Ex vivo effect of JAK inhibition on JAK-STAT1 pathway hyperactivation in patients with dominant negative STAT3 mutations (original) (raw)
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Background: Natural Killer (NK) cells are critical innate effector cells whose development is dependent on the JAK-STAT pathway. NK deficiency can result in severe or refractory viral infections. Patients with Signal Transducer and Activator of Transcription (STAT)1 gain of function (GOF) mutations have increased viral susceptibility. Objective: We sought to investigate NK cell function in STAT1 GOF patients. Methods: NK cell phenotype and function were determined in 16 STAT1 GOF patients. NK cell lines expressing patient mutations were generated with CRISPR-Cas9 mediated gene editing. STAT1 GOF NK cells were treated in vitro with ruxolitinib. Results: Peripheral blood NK cells from of STAT1 GOF patients had impaired terminal maturation. Specifically, patients with STAT1 GOF mutations have immature CD56dim NK cells with decreased expression of CD16, perforin, CD57 and impaired cytolytic function. STAT1 phosphorylation was elevated but STAT5 was aberrantly phosphorylated in response ...
The Journal of allergy and clinical immunology, 2017
Gain-of-function (GOF) mutations in the human signal transducer and activator of transcription 1 (STAT1) manifest in immunodeficiency and autoimmunity with impaired TH17 cell differentiation and exaggerated responsiveness to type I and II interferons. Allogeneic bone marrow transplantation has been attempted in severely affected patients, but outcomes have been poor. 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. We used in vitro polarization assays, as well as phenotypic and functional analysis of STAT1-mutated patient cells. We report a child with a novel mutation in the linker domain of STAT1 who had life-threatening autoimmune cytopenias and chronic mucocutaneous candidiasis. Naive lymphocytes from the affected patient displayed increased TH1 and follicular T helper cell and suppressed TH17 cell responses. The mutation a...
2022
Introduction. Since the first description of gain of function (GOF) mutations in Signal Transducer and Activator of Transcription (STAT) 1, more than 300 patients have been described with a broad clinical phenotype including infections and severe immune dysregulation. Whilst Jak inhibitors (JAKinibs) have demonstrated benefits in several reported cases, its indications, dosing and monitoring remain to be established. Methods. A retrospective, multicenter study recruiting pediatric patients with STAT1 GOF under JAKinib treatment was performed and, when applicable, compared with the available reports from the literature. Results. Ten children (median age 8.5y (3-18), receiving JAKinibs (ruxolitinib (n=9) and baricitinib (n=1)) with a median follow-up of 18m (2-42) from 6 inborn errors of immunity (IEI) reference centers were included. Clinical profile and JAKinib indications in our series were similar to the previously published 14 pediatric patients. 9/10 (our cohort) and 14/14 patie...
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 fungal infections, autoimmunity, autoinflammatory manifestations, vascular complications, or malignancies. The spectrum of immunological abnormalities may vary and influence the infectious morbidity. Methods. We investigated the mechanisms that may determine T lymphopenia in STAT1-GOF patients and evaluate the interferon signature in patients exhibiting autoimmunity. Results. STAT1-GOF patients may manifest T lymphopenia particularly by adult age. We observed how the hyperactivation of STAT1 associated with a disrupted pattern of apoptosis as the stimulation with IFNα increased the expression of markers of apoptosis via caspase activation and significantly increased the apoptosis of T cells in STAT1-GOF patients. The use of a JA...
Distinct Clinical Phenotypes Associated with JAK2V617F Reflect Differential STAT1 Signaling
Cancer Cell, 2010
The JAK2V617F mutation is associated with distinct myeloproliferative neoplasms, including polycythemia vera (PV) and essential thrombocythemia (ET), but it remains unclear how it generates disparate disorders. By comparing clonally-derived mutant and wild-type cells from individual patients, we demonstrate that the transcriptional consequences of JAK2V617F are subtle, and that JAK2V617F-heterozygous erythroid cells from ET and PV patients exhibit differential interferon signaling and STAT1 phosphorylation. Increased STAT1 activity in normal CD34-positive progenitors produces an ET-like phenotype, whereas downregulation of STAT1 activity in JAK2V617F-heterozygous ET progenitors produces a PV-like phenotype. Our results illustrate the power of clonal analysis, indicate that the consequences of JAK2V617F reflect a balance between STAT5 and STAT1 activation and are relevant for other neoplasms associated with signaling pathway mutations.
