Fatal COVID-19 Infection in Two Children with STAT1 Gain-of-Function

Staines-Boone, Aidé Tamara; Vignesh, Pandiarajan; Tsumura, Miyuki; de la Garza Fernández, Germán; Tyagi, Reva; Rawat, Amit; Das, Jhumki; Tomomasa, Dan; Asano, Takaki; Hijikata, Atsushi; Salazar-Gálvez, Yuridia; Kanegane, Hirokazu; Okada, Satoshi; Reyes, Saul O Lugo

doi:10.1007/s10875-023-01634-0

J Clin Immunol

2023

DOI: 10.1007/s10875-023-01634-0

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Fatal COVID-19 Infection in Two Children with STAT1 Gain-of-Function

Aidé Tamara Staines-Boone,

Pandiarajan Vignesh,

Miyuki Tsumura

et al.

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Cited by 3 publications

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Patients with STAT1 Gain-of-function Mutations Display Increased Apoptosis which is Reversed by the JAK Inhibitor Ruxolitinib

Dotta,

Todaro,

Baronio

et al. 2024

J Clin Immunol

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Introduction The signal transducer and activator of transcription (STAT1) gain-of-function (GOF) syndrome accounts for most cases of chronic mucocutaneous candidiasis but is characterized by a broader clinical phenotype that may include bacterial, viral, or invasive fungal infections, autoimmunity, autoinflammatory manifestations, vascular complications, or malignancies. The severity of lymphopenia may vary and influence the infectious morbidity. Methods In our cohort of seven STAT1-GOF patients, we investigated the mechanisms that may determine T lymphopenia, we characterized the interferon gene signature (IGS) and analyzed the effect of ruxolitinib in reverting the immune dysregulation. Results STAT1-GOF patients exhibited increased T lymphocyte apoptosis that was significantly augmented in both resting conditions and following stimulation with mitogens and IFNα, as evaluated by flow cytometry by Annexin V/ Propidium iodide assay. The JAK inhibitor ruxolitinib significantly reduced the IFNα-induced hyperphosphorylation of STAT1 and reverted the stimulation-induced T-cell apoptosis, in vitro. In two adult STAT1-GOF patients, the JAKinib treatment ameliorated chronic mucocutaneous candidiasis and lymphopenia. Most STAT1-GOF patients, particularly those who had autoimmunity, presented increased IGS that significantly decreased in the two patients during ruxolitinib treatment. Conclusion In STAT1-GOF patients, T lymphocyte apoptosis is increased, and T lymphopenia may determine higher risk of severe infections. The JAKinib target therapy should be evaluated to treat severe chronic candidiasis and lymphopenia, and to downregulate the IFNs in patients with autoinflammatory or autoimmune manifestations.

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Patients with STAT1 Gain-of-function Mutations Display Increased Apoptosis which is Reversed by the JAK Inhibitor Ruxolitinib

Dotta,

Todaro,

Baronio

et al. 2024

J Clin Immunol

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STAT1 and STAT3 gain of function: clinically heterogenous immune regulatory disorders

Olbrich,

Freeman

2024

Current Opinion in Allergy &Amp; Clinical Immunology

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Purpose of review The identification of STAT1 gain-of-function (GOF) in 2011 and STAT3 GOF in 2014 has advanced our understanding of the host immunity along the JAK/STAT pathway and allowed targeted treatment approaches. We review the clinical features and pathogenesis of STAT1 and STAT3 GOF and how this has shaped new approaches to therapy. Recent findings STAT1 GOF, initially described in patients with chronic mucocutaneous candidiasis (CMC) and autoimmune thyroid disease, is now recognized to cause early-onset multisystem autoimmunity and a range of infections. STAT3 GOF comprises mostly lymphoproliferation and autoimmunity but also with varying severity, including some with life threatening organ dysfunction. Treatment has evolved along with the understanding of the pathogenesis, with patients now receiving JAK inhibition to block upstream of the STAT defect with good response in autoimmunity and CMC in STAT1 GOF. Blockade of IL-6 signaling has also been used in STAT3 GOF. Hematopoietic cell transplantation had initial poor outcomes, but outcomes are now improving with focus on the control of inflammation pretransplant. Summary Understanding the pathogenesis of STAT1 and STAT3 GOF has allowed great recent advancements in therapy, but many questions remain as to the best approach to therapy for each patient's clinical presentation as well as the durability of these therapies.

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Human STAT1 gain of function with chronic mucocutaneous candidiasis: A comprehensive review for strengthening the connection between bedside observations and laboratory research

Asano,

Noma,

Mizoguchi

et al. 2023

Immunological Reviews

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SummaryGermline human heterozygous STAT1 gain‐of‐function (GOF) variants were first discovered a common cause of chronic mucocutaneous candidiasis (CMC) in 2011. Since then, numerous STAT1 GOF variants have been identified. A variety of clinical phenotypes, including fungal, viral, and bacterial infections, endocrine disorders, autoimmunity, malignancy, and aneurysms, have recently been revealed for STAT1 GOF variants, which has led to the expansion of the clinical spectrum associated with STAT1 GOF. Among this broad range of complications, it has been determined that invasive infections, aneurysms, and malignancies are poor prognostic factors for STAT1 GOF. The effectiveness of JAK inhibitors as a therapeutic option has been established, although further investigation of their long‐term utility and side effects is needed. In contrast to the advancements in treatment options, the precise molecular mechanism underlying STAT1 GOF remains undetermined. Two primary hypotheses for this mechanism involve impaired STAT1 dephosphorylation and increased STAT1 protein levels, both of which are still controversial. A precise understanding of the molecular mechanism is essential for not only advancing diagnostics but also developing therapeutic interventions. Here, we provide a comprehensive review of STAT1 GOF with the aim of establishing a stronger connection between bedside observations and laboratory research.

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Fatal COVID-19 Infection in Two Children with STAT1 Gain-of-Function

Cited by 3 publications

References 35 publications

Patients with STAT1 Gain-of-function Mutations Display Increased Apoptosis which is Reversed by the JAK Inhibitor Ruxolitinib

Patients with STAT1 Gain-of-function Mutations Display Increased Apoptosis which is Reversed by the JAK Inhibitor Ruxolitinib

STAT1 and STAT3 gain of function: clinically heterogenous immune regulatory disorders

Human STAT1 gain of function with chronic mucocutaneous candidiasis: A comprehensive review for strengthening the connection between bedside observations and laboratory research

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