Dysregulated STAT1 gain-of-function: Pathogen-free autoimmunity and fungal infection DOI Creative Commons
Liping Guo,

Dongli Lian,

Yuchen Gu

и другие.

hLife, Год журнала: 2024, Номер 2(8), С. 397 - 418

Опубликована: Март 7, 2024

Inborn errors of the signal transducer and activator transcription 1 (STAT1) result in 4 types immunodeficiency disease with varying degrees impaired STAT1 function: autosomal recessive (AR) complete deficiency, AR partial dominant (AD) AD gain-of-function (STAT1-GOF). Of which, STAT1-GOF mutations promote a clinical syndrome immune dysregulation characterized by recurrent infections, especially chronic mucocutaneous candidiasis (CMC) Talaromyces marneffei infection predisposition to humoral autoimmunity. mutation leads enhanced phosphorylation (pSTAT1), delayed dephosphorylation, nuclear dephosphorylation. As result, development T helper (Th) 17 cells is impaired, limiting production interleukin (IL-) 17, which plays an important role antifungal immunity. Additionally, can also cause decrease proportion CD4+, CD8+, natural killer (NK) cells. Recent research demonstrated that absence overt infection, STAT-GOF mice disrupt naïve CD4+ cell homeostasis expansion differentiation abnormal T-follicular helper/T-helper 1-like (Tfh/Th1-like) germinal center-like (GC-like) B cells, thus reminds us complex molecular mechanism autoimmune with/without fungal may further involve specific treatment including anti-autoimmunity therapies. In addition, sex location were associated phenotype. Individuals DNA binding domain (DBD) had higher prevalence autoimmunity aberrant activation. Disrupted occurred sooner more robustly females, highlighting importance normalize expression restore tolerance patients syndrome. Here, we provide comprehensive review aiming clarify regulatory cellular deficiency or without

Язык: Английский

JAK Inhibition in STAT1 Gain-of-Function–Mediated Treatment-Resistant Autoimmune Hepatitis DOI
Nedim Hadžić,

Maesha Deheragoda,

Austen Worth

и другие.

New England Journal of Medicine, Год журнала: 2024, Номер 390(3), С. 284 - 286

Опубликована: Янв. 17, 2024

Autoimmune hepatitis has a complex pathogenesis. Treatment-resistant cases may benefit from genetic analysis and more targeted immune treatments.

Язык: Английский

Процитировано

11
Haploinsufficiency in PTPN2 leads to early-onset systemic autoimmunity from Evans syndrome to lupus DOI Creative Commons
Marie Jeanpierre, Jade Cognard,

Maud Tusseau

и другие.

The Journal of Experimental Medicine, Год журнала: 2024, Номер 221(9)

Опубликована: Июль 19, 2024

An exome sequencing strategy employed to identify pathogenic variants in patients with pediatric-onset systemic lupus or Evans syndrome resulted the discovery of six novel monoallelic mutations PTPN2. PTPN2 is a phosphatase that acts as an essential negative regulator JAK/STAT pathways. All led loss regulatory function evidenced by vitro assays and hyperproliferation patients’ T cells. Furthermore, exhibited high serum levels inflammatory cytokines, mimicking profile observed individuals gain-of-function STAT factors. Flow cytometry analysis blood cells revealed typical alterations associated autoimmunity all presented autoantibodies. These findings further supported notion regulators cytokine pathways can lead broad spectrum autoimmune manifestations along SOCS1 haploinsufficiency constitute new group monogenic diseases benefit from targeted therapy.

Язык: Английский

Процитировано

11
The oncogenic mechanisms of the Janus kinase-signal transducer and activator of transcription pathway in digestive tract tumors DOI Creative Commons

Ruihong Zhao,

Zhangmin Hu,

Xiaoli Zhang

и другие.

Cell Communication and Signaling, Год журнала: 2024, Номер 22(1)

Опубликована: Янв. 25, 2024

Abstract Digestive tract tumors are heterogeneous and involve the dysregulation of multiple signaling pathways. The Janus kinase-signal transducer activator transcription (JAK–STAT) pathway plays a notable role in oncogenesis digestive tumors. Typically activated by pro-inflammatory cytokines, it regulates important biological processes, such as cell growth, differentiation, apoptosis, immune responses, inflammation. aberrant activation this manifests different forms, including mutations JAKs, overexpression cytokine receptors, sustained STAT activation, contributes to promoting malignant characteristics cancer cells, uncontrolled proliferation, resistance enhanced invasion metastasis, angiogenesis, acquisition stem-like properties, drug resistance. Numerous studies have shown that JAK-STAT is closely related development progression tumors, contributing tumor survival, changes microenvironment, even escape processes. In addition, also affects sensitivity chemotherapy targeted therapy. Therefore, crucial comprehensively understand oncogenic mechanisms underlying order develop effective therapeutic strategies against Currently, several JAK–STAT inhibitors undergoing clinical preclinical trials potential treatments for various human diseases. However, further investigation required determine pathway, well effectiveness safety its inhibitors, especially context review, we provide an overview structure, classic negative regulation pathway. Furthermore, discuss pathogenic with aim identifying novel targets.

Язык: Английский

Процитировано

5
Preclinical development and clinical studies of targeted JAK/STAT combined Anti-PD-1/PD-L1 therapy DOI
Miaomiao Chen, Si-Liang Wang

International Immunopharmacology, Год журнала: 2024, Номер 130, С. 111717 - 111717

Опубликована: Фев. 21, 2024

Язык: Английский

Процитировано

5
Genetic variants regulating the immune response improve the prediction of COVID-19 severity provided by clinical variables DOI Creative Commons
Pablo Delgado‐Wicke, Sara Fernández de Córdoba‐Oñate,

Emilia Roy‐Vallejo

и другие.

