Ruxolitinib Improves Immune-Dysregulation Features but Not Epigenetic Abnormality in a Patient with STAT1 GOF

Overview

Journal J Clin Immunol

Publisher Springer

Specialty Allergy & Immunology

Date 2024 Apr 5

PMID 38578320

Authors

June-Young Koh

Doo Ri Kim

Sohee Son

Hwanhee Park

Kyung-Ran Kim

Sunwoo Min

Ha Seok Lee

Byung Woo Jhun

Eun-Suk Kang

Inkyung Jung

Ji-Man Kang

Yae-Jean Kim

Eui-Cheol Shin

Affiliations

Soon will be listed here.

Abstract

Purpose: Patients with STAT1 gain-of-function (GOF) mutations often exhibit autoimmune features. The JAK1/2 inhibitor ruxolitinib can be administered to alleviate autoimmune symptoms; however, it is unclear how immune cells are molecularly changed by ruxolitinib treatment. Then, we aimed to investigate the trnscriptional and epigenetic status of immune cells before and after ruxolitinib treatment in a patient with STAT1 GOF.

Methods: A patient with a heterozygous STAT1 GOF variant (p.Ala267Val), exhibiting autoimmune features, was treated with ruxolitinib, and peripheral blood mononuclear cells (PBMCs) were longitudinally collected. PBMCs were transcriptionally analyzed by single-cell cellular indexing of the transcriptomes and epitopes by sequencing (CITE-seq), and epigenetically analyzed by assay of transposase-accessible chromatin sequencing (ATAC-seq).

Results: CITE-seq analysis revealed that before treatment, the patient's PBMCs exhibited aberrantly activated inflammatory features, especially IFN-related features. In particular, monocytes showed high expression levels of a subset of IFN-stimulated genes (ISGs). Ruxolitinib treatment substantially downregulated aberrantly overexpressed ISGs, and improved autoimmune features. However, epigenetic analysis demonstrated that genetic regions of ISGs-e.g., STAT1, IRF1, MX1, and OAS1-were highly accessible even after ruxolitinib treatment. When ruxolitinib was temporarily discontinued, the patient's autoimmune features were aggravated, which is in line with sustained epigenetic abnormality.

Conclusions: In a patient with STAT1 GOF, ruxolitinib treatment improved autoimmune features and downregulated aberrantly overexpressed ISGs, but did not correct epigenetic abnormality of ISGs.

References

Vargas-Hernandez A, Mace E, Zimmerman O, Zerbe C, Freeman A, Rosenzweig S . 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. 2017; 141(6):2142-2155.e5. PMC: 5924437. DOI: 10.1016/j.jaci.2017.08.040. View

Stuart T, Srivastava A, Madad S, Lareau C, Satija R . Single-cell chromatin state analysis with Signac. Nat Methods. 2021; 18(11):1333-1341. PMC: 9255697. DOI: 10.1038/s41592-021-01282-5. View

Bernasconi A, Yancoski J, Villa M, Oleastro M, Galicchio M, Rossi J . Increased STAT1 Amounts Correlate with the Phospho-STAT1 Level in STAT1 Gain-of-function Defects. J Clin Immunol. 2018; 38(7):745-747. DOI: 10.1007/s10875-018-0557-0. View

Merkel P, Herlyn K, Martin R, Anderson J, Mayes M, Bell P . Measuring disease activity and functional status in patients with scleroderma and Raynaud's phenomenon. Arthritis Rheum. 2002; 46(9):2410-20. DOI: 10.1002/art.10486. View

Liu L, Okada S, Kong X, Kreins A, Cypowyj S, Abhyankar A . Gain-of-function human STAT1 mutations impair IL-17 immunity and underlie chronic mucocutaneous candidiasis. J Exp Med. 2011; 208(8):1635-48. PMC: 3149226. DOI: 10.1084/jem.20110958. View

