Dominant gain-of-function STAT1 mutations in FOXP3 wild-type immune dysregulation– polyendocrinopathy–enteropathy–X-linked–like syndrome Gulbu Uzel, MD,

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Presentation transcript:

Dominant gain-of-function STAT1 mutations in FOXP3 wild-type immune dysregulation– polyendocrinopathy–enteropathy–X-linked–like syndrome Gulbu Uzel, MD, Elizabeth P. Sampaio, MD, PhD, Monica G. Lawrence, MD, Amy P. Hsu, BA, Mary Hackett, BSN, Morna J. Dorsey, MD, Richard J. Noel, MD, James W. Verbsky, MD, PhD, Alexandra F. Freeman, MD, Erin Janssen, MD, Francisco A. Bonilla, MD, PhD, Joseph Pechacek, MS, Prabha Chandrasekaran, PhD, Sarah K. Browne, MD, Anahita Agharahimi, MSN, CRNP, Ahmed M. Gharib, MD, Sara C. Mannurita, MD, Jae Joon Yim, MD, MPH, Eleonora Gambineri, MD, Troy Torgerson, MD, PhD, Dat Q. Tran, MD, Joshua D. Milner, MD, Steven M. Holland, MD Journal of Allergy and Clinical Immunology Volume 131, Issue 6, Pages 1611-1623.e3 (June 2013) DOI: 10.1016/j.jaci.2012.11.054 Copyright © 2013 Terms and Conditions

Fig 1 Clinical phenotypes. A, Patient 1: extensive candidiasis of nails, causing dystrophy and paronychia. B, Patient 3: multiple intracranial aneurysms in the circle of Willis, as detected by using computed tomographic angiography and magnetic resonance angiography. C, Bilateral lower lobe bronchiectasis with endobronchial/peribronchial consolidation seen on chest computed tomography. D, Multiple calcifications in the descending aorta detected by means of computed tomography in patient 3. Journal of Allergy and Clinical Immunology 2013 131, 1611-1623.e3DOI: (10.1016/j.jaci.2012.11.054) Copyright © 2013 Terms and Conditions

Fig 1 Clinical phenotypes. A, Patient 1: extensive candidiasis of nails, causing dystrophy and paronychia. B, Patient 3: multiple intracranial aneurysms in the circle of Willis, as detected by using computed tomographic angiography and magnetic resonance angiography. C, Bilateral lower lobe bronchiectasis with endobronchial/peribronchial consolidation seen on chest computed tomography. D, Multiple calcifications in the descending aorta detected by means of computed tomography in patient 3. Journal of Allergy and Clinical Immunology 2013 131, 1611-1623.e3DOI: (10.1016/j.jaci.2012.11.054) Copyright © 2013 Terms and Conditions

Fig 2 STAT1 staining. A, Intracellular staining of phospho-tyrosine 701 STAT1 in CD3+ lymphocytes isolated from healthy control subjects and patients with STAT1 gain-of-function mutations (patients 2 and 3) after stimulation with IFN-γ, IL-6, or IL-21 for 15 minutes. B, Kinetics of the STAT1 phosphorylation were studied by using intracellular phospho-tyrosine 701 STAT1 staining in U3A cells transfected with mutant or WT constructs and stimulated with IFN-γ. Stimulation indices at 60 minutes after stimulation (stimulation index: mean fluorescence index phospho-STAT1 at 60 minutes after stimulation/mean fluorescence index phospho-STAT1 at rest) were higher for mutants (stimulation index: 2.6 for R210I, 4.0 for L358W, and 4.4 for T385M) than for WT STAT1 (stimulation index of 0.9, P < .05). Journal of Allergy and Clinical Immunology 2013 131, 1611-1623.e3DOI: (10.1016/j.jaci.2012.11.054) Copyright © 2013 Terms and Conditions

Fig 3 Treg cell subsets, FOXP3 expression, cytokine profiles, and STAT5 signaling. A, Percentage and level of FOXP3 and HELIOS expression within CD3+CD4+ gated T cells from patients 2 and 3 compared with healthy control subjects. B, Induction of FOXP3 and absence of HELIOS expression in naive T cells from healthy control subjects and patients 2 and 3 on day 5 after anti-CD3/CD28 stimulation in the presence of IL-2 (NONE) only, IL-2 plus TGF-β1, IL-2 plus TGF-β1 and IFN-γ, or IL-2 plus TGF-β1 and IL-21. C, Comparison of cytokine expression between FOXP3+ and FOXP3− CD4+ T cells within fresh PBMCs of healthy control subjects and patients 2 and 3 stimulated with phorbol 12-myristate 13-acetate/ionomycin. D, Normal IL-2–induced STAT5 phosphorylation in CD3+ lymphocytes of patient 3 (solid line histogram) compared with healthy control (dashed histogram) and unstimulated (shaded histogram) cells. Patient 2 had a similar expression profile (data not shown). Journal of Allergy and Clinical Immunology 2013 131, 1611-1623.e3DOI: (10.1016/j.jaci.2012.11.054) Copyright © 2013 Terms and Conditions

