Leaders in Research

The Immune Dysregulation Program team is actively involved in multiple research projects and publishes extensively related to:

• the functions of immune cells,
• genetic causes for immune dysregulation disorders, and
• novel treatments for patients who may not respond to current treatments.

Below are some of our most current publications, separated by topic area.

Cytokine Release Syndrome

Diorio C, Shraim R, Myers R, Behrens E, Canna S, Bassiri H, Aplenc R, Burudpakdee C, Chen F, DiNofia A, Gill S, Gonzalez V, Lambert M, Leahy A, Levine B, Lindell RB, Maude SL, Melenhorst JJ, Newman H, Perazzelli J, Seif AE, Lacey SF, June CH, Barrett DM, Grupp SA, Teachey DT: Comprehensive Serum Proteome Profiling of Cytokine Release Syndrome and Immune Effector Cell Associated Neurotoxicity Syndrome in Patients Receiving CART19. Clinical Cancer Research, 28(17): 3804-13, September 2022. PMCID: PMC9444956. https://pubmed.ncbi.nlm.nih.gov/35705524/

Fitzgerald J, Weiss SL, Maude SL, Barrett DM, Lacey SF, Melenhorst JJ, Shaw PA, Berg RA, June CH, Porter DL, Frey NV, Grupp SA, Teachey DT: Cytokine Release Syndrome after chimeric antigen receptor T cell therapy for acute lymphoblastic leukemia. Critical Care Medicine, 45(2): e124-131, February 2017. PMCID: PMC5452983. https://pubmed.ncbi.nlm.nih.gov/27632680/

Teachey DT, Lacey SF, Shaw P, Melenhorst J, Maude SL, Frey N, Pequignot E, Gonzalez V, Chen F, Finklestein J, Barrett D, Weiss S, Fitzgerald J, Berg R, Aplenc R, Callahan C, Rheingold SR, Zheng Z, Rose-John S, White J, Nazimuddin F, Wertheim G, Levine B, June CH, Porter DL, Grupp SA: Identification of Predictive Biomarkers for Cytokine Release Syndrome after Chimeric Antigen Receptor T cell Therapy for Acute Lymphoblastic Leukemia. Cancer Discovery, 6(6): 664-79, June 2016. PMCID: PMC5448406. https://pubmed.ncbi.nlm.nih.gov/27076371/

Hemophagocytic Lymphohistiocytosis (HLH)/Macrophage Activation Syndrome (MAS)

Weiss ES, Girard-Guyonvarc'h C, Holzinger D, de Jesus AA, Tariq Z, Picarsic J, Schiffrin EJ, Foell D, Grom AA, Ammann S, Ehl S, Hoshino T, Goldbach-Mansky R, Gabay C, Canna SW. Interleukin-18 diagnostically distinguishes and pathogenically promotes human and murine macrophage activation syndrome. Blood, 2018; 131(13): 1442-55. PMID: 29326099; PMCID: PMC5877443. https://pubmed.ncbi.nlm.nih.gov/29326099/

Diamond T, Burn TN, Nishiguchi MA, Minichino D, Chase J, Chu N, Kreiger PA, Behrens EM. Familial hemophagocytic lymphohistiocytosis hepatitis is mediated by IFN-γ in a predominantly hepatic-intrinsic manner. PLoS One, 2022 Jun 7; 17(6): e0269553. doi: 10.1371/journal.pone.0269553. eCollection 2022.PMID: 35671274. https://pubmed.ncbi.nlm.nih.gov/35671274/

Si Stephanie, Tasian S, Bassiri H, Fisher B, Atalla J, Patel R, Romberg N, Lambert MP, Paessler M, Behrens E, Teachey DT, and Sullivan KE: Diagnostic Challenges in Pediatric Hemophagocytic Lymphohistiocytosis. Journal of Clinical Immunology 41(6): 1213-8, August 2021. PMCID: PMC7988244. https://pubmed.ncbi.nlm.nih.gov/33761058/

