genetic association between TLR2 rs5743708 and RA risk.
TLR4 plays an important role in mediating immune response. It can recognize endogenous ligands including HSPs, fragments of hyaluronic acid, and fibronectin, which are released by cells undergoing stress, damage, or necrotic death, and are abundantly present in inflamed synovial joints of patients with RA [31]. Ren et al. showed that TLR4 expression on the surface of CD14+ monocytes in peripheral blood of RA patients was up-regulated and positively correlated with serum IL-18 level, while negatively correlated with DAS28, suggesting that TLR4 may indirectly participate in the pathogenesis of RA [32]. TLR4 rs4986790 and rs4986791 causing change in amino acid were identified to reduce the response of TLR4 to stimulation with LPS and probably endogenous ligands [33]. Lines of studies have reported the association between TLR4 rs4986790 and rs4986791 and RA in multiple populations. However, the results were inconsistent in different ethnicity groups. Radstake et al. found that TLR4 rs4986790 was associated with RA susceptibility, but not with RA disease activity and prognosis in a Dutch population [15]. However, no association was found between the TLR4 rs4986790 and rs4986791 and RA in other Caucasian populations including French [18], Finn [34], Spanish [17], and British [16]. The results of the relationship of TLR4 rs4986790 and rs4986791 and RA in Asian populations were more complex. In the present study, both the TLR4 rs4986790 and rs4986791 were found to be not polymorphismic, which was similar with the previous results reported by Zheng et al. [14], Yuan et al. [35], and Kang et al. [36]. In addition, no significant association between the TLR4 rs4986790 and rs4986791 polymorphisms and RA risk was identified by meta-analysis [37–38]. Thus, we may conclude that the TLR4 rs4986790 and rs4986791 did not contribute to the pathogenesis of RA. These results need to be confirmed in larger number of case-control studies.
TLR1 and TLR6 are TLR2 co-receptors that increasing the number of ligands and inducing different transduction pathways [39–40]. Studies have revealed that TLR1 rs5743610 and rs5743618 were associated with complicated skin and skin structure infections (cSSSIs) [41] and Crohn's disease [42]. In addition, the TLR6 rs5743810 was shown to be associated with a reduced risk of childhood asthma [43] and an increased risk of invasive aspergillosis [44]. To our knowledge, this is the first study of the genetic association between the allelic, dominant and recessive models of TLR1 rs5743610, rs5743618, and TLR6 rs5743810 and RA susceptibility was conducted. Although, no evidence of which was detected in our study, we could not draw the conclusion that TLR1 rs5743610, rs5743618, and TLR6 rs5743810 were not associated with RA susceptibility for the relatively small sample size. Notable, significant associations were observed between the TLR6 rs5743810, but not the TLR1 rs5743610, rs5743618 and RA status, as well as anti-CCP status, which was different form the results reported by Jaen et al. [18]. This inconsistent may due to the different genetic background in the two populations. For the function of this SNP is still hardly known. We hypothesized that TLR6 rs5743810 might be associated with disease severity by increasing autoantibody production. To confirm this result, functional study is necessary in the future.