{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,6,30]],"date-time":"2026-06-30T01:43:27Z","timestamp":1782783807628,"version":"3.54.5"},"reference-count":52,"publisher":"Frontiers Media SA","license":[{"start":{"date-parts":[[2025,1,23]],"date-time":"2025-01-23T00:00:00Z","timestamp":1737590400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":["frontiersin.org"],"crossmark-restriction":true},"short-container-title":["Front. Immunol."],"abstract":"<jats:sec><jats:title>Objective<\/jats:title><jats:p>The primary outcome was the evaluation of the T-cell phenotype in autoimmune primary adrenal insufficiency (PAI). Secondary outcomes included the evaluation of the CD4<jats:sup>+<\/jats:sup>CD25<jats:sup>+<\/jats:sup>Foxp3<jats:sup>+<\/jats:sup> Treg population and the gene expression levels of IL-6, IL-17A, cyclooxygenase (COX)-2, heat shock proteins (HSP)-70, indoleamine-2,3-dioxygenase (IDO), programmed death-ligand 1 (PD-L1), inducible nitric oxide synthase (iNOS), and thioredoxin (TXN)-1.<\/jats:p><\/jats:sec><jats:sec><jats:title>Methods<\/jats:title><jats:p>We prospectively included 15 patients with PAI on conventional glucocorticoid (GC) replacement therapy, 15 switched to dual-release hydrocortisone (DR-HC), and 20 healthy controls. Serum inflammatory parameters and peripheral blood mononuclear cells (PBMCs) were evaluated at baseline and after 12 months of treatment.<\/jats:p><\/jats:sec><jats:sec><jats:title>Result<\/jats:title><jats:p>At baseline, significantly higher CD4<jats:sup>+<\/jats:sup> and CD8<jats:sup>+<\/jats:sup> (both <jats:italic>p<\/jats:italic> &amp;lt; 0.001) T-cell percentages, a lower CD4<jats:sup>+<\/jats:sup>\/CD8<jats:sup>+<\/jats:sup> ratio (<jats:italic>p<\/jats:italic> &amp;lt; 0.05), and higher CD25<jats:sup>+<\/jats:sup> and CD4<jats:sup>+<\/jats:sup>\/CD25<jats:sup>+<\/jats:sup> T cells (both <jats:italic>p<\/jats:italic> &amp;lt; 0.001) were observed in PAI compared to controls. After 12 months of DR-HC treatment, we found significantly lower IL-6 (<jats:italic>p<\/jats:italic> = 0.019), IL-17A (<jats:italic>p<\/jats:italic> = 0.046), COX-2 (<jats:italic>p<\/jats:italic> &amp;lt; 0.001), HSP-70 (<jats:italic>p<\/jats:italic> = 0.006), and TXN-1 (<jats:italic>p<\/jats:italic> = 0.008) and higher PD-L1 (<jats:italic>p<\/jats:italic> &amp;lt; 0.001) and IDO (<jats:italic>p<\/jats:italic> &amp;lt; 0.001) mRNA values compared to baseline. After 12 months of DR-HC treatment, a significant increase in CD4<jats:sup>+<\/jats:sup> T cells (<jats:italic>p<\/jats:italic> = 0.012), PD-L1 (<jats:italic>p<\/jats:italic> = 0.003), and IDO (<jats:italic>p<\/jats:italic> &amp;lt; 0.001) and a decrease in CD8<jats:sup>+<\/jats:sup> T cells (<jats:italic>p<\/jats:italic> &amp;lt; 0.001), IL-6 (<jats:italic>p<\/jats:italic> = 0.003), IL-17A (<jats:italic>p<\/jats:italic> = 0.0014), COX-2 (<jats:italic>p<\/jats:italic> &amp;lt; 0.001), HSP-70 (<jats:italic>p<\/jats:italic> = 0.005), and TXN-1 (<jats:italic>p<\/jats:italic> = 0.0008), as well as a significantly higher conversion in the CD4<jats:sup>+<\/jats:sup>\/CD8<jats:sup>+<\/jats:sup> ratio (<jats:italic>p<\/jats:italic> = 0.033), were observed compared to conventional GCs.<\/jats:p><\/jats:sec><jats:sec><jats:title>Conclusions<\/jats:title><jats:p>The switch from conventional GCs to DR-HC treatment altered the T lymphocyte phenotype and CD4<jats:sup>+<\/jats:sup>\/CD8<jats:sup>+<\/jats:sup> ratio in a Treg-independent manner, inducing significant improvements in the immune and inflammatory profile in PAI.