Hematologic disorders and malignancies

Adang LA, Gavazzi F, D'Aiello R, Isaacs D, Bronner N, Arici ZS, Flores Z, Jan A, Scher C, Sherbini O, Behrens EM, Goldbach-Mansky R, Olson TS, Lambert MP, Sullivan KE, Teachey DT, Witmer C, Vanderver A, Shults J. Hematologic abnormalities in Aicardi Goutières Syndrome. Mol Genet Metab, 2022 Aug; 136(4): 324-329. doi: 10.1016/j.ymgme.2022.06.003. Epub 2022 Jun 16. PMID: 35786528. https://pubmed.ncbi.nlm.nih.gov/35786528/

Hillier K, Rothman JA, Klaassen RJ, Neunert C, Rose MJ, Grace RF, Lambert MP. SARS-CoV-2 vaccination in pediatric patients with immune thrombocytopenia. Pediatr Blood Cancer, 2022 Jul;6 9(7): e29760. doi: 10.1002/pbc.29760. Epub 2022 May 13. PMID: 35561101. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9347939/

Seif AE, Li Y, Monos DS, Heidemann SC, Aplenc R, Barrett DM, Casper JT, Freedman JL, Grupp SA, Margolis DA, Olson TS, Teachey DT, Keever-Taylor CA, Wang Y, Talano JM, Bunin NJ. Partially CD3+-Depleted Unrelated and Haploidentical Donor Peripheral Stem Cell Transplantation Has Favorable Graft-versus-Host Disease and Survival Rates in Pediatric Hematologic Malignancy. Biol Blood Marrow Transplant, 2020 Mar; 26(3): 493-501. doi: 10.1016/j.bbmt.2019.11.022. Epub 2019 Nov 22.PMID: 31765697. https://pubmed.ncbi.nlm.nih.gov/31765697/

Sabulski A, Abdullah S, Luebbering N, Aunins B, Castillo C, Lake K, Duell A, Strecker L, Giordullo L, Broomhead W, Dimeo S, Odegard EA, Blackard JT, Ziady A, Seif AE, Dandoy CE, Laskin BL, Jodele S, Davies SM. Circulating endothelial cells and the study of vascular injury in children undergoing hematopoietic stem cell transplant. Haematologica, 2022 Aug 18. doi: 10.3324/haematol.2022.280788. Online ahead of print. PMID: 35979718. https://pubmed.ncbi.nlm.nih.gov/35979718/

Arnold DE, MacMath D, Seif AE, Heimall JR, Wang Y, Monos D, Grupp SA, Bunin NJ. Immune Reconstitution Following TCRαβ/CD19-Depleted Hematopoietic Cell Transplantation for Hematologic Malignancy in Pediatric Patients. Transplant Cell Ther, 2021 Feb; 27(2): 169.e1-169.e9. doi: 10.1016/j.jtct.2020.10.006. Epub 2020 Dec 10.PMID: 33830028. https://pubmed.ncbi.nlm.nih.gov/33830028/

Laskin BL, Denburg MR, Furth SL, Moatz T, Altrich M, Kleiboeker S, Lutzko C, Zhu X, Blackard JT, Jodele S, Lane A, Wallace G, Dandoy CE, Lake K, Duell A, Litts B, Seif AE, Olson T, Bunin N, Davies SM. The Natural History of BK Polyomavirus and the Host Immune Response After Stem Cell Transplantation. Clin Infect Dis, 2020 Dec 15; 71(12): 3044-3054. doi: 10.1093/cid/ciz1194. PMID: 31851312. https://pubmed.ncbi.nlm.nih.gov/31851312/

Bride KL, Vincent T, Smith-Whitley K, Lambert MP, Bleesing JJ, Seif AE, Manno CS, Casper J, Grupp SA, Teachey DT: Sirolimus is effective in relapsed/refractory autoimmune cytopenias: Results of a prospective multi-institutional trial. Blood, 127(1): 17-28, January 2016 Notes: *Plenary paper with featured commentary. PMCID: PMC4705607. https://pubmed.ncbi.nlm.nih.gov/26504182/

