Three Adult Cases of STAT1 Gain-of-Function with Chronic Mucocutaneous Candidiasis Treated with JAK Inhibitors.
JAK inhibitor
Olink
STAT1
chronic mucocutaneous candidiasis
mass cytometry
Journal
Journal of clinical immunology
ISSN: 1573-2592
Titre abrégé: J Clin Immunol
Pays: Netherlands
ID NLM: 8102137
Informations de publication
Date de publication:
01 2023
01 2023
Historique:
received:
03
03
2022
accepted:
08
08
2022
pubmed:
2
9
2022
medline:
18
1
2023
entrez:
1
9
2022
Statut:
ppublish
Résumé
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. 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. 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. 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.
Identifiants
pubmed: 36050429
doi: 10.1007/s10875-022-01351-0
pii: 10.1007/s10875-022-01351-0
pmc: PMC9840596
doi:
Substances chimiques
baricitinib
ISP4442I3Y
Janus Kinase Inhibitors
0
Biomarkers
0
STAT1 Transcription Factor
0
STAT1 protein, human
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
136-150Informations de copyright
© 2022. The Author(s).
Références
Dadak M, Jacobs R, Skuljec J, Jirmo AC, Yildiz Ö, Donnerstag F, et al. Gain-of-function STAT1 mutations are associated with intracranial aneurysms. Clin Immunol. 2017;178:79–85.
doi: 10.1016/j.clim.2017.01.012
Liu L, Okada S, Kong XF, Kreins AY, Cypowyj S, Abhyankar A, et al. Gain-of-function human STAT1 mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis. J Exp Med. 2011;208(8):1635–48.
doi: 10.1084/jem.20110958
Okada S, Asano T, Moriya K, Boisson-Dupuis S, Kobayashi M, Casanova JL, et al. Human STAT1 gain-of-function heterozygous mutations: chronic mucocutaneous candidiasis and type I interferonopathy. J Clin Immunol. 2020;40(8):1065–81.
doi: 10.1007/s10875-020-00847-x
Olbrich P, Freeman AF. STAT1 and STAT3 mutations: important lessons for clinical immunologists. Expert Rev Clin Immunol. 2018;14(12):1029–41.
doi: 10.1080/1744666X.2018.1531704
Casanova JL, Holland SM, Notarangelo LD. Inborn errors of human JAKs and STATs. Immunity. 2012;36(4):515–28.
doi: 10.1016/j.immuni.2012.03.016
Levy DE, Darnell JE. STATs: transcriptional control and biological impact. Nat Rev Mol Cell Biol. 2002;3(9):651–62.
doi: 10.1038/nrm909
Hiller J, Hagl B, Effner R, Puel A, Schaller M, Mascher B, et al. STAT1 gain-of-function and dominant negative STAT3 mutations impair IL-17 and IL-22 immunity associated with CMC. J Invest Dermatol. 2018;138(3):711–4.
doi: 10.1016/j.jid.2017.09.035
Giovannozzi S, Demeulemeester J, Schrijvers R, Gijsbers R. Transcriptional profiling of STAT1 gain-of-function reveals common and mutation-specific fingerprints. Front Immunol. 2021;12:632997.
doi: 10.3389/fimmu.2021.632997
Pilar Blanco Lobo 1 PG-H, Isabel Villaoslada 1, Beatriz de Felipe 1, Carmen Carreras 2, Hector Rodriguez 2, Begoña Carazo-Gallego 3, Ana Méndez-Echevarria 4, José Manuel Lucena 5, Pilar Ortiz Aljaro 5, María José Castro 6, José Francisco Noguera-Uclés 7, Joshua D Milner 8, Katelyn McCann 9, Ofer Zimmerman 10, Alexandra F Freeman 9, Michail S Lionakis 11, Steven M Holland 9, Olaf Neth 12, Peter Olbrich. Ex vivo effect of JAK inhibition on JAK-STAT1 pathway hyperactivation in patients with dominant-negative STAT3 mutations. J Clin Immunol. 2022. https://doi.org/10.1007/s10875-022-01273-x .
