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Cited by 32Down syndrome and intellectual disability researchImmunodeficiency and Autoimmune DisordersCytokine Signaling Pathways and Interactions

JAK inhibition decreases the autoimmune burden in Down syndrome

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Rachubinski, Angela L, Wallace, Elizabeth, Gurnee, Emily, Enriquez-Estrada, Belinda A, Worek, Kayleigh R, Smith, Keith P, Araya, Paula, Waugh, Katherine A +14 more·2024·eLife
DOI 10.7554/elife.99323PMC PMC11687933

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Abstract

Background: Individuals with Down syndrome (DS), the genetic condition caused by trisomy 21 (T21), display clear signs of immune dysregulation, including high rates of autoimmunity and severe complications from infections. Although it is well established that T21 causes increased interferon responses and JAK/STAT signaling, elevated autoantibodies, global immune remodeling, and hypercytokinemia, the interplay between these processes, the clinical manifestations of DS, and potential therapeutic interventions remain ill defined. Methods: We report a comprehensive analysis of immune dysregulation at the clinical, cellular, and molecular level in hundreds of individuals with DS, including autoantibody profiling, cytokine analysis, and deep immune mapping. We also report the interim analysis of a Phase II clinical trial investigating the safety and efficacy of the JAK inhibitor tofacitinib through multiple clinical and molecular endpoints. Results: We demonstrate multi-organ autoimmunity of pediatric onset concurrent with unexpected autoantibody-phenotype associations in DS. Importantly, constitutive immune remodeling and hypercytokinemia occur from an early age prior to autoimmune diagnoses or autoantibody production. Analysis of the first 10 participants to complete 16 weeks of tofacitinib treatment shows a good safety profile and no serious adverse events. Treatment reduced skin pathology in alopecia areata, psoriasis, and atopic dermatitis, while decreasing interferon scores, cytokine scores, and levels of pathogenic autoantibodies without overt immune suppression. Conclusions: JAK inhibition is a valid strategy to treat autoimmune conditions in DS. Additional research is needed to define the effects of JAK inhibition on the broader developmental and clinical hallmarks of DS. Funding: NIAMS, Global Down Syndrome Foundation. Clinical trial number: NCT04246372 .

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Authors
Rachubinski, A. L., Wallace, E., Gurnee, E., Enriquez-Estrada, B. A., Worek, K. R., Smith, K. P., Araya, P., Waugh, K. A., Granrath, R. E., Britton, E., Lyford, H. R., Donovan, M. G., Eduthan, N. P., Hill, A. A., Martin, B., Sullivan, K. D., Patel, L., Fidler, D. J., Galbraith, M. D., Dunnick, C. A., Norris, D. A., & Espinosa, J. M.
Affiliations
  • University of Kansas Medical Center (US)
  • Linda Crnic Institute for Down Syndrome, University of Colorado Anschutz Medical Campus
Corresponding author
Rachubinski, Angela L
ORCID
Venue
eLife
Publisher
eLife Sciences Publications, Ltd
Published
2024-12-31
Volume
13
ISSN
2050-084X (ISSN-L)
DOI
10.7554/elife.99323
PMC
PMC11687933
OpenAlex
W4401418906
Cited by
32
References
9
Citations by year
2026: 19 · 2025: 11 · 2024: 2
Type
posted content
Language
en
Open access
Licence
Locations
  • eLife (publishedVersion, cc-by)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • National Institute of Arthritis and Musculoskeletal and Skin Diseases (R61AR077495, 2T32AR007411-31)
  • National Institute of Allergy and Infectious Diseases (R01AI150305)
  • National Cancer Institute (T32CA190216, P30CA046934)
  • National Center for Advancing Translational Sciences (UM1TR004399)
  • Global Down Syndrome Foundation
  • Anna and John J. Sie Foundation
  • Boettcher Foundation
  • Fast Grants
Topics
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Down syndrome and intellectual disability research
  • Life Sciences › Immunology and Microbiology › Immunology › Immunodeficiency and Autoimmune Disorders
  • Health Sciences › Medicine › Oncology › Cytokine Signaling Pathways and Interactions
Keywords
Down syndrome, JAK inhibition, tofacitinib, autoimmune disease, immune dysregulation, autoantibodies, interferon signaling, JAK/STAT signaling, cytokine storm, immune remodeling, alopecia areata, psoriasis, atopic dermatitis, pediatric autoimmunity
MeSH terms
Janus Kinase Inhibitors, Adolescent, Adult, Autoantibodies, Child, Child, Preschool, Down Syndrome, Female, Humans, Infant, Male, Middle Aged, Piperidines, Pyrimidines, Pyrroles, Autoimmunity, Cytokines, Young Adult

About these checks

Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

Statistics and arithmetic are recomputed, not judged.

Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.

What counts as a claim ›How we measure confidence ›How we check this ›

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