Stéphanie Humblet-Baron1, Susann Schönefeldt1, Josselyn E Garcia-Perez1, Frédéric Baron2, Emanuela Pasciuto1, Adrian Liston3. 1. VIB Center for Brain & Disease Research, Leuven, Belgium; KU Leuven, Department of Microbiology and Immunology, Leuven, Belgium. 2. GIGA I(3) and Department of Hematology, University of Liege, Liege, Belgium. 3. VIB Center for Brain & Disease Research, Leuven, Belgium; KU Leuven, Department of Microbiology and Immunology, Leuven, Belgium. Electronic address: adrian.liston@vib.be.
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: Dclre1cleaky mice 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. Dclre1cleaky mice 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. CONCLUSION: 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.
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: Dclre1cleaky mice 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. Dclre1cleaky mice 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. CONCLUSION: 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: Ellis J Powell; Jared Graham; N M Ellinwood; Jesse Hostetter; Michael Yaeger; Chak-Sum Ho; Lynden Gault; Veronica Norlin; Elizabeth N Snella; Jackie Jens; Emily H Waide; Adeline N Boettcher; Maureen Kerrigan; Raymond R R Rowland; Jason W Ross; Jack C M Dekkers; Christopher K Tuggle Journal: Front Immunol Date: 2017-07-12 Impact factor: 7.561
Authors: Adeline N Boettcher; A Giselle Cino-Ozuna; Yash Solanki; Jayne E Wiarda; Ellie Putz; Jeana L Owens; Sara A Crane; Amanda P Ahrens; Crystal L Loving; Joan E Cunnick; Raymond R R Rowland; Sara E Charley; Jack C M Dekkers; Christopher K Tuggle Journal: Front Immunol Date: 2020-03-31 Impact factor: 7.561