Polymorphisms in genes TLR1, 2 and 4 are associated with differential cytokine and chemokine serum production in patients with leprosy

Abstract

BACKGROUND Leprosy or hansen’s disease is a spectral disease whose clinical forms mostly depends on host’s immune and genetic factors. Different Toll-like receptors (TLR) variants have been described associated with leprosy, but with some lack of replication across different populations.OBJECTIVES To evaluate the role of polymorphisms in genes TLR1, TLR2 and TLR4 and susceptibility to leprosy in a genetic case control study; to verify the association between genotypes of these markers and the immunological profile in the serum of patients with leprosy.METHODS Pre-designed TaqMan® assays were used to genotype markers at TLR1 (rs4833095, rs5743551), TLR2 (rs7656411, rs3804099) and TLR4 (rs1927914, rs1927911). A panel of cytokines and chemokines was accessed by enzime-linked immunosorbent assay (ELISA) test in the serum of a subgroup of patients with and without leprosy reactions.FINDINGS Our results show an association between the T allele of rs3804099 at the TLR2 gene and increased risk for leprosy per se [Odds ratio (OR) = 1.296, p = 0,022]. In addition, evaluating the association between different genotypes of the TLR1, 2 and 4 markers and cytokine/chemokine serological levels, IL-17 appears as an immunological marker regulated by the polymorphism of the three TLR genes evaluated, whereas different TLR1 genotypes were associated with differential production of IL-12p40 and MCP-1(CCL2). Furthermore, other relevant serum markers such as CXCL-10 and IL-6 seemed to be regulated by TLR2 variants and IL-1β was related to TLR4 genotypes.MAIN CONCLUSIONS All together our data points that the tested TLR markers may have a regulatory role in the immunity against Mycobacterium leprae, by driving the host’s production of key cytokines and chemokines involved in the pathogenesis of this disease.

Genetic Variation in Pattern-Recognition Receptors and Association with Leprosy

“…In this same study, an intronic transition of SNP in TLR2 rs7656411 (G3724 T) presented no association with leprosy in Brazilian population. However, individuals carrying G allele presented high levels of CXCL10 production [23]. Although no association of rs3804099 (C/T N199 N) with leprosy was found, Bochud and coll.…”

“…The A > G substitution in an intergenic upstream region (rs1927914) and A > G substitution in an intronic region (rs1927911) were associated with both leprosy per se and leprosy reactions. Although rs1927911 induces no differences in cytokines and chemokines level of production, the allele A of rs1927914 is associated with a higher expression of IL-17 and IL-1β, which is highly produced in multibacillary leprosy patients [23].…”

“…(2017) in another study with a Brazilian sample. However, they found association of rs4833095 with differential production of IL-17 and IL-12p40 [23]. These variations in TLR1 highlight the functional role of these genetic determinants in modulating the immune response during M. leprae infection.…”

Polymorphisms of the Toll-Like Receptor-2 Gene in Patients with Leprosy and Their Healthy Contacts

“…These receptors recognize lipoproteins present in the bacillus and promote the differentiation of monocytes into macrophages and CD1b + dendritic cells, which in turn activate lymphocytes that release cytokines such as TNF-α and IL-12, promoting antimicrobial activity. Of all mammalian TLRs, TLR2 is the one that detects the broadest repertoire of molecular patterns in a wide variety of pathogens, including mycobacteria, which makes it of particular clinical importance [8] [9]. Because M. leprae, in the host, initiates cell signaling by activating the TLR1/TLR2 heterodimer, changes in these genes may be able to confer susceptibility to leprosy [8].…”

“…Of all mammalian TLRs, TLR2 is the one that detects the broadest repertoire of molecular patterns in a wide variety of pathogens, including mycobacteria, which makes it of particular clinical importance [8] [9]. Because M. leprae, in the host, initiates cell signaling by activating the TLR1/TLR2 heterodimer, changes in these genes may be able to confer susceptibility to leprosy [8]. Thus, a study involving the detection of SNPs 2029 (rs121917864; exchange of cytokine to thymine) and 2258 (rs137853176; exchange of guanine to adenine) in the TLR2 gene in leprosy patients and their healthy contacts, relating to the immune response may elucidate important aspects susceptibility of individuals to leprosy.…”