Anti-IL27 monoclonal antibody, clone 4I23

Author summary Schistosomiasis mansoni is a millennial disease and covers mainly tropical and economically disadvantaged regions. The disease mostly affects the liver, causing necrosis and fibrosis. Our study evaluated the effect of the immune system in modulating the oviposition of worms and the expression of genes mainly related to epigenetic regulation in worms. We also examined how methylation of liver DNA and the expression of related genes are influenced during Schistosoma mansoni infection depending on the type of immune response presented by the host. Our results revealed increased DNA demethylation during infection of EBi3(-/-) mice, while wild-type mice do not altered the methylation during infection. S. mansoni oviposition was decreased in infected EBi3(-/-) mice compared with wild-type mice, proving adaptation of the parasites to the type of host response. The livers of infected EBi3(-/-) mice presented less damage than those of wild-type mice, suggesting a protective hepatic effect conferred by the decrease in Th1 caused by IL27 and IL35 pathway knockout. Schistosoma mansoni adaptive success is related to regulation of replication, transcription and translation inside and outside the intermediate and definitive host. We hypothesize that S. mansoni alters its epigenetic state in response to the mammalian host immune system, reprogramming gene expression and altering the number of eggs. In response, a change in the DNA methylation profile of hepatocytes could occurs, modulating the extent of hepatic granuloma. To investigate this hypothesis, we used the EBi3(-/-) murine (Mus musculus) model of S. mansoni infection and evaluated changes in new and maintenance DNA methylation profiles in the liver after 55 days of infection. We evaluated expression of epigenetic genes and genes linked to histone deubiquitination in male and female S. mansoni worms. Comparing TET expression with DNMT expression indicated that DNA demethylation exceeds methylation in knockout infected and uninfected mice and in wild-type infected and uninfected mice. S. mansoni infection provokes activation of demethylation in EBi3(-/-)I mice (knockout infected). EBi3(-/-)C (knockout uninfected) mice present intrinsically higher DNA methylation than WTC (control uninfected) mice. EBi3(-/-)I mice show decreased hepatic damage considering volume and reduced number of granulomas compared to WTI mice; the absence of IL27 and IL35 pathways decreases the Th1 response resulting in minor liver damage. S. mansoni males and females recovered from EBi3(-/-)I mice have reduced expression of a deubiquitinating enzyme gene, orthologs of which target histones and affect chromatin state. SmMBD and SmHDAC1 expression levels are downregulated in male and female parasites recovered from EBi3(-/-), leading to epigenetic gene downregulation in S. mansoni. Changes to the immunological background thus induce epigenetic changes in hepatic tissues and alterations in S. mansoni gene expression, which attenuate liver symptoms in the acute phase of schistosomiasis.

Although genome-wide association studies have greatly advanced our understanding of the contribution of common noncoding variants to leprosy susceptibility, protein-coding variants have not been systematically investigated. We carried out a three-stage genome-wide association study of protein-coding variants in Han Chinese, of whom were 7,048 leprosy patients and 14,398 were healthy control subjects. Seven coding variants of exome-wide significance were discovered, including two rare variants: rs145562243 in NCKIPSD (P = 1.71 x 10(-9), odds ratio [OR] = 4.35) and rs149308743 in CARD9 (P = 2.09 x 10(-8), OR = 4.75); three low-frequency variants: rs76418789 in IL23R (P = 1.03 x 10(-10), OR = 1.36), rs146466242 in FLG (P = 3.39 x 10(-12), OR = 1.45), and rs55882956 in TYK2 (P = 1.04 x 10(-6), OR = 1.30); and two common variants: rs780668 in SLC29A3 (P = 2.17 x 10(-9), OR = 1.14) and rs181206 in IL27 (P = 1.08 x 10(-7), OR = 0.83). Discovered protein-coding variants, particularly low-frequency and rare ones, showed involvement of skin barrier and endocytosis/phagocytosis/autophagy, in addition to known innate and adaptive immunity, in the pathogenesis of leprosy, highlighting the merits of protein-coding variant studies for complex diseases.