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

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 investiga...

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Published in:Journal of clinical immunology 2024-04, Vol.44 (4), p.84, Article 84
Main Authors: Koh, June-Young, Kim, Doo Ri, Son, Sohee, Park, Hwanhee, Kim, Kyung-Ran, Min, Sunwoo, Lee, Ha Seok, Jhun, Byung Woo, Kang, Eun-Suk, Jung, Inkyung, Kang, Ji-Man, Kim, Yae-Jean, Shin, Eui-Cheol
Format: Article
Language:English
Subjects:
Autoimmune diseases
Biomedical and Life Sciences
Biomedicine
Chromatin
Down-regulation
Epigenetics
Epitopes
Gain of Function Mutation - genetics
Genetic analysis
Humans
Immunology
Infectious Diseases
Inflammation
Interferon regulatory factor 1
Internal Medicine
Janus kinase
Leukocytes (mononuclear)
Leukocytes, Mononuclear - metabolism
Medical Microbiology
Monocytes
Nitriles - pharmacology
Original
Original Article
Peripheral blood mononuclear cells
Pyrazoles - pharmacology
Pyrimidines - pharmacology
Stat1 protein
STAT1 Transcription Factor - genetics
Transcriptomes
Transposase
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Summary: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.
ISSN:0271-9142
1573-2592
1573-2592
DOI:10.1007/s10875-024-01687-9