Early‐onset, fatal interstitial lung disease in STAT3 gain‐of‐function patients

Gothe, Florian; Gehrig, Jonathan; Rapp, Christina; Knoflach, Katrin; Reu‐Hofer, Simone; Schramm, Dirk; Ley‐Zaporozhan, Julia; Ehl, Stephan; Schwerk, Nicolaus; Faletti, Laura; Griese, Matthias

doi:10.1002/ppul.25684

Cited by 11 publications

(7 citation statements)

References 23 publications

(48 reference statements)

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“…So far, there is no standard treatment guideline available for STAT3 GOF syndrome ( 10 , 11 ). Nontargeted immunosuppressive therapies were found to be overall ineffective in STAT3 GOF-related ILD, potentially increasing the risk of infections ( 12 – 15 ). The monotherapy with tocilizumab is also insufficient to improve respiratory status ( 14 ).…”

Section: Discussionmentioning

confidence: 99%

“…Both the immunosuppressive agents and targeted treatments have been reported. Whereas the former drugs were found to be overall ineffective, and instead, they increased the risk of infections ( 12 – 15 ). Targeted treatments such as JAK inhibitors and monoclonal antibodies against the interleukin 6 (IL-6) receptor have been proven to target the JAK-STAT pathway indirectly and shown promising results in STAT3 GOF diseases ( 4 , 16 ).…”

Section: Introductionmentioning

confidence: 99%

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A Novel STAT3 Gain-of-Function Mutation in Fatal Infancy-Onset Interstitial Lung Disease

Deng

et al. 2022

Front. Immunol.

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Signal transducer and activator of transcription 3 (STAT3) gain-of-function (GOF) mutations cause early-onset immune dysregulation syndrome, characterized by multi-organ autoimmunity and lymphoproliferation. Of them, interstitial lung disease (ILD) usually develops after the involvement of other organs, and the onset time is childhood and beyond rather than infancy. Here, we reported a patient who presented with fatal infancy-onset ILD, finally succumbing to death. Next-generation sequencing identified a novel heterozygous mutation in STAT3 (c.989C>G, p.P330R). Functional experiments revealed it was a gain-of-function mutation. Upon interleukin 6 stimulation, this mutation caused a much higher activation of STAT3 than the wild-type control. In addition, the mutation also activated STAT3 under the steady state. The T helper 17 cell level in the patient was significantly higher than that in normal controls, which may contribute to the autoimmune pathology caused by the STAT3P330R mutation. Apart from Janus kinase (JAK) inhibitors, we also provided experimental evidence of a STAT3 selective inhibitor (Stattic) effectively suppressing the activation of mutant STAT3 in vitro. Collectively, our study expanded the clinical spectrum of STAT3 GOF syndrome. STAT3 GOF mutation appears as a new etiology of ILD and should be considered in patients with early-onset ILDs. In addition to JAK inhibitors, the specific STAT3 inhibitor would be an appealing option for the targeted treatment.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

A Novel STAT3 Gain-of-Function Mutation in Fatal Infancy-Onset Interstitial Lung Disease

Deng

et al. 2022

Front. Immunol.

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“…Previous studies have shown that the STAT3 protein family is closely related to the inflammatory response and immune response. As a transcription factor, STAT3 can participate in the regulation of the expression of inflammation-related genes (24,25). At the same time, a study has shown that STAT3 is closely related to the degree of tissue fibrosis.…”

Section: Discussionmentioning

confidence: 99%

Pirfenidone inhibits cell fibrosis in connective tissue disease-associated interstitial lung disease by targeting the TNF-α/STAT3/KL6 pathway