Acosta-Rodriguez EV, Napolitani G, Lanzavecchia A, Sallusto F. Interleukins 1beta and 6 but not transforming growth factor-beta are essential for the differentiation of interleukin 17-producing human T helper cells. Nat Immunol. 2007;8(9):942–9.
doi: 10.1038/ni1496
Korn T, Bettelli E, Gao W, Awasthi A, Jäger A, Strom TB, et al. IL-21 initiates an alternative pathway to induce proinflammatory T(H)17 cells. Nature. 2007;448(7152):484–7.
doi: 10.1038/nature05970
Volpe E, Servant N, Zollinger R, Bogiatzi SI, Hupé P, Barillot E, et al. A critical function for transforming growth factor-beta, interleukin 23 and proinflammatory cytokines in driving and modulating human T(H)-17 responses. Nat Immunol. 2008;9(6):650–7.
doi: 10.1038/ni.1613
Hirahara K, Ghoreschi K, Laurence A, Yang XP, Kanno Y, O’Shea JJ. Signal transduction pathways and transcriptional regulation in Th17 cell differentiation. Cytokine Growth Factor Rev. 2010;21(6):425–34.
doi: 10.1016/j.cytogfr.2010.10.006
Richardson JP, Moyes DL. Adaptive immune responses to Candida albicans infection. Virulence. 2015;6(4):327–37.
doi: 10.1080/21505594.2015.1004977
Iwasawa MT, Miyachi H, Wakabayashi S, Sugihira T, Aoyama R, Nakagawa S, et al. Epidermal clearance of Candida albicans is mediated by IL-17 but independent of fungal innate immune receptors. Int Immunol. 2022;34(8):409–20.
Aggor FEY, Break TJ, Trevejo-Nuñez G, Whibley N, Coleman BM, Bailey RD, et al. Oral epithelial IL-22/STAT3 signaling licenses IL-17-mediated immunity to oral mucosal candidiasis. Sci Immunol. 2020;5(48):eaba0570. https://doi.org/10.1126/sciimmunol.aba0570 .
Zhang W, Chen X, Gao G, Xing S, Zhou L, Tang X, et al. Clinical relevance of gain- and loss-of-function germline mutations in STAT1: a systematic review. Front Immunol. 2021;12:654406.
doi: 10.3389/fimmu.2021.654406
Davidson L, Netea MG, Kullberg BJ. Patient susceptibility to candidiasis—a potential for adjunctive immunotherapy. J Fungi (Basel). 2018;4(1):9. https://doi.org/10.3390/jof4010009 .
doi: 10.3390/jof4010009
Acker KP, Borlack R, Iuga A, Remotti HE, Soderquist CR, Okada S, et al. Ruxolitinib response in an infant with very-early-onset inflammatory bowel disease and gain-of-function STAT1 mutation. J Pediatr Gastroenterol Nutr. 2020;71(4):e132–3.
doi: 10.1097/MPG.0000000000002854
Al Shehri T, Gilmour K, Gothe F, Loughlin S, Bibi S, Rowan AD, et al. Novel gain-of-function mutation in Stat1 sumoylation site leads to CMC/CID phenotype responsive to ruxolitinib. J Clin Immunol. 2019;39(8):776–85.
doi: 10.1007/s10875-019-00687-4
Baris S, Alroqi F, Kiykim A, Karakoc-Aydiner E, Ogulur I, Ozen A, et al. Severe early-onset combined immunodeficiency due to heterozygous gain-of-function mutations in STAT1. J Clin Immunol. 2016;36(7):641–8.
doi: 10.1007/s10875-016-0312-3
Bloomfield M, Kanderova V, Parackova Z, Vrabcova P, Svaton M, Fronkova E, et al. utility of ruxolitinib in a child with chronic mucocutaneous candidiasis caused by a novel STAT1 gain-of-function mutation. J Clin Immunol. 2018;38(5):589–601.
doi: 10.1007/s10875-018-0519-6
Chaimowitz NS, Ebenezer SJ, Hanson IC, Anderson M, Forbes LR. STAT1 gain of function, type 1 diabetes, and reversal with JAK inhibition. N Engl J Med. 2020;383(15):1494–6.
doi: 10.1056/NEJMc2022226
Deyà-Martínez A, Rivière JG, Roxo-Junior P, Ramakers J, Bloomfield M, Guisado Hernandez P, et al. Impact of JAK inhibitors in pediatric patients with STAT1 gain of function (GOF) mutations-10 children and review of the literature. J Clin Immunol. 2022;42(5):1071–82. https://doi.org/10.1007/s10875-022-01257-x .
doi: 10.1007/s10875-022-01257-x
Forbes LR, Vogel TP, Cooper MA, Castro-Wagner J, Schussler E, Weinacht KG, et al. Jakinibs for the treatment of immune dysregulation in patients with gain-of-function signal transducer and activator of transcription 1 (STAT1) or STAT3 mutations. J Allergy Clin Immunol. 2018;142(5):1665–9.