Scientific Reports, Год журнала: 2024, Номер 14(1)

Опубликована: Сен. 5, 2024

Язык: Английский

Процитировано

4
C6 Ceramide Inhibits Canine Mammary Cancer Growth and Metastasis by Targeting EGR3 through JAK1/STAT3 Signaling DOI Creative Commons
Jiayue Liu,

Fangying Zhao,

Yan Zhang

и другие.

Animals, Год журнала: 2024, Номер 14(3), С. 422 - 422

Опубликована: Янв. 27, 2024

Cancer is the leading cause of death in both humans and companion animals. Canine mammary tumor an important disease with a high incidence metastasis rate, its poor prognosis remains serious clinical challenge. C6 ceramide short-chain sphingolipid metabolite powerful potential as suppressor. However, specific impact on canine cancer unclear. effects are still Therefore, we investigated role progress explored mechanism. inhibited cell growth by regulating cycle without involving apoptosis. Additionally, migration invasion CHMp cells. In vivo, decreased lungs side effects. Further investigation found that knockdown EGR3 expression led to noticeable increase proliferation upregulating expressions pJAK1 pSTAT3, thus activating JAK1/STAT3 signaling pathway. conclusion, inhibits targeting through regulation This study implicates mechanisms underlying anti-tumor activity demonstrates novel target for treating cancer.

Язык: Английский

Процитировано

3
The molecular effects underlying the pharmacological activities of daphnetin DOI Creative Commons
Zhifeng Wei, Na Wei, Long Su

и другие.

Frontiers in Pharmacology, Год журнала: 2024, Номер 15

Опубликована: Июль 1, 2024

As an increasingly well-known derivative of coumarin, daphnetin (7,8-dithydroxycoumarin) has demonstrated various pharmacological activities, including anti-inflammation, anti-cancer, anti-autoimmune diseases, antibacterial, organ protection, and neuroprotection properties. Various studies have been conducted to explore the action mechanisms synthetic methods daphnetin, given its therapeutic potential in clinical. Despite these initial insights, precise underlying activities remain largely unknown. In order address this knowledge gap, we molecular effects from perspectives signaling pathways, NOD-like receptor protein 3 (NLRP3) inflammasome inflammatory factors; try find out how can be utilized inform new combined strategies.

Язык: Английский

Процитировано

3
The past 25 years in paediatric rheumatology: insights from monogenic diseases DOI
Seza Özen, Ivona Aksentijevich

Nature Reviews Rheumatology, Год журнала: 2024, Номер 20(9), С. 585 - 593

Опубликована: Авг. 7, 2024

Язык: Английский

Процитировано

3
Formin protein DAAM1 positively regulates PD-L1 expression via mediating the JAK1/STAT1 axis in pancreatic cancer DOI Creative Commons
Rui Xu,

Mengyun Wan,

Jiadong Pan

и другие.

Cancer Cell International, Год журнала: 2025, Номер 25(1)

Опубликована: Янв. 29, 2025

Dishevelled-associated activator of morphogenesis1 (DAAM1) is a member the evolutionarily conserved Formin family and plays significant role in malignant progression various human cancers. This study aims to explore clinical biological significance DAAM1 pancreatic cancer. Multiple public datasets an in-house cohort were utilized assess relevance The LinkedOmics platform was employed perform enrichment analysis DAAM1-associated molecular pathways Subsequently, series vitro vivo experiments conducted evaluate roles cancer cells its effects on intratumoral T cells. found be upregulated tissues, with higher expression levels observed tumor Additionally, high associated poor prognosis. acted as oncogene cancer, inhibition suppressed cell proliferation, migration, invasion, while promoted apoptosis. Furthermore, involved JAK1/STAT1 signaling pathway regulated PD-L1 also significantly reduced exhaustion CD8+ In conclusion, functions immunologically implicated these findings suggest that may serve promising therapeutic target for management

Язык: Английский

Процитировано

0
How (Ultra‐)Rare Gene Variants Improve Our Understanding of More Common Autoimmune and Inflammatory Diseases DOI Creative Commons
Alexandre Bélot,

Maud Tusseau,

Jade Cognard

и другие.

ACR Open Rheumatology, Год журнала: 2025, Номер 7(2)

Опубликована: Фев. 1, 2025

The aim of this study was to explore the impact rare and ultra‐rare genetic variants on understanding treatment autoimmune autoinflammatory diseases with a focus systemic lupus erythematosus (SLE) Behçet syndrome. This review summarizes current research monogenic causes SLE syndrome, highlighting various pathways that can be responsible for these unique phenotypes. In SLE, identification complement DNASE1L3 deficiencies has elucidated mechanisms apoptotic body accumulation extracellular nucleic acid sensing. Type I interferonopathies underline specific role DNA/RNA sensing interferon overexpression in development autoimmunity. Other significant defects include Toll‐like receptor hypersignaling JAK/STATopathies, which contribute breakdown immune tolerance. To date, directly affecting B T cell biology only account minority identified lupus, importance tight regulation mechanistic target rapamycin RAS (Rat sarcoma GTPase)/MAPK (mitogen‐activated protein kinase) signaling lupus. TNFAIP3, RELA , NFKB1 genes have been identified, underscoring NF‐κB overactivation. Additional such as ELF4, WDR1 mutations trisomy 8 further illustrate complexity condition. Observations from studies syndrome highlight inflammatory distinct molecular caused by single‐gene promote or syndromes, often unrecognizable their genetically complex “classical” forms. Insights gained studying enhance our function health disease, paving way targeted therapies personalized medicine.

Язык: Английский

Процитировано

0