Gain-of-function STAT1 mutations are associated with intracranial aneurysms

Dadak, Mete; Jacobs, Roland; Škuljec, Jelena; Jirmo, Adan Chari; Yildiz, Oezlem; Donnerstag, Frank; Baerlecken, N.T.; Schmidt, Reinhold; Lanfermann, Heinrich; Skripuletz, Thomas; Schwenkenbecher, Philipp; Kleinschnitz, Christoph; Tumani, Hayrettin; Stangel, Martin; Pul, Refik

doi:10.1016/j.clim.2017.01.012

Cited by 20 publications

(17 citation statements)

References 40 publications

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“…Many patients with STAT1 mutations also display autoimmune manifestations (37%), mainly hypothyroidism [ 95 ]. Esophageal carcinoma and cerebral aneurysms have also been linked to gain-of-function STAT1 mutations [ 95 , 96 ]. The increased risk of invasive infections, squamous cell carcinoma and cerebral aneurysms make this disease potentially life-threatening.…”

Section: Mucocutaneous Candidiasismentioning

confidence: 99%

Patient Susceptibility to Candidiasis—A Potential for Adjunctive Immunotherapy

Davidson

Netea

Kullberg

2018

JoF

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Candida spp. are colonizing fungi of human skin and mucosae of the gastrointestinal and genitourinary tract, present in 30-50% of healthy individuals in a population at any given moment. The host defense mechanisms prevent this commensal fungus from invading and causing disease. Loss of skin or mucosal barrier function, microbiome imbalances, or defects of immune defense mechanisms can lead to an increased susceptibility to severe mucocutaneous or invasive candidiasis. A comprehensive understanding of the immune defense against Candida is essential for developing adjunctive immunotherapy. The important role of underlying genetic susceptibility to Candida infections has become apparent over the years. In most patients, the cause of increased susceptibility to fungal infections is complex, based on a combination of immune regulation gene polymorphisms together with other non-genetic predisposing factors. Identification of patients with an underlying genetic predisposition could help determine which patients could benefit from prophylactic antifungal treatment or adjunctive immunotherapy. This review will provide an overview of patient susceptibility to mucocutaneous and invasive candidiasis and the potential for adjunctive immunotherapy.

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Section: Mucocutaneous Candidiasismentioning

confidence: 99%

Patient Susceptibility to Candidiasis—A Potential for Adjunctive Immunotherapy

Davidson

Netea

Kullberg

2018

JoF

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“…While CMC is still the hallmark of this disease—it was present in 98% of patients from an international cohort of 274 STAT1 GOF patients ( 24 )—as more patients were described, the phenotype was proven to be much more diverse than initially assumed ( 22 , 24 ). These patients are at higher risk of other infections (bacterial/viral/fungal) ( 25 – 27 ), autoimmunity ( 28 , 29 ), aneurisms ( 30 , 31 ), and malignancies ( 32 , 33 ). Many of these manifestations cannot be solely explained by a reduction of Th17 cells, implying that excessive activation of STAT1 potentially impairs immunity through other mechanisms not yet fully understood ( 29 , 34 , 35 ).…”

Section: Gain-of-function (Gof) Mutations In Signal Transducer and Acmentioning

confidence: 99%

“…Twenty-seven reports of mycobacterial infections could be retrieved from more than 350 published STAT1 GOF patients ( 20 , 24 , 25 , 27 , 29 , 31 , 33 , 34 , 36 – 40 ). Vaccination status was not addressed in most descriptions ( 3 , 18 – 22 , 24 – 34 , 36 – 39 , 41 – 72 ).…”

Section: Gain-of-function (Gof) Mutations In Signal Transducer and Acmentioning

confidence: 99%

“…BCG complications were seen in seven patients. Three patients had local reactions [( 29 , 37 , 38 ), and Acknowledgments] and four experienced disseminated disease ( 24 , 25 , 31 ). In addition to BCG, other mycobacteria also seem to threaten a subset of these patients (Table 2 ).…”

Section: Gain-of-function (Gof) Mutations In Signal Transducer and Acmentioning

confidence: 99%

“…In addition to BCG, other mycobacteria also seem to threaten a subset of these patients (Table 2 ). Disseminated disease was observed in eight more patients (six cases of Mycobacterium tuberculosis and two of NTM) ( 24 , 31 , 34 , 38 , 39 ), four patients had pulmonary infections caused by environmental mycobacteria ( 24 , 29 , 33 ), and two patients had lymphadenitis caused by Mycobacterium fortuitum ( 27 , 37 ). M. tuberculosis caused pulmonary disease in five patients ( 24 , 36 , 37 ) and extrapulmonary localized disease in one patient ( 20 ).…”

Section: Gain-of-function (Gof) Mutations In Signal Transducer and Acmentioning

confidence: 99%

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Bacille Calmette–Guerin Complications in Newly Described Primary Immunodeficiency Diseases: 2010–2017

Nunes-Santos

Rosenzweig

2018

Front. Immunol.

