Defective actin accumulation impairs human natural killer cell function in patients with dedicator of cytokinesis 8 deficiency Melissa C. Mizesko, MD,

Slides:

Advertisements

Similar presentations

Beneficial IFN-α treatment of tumorous herpes simplex blepharoconjunctivitis in dedicator of cytokinesis 8 deficiency Cihan Papan, MD, Beate Hagl, PhD,

Advertisements

Immune deficiency caused by impaired expression of nuclear factor-κB essential modifier (NEMO) because of a mutation in the 5′ untranslated region of.

Plasmacytoid dendritic cell depletion in DOCK8 deficiency: Rescue of severe herpetic infections with IFN-α 2b therapy Sevgi Keles, MD, Haifa H. Jabara,

Expression of IL-9 receptor α chain on human germinal center B cells modulates IgE secretion Lama M. Fawaz, PhD, Ehssan Sharif-Askari, PhD, Oumnia Hajoui,

Defective natural killer–cell cytotoxic activity in NFKB2-mutated CVID-like disease Vassilios Lougaris, MD, Giovanna Tabellini, PhD, Massimiliano Vitali,

The importance of being “pure” neutrophils

Beneficial IFN-α treatment of tumorous herpes simplex blepharoconjunctivitis in dedicator of cytokinesis 8 deficiency Cihan Papan, MD, Beate Hagl, PhD,

Epigenetic regulation of established human type 1 versus type 2 cytokine responses Ruey-Chyi Su, PhD, Allan B. Becker, MD, Anita L. Kozyrskyj, PhD, Kent.

A case of partial dedicator of cytokinesis 8 deficiency with altered effector phenotype and impaired CD8+ and natural killer cell cytotoxicity Raquel.

Impaired TH17 responses in patients with chronic mucocutaneous candidiasis with and without autoimmune polyendocrinopathy–candidiasis–ectodermal dystrophy

Chediak-Higashi syndrome: Lysosomal trafficking regulator domains regulate exocytosis of lytic granules but not cytokine secretion by natural killer cells

Proviral integration site for Moloney murine leukemia virus 1, but not phosphatidylinositol-3 kinase, is essential in the antiapoptotic signaling cascade.

MiR-155 is overexpressed in patients with atopic dermatitis and modulates T-cell proliferative responses by targeting cytotoxic T lymphocyte–associated.

Toll-like receptor 7–induced naive human B-cell differentiation and immunoglobulin production Mark C. Glaum, MD, PhD, Shilpi Narula, MD, Decheng Song,

Anti–IL-5 (mepolizumab) therapy reduces eosinophil activation ex vivo and increases IL- 5 and IL-5 receptor levels Miguel L. Stein, MD, Joyce M. Villanueva,

Chronic mucocutaneous candidiasis associated with an SH2 domain gain-of-function mutation that enhances STAT1 phosphorylation Ali Sobh, MD, Janet Chou,

Reduction of CRKL expression in patients with partial DiGeorge syndrome is associated with impairment of T-cell functions Mauro Giacomelli, PhD, Rajesh.

Dedicator of cytokinesis 8–deficient patients have a breakdown in peripheral B-cell tolerance and defective regulatory T cells Erin Janssen, MD, PhD,

Type 3 innate lymphoid cells induce proliferation of CD94+ natural killer cells Shuo Li, PhD, Hideaki Morita, MD, PhD, Beate Rückert, Sci Tec, Tadech.

Differential control of TH1 versus TH2 cell responses by the combination of low-dose steroids with β2-adrenergic agonists Elena Goleva, PhD, Annegret.

Molecular mechanisms of functional natural killer deficiency in patients with partial DiGeorge syndrome Peilin Zheng, PhD, Lenora M. Noroski, MD, Imelda.

Recurrent viral infections associated with a homozygous CORO1A mutation that disrupts oligomerization and cytoskeletal association Christina S. Yee,

Dawn C. Newcomb, PhD, Madison G

CD19 controls Toll-like receptor 9 responses in human B cells

IL-13 involvement in eosinophilic esophagitis: Transcriptome analysis and reversibility with glucocorticoids Carine Blanchard, PhD, Melissa K. Mingler,

RNA sequencing reveals the consequences of a novel insertion in dedicator of cytokinesis-8 Shaheen Khan, PhD, Merin Kuruvilla, MD, David Hagin, MD, PhD,

Insights into primary immune deficiency from quantitative microscopy

Distinct mutations at the same positions of STAT3 cause either loss or gain of function Prabha Chandrasekaran, PhD, Ofer Zimmerman, MD, Michelle Paulson,

Hemophagocytic lymphohistiocytosis in 2 patients with underlying IFN-γ receptor deficiency Bianca Tesi, MD, Elena Sieni, MD, Conceição Neves, MD, Francesca.

Human dendritic cell subset 4 (DC4) correlates to a subset of CD14dim/−CD16++ monocytes Federica Calzetti, BS, Nicola Tamassia, PhD, Alessandra Micheletti,

Diagnostic approach to the hyper-IgE syndromes: Immunologic and clinical key findings to differentiate hyper-IgE syndromes from atopic dermatitis Lena.