Hao Y, Hao S, Andersen-Nissen E, Mauck 3rd W, Zheng S, Butler A . Integrated analysis of multimodal single-cell data. Cell. 2021; 184(13):3573-3587.e29. PMC: 8238499. DOI: 10.1016/j.cell.2021.04.048. View

Stark G, Darnell Jr J . The JAK-STAT pathway at twenty. Immunity. 2012; 36(4):503-14. PMC: 3909993. DOI: 10.1016/j.immuni.2012.03.013. View

Deya-Martinez A, Riviere J, Roxo-Junior P, Ramakers J, Bloomfield M, Guisado Hernandez P . 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):1071-1082. PMC: 9402491. DOI: 10.1007/s10875-022-01257-x. View

Majoros A, Platanitis E, Szappanos D, Cheon H, Vogl C, Shukla P . Response to interferons and antibacterial innate immunity in the absence of tyrosine-phosphorylated STAT1. EMBO Rep. 2016; 17(3):367-82. PMC: 4772975. DOI: 10.15252/embr.201540726. View

10.

Bloomfield M, Kanderova V, Parackova Z, Vrabcova P, Svaton M, Fronkova E . 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. View

11.

Maeshima K, Ishii K, Shibata H . An Adult Fatal Case with a Gain-of-function Mutation Associated with Multiple Autoimmune Diseases. J Rheumatol. 2018; 46(3):325-327. DOI: 10.3899/jrheum.180210. View

12.

Stuart T, Butler A, Hoffman P, Hafemeister C, Papalexi E, Mauck 3rd W . Comprehensive Integration of Single-Cell Data. Cell. 2019; 177(7):1888-1902.e21. PMC: 6687398. DOI: 10.1016/j.cell.2019.05.031. View

13.

Kuleshov M, Jones M, Rouillard A, Fernandez N, Duan Q, Wang Z . Enrichr: a comprehensive gene set enrichment analysis web server 2016 update. Nucleic Acids Res. 2016; 44(W1):W90-7. PMC: 4987924. DOI: 10.1093/nar/gkw377. View

14.

. The Gene Ontology Resource: 20 years and still GOing strong. Nucleic Acids Res. 2018; 47(D1):D330-D338. PMC: 6323945. DOI: 10.1093/nar/gky1055. View

15.

Papalexi E, Satija R . Single-cell RNA sequencing to explore immune cell heterogeneity. Nat Rev Immunol. 2017; 18(1):35-45. DOI: 10.1038/nri.2017.76. View

16.

Huh H, Jhun B, Choi S, Kim Y, Yun S, Nham E . Bronchiectasis and Recurrent Respiratory Infections with a Gain-of-Function Variant: First Case in Korea. Yonsei Med J. 2018; 59(8):1004-1007. PMC: 6127433. DOI: 10.3349/ymj.2018.59.8.1004. View

17.

Zimmerman O, Olbrich P, Freeman A, Rosen L, Uzel G, Zerbe C . Gain-of-Function Mutations Cause High Total STAT1 Levels With Normal Dephosphorylation. Front Immunol. 2019; 10:1433. PMC: 6635460. DOI: 10.3389/fimmu.2019.01433. View

18.

Cheon H, Holvey-Bates E, McGrail D, Stark G . PD-L1 sustains chronic, cancer cell-intrinsic responses to type I interferon, enhancing resistance to DNA damage. Proc Natl Acad Sci U S A. 2021; 118(47). PMC: 8617513. DOI: 10.1073/pnas.2112258118. View

19.

Sampaio E, Hsu A, Pechacek J, Bax H, Dias D, Paulson M . Signal transducer and activator of transcription 1 (STAT1) gain-of-function mutations and disseminated coccidioidomycosis and histoplasmosis. J Allergy Clin Immunol. 2013; 131(6):1624-34. PMC: 3746066. DOI: 10.1016/j.jaci.2013.01.052. View

20.

Forbes L, Vogel T, Cooper M, Castro-Wagner J, Schussler E, Weinacht K . 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):1665-1669. PMC: 6322659. DOI: 10.1016/j.jaci.2018.07.020. View