한빛사 논문
SuJin Hwang, Ph.D.1#; Christina Tatsi, M.D., Ph.D.2#; Hye Sun Kuehn, Ph.D.1#; Julie E. Niemela, MS, MLS.1; Jennifer Stoddard, BS1; Yan Su, BS1; Maya Lodish, M.D., MHSc.2; Gulbu Uzel, M.D.3; Rosanne Spolski, Ph.D.4; Warren J Leonard, M.D.4; Steven M Holland, M.D.3; Thomas A Fleisher, M.D.1; Constantine A. Stratakis, M.D., D(Med)Sc.2; Sergio D. Rosenzweig, M.D., Ph.D.1*
1Immunology Service, Department of Laboratory Medicine, NIH Clinical Center, NIH, Bethesda, MD, USA, 20892 2Section on Endocrinology and Genetics, Eunice Kennedy Shriver NICHD, NIH, Bethesda, MD, USA, 20892 3Laboratory of Clinical Immunology and Microbiology, NIAID, NIH, Bethesda, MD, USA, 20892 4Laboratory of Molecular Immunology, Immunology Center, NHLBI, NIH, Bethesda, United States
#Contributed equally to this work.
*Corresponding author
Abstract
Background
Pediatric endogenous Cushing syndrome is mainly caused by pituitary corticotropin-producing adenomas and most glucocorticoid-dependent effects progressively regress upon tumor removal. Endogenous Cushing syndrome reproduces long-term high-dose glucocorticoid therapy, representing a clean, natural and unbiased model in which to study glucocorticoid bona-fide effects on immunity.
Objectives
To perform extensive immunologic studies in otherwise healthy pediatric patients with endogenous Cushing syndrome before and 6-13 months after tumor resection, as well as in in-vitro glucocorticoid-treated control cells.
Methods
Flow cytometry, immunoblotting, ELISA, qRT-PCR and RNA-seq techniques were used to characterize patients’ and in-vitro glucocorticoid treated cells.
Results
Reduced thymic output, decreased naïve T cells, diminished proliferation, and increased T-cell apoptosis were detected before surgery, and 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 anti-apoptotic BCL2 expression and rescued T-cell apoptosis in a PI3K pathway- dependent manner. Similar and reproducible findings were confirmed in endogenous Cushing syndrome 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 endogenous Cushing syndrome 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 pro-apoptotic 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.
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