MIS-C

Vella LA, Giles JR, Baxter AE, Oldridge DA, Diorio C, Alanio C, Pampena MB, Wu JE, Chen Z, Huang YJ, Anderson EM, Gouma S, McNerney KO, Chase J, Burudpakdee C, Lee JH, Apostolidis SA, Huang AC, Mathew D, Kuthuru O, Goodwin EC, Weirick ME, Bolton MJ, Arevalo CP, Ramos A, Jasen C, Giannini HM, D'Andrea K, The UPenn COVID Processing Unit, Meyer NJ, Behrens EM, Bassiri H, Hensley SE, Henrickson SE, Teachey DT, Betts MR, Wherry EJ. Deep immune profiling of MIS-C demonstrates marked but transient immune activation as compared to adult and pediatric COVID-19. Science Immunology, 6(57): eabf7570, doi: 10.1126/sciimmunol.abf7570 (2021).

Chang JC, Matsubara D, Morgan R, Diorio C, Nadaraj S, Teachey DT, Bassiri H, Behrens EM, Banerjee A. Skewed cytokine responses rather than the magnitude of the cytokine storm may be responsible for cardiac dysfunction in multi-system inflammatory syndrome in children. Journal of the American Heart Association, 10(16): e021428, doi.org/10.1161/JAHA.121.021428 (2021).

Diorio C, Shraim R, Vella LA, Giles JR, Baxter AE, Oldridge DA, Canna SW, Henrickson SE, McNerney KO, Balamuth F, Burudpakdee C, Lee J, Leng T, Farrel A, Lambert MP, Sullivan KE, Wherry EJ, Teachey DT, Bassiri H, Behrens EM. Proteomic profiling of MIS-C patients indicates heterogeneity relating to interferon gamma dysregulation and vascular endothelial dysfunction. Nat Commun, 2021 Dec 10;12(1): 7222. doi: 10.1038/s41467-021-27544-6. PMID: 34893640. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8077582/

Diorio C, Henrickson S, Vella L, McNerney K, Chase J, Burudpakdee C, Lee J, Jasen C, Balamuth F, Barrett D, Banwell B, Bernt K, Blatz AM, Chiotos K, Fisher B, Fitzgerald J, Gerber J, Gollomp K, Gray C, Grupp S, Harris R, Kilbaugh T, Odom John A, Lambert MP, Liebling E, Paessler M, Petrosa W, Phillips C, Reilly A, Romberg N, Seif AE, Sesok-Pizzini D, Sullivan K, Vardaro J, Behrens E*, Teachey DT*, Bassiri H*, (*Equal Contribution): Multisystem inflammatory system in children and COVID-19 are distinct pathophysiologic presentations of SARS-CoV-2. Journal of Clinical Investigation, 130(11): 5967-75, November 2020. PMCID: PMC7598044. https://pubmed.ncbi.nlm.nih.gov/32730233/

Treatment of hyperinflammatory disorders

Chiotos K, Corwin D, Sartori L, Congdon M, Lavelle J, Swami S, Burnham J, Bassiri H, John A, Balamuth F, Cohn K, Blackstone M, Callahan J, Kampalath V, Rempell R, Elias M, Giglia T, Witmer C, Davis D, Kerman C, Whitney D, Behrens E, Teachey D, Jacobstein C. Multisystem inflammatory syndrome in children (MIS-C) clinical pathway. www.chop.edu/clinical-pathway/multisystem-inflammatory-syndrome-mis-c-clinical-pathway (2020).

