Emilie W Borgström1,2, Marie Edvinsson3, Lucía P Pérez4, Anna C Norlin5,6, Sara L Enoksson6, Susanne Hansen5, Anders Fasth7, Vanda Friman8, Olle Kämpe9, Robert Månsson4, Hernando Y Estupiñán4,10, Qing Wang4, Tan Ziyang11, Tadepally Lakshmikanth11, Carl Inge E Smith5,12, Petter Brodin11,13, Peter Bergman14,5. 1. Department of Laboratory Medicine, Clinical Microbiology, Stockholm, Sweden. emilie.wahren-borgstrom@regionstockholm.se. 2. Department of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden. emilie.wahren-borgstrom@regionstockholm.se. 3. Department of Medical Sciences, Section of Infectious Diseases, Uppsala University Hospital, Uppsala, Sweden. 4. Department of Laboratory Medicine, Biomolecular and Cellular Medicine, Karolinska Institutet, Stockholm, Sweden. 5. Department of Infectious Diseases, Karolinska University Hospital, Stockholm, Sweden. 6. Department of Clinical Immunology and Transfusion Medicine, Karolinska University Hospital, Stockholm, Sweden. 7. Department of Pediatrics, Institute of Clinical Sciences, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. 8. Department of Infectious Diseases, Institute of Biomedicine, Sahlgrenska Academy, University of Gothenburg, Gothenburg, Sweden. 9. Experimental Endocrinology, Department of Medicine, Karolinska Institutet, Solna, Stockholm, Sweden. 10. Departamento de Ciencias Básicas, Universidad Industrial de Santander, 680002, Bucaramanga, Colombia. 11. Science for Life Laboratory, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden. 12. Department of Laboratory Medicine, Translational Research Center Karolinska (TRACK), Stockholm, Sweden. 13. Department of Immunology and Inflammation, Imperial College London, London, UK. 14. Department of Laboratory Medicine, Clinical Microbiology, Stockholm, Sweden.
Abstract
PURPOSE: The aim of this study was to characterize clinical effects and biomarkers in three patients with chronic mucocutaneous candidiasis (CMC) caused by gain-of-function (GOF) mutations in the STAT1 gene during treatment with Janus kinase (JAK) inhibitors. METHODS: Mass cytometry (CyTOF) was used to characterize mononuclear leukocyte populations and Olink assay to quantify 265 plasma proteins. Flow-cytometric Assay for Specific Cell-mediated Immune-response in Activated whole blood (FASCIA) was used to quantify the reactivity against Candida albicans. RESULTS: Overall, JAK inhibitors improved clinical symptoms of CMC, but caused side effects in two patients. Absolute numbers of neutrophils, T cells, B cells, and NK cells were sustained during baricitinib treatment. Detailed analysis of cellular subsets, using CyTOF, revealed increased expression of CD45, CD52, and CD99 in NK cells, reflecting a more functional phenotype. Conversely, monocytes and eosinophils downregulated CD16, consistent with reduced inflammation. Moreover, T and B cells showed increased expression of activation markers during treatment. In one patient with a remarkable clinical effect of baricitinib treatment, the immune response to C. albicans increased after 7 weeks of treatment. Alterations in plasma biomarkers involved downregulation of cellular markers CXCL10, annexin A1, granzyme B, granzyme H, and oncostatin M, whereas FGF21 was the only upregulated marker after 7 weeks. After 3 months, IFN-ɣ and CXCL10 were downregulated. CONCLUSIONS: The clinical effect of JAK inhibitor treatment of CMC is promising. Several biological variables were altered during baricitinib treatment demonstrating that lymphocytes, NK cells, monocytes, and eosinophils were affected. In parallel, cellular reactivity against C. albicans was enhanced.
PURPOSE: The aim of this study was to characterize clinical effects and biomarkers in three patients with chronic mucocutaneous candidiasis (CMC) caused by gain-of-function (GOF) mutations in the STAT1 gene during treatment with Janus kinase (JAK) inhibitors. METHODS: Mass cytometry (CyTOF) was used to characterize mononuclear leukocyte populations and Olink assay to quantify 265 plasma proteins. Flow-cytometric Assay for Specific Cell-mediated Immune-response in Activated whole blood (FASCIA) was used to quantify the reactivity against Candida albicans. RESULTS: Overall, JAK inhibitors improved clinical symptoms of CMC, but caused side effects in two patients. Absolute numbers of neutrophils, T cells, B cells, and NK cells were sustained during baricitinib treatment. Detailed analysis of cellular subsets, using CyTOF, revealed increased expression of CD45, CD52, and CD99 in NK cells, reflecting a more functional phenotype. Conversely, monocytes and eosinophils downregulated CD16, consistent with reduced inflammation. Moreover, T and B cells showed increased expression of activation markers during treatment. In one patient with a remarkable clinical effect of baricitinib treatment, the immune response to C. albicans increased after 7 weeks of treatment. Alterations in plasma biomarkers involved downregulation of cellular markers CXCL10, annexin A1, granzyme B, granzyme H, and oncostatin M, whereas FGF21 was the only upregulated marker after 7 weeks. After 3 months, IFN-ɣ and CXCL10 were downregulated. CONCLUSIONS: The clinical effect of JAK inhibitor treatment of CMC is promising. Several biological variables were altered during baricitinib treatment demonstrating that lymphocytes, NK cells, monocytes, and eosinophils were affected. In parallel, cellular reactivity against C. albicans was enhanced.
Authors: Eva V Acosta-Rodriguez; Giorgio Napolitani; Antonio Lanzavecchia; Federica Sallusto Journal: Nat Immunol Date: 2007-08-05 Impact factor: 25.606
Authors: Mete Dadak; Roland Jacobs; Jelena Skuljec; Adan Chari Jirmo; Özlem Yildiz; Frank Donnerstag; Niklas Thomas Baerlecken; Reinhold Ernst Schmidt; Heinrich Lanfermann; Thomas Skripuletz; Philipp Schwenkenbecher; Christoph Kleinschnitz; Hayrettin Tumani; Martin Stangel; Refik Pul Journal: Clin Immunol Date: 2017-02-02 Impact factor: 3.969