Miriam Wittmann, MD, Jana Zeitvogel, Dong Wang, MD, Thomas Werfel, MD

Kathleen R. Bartemes, BA, Gail M. Kephart, BS, Stephanie J

CD94/NKG2C is a killer effector molecule in patients with Stevens-Johnson syndrome and toxic epidermal necrolysis Esther Morel, PhD, Salvador Escamochero,

Comèl-Netherton syndrome defined as primary immunodeficiency

IL-13 dampens human airway epithelial innate immunity through induction of IL-1 receptor–associated kinase M Qun Wu, MD, PhD, Di Jiang, BS, Sean Smith,

Dedicator of cytokinesis 8–deficient patients have a breakdown in peripheral B-cell tolerance and defective regulatory T cells Erin Janssen, MD, PhD,

Interleukin receptor-associated kinase-4 deficiency impairs Toll-like receptor–dependent innate antiviral immune responses Douglas R. McDonald, MD, PhD,

Hematopoietic stem cell transplantation outcomes for 11 patients with dedicator of cytokinesis 8 deficiency Waleed Al-Herz, MD, Julia I. Chu, MD, Jet.

A novel Rab27a mutation binds melanophilin, but not Munc13-4, causing immunodeficiency without albinism Petra Netter, PhD, Sanny K. Chan, MD, PhD, Pinaki.

Corticosteroid-resistant asthma is associated with classical antimicrobial activation of airway macrophages Elena Goleva, PhD, Pia J. Hauk, MD, Clifton.

T-box 21 transcription factor is responsible for distorted TH2 differentiation in human peripheral CD4+ T cells Osamu Kaminuma, DVM, PhD, Fujiko Kitamura,

Antiviral activity of human β-defensin 3 against vaccinia virus

Impaired natural killer cell functions in patients with signal transducer and activator of transcription 1 (STAT1) gain-of-function mutations Giovanna.

A peptide derived from the Wiskott-Aldrich syndrome (WAS) protein-interacting protein (WIP) restores WAS protein level and actin cytoskeleton reorganization.

The Editors' Choice Journal of Allergy and Clinical Immunology

Novel mutation in STXBP2 prevents IL-2–induced natural killer cell cytotoxicity Rushani W. Saltzman, MD, Linda Monaco-Shawver, BA, Kejian Zhang, MD, MBA,

Immune deficiency caused by impaired expression of nuclear factor-κB essential modifier (NEMO) because of a mutation in the 5′ untranslated region of.

Baricitinib treatment in a patient with a gain-of-function mutation in signal transducer and activator of transcription 1 (STAT1) Kornvalee Meesilpavikkai,

Joris M. van Montfrans, MD, PhD, Andy I. M

Expression of IL-9 receptor α chain on human germinal center B cells modulates IgE secretion Lama M. Fawaz, PhD, Ehssan Sharif-Askari, PhD, Oumnia Hajoui,

Invasive fungal disease in autosomal-dominant hyper-IgE syndrome

Autoimmune lymphoproliferative syndrome caused by a homozygous FasL mutation that disrupts FasL assembly Ali Sobh, MD, Elena Crestani, MD, Brittney Cangemi,

IL-13 dampens human airway epithelial innate immunity through induction of IL-1 receptor–associated kinase M Qun Wu, MD, PhD, Di Jiang, BS, Sean Smith,

Allogeneic transplantation successfully corrects immune defects, but not susceptibility to colitis, in a patient with nuclear factor-κB essential modulator.

Huie Jing, PhD, Qian Zhang, MD, Yu Zhang, PhD, Brenna J

Jenny Seltmann, PhD, Lennart M

CCL17/thymus and activation-regulated chemokine induces calcitonin gene–related peptide in human airway epithelial cells through CCR4 Kandace Bonner,

The Editors' Choice Journal of Allergy and Clinical Immunology

CD25 deficiency causes an immune dysregulation, polyendocrinopathy, enteropathy, X- linked–like syndrome, and defective IL-10 expression from CD4 lymphocytes

Severe cutaneous human papillomavirus infection associated with natural killer cell deficiency following stem cell transplantation for severe combined.

Cigarette smoke exposure is associated with vitamin D3 deficiencies in patients with chronic rhinosinusitis Jennifer K. Mulligan, PhD, Whitney Nagel,

Janet Chou, MD, Maxim Lutskiy, MD, PhD, Erdyni Tsitsikov, PhD, Luigi D

Neuropeptide signaling through neurokinin-1 and neurokinin-2 receptors augments antigen presentation by human dendritic cells Junya Ohtake, PhD, Shun.

Hematopoietic stem cell transplantation for CD3δ deficiency

Intact IL-12 signaling is necessary for the generation of human natural killer cells with enhanced effector function after restimulation Venkateswara.

