Ruxolitinib Improves Immune-Dysregulation Features but not Epigenetic Abnormality in a Patient with STAT1 GOF
© 2024. The Author(s)..
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.
| Medienart: |
E-Artikel |
|---|
| Erscheinungsjahr: |
2024 |
|---|---|
| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:44 |
|---|---|
| Enthalten in: |
Journal of clinical immunology - 44(2024), 4 vom: 05. Apr., Seite 84 |
| Sprache: |
Englisch |
|---|
| Beteiligte Personen: |
Koh, June-Young [VerfasserIn] |
|---|
| Links: |
|---|
| Themen: |
82S8X8XX8H |
|---|
| Anmerkungen: |
Date Completed 08.04.2024 Date Revised 09.04.2024 published: Electronic Citation Status MEDLINE |
|---|
| doi: |
10.1007/s10875-024-01687-9 |
|---|
| funding: |
|
|---|---|
| Förderinstitution / Projekttitel: |
|
| PPN (Katalog-ID): |
NLM370677323 |
|---|
| LEADER | 01000caa a22002652 4500 | ||
|---|---|---|---|
| 001 | NLM370677323 | ||
| 003 | DE-627 | ||
| 005 | 20240409232804.0 | ||
| 007 | cr uuu---uuuuu | ||
| 008 | 240405s2024 xx |||||o 00| ||eng c | ||
| 024 | 7 | |a 10.1007/s10875-024-01687-9 |2 doi | |
| 028 | 5 | 2 | |a pubmed24n1370.xml |
| 035 | |a (DE-627)NLM370677323 | ||
| 035 | |a (NLM)38578320 | ||
| 040 | |a DE-627 |b ger |c DE-627 |e rakwb | ||
| 041 | |a eng | ||
| 100 | 1 | |a Koh, June-Young |e verfasserin |4 aut | |
| 245 | 1 | 0 | |a Ruxolitinib Improves Immune-Dysregulation Features but not Epigenetic Abnormality in a Patient with STAT1 GOF |
| 264 | 1 | |c 2024 | |
| 336 | |a Text |b txt |2 rdacontent | ||
| 337 | |a ƒaComputermedien |b c |2 rdamedia | ||
| 338 | |a ƒa Online-Ressource |b cr |2 rdacarrier | ||
| 500 | |a Date Completed 08.04.2024 | ||
| 500 | |a Date Revised 09.04.2024 | ||
| 500 | |a published: Electronic | ||
| 500 | |a Citation Status MEDLINE | ||
| 520 | |a © 2024. The Author(s). | ||
| 520 | |a 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 | ||
| 520 | |a 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) | ||
| 520 | |a 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 | ||
| 520 | |a 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 | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a ATAC sequencing | |
| 650 | 4 | |a Inborn errors of immunity | |
| 650 | 4 | |a JAK inhibitor | |
| 650 | 4 | |a STAT1 GOF | |
| 650 | 7 | |a Nitriles |2 NLM | |
| 650 | 7 | |a Pyrazoles |2 NLM | |
| 650 | 7 | |a Pyrimidines |2 NLM | |
| 650 | 7 | |a ruxolitinib |2 NLM | |
| 650 | 7 | |a 82S8X8XX8H |2 NLM | |
| 650 | 7 | |a STAT1 protein, human |2 NLM | |
| 650 | 7 | |a STAT1 Transcription Factor |2 NLM | |
| 700 | 1 | |a Kim, Doo Ri |e verfasserin |4 aut | |
| 700 | 1 | |a Son, Sohee |e verfasserin |4 aut | |
| 700 | 1 | |a Park, Hwanhee |e verfasserin |4 aut | |
| 700 | 1 | |a Kim, Kyung-Ran |e verfasserin |4 aut | |
| 700 | 1 | |a Min, Sunwoo |e verfasserin |4 aut | |
| 700 | 1 | |a Lee, Ha Seok |e verfasserin |4 aut | |
| 700 | 1 | |a Jhun, Byung Woo |e verfasserin |4 aut | |
| 700 | 1 | |a Kang, Eun-Suk |e verfasserin |4 aut | |
| 700 | 1 | |a Jung, Inkyung |e verfasserin |4 aut | |
| 700 | 1 | |a Kang, Ji-Man |e verfasserin |4 aut | |
| 700 | 1 | |a Kim, Yae-Jean |e verfasserin |4 aut | |
| 700 | 1 | |a Shin, Eui-Cheol |e verfasserin |4 aut | |
| 773 | 0 | 8 | |i Enthalten in |t Journal of clinical immunology |d 1981 |g 44(2024), 4 vom: 05. Apr., Seite 84 |w (DE-627)NLM012677426 |x 1573-2592 |7 nnns |
| 773 | 1 | 8 | |g volume:44 |g year:2024 |g number:4 |g day:05 |g month:04 |g pages:84 |
| 856 | 4 | 0 | |u http://dx.doi.org/10.1007/s10875-024-01687-9 |3 Volltext |
| 912 | |a GBV_USEFLAG_A | ||
| 912 | |a GBV_NLM | ||
| 951 | |a AR | ||
| 952 | |d 44 |j 2024 |e 4 |b 05 |c 04 |h 84 | ||