doi: 10.1016/j.jaci.2018.07.020
Higgins E, Al Shehri T, McAleer MA, Conlon N, Feighery C, Lilic D, et al. Use of ruxolitinib to successfully treat chronic mucocutaneous candidiasis caused by gain-of-function signal transducer and activator of transcription 1 (STAT1) mutation. J Allergy Clin Immunol. 2015;135(2):551–3.
doi: 10.1016/j.jaci.2014.12.1867
Kayaoglu B, Kasap N, Yilmaz NS, Charbonnier LM, Geckin B, Akcay A, et al. Stepwise reversal of immune dysregulation due to STAT1 gain-of-function mutation following ruxolitinib bridge therapy and transplantation. J Clin Immunol. 2021;41(4):769–79.
doi: 10.1007/s10875-020-00943-y
Moriya K, Suzuki T, Uchida N, Nakano T, Katayama S, Irie M, et al. Ruxolitinib treatment of a patient with steroid-dependent severe autoimmunity due to STAT1 gain-of-function mutation. Int J Hematol. 2020;112(2):258–62.
doi: 10.1007/s12185-020-02860-7
Mossner R, Diering N, Bader O, Forkel S, Overbeck T, Gross U, et al. Ruxolitinib induces interleukin 17 and ameliorates chronic mucocutaneous candidiasis caused by STAT1 gain-of-function mutation. Clin Infect Dis. 2016;62(7):951–3.
doi: 10.1093/cid/ciw020
Weinacht KG, Charbonnier LM, Alroqi F, Plant A, Qiao Q, Wu H, et al. Ruxolitinib reverses dysregulated T helper cell responses and controls autoimmunity caused by a novel signal transducer and activator of transcription 1 (STAT1) gain-of-function mutation. J Allergy Clin Immunol. 2017;139(5):1629-40.e2.
doi: 10.1016/j.jaci.2016.11.022
Zimmerman O, Rosler B, Zerbe CS, Rosen LB, Hsu AP, Uzel G, et al. Risks of ruxolitinib in STAT1 gain-of-function-associated severe fungal disease. Open forum Infect Dis. 2017;4(4):ofx202.
Tremblay D, Mascarenhas J. Novel therapies in polycythemia vera. Curr Hematol Malig Rep. 2020;15(2):133–40.
doi: 10.1007/s11899-020-00564-7
Plosker GL. Ruxolitinib: a review of its use in patients with myelofibrosis. Drugs. 2015;75(3):297–308.
doi: 10.1007/s40265-015-0351-8
Wang F, Qiu T, Wang H, Yang Q. State-of-the-Art review on myelofibrosis therapies. Clin Lymphoma, Myeloma Leuk. 2022;22(5):e350–62.
doi: 10.1016/j.clml.2021.11.007
Verstovsek S, Mesa RA, Gotlib J, Gupta V, DiPersio JF, Catalano JV, et al. Long-term treatment with ruxolitinib for patients with myelofibrosis: 5-year update from the randomized, double-blind, placebo-controlled, phase 3 COMFORT-I trial. J Hematol Oncol. 2017;10(1):55.
doi: 10.1186/s13045-017-0417-z
Taylor PC, Keystone EC, van der Heijde D, Weinblatt ME, Del Carmen ML, Reyes Gonzaga J, et al. Baricitinib versus placebo or adalimumab in rheumatoid arthritis. N Engl J Med. 2017;376(7):652–62.
doi: 10.1056/NEJMoa1608345
Le M, Berman-Rosa M, Ghazawi FM, Bourcier M, Fiorillo L, Gooderham M, et al. Systematic review on the efficacy and safety of oral janus kinase inhibitors for the treatment of atopic dermatitis. Front Med. 2021;8:682547.
doi: 10.3389/fmed.2021.682547
A TV, Haikarainen T, Raivola J, Silvennoinen O. Selective JAKinibs: Prospects in inflammatory and autoimmune diseases. BioDrugs: Clin Immunotherapeutics, Biopharmaceuticals Gene Ther. 2019;33(1):15–32.
Choy EHS, Miceli-Richard C, González-Gay MA, Sinigaglia L, Schlichting DE, Meszaros G, et al. The effect of JAK1/JAK2 inhibition in rheumatoid arthritis: efficacy and safety of baricitinib. Clin Exp Rheumatol. 2019;37(4):694–704.
