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Open Access 01-04-2024 | Ruxolitinib | Original Article

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

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

Published in: Journal of Clinical Immunology | Issue 4/2024

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.

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Title: Ruxolitinib Improves Immune-Dysregulation Features but not Epigenetic Abnormality in a Patient with STAT1 GOF
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
Publication date: 01-04-2024
Publisher: Springer US
Keywords: Ruxolitinib
Epigenetics
Interferon
Published in: Journal of Clinical Immunology / Issue 4/2024
Print ISSN: 0271-9142
Electronic ISSN: 1573-2592
DOI: https://doi.org/10.1007/s10875-024-01687-9

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