Multisystem autoimmune disease caused by increased STAT3 phosphorylation and dysregulated gene expression

Todaro, Francesca; Tamassia, Nicola; Pinelli, Marinella; Moratto, Daniele; Dotta, Laura; Grassi, Alessia; Consonni, Filippo; Giacomelli, Mauro; Lionetti, Paolo; Gardiman, Elisa; Cassatella, Marco A.; Gambineri, Eleonora; Canani, Roberto Berni; Badolato, Raffaele

doi:10.3324/haematol.2018.202374

Cited by 16 publications

(11 citation statements)

References 17 publications

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“…In accordance with this, next-generation sequencing analyses in these patients identified pathogenic or likely pathogenic mutations in signal transducer and activator of transcription 3 (STAT3), inhibitor of nuclear factor kappa B kinase regulatory subunit gamma/NF-kappa-B essential modulator (IKBKG/NEMO), perforin 1 (PRF1), and recombination activating 1 (RAG1). Such findings are consistent with ALPS-like features previously described in patients carrying defects in the same genes, even though the overall clinical phenotypes of these disorders are extremely heterogeneous and different from ALPS [38][39][40][41][42][43][44].…”

Section: Alps-u: Determining the Undeterminedsupporting

confidence: 91%

ALPS, FAS, and beyond: from inborn errors of immunity to acquired immunodeficiencies

2022

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Autoimmune lymphoproliferative syndrome (ALPS) is a primary immune regulatory disorder characterized by benign or malignant lymphoproliferation and autoimmunity. Classically, ALPS is due to mutations in FAS and other related genes; however, recent research revealed that other genes could be responsible for similar clinical features. Therefore, ALPS classification and diagnostic criteria have changed over time, and several ALPS-like disorders have been recently identified. Moreover, mutations in FAS often show an incomplete penetrance, and certain genotypes have been associated to a dominant or recessive inheritance pattern. FAS mutations may also be acquired or could become pathogenic when associated to variants in other genes, delineating a possible digenic type of inheritance. Intriguingly, variants in FAS and increased TCR αβ double-negative T cells (DNTs, a hallmark of ALPS) have been identified in multifactorial autoimmune diseases, while FAS itself could play a potential role in carcinogenesis. These findings suggest that alterations of FAS-mediated apoptosis could trespass the universe of inborn errors of immunity and that somatic mutations leading to ALPS could only be the tip of the iceberg of acquired immunodeficiencies.

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Section: Alps-u: Determining the Undeterminedsupporting

confidence: 91%

ALPS, FAS, and beyond: from inborn errors of immunity to acquired immunodeficiencies

2022

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“…In ALPS (P14), for instance, sirolimus has already demonstrated to induce a partial normalization of biomarkers (22). On the other hand, ALPS-like disorders such as STAT3 GOF disease (P18) and APDS (P15) (68)(69)(70), as well as CARD11 loss-of-function mutations (P16) (46), distort intracellular signaling cascades, leading to the previously described altered immunophenotype. Interestingly, hyperactivation of PI3Kd (P15) enhances mTOR signaling, skewing the differentiation of CD8+ T cells towards short-living effector cells and impairing the development of memory T and B cells (71).…”

Section: Discussionmentioning

confidence: 99%

Autoimmune Cytopenias and Dysregulated Immunophenotype Act as Warning Signs of Inborn Errors of Immunity: Results From a Prospective Study

