Systemic inflammation and chronic kidney disease in a patient due to the RNASEH2B defect

Abstract

Introduction: Aicardi-Goutières (AGS) is a rare immune dysregulated disease due to mutations in TREX1, RNASEH2A, RNASEH2B, RNASEH2C, SAMHD1, ADAR1, or IFIH1. Clinical features include basal ganglia calcifications, white matter abnormalities, and cerebral atrophy. Severe systemic inflammation and chronic kidney disease (CKD) are extremely rare in AGS. Herein, we report a patient presenting with systemic inflammation and CKD to broaden the clinical phenotype spectrum of the RNASEH2B defect. Methods: All testing and molecular genetic analysis were performed after obtaining the informed consent of the parents. Demographic, clinical, and laboratory findings were abstracted from outpatient and inpatient encounters. Cerebral magnetic resonance imaging (MRI), computed tomography (CT) scans, and renal biopsy histopathology reports were reviewed and summarized. Whole exome sequencing (WES) was performed on peripheral blood cells. After exposure to cGAMP in vitro for 24 hours, mRNA expression of twelve IFN-stimulated cytokine genes in PBMCs was assessed. Serum cytokine levels were detected by Milliplex. Results: A 11-year-old girl presented with recurrent aseptic fever, arthritis, chilblains, failure to thrive, mild hearing loss, and neurological manifestations. Laboratory and immunologic findings demonstrated lymphopenia, low complement levels, positive autoantibodies, elevated levels of acute-phase reactants and inflammatory cytokines. Cerebral imaging showed cerebral atrophy, white matter abnormalities, and intracranial calcification. Renal biopsy showed glomerular sclerosis in three of fourteen glomeruli, infiltration of lymphocytes and other mononuclear cells. WES revealed a homozygous and heterozygous mutations in RNASEH2B . Over-expression of IFN-stimulated cytokine genes was observed, including IFI44, IFI27, IFIT1, IFIT2, IFIT3, ISG15, OAS1, and SIGLEC1. Conclusions: To date, only two cases with AGS have been reported to have renal disease. Here, we describe a patient with both homozygous and heterozygous variants in RNASEH2B, presenting with neurological manifestations, persistently systemic autoinflammation, and CKD. CKD has never been reported in patients with AGS due to the RNASEH2B defect .

DNA damage contributes to neurotoxic inflammation in Aicardi-Goutières syndrome astrocytes

“…Our data suggest that type I IFN pathways may not be the major driver of disease in AGS with a relevant contribution of DNA damage-associated apoptotic and proinflammatory responses. In agreement, both TREX1 and RNASEH2B deficiencies have been clinically associated with inflammatory symptoms such as inflammatory myopathy (Tumiene et al, 2017) and systemic inflammation (He et al, 2021). Although links between JAK-STAT signaling, type I IFN induction, and neurotoxicity warrant further investigation in our experimental system through pharmacological inhibitors such as ruxolitinib, IFNα receptor blocking antibodies, or genetic modifications of key players, our observations are in line with a recent report in which type I IFN-independent genomic instability was shown to cause AGS-like cell toxicity in a murine model of neural Rnaseh2b inactivation (Aditi et al, 2021).…”

Blood Transcriptomes of Anti-SARS-CoV-2 Antibody-Positive Healthy Individuals Who Experienced Asymptomatic Versus Clinical Infection

“…However, on the basis of these findings some assumptions can be made, since, indeed, the first 6 genes with higher expression in individuals with clinical infection compared to asymptomatic individuals, namely IFIT3, IFI44L, FOLR3, RSAD3, PI3, and ALOX15 , share some common characteristics that can be relevant. For example, IFIT3, IFI44L and RSAD3 expression can be induced by viruses which in turn enhances the progress of the viral infection ( 62 – 64 ), whereas higher intrinsic expression of IFIT3, FOLR3, PI3 and ALOX-15 have all been associated with immune-mediated chronic diseases ( 65 – 68 ) In contrast, a protective effect of GZMH, CLEC1B, CLEC12A , that have a higher expression in asymptomatic individuals, may be associated with the effectiveness of GZMH in viral eradication ( 69 ) and the ability of CLEC1B and CLEC12A to enhance neutrophil extracellular trap formation, thus presenting an antiviral effect that helps to control systemic virus levels ( 70 ). Despite the fact that our findings have to be validated in a larger independent cohort of prior SARS-CoV-2 infected individuals, taken together with those of the literature support the hypothesis that there are differences in the innate immune responses between clinical and asymptomatic individuals during SARS-CoV-2 infections ( 15 , 16 ).…”