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Hwang S, Tatsi C, Kuehn HS, et al. Cushing syndrome and glucocorticoids: T-cell lymphopenia, apoptosis, and rescue by IL-21. J Allergy Clin Immunol. 2021;149(1):302-314doi: 10.1016/j.jaci.2021.05.031.
Hwang, S., Tatsi, C., Kuehn, H. S., Niemela, J. E., Stoddard, J., Su, Y., Lodish, M., Uzel, G., Spolski, R., Leonard, W. J., Holland, S. M., Fleisher, T. A., Stratakis, C. A., & Rosenzweig, S. D. (2022). Cushing syndrome and glucocorticoids: T-cell lymphopenia, apoptosis, and rescue by IL-21. The Journal of allergy and clinical immunology, 149(1), 302-314. https://doi.org/10.1016/j.jaci.2021.05.031
Hwang, SuJin, et al. "Cushing syndrome and glucocorticoids: T-cell lymphopenia, apoptosis, and rescue by IL-21." The Journal of allergy and clinical immunology vol. 149,1 (2022): 302-314. doi: https://doi.org/10.1016/j.jaci.2021.05.031
Hwang S, Tatsi C, Kuehn HS, Niemela JE, Stoddard J, Su Y, Lodish M, Uzel G, Spolski R, Leonard WJ, Holland SM, Fleisher TA, Stratakis CA, Rosenzweig SD. Cushing syndrome and glucocorticoids: T-cell lymphopenia, apoptosis, and rescue by IL-21. J Allergy Clin Immunol. 2022 Jan;149(1):302-314. doi: 10.1016/j.jaci.2021.05.031. Epub 2021 Jun 02. PMID: 34089750; PMCID: PMC8636539.
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J Allergy Clin Immunol. 2022 Jan;149(1):302-314. doi: 10.1016/j.jaci.2021.05.031. Epub 2021 Jun 02.

Cushing syndrome and glucocorticoids: T-cell lymphopenia, apoptosis, and rescue by IL-21.

The Journal of allergy and clinical immunology

SuJin Hwang, Christina Tatsi, Hye Sun Kuehn, Julie E Niemela, Jennifer Stoddard, Yan Su, Maya Lodish, Gulbu Uzel, Rosanne Spolski, Warren J Leonard, Steven M Holland, Thomas A Fleisher, Constantine A Stratakis, Sergio D Rosenzweig

Affiliations

  1. Immunology Service, Department of Laboratory Medicine, NIH Clinical Center, National Institutes of Health (NIH), Bethesda, Md.
  2. Section on Endocrinology and Genetics, Eunice Kennedy Shriver National Institute of Child Health and Human Development, National Institutes of Health (NIH), Bethesda, Md.
  3. Laboratory of Clinical Immunology and Microbiology, National Institute of Allergy and Infectious Diseases, National Institutes of Health (NIH), Bethesda, Md.
  4. Laboratory of Molecular Immunology, Immunology Center, National Heart, Lung, and Blood Institute, National Institutes of Health (NIH), Bethesda, Md.
  5. Immunology Service, Department of Laboratory Medicine, NIH Clinical Center, National Institutes of Health (NIH), Bethesda, Md. Electronic address: [email protected].

PMID: 34089750 PMCID: PMC8636539 DOI: 10.1016/j.jaci.2021.05.031

Abstract

BACKGROUND: Pediatric endogenous Cushing syndrome (eCs) is mainly caused by pituitary corticotropin-producing adenomas, and most glucocorticoid-dependent effects progressively regress upon tumor removal. eCs reproduces long-term, high-dose glucocorticoid therapy, representing a clean, natural, and unbiased model in which to study glucocorticoid bona fide effects on immunity.

OBJECTIVE: We performed extensive immunologic studies in otherwise healthy pediatric patients with eCs before and 6 to 13 months after tumor resection, as well as in in vitro glucocorticoid-treated control cells.

METHODS: Flow cytometry, immunoblotting, enzyme-linked immunosorbent assay, real-time quantitative PCR, and RNA-Seq techniques were used to characterize patients' and in vitro glucocorticoid treated cells.

RESULTS: Reduced thymic output, decreased naive T cells, diminished proliferation, and increased T-cell apoptosis were detected before surgery; all these defects eventually normalized after tumor removal in patients. In vitro studies also showed increased T-cell apoptosis, with correspondingly diminished NF-κB signaling and IL-21 levels. In this setting, IL-21 addition upregulated antiapoptotic BCL2 expression and rescued T-cell apoptosis in a PI3K pathway-dependent manner. Similar and reproducible findings were confirmed in eCs patient cells as well.

CONCLUSIONS: We identified decreased thymic output and lymphocyte proliferation, together with increased apoptosis, as the underlying causes to T-cell lymphopenia in eCs patients. IL-21 was decreased in both natural and in vitro long-term, high-dose glucocorticoid environments, and in vitro addition of IL-21 counteracted the proapoptotic effects of glucocorticoid therapy. Thus, our results suggest that administration of IL-21 in patients receiving long-term, high-dose glucocorticoid therapy may contribute to ameliorate lymphopenia and the complications associated to it.

Published by Elsevier Inc.

Keywords: BCL2; NF-κB; PI3K; cytokines; infections; interleukins

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