Henderson LA, Canna SW, Friedman KG, Gorelik M, Lapidus SK, Bassiri H, Behrens EM, Ferris A, Kernan KF, Schulert GS, Seo P, Son MB, Tremoulet AH, Yeung RSM, Mudano AS, Turner AS, Karp DR, Mehta J. American College of Rheumatology clinical guidance for pediatric patients with Multisystem Inflammatory Syndrome in Children (MIS-C) associated with SARS-CoV-2 and hyperinflammation in COVID-19. Arthritis and Rheumatology, Version 1: 72(11): 1791-1805, doi.org/10.1002/art.41454 (2020); Version 2: http://dx.doi.org/10.1002/art.41616 (2020); Version 3: https://doi.org/10.1002/art.42062 (2022).

Dulek DE, Fuhlbrigge RC, Tribble AC, Connelly JA, Loi MM, El Chebib H, Chandrakasan S, Otto WR, Diorio C, Keim G, Walkovich K, Jaggi P, Girotto JE, Yarbrough A, Behrens EM, Cron RQ, Bassiri H. Multi-disciplinary guidance regarding the use of immunomodulatory therapies for acute COVID-19 in pediatric patients. Journal of the Pediatric Infectious Diseases Society, 9(6):716-37, doi.org/10.1093/jpids/piaa098 (2020).

Canna SW, Girard C, Malle L, de Jesus A, Romberg N, Kelsen J, Surrey LF, Russo P, Sleight A, Schiffrin E, Gabay C, Goldbach-Mansky R, Behrens EM. Life-threatening NLRC4-associated hyperinflammation successfully treated with Interleukin-18 inhibition. The Journal of Allergy and Clinical Immunology, 2016;139(5): 1698-701 PMID: 27876626; PMCID: PMC5846100. https://pubmed.ncbi.nlm.nih.gov/27876626/

Rood JE, Rezk A, Pogoriler J, Finn LS, Burnham JM, Josephson MB, Bar-Or A, Behrens EM, Canna SW. Improvement of Refractory Systemic Juvenile Idiopathic Arthritis-Associated Lung Disease with Single-Agent Blockade of IL-1β and IL-18. J Clin Immunol, 2022 Aug 25. doi: 10.1007/s10875-022-01353-y. Online ahead of print. PMID: 36006569. https://pubmed.ncbi.nlm.nih.gov/36006569/

Triebwasser MP, Barrett DM, Bassiri H, Bunin N, Elgarten C, Freedman J, Geera AS, Monos D, Lambert MP, Olson T, Seif AE, Paessler M, Petrosa W, Reilly AF, Romberg N, Sullivan KE, Quinn G, Behrens E, and Teachey DT: Combined use of Emapalumab and Ruxolitinib in a Patient with Refractory Hemophagocytic Syndrome was Safe and Effective. Pediatric Blood & Cancer, 68(7): e29026, July 2021. PMCID: PMC9269994. https://pubmed.ncbi.nlm.nih.gov/33754483/

Other hyperinflammatory syndromes

Chen G, Deutsch G, Schulert GS, Zheng H, Jang S, Trapnell B, Lee P, Macaubas C, Ho K, Schneider C, Saper VE, de Jesus AA, Krasnow M, Grom AA, Goldbach-Mansky R, Khatri P, Mellins ED, Canna SW. Serum proteome analysis of Systemic JIA and related lung disease identifies distinct inflammatory programs and biomarkers. Arthritis & Rheumatology, 2022. Epub 2/21/22. PMID: 35189047. https://www.medrxiv.org/content/10.1101/2021.01.20.21250141v2.full

Canna SW, de Jesus AA, Gouni S, Brooks SR, Marrero B, Liu Y, DiMattia MA, Zaal KJ, Sanchez GA, Kim H, Chapelle D, Plass N, Huang Y, Villarino AV, Biancotto A, Fleisher TA, Duncan JA, O'Shea JJ, Benseler S, Grom A, Deng Z, Laxer RM, Goldbach-Mansky R. An activating NLRC4 inflammasome mutation causes autoinflammation with recurrent macrophage activation syndrome. Nat Genet, 2014;46(10): 1140-6. PMID: 25217959; PMCID: 4177369. https://pubmed.ncbi.nlm.nih.gov/25217959/