<\/jats:p><\/jats:sec>","DOI":"10.3389\/fimmu.2025.1489254","type":"journal-article","created":{"date-parts":[[2025,1,23]],"date-time":"2025-01-23T06:58:30Z","timestamp":1737615510000},"update-policy":"https:\/\/doi.org\/10.3389\/crossmark-policy","source":"Crossref","is-referenced-by-count":3,"title":["Dual-release hydrocortisone treatment improves serum and peripheral blood mononuclear cell inflammatory and immune profiles in patients with autoimmune primary adrenal insufficiency"],"prefix":"10.3389","volume":"16","author":[{"given":"Laura","family":"Tomasello","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Antonina","family":"Coppola","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giuseppe","family":"Pizzolanti","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Carla","family":"Giordano","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Giorgio","family":"Arnaldi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Valentina","family":"Guarnotta","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1965","published-online":{"date-parts":[[2025,1,23]]},"reference":[{"key":"B1","doi-asserted-by":"publisher","DOI":"10.1016\/j.beem.2020.101379","article-title":"Autoimmune Addison\u2019s disease","volume":"34","author":"Saverino","year":"2020","journal-title":"Best Pract Res Clin Endocrinol Metab"},{"key":"B2","doi-asserted-by":"publisher","DOI":"10.3390\/ijms19030730","article-title":"The Balance of Th17 versus Treg Cells in Autoimmunity","volume":"19","author":"Lee","year":"2018","journal-title":"Int J Mol Sci"},{"key":"B3","doi-asserted-by":"publisher","DOI":"10.1038\/s41423-021-00656-1","article-title":"Single-cell analysis reveals the origins and intrahepatic development of liver-resident IFN-\u03b3-producing \u03b3\u03b4 T cells","volume":"18","author":"Hu","year":"2021","journal-title":"Cell Mol Immunol"},{"key":"B4","doi-asserted-by":"publisher","DOI":"10.1084\/jem.20051776","article-title":"Tissue expression of PD-L1 mediates peripheral T cell tolerance","volume":"203","author":"Keir","year":"2006","journal-title":"J Exp Med"},{"key":"B5","doi-asserted-by":"publisher","DOI":"10.1371\/journal.pbio.3001272","article-title":"Programmed cell death 1 ligand (PD-L1) on T cells generates Treg suppression from memory","volume":"19","author":"Kazanova","year":"2021","journal-title":"PLoS Biol"},{"key":"B6","doi-asserted-by":"publisher","DOI":"10.2174\/0929867325666180514112124","article-title":"Cyclooxygenase-2 inhibitors as a therapeutic target in inflammatory diseases","volume":"26","author":"Ferrer","year":"2019","journal-title":"Curr Med Chem"},{"key":"B7","doi-asserted-by":"publisher","DOI":"10.3892\/mmr.2018.8537","article-title":"Indoleamine 2, 3-dioxygenase regulation of immune response (Review)","volume":"17","author":"Wu","year":"2018","journal-title":"Mol Med Rep"},{"key":"B8","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2012.00095","article-title":"The anti-inflammatory mechanisms of Hsp70","volume":"3","author":"Borges","year":"2012","journal-title":"Front Immunol"},{"key":"B9","doi-asserted-by":"publisher","DOI":"10.1038\/s41467-018-04274-w","article-title":"The thioredoxin-1 system is essential for fueling DNA synthesis during T-cell metabolic reprogramming and proliferation","volume":"9","author":"Muri","year":"2018","journal-title":"Nat Commun"},{"key":"B10","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2019.03100","article-title":"Treg heterogeneity, function, and homeostasis","volume":"10","author":"Shevyrev","year":"2020","journal-title":"Front Immunol"},{"key":"B11","doi-asserted-by":"publisher","DOI":"10.1530\/EJE-22-0454","article-title":"Susceptibility and characteristics of infections in patients with glucocorticoid excess or insufficiency: the ICARO tool","volume":"187","author":"Minnetti","year":"2022","journal-title":"Eur J Endocrinol"},{"key":"B12","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-022-04904-w","article-title":"Prediction of diabetes mellitus induced by steroid overtreatment in adrenal insufficiency","volume":"12","author":"Guarnotta","year":"2022","journal-title":"Sci Rep"},{"key":"B13","doi-asserted-by":"publisher","DOI":"10.1093\/ejendo\/lvae107","article-title":"Conventional steroids vs. dual-release hydrocortisone on metabolic, cardiovascular, and bone outcomes in adrenal insufficiency: a 10-year study","volume":"191","author":"Guarnotta","year":"2024","journal-title":"Eur J Endocrinol"},{"key":"B14","doi-asserted-by":"publisher","DOI":"10.1016\/j.coph.2021.07.003","article-title":"Metabolic