Perturbations of natural killer cell regulatory functions in respiratory allergic diseases Francesca Scordamaglia, MD, Mirna Balsamo, PhD, Antonio Scordamaglia,

CCL17/thymus and activation-regulated chemokine induces calcitonin gene–related peptide in human airway epithelial cells through CCR4 Kandace Bonner,

Combined immunodeficiency in a patient with c-Rel deficiency

Invariant natural killer T cells from children with versus without food allergy exhibit differential responsiveness to milk-derived sphingomyelin Soma.

Presentation transcript:

Defective actin accumulation impairs human natural killer cell function in patients with dedicator of cytokinesis 8 deficiency Melissa C. Mizesko, MD, Pinaki P. Banerjee, PhD, Linda Monaco-Shawver, BA, Emily M. Mace, PhD, William E. Bernal, MD, Julie Sawalle-Belohradsky, Bernd H. Belohradsky, MD, Valerie Heinz, Alexandra F. Freeman, MD, Kathleen E. Sullivan, MD, PhD, Steven M. Holland, MD, Troy R. Torgerson, MD, PhD, Waleed Al-Herz, MD, Janet Chou, MD, Imelda C. Hanson, MD, Michael H. Albert, MD, Raif S. Geha, MD, Ellen D. Renner, MD, Jordan S. Orange, MD, PhD Journal of Allergy and Clinical Immunology Volume 131, Issue 3, Pages 840-848 (March 2013) DOI: 10.1016/j.jaci.2012.12.1568 Copyright © 2013 Terms and Conditions

Fig 1 DOCK8 deficiency impairs NK cell cytotoxicity, which is not restored by IL-2. Control donor PBMCs (n = 15) and PBMCs from DOCK8-deficient and STAT3 mutant patients were used in chromium-release assays ex vivo without (A) or with (B) 4 hours of stimulation with 1000 U of IL-2. Cytotoxic function was expressed as lytic units (LU)10/NK cell. Error bars represent means ± SEMs for patients analyzed 3 times. Journal of Allergy and Clinical Immunology 2013 131, 840-848DOI: (10.1016/j.jaci.2012.12.1568) Copyright © 2013 Terms and Conditions

Fig 2 DOCK8-deficient patients have NK cells. Results of flow cytometric analysis of the percentage of CD56+CD3− cells in PBMCs are shown. Dotted lines display ranges for the control donors (n = 15). Error bars represent means ± SDs for patients analyzed 3 times. The inset displays the mean NK cell percentages for DOCK8-deficient patients compared with control donors and STAT3-deficient patients. Journal of Allergy and Clinical Immunology 2013 131, 840-848DOI: (10.1016/j.jaci.2012.12.1568) Copyright © 2013 Terms and Conditions

Fig 3 F-actin content is normal in DOCK8-deficient patients. Flow cytometry was performed for F-actin content within CD56+CD3− PBMCs from patients and control subjects (n = 15). Values were normalized to each specific control used. Error bars represent means ± SDs for patients analyzed 3 times. The inset displays the mean NK cell F-actin content for DOCK8-deficient patients compared with control subjects and STAT3-deficient patients. Journal of Allergy and Clinical Immunology 2013 131, 840-848DOI: (10.1016/j.jaci.2012.12.1568) Copyright © 2013 Terms and Conditions

Fig 4 Abnormal F-actin accumulation at the DOCK8-deficient NK cell IS. A, Representative confocal immunofluorescent micrographs of ex vivo natural killer (eNK):K562 cell conjugates showing differential interference contrast (DIC) F-actin (red), CD18 (green), perforin (blue), pericentrin (pink), and an overlay. B-D, Measurement of F-actin accumulation (Fig 4, B) at, CD18 accumulation (Fig 4, C) at, and MTOC polarization (Fig 4, D) to the IS. Points represent single cell values. Error bars represent means ± SDs. *P < .05. Journal of Allergy and Clinical Immunology 2013 131, 840-848DOI: (10.1016/j.jaci.2012.12.1568) Copyright © 2013 Terms and Conditions

Fig 5 Stable knockdown of DOCK8 inhibits NK cell cytotoxicity. A, NK cell lines (YTS) transduced with empty vector (EV), shRNA targeting DOCK8 (DOCK8 kd), or a scramble sequence were used in chromium-release cytotoxicity assays. B, DOCK8 expression measured by using real-time PCR normalized to human glyceraldehyde-3-phosphate dehydrogenase (GAPDH) expression. Experiments were performed in triplicate, and representative graphs are depicted. Journal of Allergy and Clinical Immunology 2013 131, 840-848DOI: (10.1016/j.jaci.2012.12.1568) Copyright © 2013 Terms and Conditions

Fig 6 DOCK8 knockdown abrogates synaptic F-actin accumulation and granule polarization. Representative confocal immunofluorescence micrographs of conjugates between YTS cells containing DOCK8-targeting or control scrambled shRNA and KT86 target cells are shown. Differential interference contrast (DIC) with localization of F-actin (red), CD18 (green), perforin (pink), and an overlay are shown. Journal of Allergy and Clinical Immunology 2013 131, 840-848DOI: (10.1016/j.jaci.2012.12.1568) Copyright © 2013 Terms and Conditions