O envolvimento de polimorfismos dos genes IL4 e IL13 em perfis de citocinas Th2 em indivíduos com leishmaniose cutânea causada por Leishmania guyanensis no estado do Amazonas

Abstract

Leishmaniasis are parasitic diseases caused by protozoans of the Leishmania genus. They are transmitted to the host by infected phlebotomine vectors during blood meal. Leishmania are obligate intracellular parasites that invade host phagocytic cells causing a variety of clinical manifestations. Cutaneous leishmaniasis (CL) is most common clinical form and affect million people worldwide per year. The defense response against the parasite is driven by the host immune system and genetic background. Pro-inflammatory and anti-inflammatory cytokines are key mediators of the adaptative immune response to Leishmania. While IFN-γ, secreted by Th1 cells, induces protection against the parasite, IL-4 and IL-13 cytokines secreted by Th2 cells promote susceptibility to CL. In this study, we investigated IL4 and IL13 genes on CL caused by Leishmania guyanensis (Lg-CL) and their effects on Th2 cytokines expressions. Nine variants in IL13 gene and eight variants in IL4 gene were genotyped in 855 patients with CL and 859 healthy controls (controls) by de RFLP (Restriction Fragment Length Polymorphisms) and nucleotide sequencing. Of nine variants in IL13 gene none was associated to developing of Lg-CL. However, haplotype analysis with nine variants of IL13 revealed that carries to H8 haplotype have 180% increased risk to develop Lg-CL (OR = 2.8 [95% IC 1.7 – 4.2]; p-value 3 x 10-6). H11 haplotype also is associated to susceptibility to increased risk to Lg-CL (OR = 2.5 [95% CI 1.5 – 4.1]; p-value 0.5 x 10-5). Conversely, carries to H10 have 94% decreased risk to develop Lg-CL (OR = 0.06 [95% CI 0.03 – 0.14]; p-value 1.3 x 10-17). H12 carries (OR = 0.04 [95% CI 0.01 – 0.15]; p-value 1.1 x 10-10) and H13 (OR = 0.07 [95% CI 0.02 – 0.2]; p-value 2.5 x 10-8). The genotypes of rs2069744, rs20541, rs1295685, rs847 and rs848 were found to be correlated with plasma IL-5 levels among the patients with Lg-CL. Additionally, rs20541 exhibited a correlation with plasma IL-13 levels among patients with Lg-CL. rs2069744 and rs848 showed a correlation with plasma IL-4 levels among patients with Lg-CL. In the IL4 gene, genetic association analysis was not done due to limitation by sample size. In total, our study revealed the presence of three haplotypes of IL13 associated with resistance to disease development and two haplotypes linked to susceptibility. These findings indicate the possibility that there could be a variant located outside the gene region that may be associated with susceptibility.