Defining the regulation and roles of allergy-associated factors in rheumatic diseases and beyond
RESEARCH & PUBLICATIONS
Major Areas of Research
- Identifying the molecular and epigenetic mechanisms underlying human T helper 9 lineage identity and function
- Identifying the mechanisms by which human T helper 9 cells promote end-organ pathology in patients with psoriasis and other systemic autoimmune diseases
- Investigation of cellular and molecular pathways responsible for the symptoms characteristic of haploinsufficiency of A20 (HA20) and related diseases
Program Description
Diseases of immune activation are common and devastating, affecting up to 15% of the U.S. population and causing severe morbidity. Although identifying and targeting pathogenic cytokines has revolutionized disease treatment, many syndromes are treatment-refractory due to an incomplete understanding of the factors driving pathology. Our group seeks to improve the basic understanding of human immune activation by investigating relationships between allergic inflammation and autoimmune/autoinflammatory disorders. Notably, allergic factors have historically been thought to suppress these diseases, but recent evidence implicates allergic cells and cytokines as critical drivers of autoimmune pathology. We therefore aim to dissect the regulation and roles of allergy-associated cytokines in the context of autoimmune and autoinflammatory disease, using a multifaceted approach that combines mouse models with studies involving human patients.
Selected Publications
Son A, Meylan F, Gomez-Rodriguez J, Kaul Z, Sylvester M, Falduto GH, Vazquez E, Haque T, Kitakule MM, Wang C, Manthiram K, Qi CF, Cheng J, Gurram RK, Zhu J, Schwartzberg P, Milner JD, Frischmeyer-Guerrerio PA, Schwartz DM. Dynamic chromatin accessibility licenses STAT5- and STAT6-dependent innate-like function of TH9 cells to promote allergic inflammation. Nat Immunol. 2023 Apr 27. doi: 10.1038/s41590-023-01501-5.
Redmond CJ, Kitakule MM, Son A, Sylvester M, Sacco K, Delmonte O, Licciardi F, Castagnoli R, Poli MC, Espinoza Y, Astudillo C, Weber SE, Montealegre Sanchez GA, Barron KS, Magliocco M, Dobbs K, Zhang Y, Matthews H, Oguz C, Su HC, Notarangelo LD, Frischmeyer-Guerrerio P, Schwartz DM. Deep immune profiling uncovers novel associations with clinical phenotypes of multisystem inflammatory syndrome in children (MIS-C). Ann Rheum Dis. 2023 Mar;82(3):442-445. doi: 10.1136/ard-2022-223269. Epub 2022 Nov 24. PMID: 36424123; PMCID: PMC10013176.
Schwartz DM, Kitakule MM, Dizon BL, Gutierrez-Huerta C, Blackstone SA, Burma AM, Son A, Deuitch N, Rosenzweig S, Komarow H, Stone DL, Jones A, Nehrebecky M, Hoffmann P, Romeo T, de Jesus AA, Alehashemi S, Garg M, Torreggiani S, Montealegre Sanchez GA, Honer K, Souto Adeva G, Barron KS, Aksentijevich I, Ombrello AK, Goldbach-Mansky R, Kastner DL, Milner JD, Frischmeyer-Guerrerio P. Systematic evaluation of nine monogenic autoinflammatory diseases reveals common and disease-specific correlations with allergy-associated features. Ann Rheum Dis. 2021 Feb 22:annrheumdis-2020-219137. doi: 10.1136/annrheumdis-2020-219137.
Schwartz DM, Blackstone SB, Sampaio Moura N, Rosenzweig S, Burma AM, Stone D, Hoffmann P, Jones A, Romeo T, Barron KS, Waldman MA, Aksentijevich I, Kastner DL, Milner JD, Ombrello AK. Type I interferon signature predicts response to JAK inhibition in haploinsufficiency of A20. Ann Rheum Dis. 2020 Mar;79(3):429-431.
Schwartz DM, Farley T, Richoz N, Yao C, Shih HY, Petermann F, Zhang Y, Sun HW, Hayes E, Mikami Y, Jiang K, Davis FP, Kanno Y, Milner JD, Siegel R, Laurence A, Meylan F*, O’Shea JJ*. Retinoic Acid Receptor Alpha Represses a Th9 Transcriptional and Epigenomic Program to Reduce Allergic Pathology. Immunity. 2019 Jan 15;50(1):106-120.e10.
Ahuja M*, Schwartz DM*, Tandon M, Son A, Zeng M, Swaim W, Eckhaus M, Hoffman V, Cui Y, Xiao B, Worley PF, Muallem S. Orai1-Mediated Antimicrobial Secretion from Pancreatic Acini Shapes the Gut Microbiome and Regulates Gut Innate Immunity. Cell Metab. 2017 Mar 7;25(3):635-646.
