A recent study provided a comprehensive characterization of autoimmunity in patients with Down syndrome (DS) and reported promising results from a clinical trial of the Janus kinase (JAK) inhibitor tofacitinib in this population. These findings were published in eLife.
Researchers found high rates of autoimmune conditions affecting multiple organ systems in 441 individuals with DS, often presenting in childhood and co-occurring in the same individuals. Autoimmune thyroid disease was diagnosed in 53.1% of individuals with DS, autoimmune/inflammatory skin conditions in 43%, celiac disease in 9.6%, and type 1 diabetes in 2.2%. In adults, 75% had at least one condition, 38.4% had two or more, and 13.6% had three or more.
Profiling
Autoantibody profiling revealed antibodies targeting diverse tissues in nearly all adults with DS. Anti-thyroid peroxidase (TPO) antibodies were detected in 82.4%, anti-nuclear antibodies in 41.2%, and 63.3% were positive for six or more autoantibodies. Specific autoantibodies were overrepresented in DS and associated with co-occurring conditions, such as anti-TPO with ear tube placement (odds ratio [OR] = 2.3, P=0.02), anti-MUSK with neurological conditions (OR = 3.5, P=0.008), and anti-DSG3 with pneumonia (OR = 2.8, P=0.03).
Mass cytometry immune profiling showed global remodeling in DS, with increased frequencies of autoimmunity-prone subsets like basophils, plasmablasts, and terminally differentiated CD8+ T cells, and decreased total B cells and naïve T cells. These changes were consistent across clinical subgroups. Plasma proteomics revealed marked elevations in proinflammatory cytokines, chemokines, and growth factors in DS, independent of diagnosed autoimmunity and present from an early age. Many of these elevations did not increase further with age in individuals with DS.
Efficacy of Tofacitinib
In a small open-label trial, 10 participants with DS and autoimmune skin conditions received tofacitinib for 16 weeks. Seven of the 10 had improvements in global skin scores, and 8 of the 10 reported improved quality of life. Mean interferon transcriptional scores decreased from 8.2 to 2.4 (p<0.001), along with reductions in TNF-α and IL-6. Seven of seven patients with elevated anti-TPO and three of three with elevated anti-thyroglobulin at baseline had decreased autoantibody levels. No serious adverse events occurred.
The authors concluded that trisomy 21 induces pervasive autoimmunity and an autoimmunity-prone immune state. JAK inhibition may provide therapeutic benefit by attenuating interferon hyperactivity and reducing inflammatory mediators, without overt immune suppression. Further studies are needed to assess long-term effects and impact on other DS phenotypes.
Conflict of interest disclosures can be found within the study, which was published on the eLife preprint server.