Interferon signature in patients with STAT1 gain-of-function mutation is epigenetically determined.

STAT1 gain-of-function (GOF) variants lead to defective Th17 cell development and chronic mucocutaneous candidiasis (CMC), but frequently also to autoimmunity. Stimulation of cells with STAT1 inducing cytokines like interferons (IFN) result in hyperphosphorylation and delayed dephosphorylation of GOF STAT1. However, the mechanism how the delayed dephosphorylation exactly causes the increased expression of STAT1-dependent genes, and how the intracellular signal transduction from cytokine receptors is affected, remains unknown. In this study we show that the circulating levels of IFN-α were not persistently elevated in STAT1 GOF patients. Nevertheless, the expression of interferon signature genes was evident even in the patient with low or undetectable serum IFN-α levels. Chromatin immunoprecipitation (ChIP) experiments revealed that the active chromatin mark trimethylation of lysine 4 of histone 3 (H3K4me3), was significantly enriched in areas associated with interferon-stimulated genes in STAT1 GOF cells in comparison to cells from healthy donors. This suggests that the chromatin binding of GOF STAT1 variant promotes epigenetic changes compatible with higher gene expression and elevated reactivity to type I interferons, and possibly predisposes for interferon-related autoimmunity. The results also suggest that epigenetic rewiring may be responsible for treatment failure of Janus kinase 1/2 (JAK1/2) inhibitors in certain patients.

Group A rotavirus genotypes circulating prior to implementation of a National Immunization Program in Estonia.

Group A rotaviruses (RVA) are a major cause of acute gastroenteritis in children ≤ 5 y worldwide which could be prevented with two recently introduced vaccines - monovalent Rotarix (live-attenuated G1P[8] strain) and pentavalent RotaTeq (human-bovine reassortant containing serotypes G1, G2, G3, G4 and P[8]). Prior to implementation of vaccines into national immunization program we aimed to describe RVA genotype distribution in hospitalized children aged < 5 y in Estonia during 2007-2008. A total of 671 children with confirmed RVA gastroenteritis from three major pediatric hospitals were prospectively enrolled. G- and P-genotypes were detected from 124 stool samples by semi-nested reverse transcription-PCR. Severity of disease was assessed using Clark scoring system. The majority of cases (65%) occurred in infants aged 7 to 24 mo and were of moderate severity (mean Clark score 12.1 (SD 3.2)). The prevailing strain was G2P[4] (34.7%), causing significantly more cases than G4P[8] (12.9%), G1P[8] or G9P[8] (both 4.0%), G3P[8] (1.6%). Yearly differences in genotype distribution occurred, as G2P[4] (52.8%) dominated in 2007, but G4P[8] (26.9%) in 2008. One third of strains remained non-typeable. The distribution of RVA genotypes in Estonia differs from that seen in other Central and Eastern European countries, although one should bear in mind the large proportion of P-untypeable strains and natural fluctuations of dominating RVA genotypes. Nevertheless, considering the high genotype-independent efficacy of the vaccines, introduction of national immunization should be considered.