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.

Keywords: JAK-STAT; T cells; celiac disease; down syndrome; gene dosage effect; interferon receptors.

Figure 1

Common immune system-mediated disorders in DS.

Figure 2

Mild interferonopathy in Down syndrome. Left: Diagram of the type I and type II IFN-activated JAK-STAT pathway. IFNAR1, IFNAR2, IFNGR2 are located on HSA21. ISGF3 is a DNA-binding complex formed by STAT1/STAT2/IRF9; GAF is a STAT1/STAT1 homodimer. Right: summary of observations for the testing of serum, monocytes, EBV-transformed B cells, and T cells from euploid healthy controls and individuals with DS.

Figure 3

Biological implications and potential mechanisms of mild interferonopathy in DS. Interferons have pleiotropic effects on multiple organs and different effects on different cell types. IFN can drive T-cell activation and differentiation which is considered to be the third signal for T-cell development, in addition to the TCR and the costimulatory receptor. The tissue and temporal effects of interferonopathy in DS remain to be explored.