Zuo¹,

Liu²,

Xu³

et al. 2022

J Thorac Dis

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Background: To explore the effect and mechanism of pirfenidone in inhibiting pulmonary fibrosis in connective tissue disease-associated interstitial lung disease (CTD-ILD). Methods: From 2018 to 2020, 50 CTD-ILD patients were enrolled in the clinical study. Based on whether pirfenidone was used during treatment, patients were enrolled into the pirfenidone group and the control group. Pulmonary function tests were compared before and after treatment. Enzyme-linked immunosorbent assay (ELISA) was performed to detect the expression of tumor necrosis factor-α (TNF-α), signal transducer and activator of transcription 3 (STAT3), and Krebs Von den Lungen-6 (KL-6) in venous blood before and after treatment. Rat type II (RLE-6TN) lung epithelial cells were cultivated for in vitro experiments, and they were sorted into the control group, bleomycin group, pirfenidone group, TNF-α group, Stattic group, and TNF-α/Stattic combined treatment group. For the in vitro experiments, 3-(4,5-dimethylthiazol-2-yl)-2,5diphenyltetrazolium bromide (MTT) tests were used to evaluate cell proliferation, Reverse Transcription-Polymerase Chain Reaction(RT-PCR) was performed to detect STAT3 and KL-6 mRNA expression levels, ELISA was utilized to detect TNF-α and E-cadherin expression levels, and Western blotting (WB) was performed to determine α-smooth muscle actin (α-SMA), vimentin, TNF-α, STAT3, phosphorylated signal transducer and activator of transcription 3 (PSTAT3) and KL-6 expression.Results: In the clinical study, the pulmonary function indices including forced expiratory volume in one second (FEV1), forced vital capacity (FVC), FEV1/FVC, peak expiratory flow (PEF) and partial pressure (PaO 2 ) of the patients in the study group were superior to those in the control group (P<0.05). The serum TNF-α, STAT3 and KL-6 levels in the study group were significantly lower than those in the control group (P<0.05). In the in vitro experiments, the α-SMA, vimentin, STAT3 and KL-6 levels in the treatment group were significantly lower than those in the bleomycin group (P<0.05). Compared with those in the pirfenidone group, the α-SMA, vimentin, STAT3 and KL-6 levels in the TNF-α-treated group were significantly upregulated (P<0.05). Meanwhile, cell viability was further upregulated (P<0.05), and the expression of STAT3 and KL-6 was further decreased in the Stattic-treated group (P<0.05). In the group treated with infliximab combined with Stattic, TNF-α expression was significantly increased (P<0.05), cell activity was significantly restored (P<0.05), and the STAT3, KL-6 and E-cadherin expression levels were inhibited (P<0.05).Conclusions: Pirfenidone improved pulmonary function 1 and decreased TNF-α, STAT3, and KL-6 expression in CTD-ILD patients. Moreover, pirfenidone inhibits cell fibrosis through the TNF-α/STAT3/ Mucin 1(MUC1) pathway.

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“…The most common cause is pre-term delivery; in this clinical context the term chronic neonatal lung disease (CNLD) has been established for children requiring oxygen for >28 days after birth (figure 4) [51]. Comparable forms of alveolar simplification are the sequelae of pulmonary hypoplasia, either as a primary form associated with genetic abnormalities (NKX2-1 (NK2 homeobox 1; alias TTF1 (thyroid transcription factor 1)) deficiency, FLNA (filamin A) mutation, trisomy 21) (figure 5 and supplementary figure S1), or as a secondary form with impaired lung unfolding triggered by diaphragmatic hernia, oligohydramnios, thoracic skeletal dysplasia or neuromuscular disease (supplementary table S1 and figure 2) [7,44,45,52].…”

Section: Diffuse Growth Abnormalities Of Lung Parenchyma (A2)mentioning

confidence: 99%

Interstitial lung disease in infancy and early childhood: a clinicopathological primer

et al. 2022

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Children's interstitial lung disease (chILD) encompasses a wide and heterogeneous spectrum of diseases substantially different from that of adults. Established classification systems divide chILD into conditions more prevalent in infancy and other conditions occurring at any age. This categorisation is based on a multidisciplinary approach including clinical, radiological, genetic and histological findings. The diagnostic evaluation may include lung biopsies if other diagnostic approaches failed to identify a precise chILD entity, or if severe or refractory respiratory distress of unknown cause is present. As the majority of children will be evaluated and diagnosed outside of specialist centres, this review summarises relevant clinical, genetic and histological findings of chILD to provide assistance in clinical assessment and rational diagnostics.

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Early‐onset, fatal interstitial lung disease in STAT3 gain‐of‐function patients

Cited by 11 publications

References 23 publications

A Novel STAT3 Gain-of-Function Mutation in Fatal Infancy-Onset Interstitial Lung Disease

A Novel STAT3 Gain-of-Function Mutation in Fatal Infancy-Onset Interstitial Lung Disease

Pirfenidone inhibits cell fibrosis in connective tissue disease-associated interstitial lung disease by targeting the TNF-α/STAT3/KL6 pathway

Interstitial lung disease in infancy and early childhood: a clinicopathological primer

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