Aging and autoimmunity: Down syndrome gives a master class
People with Down syndrome show clinical features associated with advanced immune aging, including increased autoimmunity (up to 100x!), impaired vaccine response and increased susceptibility to infections including influenza and COVID-19. We recently built a uniquely detailed atlas of the immune system in people with Down syndrome and found that the immune system of a person with Down syndrome resembles that of a typical individual up to 17 years older! These efforts also demonstrated how Down syndrome can reveal novel programs of immune dysregulation in other autoimmune diseases like type 1 diabetes. We are working to understand how we can use immune age to better guide clinical care, and how trisomy 21 drives advanced immune aging, so that we can design therapies to reverse immune aging in people with, and ultimately without, Down syndrome. This work is in close collaboration with Dr. Rebecca Partridge and the regional Down syndrome community. Learn more about our Down syndrome biorepository.
The Druggable Treg Genome: DYRK1A
We pioneered a high-throughput unbiased discovery effort in primary T cells to discover novel small molecules that enhance Treg differentiation. This approach is a powerful complement to standard genetic techniques for at least two reason:
Naïve T cells are relatively difficult to manipulate using standard genetic methods.
Small molecules of interest may immediately represent target leads for therapeutic efforts.
Mechanistic studies of our small molecule enhancers can identify novel biology. In particular, we identified the kinases DYRK1A and CDK8 as a novel druggable regulator of Treg differentiation. Inhibition of DYRK1A or CDK8 shows great promise in reducing inflammation in model systems. We are pursuing mechanistic studies to highlight additional druggable targets and corresponding precision medicine approaches, while collaborating to develop better inhibitors with better pharmacological properties.
Novel regulators of Th differentiation: DYRK1A and CDK8
Presentation by Bernard Khor, MD, PhD, at University of Washington Laboratory Medicine Grand Rounds
Community presentation: Immune aging in people with DS
Paying back and forward to the community is a priority for us. We shared our recently published findings with LifeSPAN, a group dedicated to improving the lives of people with disabilities including Down syndrome - link here.
Lambert K, Moo KG, Arnett A, Goel G, Flynn KF, Speake C, Wiedeman AE, Greenbaum CJ, Long SA, Partridge R, Buckner JH, Khor B. Permutational immune analysis reveals architectural similarities between inflammaging, Down syndrome and autoimmunity. Sci Transl Med 2022 Jan 12; 14(627):eabi4888.
Arnett A, Moo KG, Flynn KJ, Sundberg TB, Johannessen L, Shamji AF, Gray NS, Decker T, Zheng Y, Gersuk VH, Rahman ZS, Levy DE, Marié IJ, Linsley PS, Xavier RJ, Khor B. The Cyclin-Dependent Kinase 8 (CDK8) Inhibitor DCA Promotes a Tolerogenic Chemical Immunophenotype in CD4+ T Cells via a Novel CDK8-GATA3-FOXP3 Pathway. Mol Cell Biol. 2021 Aug 24;41(9):e0008521. doi: 10.1128/MCB.00085-21. Epub 2021 Aug 24. PMID: 34124936; PMCID: PMC8384069.
Hendrix JA, Amon A, Abbeduto L, Agiovlasitis S, Alsaied T, Anderson HA, Bain LJ, Baumer N, Bhattacharyya A, Bogunovic D, Botteron KN, Capone G, Chandan P, Chase I, Chicoine B, Cieuta-Walti C, DeRuisseau LR, Durand S, Esbensen A, Fortea J, Giménez S, Granholm AC, Hahn LJ, Head E, Hillerstrom H, Jacola LM, Janicki MP, Jasien JM, Kamer AR, Kent RD, Khor B, Lawrence JB, Lemonnier C, Lewanda AF, Mobley W, Moore PE, Nelson LP, Oreskovic NM, Osorio RS, Patterson D, Rasmussen SA, Reeves RH, Roizen N, Santoro S, Sherman SL, Talib N, Tapia IE, Walsh KM, Warren SF, White AN, Wong GW, Yi JS. Opportunities, barriers, and recommendations in down syndrome research. Transl Sci Rare Dis. 2021;5(3-4):99-129. doi: 10.3233/trd-200090. Epub 2021 Apr 15. PMID: 34268067; PMCID: PMC8279178.
