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

Slides:

Advertisements

Similar presentations

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

Advertisements

Differentiation stage determines pathologic and protective allergen-specific CD4+ T-cell outcomes during specific immunotherapy Erik Wambre, PhD, Jonathan.

Epigenetic modifications and improved regulatory T-cell function in subjects undergoing dual sublingual immunotherapy Ravi S. Swamy, MD, Neha Reshamwala,

The loss of IgM memory B cells correlates with clinical disease in common variable immunodeficiency Rita Carsetti, MD, Maria Manuela Rosado, PhD, Simona.

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

Flow cytometry imaging identifies rare TH2 cells expressing thymic stromal lymphopoietin receptor in a “proallergic” milieu Amanda J. Reefer, MS, Kathryn.

Correlation of allergen-specific T follicular helper cell counts with specific IgE levels and efficacy of allergen immunotherapy Yin Yao, MD, Cai-Ling.

Induction of anergic allergen-specific suppressor T cells using tolerogenic dendritic cells derived from children with allergies to house dust mites

B-cell reconstitution after lentiviral vector–mediated gene therapy in patients with Wiskott-Aldrich syndrome Maria Carmina Castiello, PhD, Samantha.

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

Evidence for intranasal antinuclear autoantibodies in patients with chronic rhinosinusitis with nasal polyps Bruce K. Tan, MD, Quan-Zhen Li, PhD, Lydia.

IgE cross-linking impairs monocyte antiviral responses and inhibits influenza-driven TH1 differentiation Regina K. Rowe, MD, PhD, David M. Pyle, MD,

A novel mutation in CD132 causes X-CID with defective T-cell activation and impaired humoral reactivity Taco W. Kuijpers, MD, PhD, Paul A. Baars, PhD,

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

Immunologic defects in 22q11.2 deletion syndrome

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

Defective nuclear entry of hydrolases prevents neutrophil extracellular trap formation in patients with chronic granulomatous disease Susana Romao, PhD,

Peanut oral immunotherapy results in increased antigen-induced regulatory T-cell function and hypomethylation of forkhead box protein 3 (FOXP3) Aleena.

Insulin-like growth factor 2 enhances regulatory T-cell functions and suppresses food allergy in an experimental model Gui Yang, MD, Xiao-Rui Geng, MD,

Volume 29, Issue 5, Pages (November 2008)

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

Induction and maintenance of allergen-specific FOXP3+ Treg cells in human tonsils as potential first-line organs of oral tolerance Oscar Palomares, PhD,

Abnormalities of T-cell receptor repertoire in CD4+ regulatory and conventional T cells in patients with RAG mutations: Implications for autoimmunity

Dedicator of cytokinesis 8–deficient CD4+ T cells are biased to a TH2 effector fate at the expense of TH1 and TH17 cells Stuart G. Tangye, PhD, Bethany.

Autoreactivity in Human IgG+ Memory B Cells

Flow cytometric measurement of STAT1 and STAT3 phosphorylation in CD4+ and CD8+ T cells—clinical applications in primary immunodeficiency diagnostics

Nitric oxide induces human CLA+CD25+Foxp3+ regulatory T cells with skin-homing potential Cunjing Yu, PhD, Amanda Fitzpatrick, PhD, Duanduan Cong, MMedSci,

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

Human IL-31 is induced by IL-4 and promotes TH2-driven inflammation

TNF receptor superfamily member 13b (TNFRSF13B) hemizygosity reveals transmembrane activator and CAML interactor haploinsufficiency at later stages of.

Forkhead box protein 3 demethylation is associated with tolerance induction in peanut- induced intestinal allergy Meiqin Wang, MD, PhD, Ivana V. Yang,

Decreased T-cell receptor signaling through CARD11 differentially compromises forkhead box protein 3–positive regulatory versus TH2 effector cells to.

Transmembrane activator and CAML interactor (TACI) haploinsufficiency results in B- cell dysfunction in patients with Smith-Magenis syndrome Javier Chinen,

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,

Natural protective immunity against grass pollen allergy is maintained by a diverse spectrum of response types Almedina Kurtaj, MSc, Christoph Hillebrand,

Katherine G. MacDonald, BSc, Nicholas A. J

Signaling lymphocytic activation molecule (SLAM)/SLAM-associated protein pathway regulates human B-cell tolerance Laurence Menard, PhD, Tineke Cantaert,

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

Human mast cells drive memory CD4+ T cells toward an inflammatory IL-22+ phenotype Nicolas Gaudenzio, PhD, Camille Laurent, MD, Salvatore Valitutti,

Defective B-cell memory in patients with Down syndrome

Sandra Hellberg, MSc, Ratnesh B

Targeting allergen to FcγRI reveals a novel TH2 regulatory pathway linked to thymic stromal lymphopoietin receptor Kathryn E. Hulse, PhD, Amanda J. Reefer,

De novo oligoclonal expansions of circulating plasmablasts in active and relapsing IgG4- related disease Hamid Mattoo, PhD, Vinay S. Mahajan, MBBS, PhD,

Benjamin T. Prince, MD, Msci, Ashley L. Devonshire, MD, MPH, Kristin A

Specific immunotherapy modifies allergen-specific CD4+ T-cell responses in an epitope- dependent manner Erik Wambre, PhD, Jonathan H. DeLong, BSc, Eddie.

