Levels of Interleukin‐(IL)‐12p40 are Markedly Increased in Brucellosis Among Patients with Specific IL‐12B Genotypes

Abstract

Brucellosis remains a major zoonosis worldwide. Brucella antigens induce the production of T-helper 1 (Th1) cytokines such as interleukin-12 (IL-12) in humans. We aimed to investigate the association of two single nucleotide polymorphisms (SNPs) in the gene encoding the IL-12p40 cytokine (IL-12B) with brucellosis and to examine the functionality of these SNPs through measuring serum levels of IL-12p40. We genotyped IL-12B gene rs3212227, A>C; rs6887695 G>C polymorphisms in a case-control study on a total of 281 subjects including 153 patients with active brucellosis and 128 healthy controls, using RFLP and serum IL-12p40 levels, were assessed by ELISA. The rs3212227 minor allele (C) and homozygote genotype (CC) were more frequent in controls compared with patients with brucellosis (P = 0.006, OR = 0.608, 95%CI = 0.429-0.861 for the C allele; P = 0.024, OR = 0.443, 95% CI: 0.218-0.900 for the CC genotype). Comparison of IL-12B genotypes and serum levels of the IL-12p40 revealed that rs3212227 AA genotype, with higher frequency in patients than in controls, was associated with increased levels of the cytokine (P = 0.0001). Furthermore, the distribution of haplotype and genotype combinations in our study suggested that rs3212227C/rs6887695C haplotype or CC/GC or CC/CC genotype combinations may protect controls against Brucella infection by contributing to a functional downregulation of the serum IL-12p40 production in vivo, as shown by ELISA (P < 0.05). Overall, our study demonstrated that rs3212227 A variant was associated with higher levels of serum IL-12p40 and could possibly contribute to an inherited predisposition to brucellosis.

The IL4-VNTR P1 Allele, IL4-VNTR P2P2 Genotype, and IL4-VNTR_IL6-174CG P2P1-GG Genotype Are Associated with an Increased Risk of Brucellosis

“…Studies on IL-4, IL-6, and MIF are limited. In one study of the IL-6 promoter polymorphism at position -174 in Spanish brucellosis, the same results were obtained, i.e., there were no differences in the frequencies of IL-6 variants between the patients and controls (24). In contrast, 1 study in our country found that IL-6-174CG genotype was more frequent in patients than in controls (27): the authors claimed that the IL-6-174CG genotype may be a risk factor for the development of brucellosis.…”

“…One study suggested that IL-10 modulates macrophage function and contributes to an initial balance between pro-inflammatory and anti-inflammatory cytokines, thereby promoting bacterial survival and persistent infection (23). While other study showed a higher frequency of the -251 IL-8 AA genotype in patients than in controls (19), and the other study revealed a higher frequency of the IL-12B rs3212227 AA genotype in patients than in controls (24). Furthermore, the latter study suggested that the rs3212227 AA variant could contribute to an inherited predisposition to brucellosis.…”

Investigation of CTLA‐4 and CD86 gene polymorphisms in Iranian patients with brucellosis infection

“…Recently, it has been demonstrated that the CD28:B7 pathway is important in IFN‐g and TNF‐α production by peripheral blood mononuclear cells from brucellosis patients . The role of this pathway in the immune response is essential, because a signal through CD28 stimulates IL‐2 production and IL‐2R upregulation, leading to T cell proliferation and activation, a process essential to control Brucella multiplication . CTLA4, a member of the immunoglobulin superfamily, is a key component in the immune system.…”

Brucellosis in Immunocompromised Hosts

“…Genetic studies have shown that B. abortus and B. melitensis share the same lineage and differ from B. suis which has undergone few genetic mutations and has diverged from the most recent ancestor of all Brucellae [49]. Increased serum levels of IL-6, IL-8 and IL-12 have been reported in patients with brucellosis, while IL-8-251AA and rs3212227AA genotypes have been found to increase the genetic susceptibility to acquire Brucella infections [50,51]. Additionally, the neutrophil/lymphocyte ratio in the blood has been found to be significantly associated with Brucella infection in humans [52].…”