Ruxolitinib Induces Interleukin 17 and Ameliorates Chronic Mucocutaneous Candidiasis Caused by STAT1 Gain-of-Function Mutation

Mößner, Rotraut; Diering, Nina; Bader, Oliver; Forkel, Susann; Overbeck, Tobias R.; Groß, Uwe; Grimbacher, Bodo; Schön, Michael P.; Buhl, Timo

doi:10.1093/cid/ciw020

Cited by 77 publications

(48 citation statements)

References 7 publications

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“…10 Most recently, Mössner et al observed improvement of chronic mucocutaneous candidiasis on ruxolinib and a reactive increase in IL-17A/F. 25 Here we describe the immune-phenotypic analysis of a patient with life-threatening autoimmune cytopenias and a novel GOF mutation in the linker domain of STAT1. Importantly, in addition to increasing T H 1 and suppressing T H 17 cell differentiation, the augmented STAT1 activity dysregulated T FH cell responses.…”

Section: Introductionmentioning

confidence: 84%

Ruxolitinib reverses dysregulated T helper cell responses and controls autoimmunity caused by a novel signal transducer and activator of transcription 1 (STAT1) gain-of-function mutation

Weinacht

Charbonnier

Alroqi

et al. 2017

Journal of Allergy and Clinical Immunology

144

105

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Background Gain of function (GOF) mutations in the human Signal Transducer and Activator of Transcription 1 (STAT1) manifest in immunodeficiency and autoimmunity with impaired T helper (TH) 17 cell differentiation and exaggerated responsiveness to types I and II interferon. Allogeneic bone marrow transplantation has been attempted in severely affected patients but outcomes have been poor. Objective We sought to define the effect of increased STAT1 activity on T helper cell polarization and to investigate the therapeutic potential of ruxolitinib in treating autoimmunity secondary to STAT1 GOF mutations. Methods We used in vitro polarization assays as well as phenotypic and functional analysis of STAT1-mutated patient cells. Results We report on a child with a novel mutation in the linker domain of STAT1 who suffered from life-threatening autoimmune cytopenias and chronic mucocutaneous candidiasis. Naïve patient lymphocytes displayed increased TH1 and T follicular helper (TFH) cell as well as suppressed TH17 cell responses. The mutation augmented cytokine-induced STAT1 phosphorylation without affecting dephosphorylation kinetics. Treatment with the Janus kinase (JAK) 1/2 inhibitor ruxolitinib reduced hyper-responsiveness to types I and II interferon, normalized TH1 and TFH cell responses, improved TH17 differentiation, cured mucocutaneous candidiasis and maintained remission of immune mediated cytopenias. Conclusions Autoimmunity and infection due to STAT1 GOF mutations is caused by dysregulated T helper cell responses. JAK inhibitor therapy could represent an effective targeted treatment for long-term disease control in severely affected patients for whom hematopoietic stem cell transplantation is not available.

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Section: Introductionmentioning

confidence: 84%

Ruxolitinib reverses dysregulated T helper cell responses and controls autoimmunity caused by a novel signal transducer and activator of transcription 1 (STAT1) gain-of-function mutation

Weinacht

Charbonnier

Alroqi

et al. 2017

Journal of Allergy and Clinical Immunology

144

105

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“…Therefore, the mechanisms controlling these cellular regulators (i.e., the transcription factors of the JAK and STAT molecules) become of central importance in human disease. JAK- and STAT inhibitors have already been used to treat lymphoma/cancer, autoimmune diseases such as rheumatoid arthritis (40), and impaired infection control (41, 42). …”

Section: Discussionmentioning

confidence: 99%

ZNF341 controls STAT3 expression and thereby immunocompetence

et al. 2018

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Signal-transducer-and-activator-of-transcription-3 (STAT3) is a central regulator of immune homeostasis. STAT3 levels are strictly controlled and STAT3 impairment contributes to several diseases including the monogenic autosomal-dominant hyper-IgE syndrome (AD-HIES). We investigated patients of four consanguineous families with an autosomal-recessive disorder resembling the phenotype of AD-HIES, with symptoms of immunodeficiency, recurrent infections, skeletal abnormalities, and elevated IgE. Patients presented with reduced STAT3 expression and diminished Th17 cell numbers, in absence of STAT3 mutations. We identified homozygous nonsense mutations in ZNF341, encoding a zinc-finger transcription factor. Wild-type ZNF341 bound to and activated the STAT3 promoter, whereas the mutant variants showed impaired transcriptional activation, partly due to nuclear translocation failure. In summary, nonsense mutations in ZNF341 account for the STAT3-like phenotype in four autosomal-recessive kindreds. Thus, ZNF341 is a previously unrecognized regulator of immune homeostasis.