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Bacille Calmette–Guerin (BCG) vaccine is widely used as a prevention strategy against tuberculosis. BCG is a live vaccine, usually given early in life in most countries. While safe to most recipients, it poses a risk to immunocompromised patients. Several primary immunodeficiency diseases (PIDD) have been classically associated with complications related to BCG vaccine. However, a number of new inborn errors of immunity have been described lately in which little is known about adverse reactions following BCG vaccination. The aim of this review is to summarize the existing data on BCG-related complications in patients diagnosed with PIDD described since 2010. When BCG vaccination status or complications were not specifically addressed in those manuscripts, we directly contacted the corresponding authors for further clarification. We also analyzed data on other mycobacterial infections in these patients. Based on our analysis, around 8% of patients with gain-of-function mutations in STAT1 had mycobacterial infections, including localized complications in 3 and disseminated disease in 4 out of 19 BCG-vaccinated patients. Localized BCG reactions were also frequent in activated PI3Kδ syndrome type 1 (3/10) and type 2 (2/18) vaccinated children. Also, of note, no BCG-related complications have been described in either CTLA4 or LRBA protein-deficient patients; and not enough information on BCG-vaccinated NFKB1 or NFKB2-deficient patients was available to drive any conclusions about these diseases. Despite the high prevalence of environmental mycobacterial infections in GATA2-deficient patients, only one case of BCG reaction has been reported in a patient who developed disseminated disease. In conclusion, BCG complications could be expected in some particular, recently described PIDD and it remains a preventable risk factor for pediatric PIDD patients.

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Human STAT1 Gain-of-Function Heterozygous Mutations: Chronic Mucocutaneous Candidiasis and Type I Interferonopathy

et al. 2020

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Heterozygous gain-of-function (GOF) mutations in STAT1 in patients with chronic mucocutaneous candidiasis (CMC) and hypothyroidism were discovered in 2011. CMC is the recurrent or persistent mucocutaneous infection by Candida fungi, and hypothyroidism results from autoimmune thyroiditis. Patients with these diseases develop other infectious diseases, including viral, bacterial, and fungal diseases, and other autoimmune manifestations, including enterocolitis, immune cytopenia, endocrinopathies, and systemic lupus erythematosus. STAT1-GOF mutations are highly penetrant with a median age at onset of 1 year and often underlie an autosomal dominant trait. As many as 105 mutations at 72 residues, including 65 recurrent mutations, have already been reported in more than 400 patients worldwide. The GOF mechanism involves impaired dephosphorylation of STAT1 in the nucleus. Patient cells show enhanced STAT1dependent responses to type I and II interferons (IFNs) and IL-27. This impairs Th17 cell development, which accounts for CMC. The pathogenesis of autoimmunity likely involves enhanced type I IFN responses, as in other type I interferonopathies. The pathogenesis of other infections, especially those caused by intramacrophagic bacteria and fungi, which are otherwise seen in patients with diminished type II IFN immunity, has remained mysterious. The cumulative survival rates of patients with and without severe disease (invasive infection, cancer, and/or symptomatic aneurysm) at 60 years of age are 31% and 87%, respectively. Severe autoimmunity also worsens the prognosis. The treatment of patients with STAT1-GOF mutations who suffer from severe infectious and autoimmune manifestations relies on hematopoietic stem cell transplantation and/or oral JAK inhibitors.

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Gain-of-function STAT1 mutations are associated with intracranial aneurysms

Cited by 20 publications

References 40 publications

Patient Susceptibility to Candidiasis—A Potential for Adjunctive Immunotherapy

Patient Susceptibility to Candidiasis—A Potential for Adjunctive Immunotherapy

Bacille Calmette–Guerin Complications in Newly Described Primary Immunodeficiency Diseases: 2010–2017

Human STAT1 Gain-of-Function Heterozygous Mutations: Chronic Mucocutaneous Candidiasis and Type I Interferonopathy

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