comorbidities of adrenal insufficiency: Focus on steroid replacement therapy and chronopharmacology","volume":"60","author":"Guarnotta","year":"2021","journal-title":"Curr Opin Pharmacol"},{"key":"B15","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-022-13506-5","article-title":"Long-term outcomes of conventional and novel steroid replacement therapy on bone health in primary adrenal insufficiency","volume":"12","author":"Guarnotta","year":"2022","journal-title":"Sci Rep"},{"key":"B16","doi-asserted-by":"crossref","first-page":"2042018819871169","DOI":"10.1177\/2042018819871169","article-title":"Dual-release hydrocortisone improves hepatic steatosis in patients with secondary adrenal insufficiency: a real-life study","volume":"10","author":"Guarnotta","year":"2019","journal-title":"Ther Adv Endocrinol Metab"},{"key":"B17","doi-asserted-by":"publisher","DOI":"10.1530\/EC-19-0176","article-title":"Dual-release hydrocortisone vs conventional glucocorticoids in adrenal insufficiency","volume":"8","author":"Guarnotta","year":"2019","journal-title":"Endocr Connect"},{"key":"B18","doi-asserted-by":"publisher","DOI":"10.1007\/s12020-015-0681-z","article-title":"Improvement of anthropometric and metabolic parameters, and quality of life following treatment with dual-release hydrocortisone in patients with Addison\u2019s disease","volume":"51","author":"Giordano","year":"2016","journal-title":"Endocrine"},{"key":"B19","doi-asserted-by":"publisher","DOI":"10.1007\/s12020-017-1512-1","article-title":"Bone safety of dual-release hydrocortisone in patients with hypopituitarism","volume":"60","author":"Frara","year":"2018","journal-title":"Endocrine"},{"key":"B20","doi-asserted-by":"publisher","DOI":"10.1016\/S2213-8587(17)30398-4","article-title":"Effect of once-daily, modified-release hydrocortisone versus standard glucocorticoid therapy on metabolism and innate immunity in patients with adrenal insufficiency (DREAM): a single-blind, randomised controlled trial","volume":"6","author":"Isidori","year":"2018","journal-title":"Lancet Diabetes Endocrinol"},{"key":"B21","doi-asserted-by":"publisher","DOI":"10.1210\/jendso\/bvad151","article-title":"Effects of dual-release hydrocortisone on bone metabolism in primary and secondary adrenal insufficiency: A 6-year study","volume":"8","author":"Hasenmajer","year":"2023","journal-title":"J Endocr Soc"},{"key":"B22","doi-asserted-by":"publisher","DOI":"10.1530\/EC-17-0368","article-title":"Dual-release hydrocortisone treatment: glycometabolic profile and health-related quality of life","volume":"7","author":"Mongio\u00ec","year":"2018","journal-title":"Endocr Connect"},{"key":"B23","doi-asserted-by":"publisher","DOI":"10.1007\/s40618-019-01146-y","article-title":"Towards the tailoring of glucocorticoid replacement in adrenal insufficiency: the Italian Society of Endocrinology Expert Opinion","volume":"43","author":"Isidori","year":"2020","journal-title":"J Endocrinol Invest"},{"key":"B24","doi-asserted-by":"publisher","DOI":"10.1515\/jpem-2020-0158","article-title":"Clinical relevance of T lymphocyte subsets in pediatric Graves\u2019 disease","volume":"33","author":"Chen","year":"2020","journal-title":"J Pediatr Endocrinol Metab"},{"key":"B25","doi-asserted-by":"publisher","DOI":"10.1007\/s12519-013-0398-0","article-title":"The differences in T and B cell subsets in thyroid of children with Graves\u2019 disease and Hashimoto\u2019s thyroiditis","volume":"9","author":"Ben-Skowronek","year":"2013","journal-title":"World J Pediatr"},{"key":"B26","doi-asserted-by":"crossref","first-page":"9","DOI":"10.3390\/jcm9010009","article-title":"Anti-inflammatory action of heterogeneous nuclear ribonucleoprotein A2\/B1 in patients with autoimmune endocrine disorders","volume":"9","author":"Coppola","year":"2019","journal-title":"J Clin Med"},{"key":"B27","doi-asserted-by":"publisher","DOI":"10.1210\/jc.2015-1710","article-title":"Diagnosis and treatment of primary adrenal insufficiency: an endocrine society clinical practice guideline","volume":"101","author":"Bornstein","year":"2016","journal-title":"J