Zhou Q*, Wang H*, Schwartz DM, Stoffels M, Park YH, Zhang Y, Yang D, Demirkaya E, Takeuchi M, Tsai WL, Lyons JJ, Yu X, Ouyang C, Chen C, Chin DT, Zaal K, Chandrasekharappa SC, Hanson EP, Yu Z, Mulikin JC, Hasni SA, Wertz IE, Ombrello AK, Stone DL, Hoffmann P, Jones A, Barham BK, Leavis HL, van Royen-Kerkof A, Sibley C, Batu ED, Gul A, Siegel FM, Boehm M, Milner JD, Ozen S, Gadina M, Chae J, Laxer RM, Kastner DL, Aksentijevich I Loss-of-function mutations in TNFAIP3 leading to A20 haploinsufficiency cause an early-onset autoinflammatory disease. Nat Genet. 2016 Jan;48(1):67-73.
*authors contributed equally
PROJECTS
Epigenetic regulation of IL-9/Th9 cells
IL-9 and Th9 cells are implicated in the pathogenesis of allergy, autoimmunity, and antitumor immunity. We believe that studying primary IL-9-producing cells from patients with IL-9-related diseases will help us to better understand the factors modulating IL-9 production in these very different contexts, as well as the roles of IL-9 in these varied pathologies.
Role of IL-9 in autoimmune disease
We have shown that Th9 cells and IL-9 are elevated in patients with psoriasis. Now we hope to understand what Th9/IL-9 are doing in patients with psoriasis, especially in the context of extracutaneous disease.
Overlap of allergy and autoinflammation
We have shown that patients with some monogenic autoinflammatory syndromes have increased rates of allergic disease. We hope to take things a step further and understand how germline mutations in these genes might promote an allergic state, and how this might affect disease flares.
Effects of A20 haploinsufficiency
We follow a cohort of patients with complex immune dysregulation due to haploinsufficiency of A20. We hope to understand how A20 modulates inflammation by studying and treating these patients over time.
PEOPLE
Daniella Schwartz, MD
Principal Investigator
Assistant Professor of Medicine and Immunology
Division of Rheumatology and Clinical Immunology
daniella.schwartz@pitt.edu
Dr. Schwartz graduated with a B.A. in Biochemistry and French from Rice University and received an M.D. from the Wake Forest University School of Medicine in 2007. She completed her internal medicine residency training at Virginia Commonwealth University in 2010, after which she served as a chief medical resident. She completed a fellowship in clinical rheumatology at the National Institute of Arthritis and Musculoskeletal and Skin Diseases and was subsequently promoted to Metzger Scholar in Translational Research, where she did a postdoctoral fellowship in the lab of Dr. John O’Shea. In 2018, she was recruited to the NIAID intramural research program as an assistant clinical investigator. Dr. Schwartz was a recipient of the American Society of Clinical Investigation Young Physician Scientist Award in 2020.
Current Lab Members
Guido Falduto, PhD (Senior Scientist)
Senior Scientist
Ishita Baral, PhD
Postdoctoral Fellow
Urekha Karri
PhD student
Liz Kairis
MD student
Magda Harasimowicz
Clinical Fellow
Schwartz Lab Alumni
Aran Son, PhD
Biologist 2018-2022
Currently biologist at SISSA, Trieste, Italy
Aarohan Burma
Currently PhD student at UT Southwestern
Christopher Redmond, MD
Clinical fellow 2021-2022
Sarah Blackstone
Postbaccalaureate fellow 2019-2020
Currently MD/PhD student at University of South Dakota
Moses Kitakule
Postbaccalaureate fellow 2019-2021
Currently MD/PhD student at Columbia University
McKella Sylvester
Postbaccalaureate fellow 2021-2022
SCHWARTZ LAB PHILOSOPHY (IN NINE POINTS)
- No person is an island. Good science requires an environment of cooperation, support, and mutual respect.
2. Science is 1% passion and 99% perseverance. Disappointment, failure, and rejection are all normal parts of the game.
3. Your data will take you in unexpected directions – don’t love it, don't hate it, and never fudge it to fit a hypothesis. Just follow the data, and your science will keep moving forward.
4. The path to a fruitful scientific career is not always a straight line. Detours are normal, and your goals/endpoints may change.
5. You should have a life outside the lab. This will be a key part of keeping you grounded throughout the "marathon" of your scientific career.
6. But your projects do need to keep moving forward! So rest when you need a break, work hard when you're doing science, and never hesitate to ask for help.
7. Good science ≠ flashy science, and not every paper will be published in a high impact journal. But all our publications will be honest, reliable, and reflect our best work.
8. Mentoring is a two-way street. Be honest about your needs and expectations, respect your colleagues, don't be afraid to say "I don't know," be willing to ask for (or provide) help, and always strive to do your best. I'll do the same!
9. IL-9 is the best of all possible cytokines and Th9 cells are the best of all possible cells...until they’re not. Establishing a scientific direction is an opportunity to fundamentally examine (and re-examine) your scientific and career goals.