title: Cytotoxic T-lymphocyte-associated protein 4-Ig effectively controls immune activation and inflammatory disease in a novel murine model of leaky severe combined immunodeficiency.
abstract: BACKGROUND
  Severe combined immunodeficiency can be caused by loss-of-function mutations in genes involved in the DNA recombination machinery, such as recombination-activating gene 1 (RAG1), RAG2, or DNA cross-link repair 1C (DCLRE1C). Defective DNA recombination causes a developmental block in T and B cells, resulting in high susceptibility to infections. Hypomorphic mutations in the same genes can also give rise to a partial loss of T cells in a spectrum including leaky severe combined immunodeficiency (LS) and Omenn syndrome (OS). These patients not only experience life-threatening infections because of immunodeficiency but also experience inflammatory/autoimmune conditions caused by the presence of autoreactive T cells.
  
  
  OBJECTIVE
  We sought to develop a preclinical model that fully recapitulates the symptoms of patients with LS/OS, including a model for testing therapeutic intervention.
  
  
  METHODS
  We generated a novel mutant mouse (Dclre1cleaky) that develops a LS phenotype. Mice were monitored for diseases, and immune phenotype and immune function were evaluated by using flow cytometry, ELISA, and histology.
  
  
  RESULTS
  Dclre1cleakymice present with a complete blockade of B-cell differentiation, with a leaky block in T-cell differentiation resulting in an oligoclonal T-cell receptor repertoire and enhanced cytokine secretion. Dclre1cleakymice also had inflammatory symptoms, including wasting, dermatitis, colitis, hypereosinophilia, and high IgE levels. Development of a preclinical murine model for LS allowed testing of potential treatment, with administration of cytotoxic T-lymphocyte-associated protein 4-Ig reducing disease symptoms and immunologic disturbance, resulting in increased survival.
  
  
  CONCLUSIONS
  These data suggest that cytotoxic T-lymphocyte-associated protein 4-Ig should be evaluated as a potential treatment of inflammatory symptoms in patients with LS and those with OS.
authors.affiliation: VIB Center for Brain & Disease Research, Leuven, Belgium; KU Leuven, Department of Microbiology and Immunology, Leuven, Belgium.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Humblet-Baron
authors.affiliation: VIB Center for Brain & Disease Research, Leuven, Belgium; KU Leuven, Department of Microbiology and Immunology, Leuven, Belgium.
authors.forename: Susann
authors.initials: S
authors.lastname: Schönefeldt
authors.affiliation: VIB Center for Brain & Disease Research, Leuven, Belgium; KU Leuven, Department of Microbiology and Immunology, Leuven, Belgium.
authors.forename: Josselyn E
authors.initials: JE
authors.lastname: Garcia-Perez
authors.affiliation: GIGA I(3) and Department of Hematology, University of Liege, Liege, Belgium.
authors.forename: Frédéric
authors.initials: F
authors.lastname: Baron
authors.affiliation: VIB Center for Brain & Disease Research, Leuven, Belgium; KU Leuven, Department of Microbiology and Immunology, Leuven, Belgium.
authors.forename: Emanuela
authors.initials: E
authors.lastname: Pasciuto
authors.affiliation: VIB Center for Brain & Disease Research, Leuven, Belgium; KU Leuven, Department of Microbiology and Immunology, Leuven, Belgium. Electronic address: adrian.liston@vib.be.
authors.forename: Adrian
authors.initials: A
authors.lastname: Liston
mesh_terms: D000069594:Abatacept / Q000627:therapeutic use*; D000818:Animals; D001402:B-Lymphocytes / Q000502:physiology*; D002454:Cell Differentiation; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004720:Endonucleases / Q000235:genetics; D006801:Humans; D007249:Inflammation / Q000235:genetics / Q000276:immunology* / Q000628:therapy; D008213:Lymphocyte Activation; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D009687:Nuclear Proteins / Q000235:genetics; D059767:Recombinational DNA Repair / Q000235:genetics; D016511:Severe Combined Immunodeficiency / Q000235:genetics / Q000276:immunology* / Q000628:therapy; D013601:T-Lymphocytes / Q000502:physiology*
chemical_list: D009687:Nuclear Proteins; D000069594:Abatacept; D004720:Endonucleases; C473337:Dclre1c protein, mouse
keywords: Artemis; Leaky severe combined immunodeficiency; cytotoxic T-lymphocyte-associated protein 4; immune dysregulation; regulatory T cell