Interferon-Driven Immune Dysregulation in Down Syndrome: A Review of the Evidence

Abstract

Down syndrome (DS) is a unique genetic disease caused by the presence of an extra copy of chromosome 21, which carries four of the six interferon receptor (IFN-R) genes on its long arm. Recent studies reporting higher levels of interferon-stimulated gene (ISG) expression in primary immune cells studied ex vivo have suggested that the additional copies of the IFN-R genes in DS result in mild interferonopathy. In this review, we analyze the potential clinical and immunological impacts of this interferonopathy in DS. We performed a literature review to explore the epidemiology and risks of celiac disease, type 1 diabetes, thyroid dysfunction, mucocutaneous manifestations, infectious diseases (including COVID-19), and Alzheimer's disease in individuals with DS relative to the general population with or without iatrogenic exposure to interferons. We analyzed immunophenotyping data and the current experimental evidence concerning IFN-R expression, constitutive JAK-STAT activation, and ISG overexpression in DS. Despite the lack of direct evidence that implicating this mild interferonopathy directly in illnesses in individuals with DS, we highlight the challenges ahead and directions that could be taken to determine more clearly the biological impact of interferonopathy on various immune-related conditions in DS.

The Role of Vitamin D On Interferon- Levels in Indonesian Children with Down Syndrome And Its Contributing Factors: A Cross-sectional Study

“…32 and some autoimmune diseases such as celiac disease, T1DM, and thyroid dysfunction, which are more pronounced in the DS population than the non-DS population. 31 Studies building on RNA, protein, and functional data that provide insight into how IFN signaling contributes to the distinct characteristics of DS reveal potential pathways to treat the predominant diseases in children with DS. 32 In a mouse model of DS, both anti-IFN therapy and genetic methods of reducing the number of IFN-Rs on the surface of cells were shown to improve growth and brain development.…”

Spatiotemporal expression of Rest in the brain of Ts1Cje mouse model of Down syndrome

“…These observations agree with the gene dosage imbalance as four subunits of IFN receptor genes are located on human chromosome 21 (HSA21), and trisomy in Down syndrome causes their over-expression. Interestingly, we found that these IFN genes are also targeted by REST which suggests that the REST dysregulation also contributes to the IFN's upregulation in DS (Chung et al, 2021;Kirsammer & Crispino, 2016). Furthermore, the upregulated IFNs will over-activate the downstream IFN-stimulated genes (ISGs) and promote in ammatory and antiviral activity (Jagadeesh et al, 2020).…”

Development of an Effective Immune Response in Adults With Down Syndrome After Severe Acute Respiratory Syndrome Coronavirus 2 (SARS-CoV-2) Vaccination

“…Although this increase can be partially attributed to a higher prevalence of comorbidities associated with a poorer COVID-19–related prognosis, such as obesity, congenital heart disease, or respiratory diseases [ 6 , 7 ], the susceptibility to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) can be further explained by immune dysregulation. Patients with DS show higher levels of interferon (IFN)-stimulated genes, which explains their higher basal levels of IFN-α signaling and hypersensitivity to IFN stimulation [ 8 ]. Indeed, 4 subunits of IFN receptors are encoded on HSA21 (IFNAR1, IFNAR2, IFNGR2, and IL10RB), and an increase in IFNAR1 and IFNAR2 expression in different cell types from DS donors has been described [ 9 ].…”