Meesilpavikkai K, Dik WA, Schrijver B, Nagtzaam NMA, Posthumus-van Sluijs SJ, van Hagen PM, et al. Baricitinib treatment in a patient with a gain-of-function mutation in signal transducer and activator of transcription 1 (STAT1). J Allergy Clin Immunol. 2018;142(1):328-30.e2.
doi: 10.1016/j.jaci.2018.02.045
Leiding JW, Okada S, Hagin D, Abinun M, Shcherbina A, Balashov DN, et al. Hematopoietic stem cell transplantation in patients with gain-of-function signal transducer and activator of transcription 1 mutations. J Allergy Clin Immunol. 2018;141(2):704-17.e5.
doi: 10.1016/j.jaci.2017.03.049
Rao A, Kamani N, Filipovich A, Lee SM, Davies SM, Dalal J, et al. Successful bone marrow transplantation for IPEX syndrome after reduced-intensity conditioning. Blood. 2007;109(1):383–5.
doi: 10.1182/blood-2006-05-025072
Lind Enoksson S, Bergman P, Klingström J, Boström F, Da Silva RR, Winerdal ME, et al. A flow cytometry-based proliferation assay for clinical evaluation of T-cell memory against SARS-CoV-2. J Immunol Methods. 2021;499:113159.
doi: 10.1016/j.jim.2021.113159
Bandura DR, Baranov VI, Ornatsky OI, Antonov A, Kinach R, Lou X, et al. Mass cytometry: technique for real time single cell multitarget immunoassay based on inductively coupled plasma time-of-flight mass spectrometry. Anal Chem. 2009;81(16):6813–22.
doi: 10.1021/ac901049w
Bendall SC, Simonds EF, Qiu P, el Amir AD, Krutzik PO, Finck R, et al. Single-cell mass cytometry of differential immune and drug responses across a human hematopoietic continuum. Science. 2011;332(6030):687–96.
doi: 10.1126/science.1198704
Ornatsky O, Bandura D, Baranov V, Nitz M, Winnik MA, Tanner S. Highly multiparametric analysis by mass cytometry. J Immunol Methods. 2010;361(1–2):1–20.
doi: 10.1016/j.jim.2010.07.002
Traag VA, Waltman L, van Eck NJ. From Louvain to Leiden: guaranteeing well-connected communities. Sci Rep. 2019;9(1):5233.
doi: 10.1038/s41598-019-41695-z
Wolf FA, Hamey FK, Plass M, Solana J, Dahlin JS, Gottgens B, et al. PAGA: graph abstraction reconciles clustering with trajectory inference through a topology preserving map of single cells. Genome Biol. 2019;20(1):59.
doi: 10.1186/s13059-019-1663-x
Jacomy M, Venturini T, Heymann S, Bastian M. ForceAtlas2, a continuous graph layout algorithm for handy network visualization designed for the Gephi software. PLoS One. 2014;9(6):e98679.
doi: 10.1371/journal.pone.0098679
Assarsson E, Lundberg M, Holmquist G, Björkesten J, Thorsen SB, Ekman D, et al. Homogenous 96-plex PEA immunoassay exhibiting high sensitivity, specificity, and excellent scalability. PLoS One. 2014;9(4):e95192.
doi: 10.1371/journal.pone.0095192
Mulder TA, Peña-Pérez L, Berglöf A, Meinke S, Estupiñán HY, Heimersson K, et al. Ibrutinib has time-dependent on- and off-target effects on plasma biomarkers and immune cells in chronic lymphocytic leukemia. HemaSphere. 2021;5(5):e564.
doi: 10.1097/HS9.0000000000000564
Olink. Proximity Extension Assay (PEA) Technology, 2022.Contact: info@olink.com, phone number +46 (0)18 - 444 39 70. Address: Dag Hammarskjölds väg 52B SE-752 37 Uppsala, Sweden. https://www.olink.com/our-platform/our-pea-technology/
van de Veerdonk FL, Plantinga TS, Hoischen A, Smeekens SP, Joosten LA, Gilissen C, et al. STAT1 mutations in autosomal dominant chronic mucocutaneous candidiasis. N Engl J Med. 2011;365(1):54–61.
doi: 10.1056/NEJMoa1100102
Sharfe N, Nahum A, Newell A, Dadi H, Ngan B, Pereira SL, et al. Fatal combined immunodeficiency associated with heterozygous mutation in STAT1. J Allergy Clin Immunol. 2014;133(3):807–17.