et al. 2022

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Inborn errors of immunity (IEI) are genetic disorders characterized by a wide spectrum of clinical manifestations, ranging from increased susceptibility to infections to significant immune dysregulation. Among these, primary immune regulatory disorders (PIRDs) are mainly presenting with autoimmune manifestations, and autoimmune cytopenias (AICs) can be the first clinical sign. Significantly, AICs in patients with IEI often fail to respond to first-line therapy. In pediatric patients, autoimmune cytopenias can be red flags for IEI. However, for these cases precise indicators or parameters useful to suspect and screen for a hidden congenital immune defect are lacking. Therefore, we focused on chronic/refractory AIC patients to perform an extensive clinical evaluation and multiparametric flow cytometry analysis to select patients in whom PIRD was strongly suspected as candidates for genetic analysis. Key IEI-associated alterations causative of STAT3 GOF disease, IKAROS haploinsufficiency, activated PI3Kδ syndrome (APDS), Kabuki syndrome and autoimmune lymphoproliferative syndrome (ALPS) were identified. In this scenario, a dysregulated immunophenotype acted as a potential screening tool for an early IEI diagnosis, pivotal for appropriate clinical management and for the identification of new therapeutic targets.

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“…The absence or decreased expression of WAS protein and the subsequent immune impairments might be responsible for autoimmune complications in patients with WAS mutation ( 20 ). Altered phosphorylation of STAT3 in STAT3 deficiency ( 25 ) or DNA methylation in DNMT3B and ZBTB24 are probably accounted for the autoimmunity in these diseases ( 26 ).…”

Section: Discussionmentioning

confidence: 99%

Autoimmunity in monogenic combined immune deficiencies with associated or syndromic features

et al. 2022

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BackgroundCombined immune deficiencies (CIDs) with associated or syndromic features are a highly heterogeneous subgroup of inherited immune disorders. These patients represent specific clinical complications with an increased risk of autoimmune conditions.MethodsWe analyzed data of monogenic patients with syndromic CIDs adopted from the Iranian inborn errors of immunity registry up to January 2022. A comprehensive comparison in terms of demographic, clinical, and immunological features was performed between patients with and without autoimmunity and also among four mutation groups with the most registered cases including ATM, STAT3 (AD-LOF), DNMT3B/ZBTB24, and WAS mutations.ResultsA total of 137 patients with monogenic syndromic CIDs were included. Most commonly mutated genes were the ATM [80 (58.4%)] and STAT3 (AD-LOF) [19 (13.9%)], followed by DNMT3B [11 (8%)], and WAS [11 (8%)]. More than 18% of all patients with syndromic CIDs, including most DNMT3B/ZBTB24 mutations patients, were clinically diagnosed with antibody deficiencies before genetic evaluation. Patients with ATM and WAS mutations had the latest age of onset and the lowest age of diagnosis, respectively. Autoimmune disorders were diagnosed in 24 patients at a median age of 3.5 (2.6-6.0) years, 70.6% of which were diagnosed prior to the diagnosis of immunodeficiency. Lymphoproliferation, particularly hepatosplenomegaly, was significantly higher in patients with autoimmunity (p=0.004). Syndromic CID patients with autoimmunity had significantly lower IgG levels. Hematologic autoimmunity mainly immune thrombocytopenic purpura was the most frequent autoimmunity among major groups of ATM, STAT3 (AD-LOF), DNMT3B/ZBTB24, and WAS mutations, however ATM-mutated patients present more diversified involved organs including rheumatologic, gastrointestinal and dermatologic autoimmunity.ConclusionAbout 18% of patients with monogenic syndromic CIDs developed autoimmunity, mainly in the form of hematological immune diseases. Autoimmunity could be an early-onset involvement with a potential diagnostic impact on suspicious cases of syndromic CIDs.

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Multisystem autoimmune disease caused by increased STAT3 phosphorylation and dysregulated gene expression

Cited by 16 publications

References 17 publications

ALPS, FAS, and beyond: from inborn errors of immunity to acquired immunodeficiencies

ALPS, FAS, and beyond: from inborn errors of immunity to acquired immunodeficiencies

Autoimmune Cytopenias and Dysregulated Immunophenotype Act as Warning Signs of Inborn Errors of Immunity: Results From a Prospective Study

Autoimmunity in monogenic combined immune deficiencies with associated or syndromic features

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