Marié IJ, Brambilla L, Azzouz D, Chen Z, Baracho GV, Arnett A, Li HS, Liu W, Cimmino L, Chattopadhyay P, Silverman G, Watowich SS, Khor B, Levy DE. Tonic interferon restricts pathogenic IL-17-driven inflammatory disease via balancing the microbiome. Elife. 2021 Aug 11;10:e68371. doi: 10.7554/eLife.68371. PMID: 34378531; PMCID: PMC8376249.
Varma M, Kadoki M, Lefkovith A, Conway KL, Gao K, Mohanan V, Tusi BK, Graham DB, Latorre IJ, Tolonen AC, Khor B, Ng A, Xavier RJ. Cell Type- and Stimulation-Dependent Transcriptional Programs Regulated by Atg16L1 and Its Crohn's Disease Risk Variant T300A. J Immunol. 2020 Jul 15;205(2):414-424. doi: 10.4049/jimmunol.1900750. Epub 2020 Jun 10. PMID: 32522834; PMCID: PMC7364322.
Khor B, Conway KL, Omar AS, Biton M, Haber AL, Rogel N, Baxt LA, Begun J, Kuballa P, Gagnon JD, Lassen KG, Regev A, Xavier RJ. Distinct Tissue-Specific Roles for the Disease-Associated Autophagy Genes ATG16L2 and ATG16L1. J Immunol. 2019 Oct 1;203(7):1820-1829. doi: 10.4049/jimmunol.1800419. Epub 2019 Aug 26. PubMed PMID: 31451676; PubMed Central PMCID: PMC6761021.
Johannessen L, Sundberg TB, O'Connell DJ, Kolde R, Berstler J, Billings KJ, Khor B, Seashore-Ludlow B, Fassl A, Russell CN, Latorre IJ, Jiang B, Graham DB, Perez JR, Sicinski P, Phillips AJ, Schreiber SL, Gray NS, Shamji AF, Xavier RJ. Small-molecule studies identify CDK8 as a regulator of IL-10 in myeloid cells. Nat Chem Biol. 2017 Oct;13(10):1102-1108. doi: 10.1038/nchembio.2458. Epub 2017 Aug 14. PubMed PMID: 28805801; PubMed Central PMCID: PMC5693369.
Sundberg TB, Liang Y, Wu H, Choi HG, Kim ND, Sim T, Johannessen L, Petrone A, Khor B, Graham DB, Latorre IJ, Phillips AJ, Schreiber SL, Perez J, Shamji AF, Gray NS, Xavier RJ. Development of Chemical Probes for Investigation of Salt-Inducible Kinase Function in Vivo. ACS Chem Biol. 2016 Aug 19;11(8):2105-11. doi: 10.1021/acschembio.6b00217. Epub 2016 Jun 6. PubMed PMID: 27224444; PubMed Central PMCID: PMC4992440.
Khor B, Gagnon JD, Goel G, Roche MI, Conway KL, Tran K, Aldrich LN, Sundberg TB, Paterson AM, Mordecai S, Dombkowski D, Schirmer M, Tan PH, Bhan AK, Roychoudhuri R, Restifo NP, O'Shea JJ, Medoff BD, Shamji AF, Schreiber SL, Sharpe AH, Shaw SY, Xavier RJ. The kinase DYRK1A reciprocally regulates the differentiation of Th17 and regulatory T cells. Elife. 2015 May 22;4. doi: 10.7554/eLife.05920. PubMed PMID: 25998054; PubMed Central PMCID: PMC4441007.