Cerebral aneurysm in three pediatric patients with STAT1 gain-of-function mutations

Bierman-Chow, Shaia; Freeman, Alexandra F.; Holland, Steven M.; Lynch, John; Cho, Hyun Joo

doi:10.1007/s00415-022-11131-w

Cited by 4 publications

(3 citation statements)

References 18 publications

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“…Furthermore, the interaction between platelets and neutrophils also represents a driving force in various vascular diseases, such as aortic aneurysm (AA) [ 70 ], and large vessel aneurysms are one of the unexplained symptoms of STAT1 GOF CMC, present in approximately 6 % of patients [ 2 , 71 ]. AA patients have increased leukocyte-platelet aggregates, and inhibition of platelet activation factors, such as CD62P and CD40-CD40L axis, lowers AA incidence and the risk of AA rupture [ 72 – 74 ].…”

Section: Discussionmentioning

confidence: 99%

Neutrophils in STAT1 Gain-Of-Function Have a Pro-inflammatory Signature Which Is Not Rescued by JAK Inhibition

et al. 2023

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STAT1 gain-of-function (GOF) mutations cause an inborn error of immunity with diverse phenotype ranging from chronic mucocutaneous candidiasis (CMC) to various non-infectious manifestations, the most precarious of which are autoimmunity and vascular complications. The pathogenesis centers around Th17 failure but is far from being understood. We hypothesized that neutrophils, whose functions have not been explored in the context of STAT1 GOF CMC yet, might be involved in the associated immunodysregulatory and vascular pathology. In a cohort of ten patients, we demonstrate that STAT1 GOF human ex-vivo peripheral blood neutrophils are immature and highly activated; have strong propensity for degranulation, NETosis, and platelet-neutrophil aggregation; and display marked inflammatory bias. STAT1 GOF neutrophils exhibit increased basal STAT1 phosphorylation and expression of IFN stimulated genes, but contrary to other immune cells, STAT1 GOF neutrophils do not display hyperphosphorylation of STAT1 molecule upon stimulation with IFNs. The patient treatment with JAKinib ruxolitinib does not ameliorate the observed neutrophil aberrations. To our knowledge, this is the first work describing features of peripheral neutrophils in STAT1 GOF CMC. The presented data suggest that neutrophils may contribute to the immune pathophysiology of the STAT1 GOF CMC.

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Section: Discussionmentioning

confidence: 99%

Neutrophils in STAT1 Gain-Of-Function Have a Pro-inflammatory Signature Which Is Not Rescued by JAK Inhibition

et al. 2023

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“…Of note, this mechanism is also observed in the pro-inflammatory macrophages of IA lesion ( 96 ). Most recent, the STAT1 gain-of-function mutation was reported to strengthen the response of INF-γ and macrophages recruitment in IA ( 128 ). The upstream inhibitors administration shows potential to interfere patients STAT1 gain-of-function and improve immune dysregulation related clinical outcomes.…”

Section: Macrophages Relevant Signaling Pathways and Therapy Strategi...mentioning

confidence: 99%

Current understanding of macrophages in intracranial aneurysm: relevant etiological manifestations, signaling modulation and therapeutic strategies

Duan,

Zhao,

et al. 2024

Front. Immunol.

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Macrophages activation and inflammatory response play crucial roles in intracranial aneurysm (IA) formation and progression. The outcome of ruptured IA is considerably poor, and the mechanisms that trigger IA progression and rupture remain to be clarified, thereby developing effective therapy to prevent subarachnoid hemorrhage (SAH) become difficult. Recently, climbing evidences have been expanding our understanding of the macrophages relevant IA pathogenesis, such as immune cells population, inflammatory activation, intra-/inter-cellular signaling transductions and drug administration responses. Crosstalk between macrophages disorder, inflammation and cellular signaling transduction aggravates the devastating consequences of IA. Illustrating the pros and cons mechanisms of macrophages in IA progression are expected to achieve more efficient treatment interventions. In this review, we summarized the current advanced knowledge of macrophages activation, infiltration, polarization and inflammatory responses in IA occurrence and development, as well as the most relevant NF-κB, signal transducer and activator of transcription 1 (STAT1) and Toll-Like Receptor 4 (TLR4) regulatory signaling modulation. The understanding of macrophages regulatory mechanisms is important for IA patients’ clinical outcomes. Gaining insight into the macrophages regulation potentially contributes to more precise IA interventions and will also greatly facilitate the development of novel medical therapy.

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“…However, SLE, autoimmune skin conditions, inflammatory bowel disease, and autoimmune cytopenias can also occur ( 40 ). Vascular involvement has been well described in STAT1 GOF and predominantly presenting as cerebral aneurysms ( 38 , 41 ), although large-vessel vasculitis that can mimic Takeyasu's arteritis has also been reported ( 42 – 44 ).…”

Section: Stat1 Gain-of-functionmentioning

confidence: 99%

Interferonopathies masquerading as non-Mendelian autoimmune diseases: pattern recognition for early diagnosis

2023

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Type I interferonopathies are a broad category of conditions associated with increased type I interferon gene expression and include monogenic autoinflammatory diseases and non-Mendelian autoimmune diseases such as dermatomyositis and systemic lupus erythematosus. While a wide range of clinical presentations among type I interferonopathies exists, these conditions often share several clinical manifestations and implications for treatment. Presenting symptoms may mimic non-Mendelian autoimmune diseases, including vasculitis and systemic lupus erythematosus, leading to delayed or missed diagnosis. This review aims to raise awareness about the varied presentations of monogenic interferonopathies to provide early recognition and appropriate treatment to prevent irreversible damage and improve quality of life and outcomes in this unique patient population.

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Cerebral aneurysm in three pediatric patients with STAT1 gain-of-function mutations

Cited by 4 publications

References 18 publications

Neutrophils in STAT1 Gain-Of-Function Have a Pro-inflammatory Signature Which Is Not Rescued by JAK Inhibition

Neutrophils in STAT1 Gain-Of-Function Have a Pro-inflammatory Signature Which Is Not Rescued by JAK Inhibition

Current understanding of macrophages in intracranial aneurysm: relevant etiological manifestations, signaling modulation and therapeutic strategies

Interferonopathies masquerading as non-Mendelian autoimmune diseases: pattern recognition for early diagnosis

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