Abstract
Recently, we reported that genetic polymorphisms within the human IL18 gene were associated with disease susceptibility to adult-onset Still's disease (AOSD), which is characterized by extraordinarily high serum levels of IL-18. Because high serum IL-18 induction has also been observed in the systemic type of juvenile idiopathic arthritis (JIA), we investigated whether similar genetic skewing is present in this disease. Three haplotypes, S01, S02, and S03, composed of 13 genetic polymorphisms covering two distinct promoter regions, were determined for 33 JIA patients, including 17 with systemic JIA, 10 with polyarthritis, and 6 with oligoarthritis. Haplotypes were also analyzed for 28 AOSD patients, 164 rheumatoid arthritis (RA) patients, 102 patients with collagen diseases, and 173 healthy control subjects. The frequency of individuals carrying a diplotype configuration (a combination of two haplotypes) of S01/S01 was significantly higher in the JIA patients, including all subgroups, than in the healthy controls (P = 0.0045, Fischer exact probability test; odds ratio (OR) = 3.55, 95% confidence interval (CI) = 1.55–8.14). In patients with systemic JIA, its frequency did not differ statistically from that of normal controls. Nevertheless, it is possible that haplotype S01 is associated with the phenotype of high IL-18 production in systemic JIA because the patients carrying S01/S01 showed significantly higher serum IL-18 levels compared with patients with other diplotype configurations (P = 0.017, Mann-Whitney U test). We confirmed that the frequency of the diplotype configuration of S01/S01 was significantly higher in AOSD patients than in healthy control subjects (P = 0.011, OR = 3.45, 95% CI = 1.42–8.36). Furthermore, the RA patients were also more predisposed to have S01/S01 (P = 0.018, OR = 2.00, 95% CI = 1.14–3.50) than the healthy control subjects, whereas the patients with collagen diseases did not. In summary, the diplotype configuration of S01/S01 was associated with susceptibility to JIA as well as AOSD and RA, and linked to significantly higher IL-18 production in systemic JIA. Possession of the diplotype configuration of S01/S01 would be one of the genetic risk factors for susceptibility to arthritis in the Japanese population.
Highlights
IL-18 is produced by a wide range of immune cells, such as monocytes, macrophages, and dendritic cells
Polymorphisms of the human IL18 gene In the previous study, we have reported the presence of 10 single nucleotide polymorphisms (SNPs) (SNP1 to SNP10) and a single 9 bp (AACAGGACA) insertion in a 6.7 kb sequence upstream of exon 1 of the IL18 gene [26]
The present study has demonstrated a strong association between the haplotype S01 of the IL18 gene and juvenile idiopathic arthritis (JIA) as well as adult-onset Still's disease (AOSD) and rheumatoid arthritis (RA) in the Japanese population
Summary
IL-18 is produced by a wide range of immune cells, such as monocytes, macrophages, and dendritic cells. Thought to be an IFN-γ-inducing factor of T cells and natural killer cells [1,2], IL-18 has been found to have multiple biological functions. IL-18 is a unique cytokine that stimulates both T helper (Th)1- and Th2-type immune responses, depending on its cytokine milieu [3]. In combination with IL-12, IL-18 induces IFN-γ production in Th1 cells, B cells, and natural killer cells, promoting Th1-type immune responses [4]. When cultured with IL-2, IL-18 induces Th2 lineage in CD4+ T cells [5]. In basophils and mast cells, IL-18 together with IL-3 induces production of Th2 cytokines [6]. IL-18 regulates innate and acquired immune responses, con-
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