This revised application for our new Program Project Grant brings together a group of investigators who are experts in the areas of molecular and cellular immunology and human and mouse genetics. We propose to study the role of single genes in the pathogenesis of X-linked Lymphoproliferative syndrome (XLP), Common variable immunodeficiency (CVID), Omenn syndrome and Severe Combined Immunodeficiencies (SCID) in an application, entitled: """"""""Primary Immunodeficiencies Affecting Specific Stages of the Adaptive Immune Response"""""""" Because of successful preliminary analyses of patient materials, exciting findings in genetically altered mice, this application seeks to define how mutations in the SH2D1A, SH2D1B/C, TACI, RAG-1/2, DNA Ligase IV or Cernunnos genes affect T and B cell development and T cell dependent and/or T cell-independent immunoglobulin responses. We will use our recently acquired insights into the causes of these diseases in the following four interlinked projects and an Administrative Core: Project #1 Role of the SAP (SH2D1A) gene in T cell-dependent antibody responses. Cox Terhorst, Beth Israel Deaconess Medical Center. Project #2 Role of in TACI mutations in Common Variable Immunodeficiency Raif Geha, Children's Hospital of Boston. Project #3 Gene knock-in models for Omenn syndrome and leaky SCID. Luigi Notarangelo, Children's Hospital of Boston. Project #4 Mouse Models of Severe Combined Immunodeficiencies. Fred Alt, Children's Hospital of Boston. Core A Administrative Core Cox Terhorst, Beth Israel Deaconess Medical Center. The outcomes of proposed studies should lead to better understanding of the complex and often alternate disease manifestations that are caused by mutations in a single gene. The results of these studies should suggest therapeutic strategies that can be applied to these PID patients and may unravel molecular and cellular mechanisms that are generally involved in immune dysregulation, autoimmunity and cancer.

Agency
National Institute of Health (NIH)
Institute
National Institute of Allergy and Infectious Diseases (NIAID)
Type
Research Program Projects (P01)
Project #
5P01AI076210-03
Application #
8102821
Study Section
Special Emphasis Panel (ZAI1-PA-I (S1))
Program Officer
Johnson, David R
Project Start
2009-07-05
Project End
2014-06-30
Budget Start
2011-07-01
Budget End
2012-06-30
Support Year
3
Fiscal Year
2011
Total Cost
$1,808,883
Indirect Cost
Name
Beth Israel Deaconess Medical Center
Department
Type
DUNS #
071723621
City
Boston
State
MA
Country
United States
Zip Code
02215
Xing, Mengtan; Bjørås, Magnar; Daniel, Jeremy A et al. (2017) Synthetic lethality between murine DNA repair factors XLF and DNA-PKcs is rescued by inactivation of Ku70. DNA Repair (Amst) 57:133-138
Kumánovics, Attila; Lee, Yu Nee; Close, Devin W et al. (2017) Estimated disease incidence of RAG1/2 mutations: A case report and querying the Exome Aggregation Consortium. J Allergy Clin Immunol 139:690-692.e3
Yee, Christina S; Massaad, Michel J; Bainter, Wayne et al. (2016) Recurrent viral infections associated with a homozygous CORO1A mutation that disrupts oligomerization and cytoskeletal association. J Allergy Clin Immunol 137:879-88.e2
Badran, Yousef R; Massaad, Michel J; Bainter, Wayne et al. (2016) Combined immunodeficiency due to a homozygous mutation in ORAI1 that deletes the C-terminus that interacts with STIM 1. Clin Immunol 166-167:100-2
Jabara, Haifa H; Boyden, Steven E; Chou, Janet et al. (2016) A missense mutation in TFRC, encoding transferrin receptor 1, causes combined immunodeficiency. Nat Genet 48:74-8
Felgentreff, Kerstin; Lee, Yu Nee; Frugoni, Francesco et al. (2015) Functional analysis of naturally occurring DCLRE1C mutations and correlation with the clinical phenotype of ARTEMIS deficiency. J Allergy Clin Immunol 136:140-150.e7
Buchbinder, David; Baker, Rebecca; Lee, Yu Nee et al. (2015) Identification of patients with RAG mutations previously diagnosed with common variable immunodeficiency disorders. J Clin Immunol 35:119-24
Chou, Janet; Badran, Yousef R; Yee, Christina S K et al. (2015) A novel mutation in ORAI1 presenting with combined immunodeficiency and residual T-cell function. J Allergy Clin Immunol 136:479-482.e1
Walter, Jolan E; Lo, Mindy S; Kis-Toth, Katalin et al. (2015) Impaired receptor editing and heterozygous RAG2 mutation in a patient with systemic lupus erythematosus and erosive arthritis. J Allergy Clin Immunol 135:272-3
Boisson, Bertrand; Laplantine, Emmanuel; Dobbs, Kerry et al. (2015) Human HOIP and LUBAC deficiency underlies autoinflammation, immunodeficiency, amylopectinosis, and lymphangiectasia. J Exp Med 212:939-51

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