DOWN syndrome (DS), caused by trisomy of chromosome 21 (T21), affects approximately 1 in 700 live births. It is characterised by developmental delays, cognitive impairments, and increased susceptibility to numerous health conditions, including immune dysregulation. Emerging research highlights how this immune dysfunction underpins many complications associated with DS and explores potential therapeutic approaches.
Individuals with DS exhibit a hyperactive immune system marked by increased interferon (IFN) signalling and cytokine production. This state contributes to widespread autoimmunity, affecting multiple organ systems. Autoimmune thyroid disease (AITD), celiac disease, and various skin conditions such as alopecia areata and psoriasis are more common in this population. Early neuroinflammation and immune hypersensitivity are also notable features. These findings suggest that DS can be viewed as an inborn error of immunity, with similarities to interferonopathies – disorders caused by excessive IFN activity.
Research has uncovered that four IFN receptor genes on chromosome 21 drive IFN hyperactivity in DS. In mouse models, reducing IFN receptor gene copy number or using Janus kinase (JAK) inhibitors has reversed immune hypersensitivity, congenital heart defects, and cognitive impairments. Building on these findings, a clinical trial explored the effects of the JAK1/3 inhibitor tofacitinib in individuals with DS. Preliminary results demonstrate that the drug reduces key inflammatory markers, normalises IFN activity, and alleviates autoimmune skin conditions without severe side effects.
Notably, autoantibodies targeting various organs were detected in individuals with DS, even before clinical symptoms arose, suggesting a prolonged preclinical phase of autoimmunity. These autoantibodies were linked to conditions such as autoimmune hearing loss and myasthenia gravis, emphasising the need for personalised diagnostic approaches.
The findings underscore the therapeutic potential of JAK inhibitors to manage autoimmunity and inflammation in DS. Future research aims to explore their effects on neurological and developmental outcomes, potentially paving the way for comprehensive immunomodulatory treatments in DS from an early age. This growing body of evidence reinforces the critical role of immune regulation in improving health outcomes for individuals with DS.
Katie Wright, EMJ
Reference
Rachubinski AL et al. JAK inhibition decreases the autoimmune burden in Down syndrome. Elife. 2024;13:RP99323.