Chronic cat allergen exposure induces a TH2 cell–dependent IgG4 response related to low sensitization Amedee Renand, PhD, Luis D. Archila, MSc, John.

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

Brent E. Palmer, PhD, Douglas G. Mack, PhD, Allison K

Donald W. MacGlashan, MD, PhD, Sarbjit S. Saini, MD

Bet v 1–specific T-cell receptor/forkhead box protein 3 transgenic T cells suppress Bet v 1–specific T-cell effector function in an activation-dependent.

Peanut-specific type 1 regulatory T cells induced in vitro from allergic subjects are functionally impaired Laurence Pellerin, PhD, Jennifer Anne Jenks,

Autoreactivity in Human IgG+ Memory B Cells

Demonstration of circulating allergen-specific CD4+CD25highFoxp3+ T-regulatory cells in both nonatopic and atopic individuals Laura Maggi, BSc, Veronica.

Differentiation stage determines pathologic and protective allergen-specific CD4+ T-cell outcomes during specific immunotherapy Erik Wambre, PhD, Jonathan.

Exaggerated follicular helper T-cell responses in patients with LRBA deficiency caused by failure of CTLA4-mediated regulation Fayhan J. Alroqi, MD,

Dysregulated extracellular signal-regulated kinase signaling associated with impaired B- cell receptor endocytosis in patients with common variable immunodeficiency

Allergen-specific CD8+ T cells in peanut-allergic individuals

Figure 1 Central B cell tolerance is compromised in patients with NMOSD. Recombinant antibodies (rIgGs) derived from ... Figure 1 Central B cell tolerance.

CD23 surface density on B cells is associated with IgE levels and determines IgE- facilitated allergen uptake, as well as activation of allergen-specific.

Sara Paveglio, PhD, MS, Erin Bennett, MS, Kelly L. Hawley, PhD, Adam P

Defining antigen-specific responses with human MHC class II tetramers

Immune dysregulation, polyendocrinopathy, enteropathy, X-linked: Forkhead box protein 3 mutations and lack of regulatory T cells Troy R. Torgerson, MD,

Katie Frith, MD, Anne-Laure Joly, PhD, Cindy S. Ma, PhD, Stuart G

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

IL-10–producing monocytes differentiate to alternatively activated macrophages and are increased in atopic patients Antje Prasse, MD, Martin Germann,

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

IgG4 production is confined to human IL-10–producing regulatory B cells that suppress antigen-specific immune responses Willem van de Veen, MSc, Barbara.

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

Induction of anergic allergen-specific suppressor T cells using tolerogenic dendritic cells derived from children with allergies to house dust mites

Presentation transcript:

Dedicator of cytokinesis 8–deficient patients have a breakdown in peripheral B-cell tolerance and defective regulatory T cells Erin Janssen, MD, PhD, Henner Morbach, MD, Sumana Ullas, MS, Jason M. Bannock, MA, Christopher Massad, BS, Laurence Menard, PhD, Isil Barlan, MD, Gerard Lefranc, PhD, Helen Su, MD, PhD, Majed Dasouki, MD, Waleed Al-Herz, MD, Sevgi Keles, MD, Talal Chatila, MD, Raif S. Geha, MD, Eric Meffre, PhD Journal of Allergy and Clinical Immunology Volume 134, Issue 6, Pages 1365-1374 (December 2014) DOI: 10.1016/j.jaci.2014.07.042 Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 1 Autoantibodies are present in DOCK8-deficient patients. A, Heat map of the reactivity of IgG antibodies against self-antigens in 12 DOCK8-deficient patients, 2 HD control subjects, a patient with systemic lupus erythematosus (SLE), and a patient with Foxp3 deficiency (immunodysregulation–polyendocrinopathy–enteropathy–X-linked syndrome [IPEX]). Only the 14 autoantigens for which binding was significantly higher (P < .05) in the 12 DOCK8-deficient patients compared with the HDs are shown. The colors represent the fold increase relative to HD control subjects. B, HEp-2 cell reactivity of plasma from 14 DOCK8-deficient patients and 7 HDs. C, Representative photomicrographs of HEp-2 cells incubated with plasma from 2 DOCK8-deficient patients, an HD, and a patient with systemic lupus erythematosus. Green represents bound IgG antibodies, and blue 4′-6-diamidino-2-phenylindole dihydrochloride staining shows the nucleus. Journal of Allergy and Clinical Immunology 2014 134, 1365-1374DOI: (10.1016/j.jaci.2014.07.042) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 2 Mature naive B cells from DOCK8-deficient patients have an activated phenotype. A, Representative CD69, CD86, and CD25 expression profiles of CD19+CD27−CD21+ mature naive B cells from a DOCK8-deficient patient and a representative control subject. B, Mean fluorescence intensities (MFI) of CD69, CD86, and CD25 expression on mature naive B cells from 7 DOCK8-deficient patients and 25 HD control subjects. C, Representative flow cytometric plots for CD19+CD21−/lo B cells for 2 DOCK8-deficient patients and 2 HDs. D, CD19+CD27−CD10−CD21−/lo B cells as a percentage of total B cells in 7 DOCK8-deficient patients and 25 HD control subjects. Journal of Allergy and Clinical Immunology 2014 134, 1365-1374DOI: (10.1016/j.jaci.2014.07.042) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 3 The central B-cell tolerance checkpoint is intact in DOCK8-deficient patients. A, Antibodies cloned from new emigrant/transitional B cells from a representative HD control subject (HD28) and 3 DOCK8-deficient patients (Table I; patients 5, 19, and 20) were tested by means of ELISA for reactivity against dsDNA, insulin, and LPS. Dotted lines show the ED38+ control,7,20 and solid lines show binding for each cloned recombinant antibody. Horizontal lines define the cutoff for positive reactivity. For each subject, the frequency of polyreactive (solid area) and nonpolyreactive (open area) clones is summarized in a pie chart, with the total number of clones tested indicated in each center. B, Frequency of polyreactive new emigrant/transitional B cells in 3 DOCK8-deficient patients and 11 HD control subjects. C, Normal low frequency of anti-nuclear antigen–reactive new emigrant/transitional B cells in 3 DOCK8-deficient patients and 9 HD control subjects. The solid line represents the mean for each group, and the dotted line is the mean for HD control subjects in Fig 3, B and C. Journal of Allergy and Clinical Immunology 2014 134, 1365-1374DOI: (10.1016/j.jaci.2014.07.042) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 4 The peripheral B-cell tolerance checkpoint is defective in DOCK8-deficient patients. A, Antibodies from mature naive B cells from a representative HD and 3 DOCK8-deficient patients (Table I; patients 5, 19, and 20) were tested by means of ELISA for anti–HEp-2 cell reactivity. Dotted lines show ED38+ control,7,20 and solid lines show binding for each cloned recombinant antibody. Horizontal lines define cutoffs for positive reactivity. For each subject, the frequency of HEp-2–reactive (solid area) and non–HEp-2–reactive (open area) clones is summarized in pie charts, with the total number of clones tested indicated in the centers. B, Frequencies of HEp-2–reactive mature naive B cells in 3 DOCK8-deficient patients and 11 HD control subjects. C, Patterns of cytoplasmic HEp-2 staining by autoreactive antibodies from mature naive B-cell clones from DOCK8-deficient patients. D, Normal low frequencies of anti-nuclear mature naive B cells in 9 HD control subjects and 3 DOCK8-deficient patients. E, Frequencies of polyreactive mature naive B cells in 11 HD control subjects and 3 DOCK8-deficient patients. F, The evolution of polyreactivity between the new emigrant/transitional (NE) and mature naive (MN) B-cell compartments is represented. The solid line represents the mean for each group, and the dotted line is the mean for HD control subjects in Fig 4, B, D, and E. Journal of Allergy and Clinical Immunology 2014 134, 1365-1374DOI: (10.1016/j.jaci.2014.07.042) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 5 DOCK8-deficient patients have decreased Treg cell numbers. A, Dot plots showing the analysis of gated CD25hiCD127lo (left) and CD25hiFOXP3+ (right) CD4+ T cells of a representative HD control subject and a DOCK8-deficient patient. B, Decreased frequency of CD4+CD25hiCD127loFOXP3+ Treg cells in 7 DOCK8-deficient patients compared with 45 HD control subjects. Each symbol represents a subject, and horizontal bars display means. C, Expression levels of CD25, CD127, and CD45RO on CD4+ Treg cells from a representative DOCK8-deficient patient (solid black) and HD (bold). The mean fluorescence intensities (MFI) of CD25 (D) appear normal, whereas CD127 expression (E) and the frequency of CD45RO+ cells (F) are decreased in both non-Treg and Treg cells from DOCK8-deficient patients. Journal of Allergy and Clinical Immunology 2014 134, 1365-1374DOI: (10.1016/j.jaci.2014.07.042) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions

Fig 6 DOCK8-deficient Treg cells have reduced suppressive activity. A, CD4+CD25− Teff cells from an HD were loaded with CellTrace Violet and cocultured with CD4+CD25+CD127lo Treg cells from an HD (left panel) and a DOCK8-deficient patient (right panel). Cells were stimulated with anti-CD3, CD28, and CD2 beads. On day 4, proliferative profiles of the labeled Teff cells were analyzed by means of flow cytometry. B, Suppressive activity of Treg cells from 7 DOCK8-deficient patients relative to that of Treg cells from 5 HD shipping control subjects. C, Proliferation of Teff cells from DOCK8-deficient patients can be suppressed by HD Treg cells. Teff cells (CD4+CD25−) from 2 DOCK8-deficient patients were loaded with carboxyfluorescein succinimidyl ester and cocultured with either autologous CD4+CD25+CD127− Treg cells or Treg cells from a shipped HD control subject. Journal of Allergy and Clinical Immunology 2014 134, 1365-1374DOI: (10.1016/j.jaci.2014.07.042) Copyright © 2014 American Academy of Allergy, Asthma & Immunology Terms and Conditions