Clin Endocrinol Metab"},{"key":"B28","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMra1713301","article-title":"Autoimmune polyendocrine syndromes","volume":"378","author":"Husebye","year":"2018","journal-title":"N Engl J Med"},{"key":"B29","doi-asserted-by":"publisher","DOI":"10.1007\/s40618-022-01889-1","article-title":"Renin and electrolytes indicate the mineralocorticoid activity of fludrocortisone: a 6 year study in primary adrenal insufficiency","volume":"46","author":"Ceccato","year":"2023","journal-title":"J Endocrinol Invest"},{"key":"B30","doi-asserted-by":"publisher","DOI":"10.3275\/7965","article-title":"Autoimmune polyendocrinopathy-candidiasis-ectodermal-dystrophy (APECED) in Sicily: confirmation that R203X is the peculiar AIRE gene mutation","volume":"35","author":"Giordano","year":"2012","journal-title":"J Endocrinol Invest"},{"key":"B31","doi-asserted-by":"publisher","DOI":"10.1006\/meth.2001.1262","article-title":"Analysis of relative gene expression data using real-time quantitative PCR and the 2\u2013\u0394\u0394CT method","volume":"25","author":"Livak","year":"2001","journal-title":"Methods"},{"key":"B32","doi-asserted-by":"publisher","DOI":"10.3389\/fimmu.2023.1275828","article-title":"Major immunophenotypic abnormalities in patients with primary adrenal insufficiency of different etiology","volume":"14","author":"Nowotny","year":"2023","journal-title":"Front Immunol"},{"key":"B33","doi-asserted-by":"crossref","first-page":"1142","DOI":"10.3390\/ijms20051142","article-title":"Context-dependent effect of glucocorticoids on the proliferation, differentiation, and apoptosis of regulatory T cells: A review of the empirical evidence and clinical applications","volume":"20","author":"Cari","year":"2019","journal-title":"Int J Mol Sci"},{"key":"B34","doi-asserted-by":"publisher","DOI":"10.1016\/j.jim.2004.07.006","article-title":"Comparative analysis of lymphocyte activation marker expression and cytokine secretion profile in stimulated human peripheral blood mononuclear cell cultures: an in vitro model to monitor cellular immune function","volume":"293","author":"Reddy","year":"2004","journal-title":"J Immunol Methods"},{"key":"B35","doi-asserted-by":"publisher","DOI":"10.1038\/s41598-018-25384-x","article-title":"Pathological conversion of regulatory T cells is associated with loss of allotolerance","volume":"8","author":"Hua","year":"2018","journal-title":"Sci Rep"},{"key":"B36","doi-asserted-by":"publisher","DOI":"10.1038\/s41590-021-01001-4","article-title":"Regulatory T cells function in established systemic inflammation and reverse fatal autoimmunity","volume":"22","author":"Hu","year":"2021","journal-title":"Nat Immunol"},{"key":"B37","doi-asserted-by":"publisher","first-page":"47","DOI":"10.1093\/cei\/uxad087","article-title":"Regulatory T cells in autoimmune primary adrenal insufficiency","volume":"215","author":"Sj\u00f8gren","year":"2024","journal-title":"Clin Exp Immunol"},{"key":"B38","doi-asserted-by":"publisher","DOI":"10.1530\/EJE-16-0969","article-title":"Primary adrenal insufficiency is associated with impaired natural killer cell function: a potential link to increased mortality","volume":"176","author":"Bancos","year":"2017","journal-title":"Eur J Endocrinol"},{"key":"B39","doi-asserted-by":"publisher","first-page":"2998","DOI":"10.1210\/jc.2018-00346","article-title":"Circadian rhythm of glucocorticoid administration entrains clock genes in immune cells: A DREAM trial ancillary study","volume":"103","author":"Venneri","year":"2018","journal-title":"J Clin Endocrinol Metab"},{"key":"B40","doi-asserted-by":"publisher","DOI":"10.3390\/ijms23158599","article-title":"Beyond cancer: regulation and function of PD-L1 in health and immune-related diseases","volume":"23","author":"Beenen","year":"2022","journal-title":"Int J Mol Sci"},{"key":"B41","doi-asserted-by":"publisher","DOI":"10.1053\/j.seminoncol.2023.11.003","article-title":"Primary adrenal insufficiency induced by immune checkpoint inhibitors: biological, clinical, and radiological aspects","volume":"50","author":"Martella","year":"2023","journal-title":"Semin Oncol"},{"key":"B42","doi-asserted-by":"publisher","DOI":"10.1016\/j.prostaglandins.2023.106738","article-title":"Microsomal prostaglandin E synthase-1 inhibition promotes shunting in arachidonic acid metabolism during inflammatory responses in vitro","volume":"167","author":"Liu","year":"2023","journal-title":"Prostaglandins Other Lipid Mediat"},{"key":"B43","doi-asserted-by":"publisher","DOI":"10.3390\/ph17050647","article-title":"Daidzein and Equol: Ex Vivo and In Silico Approaches Targeting COX-2, iNOS, and the Canonical Inflammasome Signaling Pathway","volume":"17","author":"M\u00e1rquez-Flores","year":"2024","journal-title":"Pharm (Basel)"},{"key":"B44","doi-asserted-by":"publisher","DOI":"10.1080\/07435800.2019.1600535","article-title":"Effect of IL-21 on the balance of th17 cells\/treg cells in the pathogenesis of graves\u2019 Disease","volume":"44","author":"Tan","year":"2019","journal-title":"Endocr Res"},{"key":"B45","doi-asserted-by":"publisher","DOI":"10.1007\/s00011-023-01777-1","article-title":"Associations between anthropometric parameters and immune-phenotypical characteristics of circulating Tregs and serum cytokines","volume":"72","author":"Schmitz","year":"2023","journal-title":"Inflammation Res"},{"key":"B46","doi-asserted-by":"publisher","DOI":"10.1016\/j.nut.2013.11.023","article-title":"Modulation of adipose tissue inflammation by FOXP3+ Treg cells, IL-10, and TGF-\u03b2 in metabolically healthy class III obese individuals","volume":"30","author":"Pereira","year":"2014","journal-title":"Nutrition"},{"key":"B47","doi-asserted-by":"publisher","DOI":"10.1038\/ijo.2014.195","article-title":"The impact of adiposity on adipose tissue-resident lymphocyte activation in humans","volume":"39","author":"Travers","year":"2015","journal-title":"Int J Obes (Lond)"},{"key":"B48","doi-asserted-by":"crossref","first-page":"5","DOI":"10.1172\/JCI88876","article-title":"Role of innate and adaptive immunity in obesity-associated metabolic disease","volume":"127","author":"Mclaughlin","year":"2017","journal-title":"J Clin Invest"},{"key":"B49","doi-asserted-by":"publisher","DOI":"10.1074\/jbc.M111.218610","article-title":"Lowering glycosphingolipid levels in CD4+ T cells attenuates T cell receptor signaling, cytokine production, and differentiation to the Th17 lineage","volume":"286","author":"Zhu","year":"2011","journal-title":"J Biol Chem"},{"key":"B50","doi-asserted-by":"publisher","DOI":"10.1126\/sciadv.adk1045","article-title":"Sphingolipid biosynthesis is essential for metabolic rewiring during TH17 cell differentiation","volume":"10","author":"Abimannan","year":"2024","journal-title":"Sci Adv"},{"key":"B51","doi-asserted-by":"publisher","DOI":"10.1016\/j.steroids.2010.01.020","article-title":"The interplay between bioactive sphingolipids and steroid hormones","volume":"75","author":"Lucki","year":"2010","journal-title":"Steroids"},{"key":"B52","doi-asserted-by":"publisher","DOI":"10.3389\/fendo.2023.1238573","article-title":"Interpetrosal sphingosine-1-phosphate ratio predicting Cushing\u2019s disease tumor laterality and remission after surgery","volume":"14","author":"Sun","year":"2023","journal-title":"Front Endocrinol (Lausanne)"}],"container-title":["Frontiers in Immunology"],"original-title":[],"link":[{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1489254\/full","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2025,1,23]],"date-time":"2025-01-23T06:58:34Z","timestamp":1737615514000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.frontiersin.org\/articles\/10.3389\/fimmu.2025.1489254\/full"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2025,1,23]]},"references-count":52,"alternative-id":["10.3389\/fimmu.2025.1489254"],"URL":"https:\/\/doi.org\/10.3389\/fimmu.2025.1489254","relation":{},"ISSN":["1664-3224"],"issn-type":[{"value":"1664-3224","type":"electronic"}],"subject":[],"published":{"date-parts":[[2025,1,23]]},"article-number":"1489254"}}