The Journal of allergy and clinical immunology, 2018
of HLA-DRb, and Arg74 was linked to several autoimmune diseases, namely Hashimoto thyroiditis and autoimmune polyglandular syndromes. 9 Genetic-structural studies showed that a change at position 74 from the more common neutral amino acids Ala or Gln to the positively charged hydrophilic Arg modifies the 3-dimensional structure of the peptide-binding cleft enabling presentation of autoantigens; alternatively, Arg74 can anchor the T-cell receptor to the peptide2HLA-DRb complex more tightly. 9 Outside HLA, we found a suggestive association with the rs386813511 SNP, which is located in an intergenic region between the SYNDIG1 and CST7 genes. This SNP has unclear functional significance; however, its proxies modulate expression of the CST7 gene, which encodes cystatin F, a cysteine protease inhibitor involved in different immune cell functions. 10 In conclusion, we detected a genome-wide significant association between idiopathic RPF and HLA-DRB1*03, a marker of autoimmune diseases. This association translates into the presence of Arg74 in the peptide-binding pocket of HLA-DRb; Arg74 is also associated with autoimmunity. These findings suggest that idiopathic RPF is an autoimmune disease and invoke the presence of a disease-triggering autoantigen.
Defective JAK-STAT Pathway Signaling Contributes to Autoimmune Diseases
Current Pharmacology Reports, 2018
Purpose of Review Here, we systematically review the published literature indicating that aberrant regulation of Janus kinase/ signal transducers and activators of transcription (JAK-STAT) signaling was associated with the autoimmune disorders, rheumatoid arthritis, systemic lupus erythematosus, psoriasis/psoriatic arthritis, multiple sclerosis, inflammatory bowel diseases, and ankylosing spondylitis. Pertinent Findings The autoimmune disorders discussed in this review are characterized by several alterations resulting in abnormal JAK-STAT signaling. These abnormalities in JAK-STAT signaling include (1) constitutive activation of both the interleukin-6(IL-6)/interleukin-6 receptor (IL-6R) canonical and IL-6 trans-signaling pathway, the latter involving soluble IL-6R; (2) the hyperactivation of JAK/STAT signaling as a response to the significantly elevated levels of pro-inflammatory Bimmunocytokines^, exemplified by IL-6, IL-15, IL-17, IL-23, interferon-γ; and (3) the reduced activity of the negative regulators of JAK-STAT signaling, including suppressor of cytokine signaling and protein inhibitor of activated STATs as well as protein tyrosine phosphatases-1,-2, which was shown to inhibit STAT-signaling. Summary The involvement of abnormal JAK-STAT signaling in autoimmune disorders has led to the development of JAK small molecule inhibitors (SMIs), such as tofacitinib, ruxolitinib, and baricitinib for the therapy of rheumatoid arthritis, psoriasis/ psoriatic arthritis, and Crohn's disease. However, the extent to which treatment of these diseases with JAK SMIs will result in blunting the Bcross-talk^between the JAK-STAT signaling pathway and the other signaling pathways known to participate in autoimmune disorders remains to be determined, involving the mitogen-activated protein kinase pathway and the phosphatidylinositide/Akt/mechanistic target of rapamycin signaling pathway.
Therapeutic Targeting of the JAK/STAT Pathway
Basic & Clinical Pharmacology & Toxicology, 2014
Antibodies that block cytokine function provide a powerful therapeutic tool especially for the treatment of autoimmune diseases. Cytokines are a group of small hydrophilic glycoproteins that bind their receptors on the cell surface and subsequently activate intracellular signalling cascades, such as the JAK/STAT pathway. A bulk of evidence has demonstrated that genetic mutations in signalling molecules can cause immunodeficiencies and malignant cell growth. As a result, several drug companies have begun to develop therapeutics that inhibit the function of JAK tyrosine kinases. Currently, two JAK inhibitors, tofacitinib and ruxolitinib, are used in the clinic for treating rheumatoid arthritis and myeloproliferative diseases, respectively. Inhibiting JAK function has been shown to efficiently prevent the uncontrolled growth of cancerous cells and to harness overly active immune cells. In the future, other small molecule compounds are likely to come into clinical use, and intense work is ongoing to develop inhibitors that specifically target the constitutively active mutant JAKs. This MiniReview will summarize the basic features of the JAK/STAT pathway, its role in human disease and the therapeutic potential of JAK/STAT inhibitors.