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“…One patient (P116) was treated with JAK inhibitor ruxolitinib that led to significant clinical improvement of CMC without complete clearance of the disease. 58 Allogeneic hematopoietic stem cell transplantation (HSCT) was performed in 5 patients with severe CMC and recurrent bacterial or systemic viral infections; 3 of them died several months after HSCT, 1 from persistent hemophagocytic lymphohistiocytosis despite 3 HSCT (P157, phenotypically HLA-identical, cord blood transplantation, and haploidentical HSCT), 1 from disseminated CMV at 30 years (P160, fully matched HSCT), and the other from interstitial lung disease at 2 years (P190, HLA-identical sibling HSCT). The other 2 are currently alive without serious complications (P161, cord blood transplantation from mismatched donor and P234, phenotypically HLA-identical HSCT).…”

Section: Preventive and Curative Treatmentmentioning

confidence: 99%

“…Treatments targeting the JAK-STAT pathway, such as the JAK1/2 inhibitor ruxolitinib, which has been approved for myelofibrosis treatment, have shown significant clinical efficiency and might become the treatment of choice for severe CMC resistant to antifungals. 30,58 HSCT was performed in 5 patients with severe and recurrent fungal and viral infections, 25 but 3 of them died. HSCT does not appear to be a viable option at the present time.…”

Section: Stat1 Gof Mutations: An International Survey 3161mentioning

confidence: 99%

Heterozygous STAT1 gain-of-function mutations underlie an unexpectedly broad clinical phenotype

Toubiana

Okada

Hiller

et al. 2016

Blood

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Since their discovery in patients with autosomal dominant (AD) chronic mucocutaneous candidiasis (CMC) in 2011, heterozygous STAT1 gain-of-function (GOF) mutations have increasingly been identified worldwide. The clinical spectrum associated with them needed to be delineated. We enrolled 274 patients from 167 kindreds originating from 40 countries from 5 continents. Demographic data, clinical features, immunological parameters, treatment, and outcome were recorded. The median age of the 274 patients was 22 years (range, 1-71 years); 98% of them had CMC, with a median age at onset of 1 year (range, 0-24 years). Patients often displayed bacterial (74%) infections, mostly because of Staphylococcus aureus (36%), including the respiratory tract and the skin in 47% and 28% of patients, respectively, and viral (38%) infections, mostly because of Herpesviridae (83%) and affecting the skin in 32% of patients. Invasive fungal infections (10%), mostly caused by Candida spp. (29%), and mycobacterial disease (6%) caused by Mycobacterium tuberculosis, environmental mycobacteria, or Bacille Calmette-GuÃ©rin vaccines were less common. Many patients had autoimmune manifestations (37%), including hypothyroidism (22%), type 1 diabetes (4%), blood cytopenia (4%), and systemic lupus erythematosus (2%). Invasive infections (25%), cerebral aneurysms (6%), and cancers (6%) were the strongest predictors of poor outcome. CMC persisted in 39% of the 202 patients receiving prolonged antifungal treatment. Circulating interleukin-17A-producing T-cell count was low for most (82%) but not all of the patients tested. STAT1 GOF mutations underlie AD CMC, as well as an unexpectedly wide range of other clinical features, including not only a variety of infectious and autoimmune diseases, but also cerebral aneurysms and carcinomas that confer a poor prognosis

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Ruxolitinib Induces Interleukin 17 and Ameliorates Chronic Mucocutaneous Candidiasis Caused by STAT1 Gain-of-Function Mutation

Cited by 77 publications

References 7 publications

Ruxolitinib reverses dysregulated T helper cell responses and controls autoimmunity caused by a novel signal transducer and activator of transcription 1 (STAT1) gain-of-function mutation

Ruxolitinib reverses dysregulated T helper cell responses and controls autoimmunity caused by a novel signal transducer and activator of transcription 1 (STAT1) gain-of-function mutation

ZNF341 controls STAT3 expression and thereby immunocompetence

Heterozygous STAT1 gain-of-function mutations underlie an unexpectedly broad clinical phenotype

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