Romberg N, Al Moussawi K, Nelson-Williams C, Stiegler AL, Loring E, Choi M, Overton J, Meffre E, Khokha MK, Huttner AJ, West B, Podoltsev NA, Boggon TJ, Kazmierczak BI, Lifton RP. Mutation of NLRC4 causes a syndrome of enterocolitis and autoinflammation. Nat Genet, 2014 Oct;46(10): 1135-1139. doi: 10.1038/ng.3066. Epub 2014 Sep 14. PMID: 25217960; PMCID: PMC4177367. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC4177367/

Le Coz C, Nguyen DN, Su C, Nolan BE, Albrecht AV, Xhani S, Sun D, Demaree B, Pillarisetti P, Khanna C, Wright F, Chen PA, Yoon S, Stiegler AL, Maurer K, Garifallou JP, Rymaszewski A, Kroft SH, Olson TS, Seif AE, Wertheim G, Grant SFA, Vo LT, Puck JM, Sullivan KE, Routes JM, Zakharova V, Shcherbina A, Mukhina A, Rudy NL, Hurst ACE, Atkinson TP, Boggon TJ, Hakonarson H, Abate AR, Hajjar J, Nicholas SK, Lupski JR, Verbsky J, Chinn IK, Gonzalez MV, Wells AD, Marson A, Poon GMK, Romberg N. Constrained chromatin accessibility in PU.1-mutated agammaglobulinemia patients. J Exp Med, 2021 Jul 5;218(7): e20201750. doi: 10.1084/jem.20201750. Epub 2021 May 5. PMID: 33951726; PMCID: PMC8105723. https://pubmed.ncbi.nlm.nih.gov/33951726/

Le Coz C, Trofa M, Syrett CM, Martin A, Jyonouchi H, Jyonouchi S, Anguera MC, Romberg N. CD40LG duplication-associated autoimmune disease is silenced by nonrandom X-chromosome inactivation. J Allergy Clin Immunol, 2018 Jun;141(6): 2308-2311.e7. doi: 10.1016/j.jaci.2018.02.010. Epub 2018 Mar 2. PMID: 29499223; PMCID: PMC5994181. https://pubmed.ncbi.nlm.nih.gov/29499223/

Romberg N, Lawrence MG. Birds of a feather: Common variable immune deficiencies. Ann Allergy Asthma Immunol, 2019 Nov;123(5):461-467. doi: 10.1016/j.anai.2019.07.027. Epub 2019 Aug 2. PMID: 31382019. https://pubmed.ncbi.nlm.nih.gov/31382019/

Minichino D, Lv K, Chu N, Tong W, Behrens EM. BRAF-V600E utilizes posttranscriptional mechanisms to amplify LPS-induced TNFα production in dendritic cells in a mouse model of Langerhans cell histiocytosis. J Leukoc Biol, 2022 Jun 1. doi: 10.1002/JLB.3A0122-075RR. Online ahead of print.PMID: 35648675. https://pubmed.ncbi.nlm.nih.gov/35648675/

Chapin CA, Taylor SA, Malladi P, Neighbors K, Melin-Aldana H, Kreiger PA, Bowsher N, Schipma MJ, Loomes KM, Behrens EM, Alonso EM. Transcriptional Analysis of Liver Tissue Identifies Distinct Phenotypes of Indeterminate Pediatric Acute Liver Failure. Hepatol Commun, 2021 May 6;5(8):1373-1384. doi: 10.1002/hep4.1726. eCollection 2021 Aug.PMID: 34430782. https://pubmed.ncbi.nlm.nih.gov/34430782/

Seif AE, Manno CS, Sheen C, Grupp SA, Teachey DT: Identifying autoimmune lymphoproliferative syndrome (ALPS) in children with Evans syndrome: a multi-institutional study. Blood, 115(11): 2142-5, March 2010. https://pubmed.ncbi.nlm.nih.gov/20068224/