doi: 10.1016/j.jaci.2013.09.032
Kiykim A, Charbonnier LM, Akcay A, Karakoc-Aydiner E, Ozen A, Ozturk G, et al. hematopoietic stem cell transplantation in patients with heterozygous STAT1 gain-of-function mutation. J Clin Immunol. 2019;39(1):37–44.
doi: 10.1007/s10875-018-0575-y
Zheng J, van de Veerdonk FL, Crossland KL, Smeekens SP, Chan CM, Al Shehri T, et al. Gain-of-function STAT1 mutations impair STAT3 activity in patients with chronic mucocutaneous candidiasis (CMC). Eur J Immunol. 2015;45(10):2834–46.
doi: 10.1002/eji.201445344
Laopajon W, Pata S, Takheaw N, Surinkaew S, Khummuang S, Kasinrerk W. Triggering of CD99 on monocytes by a specific monoclonal antibody regulates T cell activation. Cell Immunol. 2019;335:51–8.
doi: 10.1016/j.cellimm.2018.10.012
Rheinländer A, Schraven B, Bommhardt U. CD45 in human physiology and clinical medicine. Immunol Lett. 2018;196:22–32.
doi: 10.1016/j.imlet.2018.01.009
Takheaw N, Earwong P, Laopajon W, Pata S, Kasinrerk W. Interaction of CD99 and its ligand upregulates IL-6 and TNF-α upon T cell activation. PLoS One. 2019;14(5):e0217393.
doi: 10.1371/journal.pone.0217393
Takheaw N, Pata S, Laopajon W, Roytrakul S, Kasinrerk W. The presence of membrane bound CD99 ligands on leukocyte surface. BMC Res Notes. 2020;13(1):496.
doi: 10.1186/s13104-020-05347-0
Zhao Y, Su H, Shen X, Du J, Zhang X, Zhao Y. The immunological function of CD52 and its targeting in organ transplantation. Inflamm Res. 2017;66(7):571–8.
doi: 10.1007/s00011-017-1032-8
Vargas-Hernández A, Mace EM, Zimmerman O, Zerbe CS, Freeman AF, Rosenzweig S, et al. Ruxolitinib partially reverses functional natural killer cell deficiency in patients with signal transducer and activator of transcription 1 (STAT1) gain-of-function mutations. J Allergy Clin Immunol. 2018;141(6):2142-55.e5.
doi: 10.1016/j.jaci.2017.08.040
Carroll DJ, Cao Y, Bochner BS, O’Sullivan JA. Siglec-8 signals through a non-canonical pathway to cause human eosinophil death in vitro. Front Immunol. 2021;12:737988.
doi: 10.3389/fimmu.2021.737988
Scott O, Sharfe N, Dadi H, Vong L, Garkaby J, Abrego Fuentes L, et al. Case report: eosinophilic esophagitis in a patient with a novel STAT1 gain-of-function pathogenic variant. Front Immunol. 2022;13:801832.
doi: 10.3389/fimmu.2022.801832
Ma CS, Wong N, Rao G, Avery DT, Torpy J, Hambridge T, et al. Monogenic mutations differentially affect the quantity and quality of T follicular helper cells in patients with human primary immunodeficiencies. J Allergy Clin Immunol. 2015;136(4):993-1006.e1.
doi: 10.1016/j.jaci.2015.05.036
Liu M, Guo S, Hibbert JM, Jain V, Singh N, Wilson NO, et al. CXCL10/IP-10 in infectious diseases pathogenesis and potential therapeutic implications. Cytokine Growth Factor Rev. 2011;22(3):121–30.
Kobbe R, Kolster M, Fuchs S, Schulze-Sturm U, Jenderny J, Kochhan L, et al. Common variable immunodeficiency, impaired neurological development and reduced numbers of T regulatory cells in a 10-year-old boy with a STAT1 gain-of-function mutation. Gene. 2016;586(2):234–8.
doi: 10.1016/j.gene.2016.04.006
Break TJ, Oikonomou V, Dutzan N, Desai JV, Swidergall M, Freiwald T, et al. Aberrant type 1 immunity drives susceptibility to mucosal fungal infections. Science. 2021;371(6526).
Purvis GSD, Solito E, Thiemermann C. Annexin-A1: therapeutic potential in microvascular disease. Front Immunol. 2019;10:938.
doi: 10.3389/fimmu.2019.00938