Abstract
Artemis is a mammalian protein, the absence of which results in SCID in Athabascan-speaking Native Americans (SCIDA). This novel protein has been implicated in DNA double-strand break repair and V(D)J recombination. We have cloned the Artemis murine counterpart, mArt, and generated a mouse with a targeted disruption of mArt. Artemis-deficient mice show a similar T-B- NK+ immunodeficiency phenotype, and carry a profound impairment in coding joint rearrangement, while retaining intact signal ends and close to normal signal joint formation. mArt-/- embryonic fibroblasts show increased sensitivity to ionizing radiation. Hemopoietic stem cell (HSC) transplantation using 500-5000 enriched congenic, but not allogeneic mismatched HSC corrected the T cell and partially corrected the B cell defect. Large numbers (40,000) of allogeneic mismatched HSC or pretreatment with 300 cGy of radiation overcame graft resistance, resulting in limited B cell engraftment. Our results suggest that the V(D)J and DNA repair defects seen in this mArt-/- mouse model are comparable to those in humans with Artemis deficiency, and that the recovery of immunity following HSC transplantation favors T rather than B cell reconstitution, consistent with what is seen in children with this form of SCID.
Publication types
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Comparative Study
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Research Support, Non-U.S. Gov't
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Research Support, U.S. Gov't, P.H.S.
MeSH terms
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Animals
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Antibody Diversity / genetics
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Antibody Diversity / radiation effects
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Bone Marrow Transplantation / immunology*
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Bone Marrow Transplantation / pathology
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Cell Death / genetics
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Cell Death / immunology
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Cell Differentiation / genetics
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Cell Differentiation / immunology
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Cell Line
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Cell Line, Transformed
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DNA-Binding Proteins
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Endonucleases
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Female
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Gene Rearrangement, B-Lymphocyte / genetics*
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Gene Rearrangement, B-Lymphocyte / radiation effects
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Gene Rearrangement, T-Lymphocyte / genetics*
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Gene Rearrangement, T-Lymphocyte / radiation effects
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Gene Targeting* / methods
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Humans
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Immunoglobulin Constant Regions / genetics
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Immunoglobulin Joining Region / genetics
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Immunoglobulin Joining Region / radiation effects
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Immunoglobulin Variable Region / genetics
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Immunoglobulin Variable Region / radiation effects
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Male
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Mice
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Mice, Inbred BALB C
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Mice, Inbred C57BL
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Mice, Knockout
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Nuclear Proteins / biosynthesis
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Nuclear Proteins / deficiency*
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Nuclear Proteins / genetics*
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Nuclear Proteins / physiology
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Radiation Tolerance / genetics
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Radiation Tolerance / immunology
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Receptors, Antigen, T-Cell / genetics
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Severe Combined Immunodeficiency / genetics*
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Severe Combined Immunodeficiency / immunology*
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Severe Combined Immunodeficiency / pathology
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Severe Combined Immunodeficiency / therapy
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Transduction, Genetic
Substances
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DNA-Binding Proteins
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Immunoglobulin Constant Regions
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Immunoglobulin Joining Region
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Immunoglobulin Variable Region
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Nuclear Proteins
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Receptors, Antigen, T-Cell
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DCLRE1C protein, human
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Endonucleases
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Dclre1c protein, mouse