Fig 3 Treg cell subsets, FOXP3 expression, cytokine profiles, and STAT5 signaling. A, Percentage and level of FOXP3 and HELIOS expression within CD3+CD4+ gated T cells from patients 2 and 3 compared with healthy control subjects. B, Induction of FOXP3 and absence of HELIOS expression in naive T cells from healthy control subjects and patients 2 and 3 on day 5 after anti-CD3/CD28 stimulation in the presence of IL-2 (NONE) only, IL-2 plus TGF-β1, IL-2 plus TGF-β1 and IFN-γ, or IL-2 plus TGF-β1 and IL-21. C, Comparison of cytokine expression between FOXP3+ and FOXP3− CD4+ T cells within fresh PBMCs of healthy control subjects and patients 2 and 3 stimulated with phorbol 12-myristate 13-acetate/ionomycin. D, Normal IL-2–induced STAT5 phosphorylation in CD3+ lymphocytes of patient 3 (solid line histogram) compared with healthy control (dashed histogram) and unstimulated (shaded histogram) cells. Patient 2 had a similar expression profile (data not shown). Journal of Allergy and Clinical Immunology 2013 131, 1611-1623.e3DOI: (10.1016/j.jaci.2012.11.054) Copyright © 2013 Terms and Conditions

Fig 4 Treg cell suppressive function. A, The responders-only histogram represents CFSE dilution on day 4 within CD4+ T cells. The histograms in the 2 right columns demonstrate the level of proliferative suppression within CFSE+ cells in the presence of one half and one quarter of the numbers of Treg and effector T cells relative to responders. The left FACS plot column shows the level of FOXP3 expression within CFSE− Treg/effector T cells and CFSE+ responders on day 4. Patient 2 and control subject 1 are allogeneic, and control subject 2 is autologous to responders and HLA-DR+ APCs. B, Suppressive function of Treg cells from patient 3 and healthy control subjects. Patient 3 and control subject 1 are allogeneic, and control subject 2 is autologous to responders and HLA-DR+ APCs. Tcons, Conventional T cells. Journal of Allergy and Clinical Immunology 2013 131, 1611-1623.e3DOI: (10.1016/j.jaci.2012.11.054) Copyright © 2013 Terms and Conditions

Fig E1 STAT1 binding activity. A, STAT1 binding activity to a GAS oligonucleotide shown as fold induction in response to IFN-γ versus no stimulation (NS) in EBV-transformed B cells from a healthy control subject and patients 1 to 4, as indicated by their mutations. The mean fold increase (2.84 ± 0.31; range 2.46 to 3.16) in STAT1 binding to a GAS oligonucleotide for all 4 mutations over WT is shown (P < .05). B, STAT1 activation of GAS-driven luciferase activity in response to IFN-γ and IFN-α in U3A cells transfected with WT and mutant STAT1 (R201I, L358W, and L385M). Activity is measured as fold increase over nonstimulated (NS) values. When compared with WT subjects, mutant constructs led to enhanced STAT1 activation (mean fold induction, 3.03 ± 0.26; range, 2.72-3.35) in response to IFN-γ (P = .04). Patients with mutations also showed similar enhanced STAT1 activation with IFN-α (mean fold induction, 3.67 ± 1.52; P < .05). This observed enhanced STAT1 response was unaffected by cotransfection of patients with mutations with WT STAT1, confirming the dominant gain-of-function nature of these mutations. Journal of Allergy and Clinical Immunology 2013 131, 1611-1623.e3DOI: (10.1016/j.jaci.2012.11.054) Copyright © 2013 Terms and Conditions

Fig E1 STAT1 binding activity. A, STAT1 binding activity to a GAS oligonucleotide shown as fold induction in response to IFN-γ versus no stimulation (NS) in EBV-transformed B cells from a healthy control subject and patients 1 to 4, as indicated by their mutations. The mean fold increase (2.84 ± 0.31; range 2.46 to 3.16) in STAT1 binding to a GAS oligonucleotide for all 4 mutations over WT is shown (P < .05). B, STAT1 activation of GAS-driven luciferase activity in response to IFN-γ and IFN-α in U3A cells transfected with WT and mutant STAT1 (R201I, L358W, and L385M). Activity is measured as fold increase over nonstimulated (NS) values. When compared with WT subjects, mutant constructs led to enhanced STAT1 activation (mean fold induction, 3.03 ± 0.26; range, 2.72-3.35) in response to IFN-γ (P = .04). Patients with mutations also showed similar enhanced STAT1 activation with IFN-α (mean fold induction, 3.67 ± 1.52; P < .05). This observed enhanced STAT1 response was unaffected by cotransfection of patients with mutations with WT STAT1, confirming the dominant gain-of-function nature of these mutations. Journal of Allergy and Clinical Immunology 2013 131, 1611-1623.e3DOI: (10.1016/j.jaci.2012.11.054) Copyright © 2013 Terms and Conditions