Abstract
Here we describe a novel, spontaneous, 4035 basepairs long deletion in the DNA cross-link repair 1C (Dclre1c)-locus in C57BL/6-mice, which leads to loss of exons 10 and 11 of the gene encoding for Artemis, a protein involved into V(D) J-recombination of antigen receptors of T and B cells. While several spontaneous mutations of Artemis have been described to cause SCID in humans, in mice, only targeted deletions by knockout technology are known to cause the same phenotype so far. The deletion we observed causes a loss of Artemis function in the C57BL/6 strain and, consequently, the absence of T and B cells, in presence of normal numbers of NK cells and cells of the myeloid lineage. Thus, for the first time we present T-B-NK+ severe combined immunodeficiency (SCID) phenotype after spontaneously occurring modification of Artemis gene in mice. Our mouse model may serve as a valuable tool to study mechanisms as well as potential therapies of SCID in humans.
Highlights
Severe combined immunodeficiency (SCID) comprises a heterogeneous group of rare genetic disorders characterized by absence of T and B cell immune response
To characterize this phenotype further, we analyzed different immune cell subsets in the spleens of these mice. These analyses revealed that besides CD4+ and CD8+ T cells B cells were missing (Figure 1A), while the cell numbers of CD11c+MHCII+ dendritic cells, CD3-NK1.1+ NK cells, CD11b+ monocytes and Gr1+ granulocytes were not significantly altered (Figure 1B)
We discovered a new T-B-NK+SCID mouse strain that lacked CD4+ and CD8+ T cells as well as B cells, but still generated normal numbers of NK cells as well as other cell types
Summary
Severe combined immunodeficiency (SCID) comprises a heterogeneous group of rare genetic disorders characterized by absence of T and B cell immune response. The B cell defects can hereby be caused either indirectly, due to missing T cell help, or directly, by intrinsic B cell deficiencies. Treatments include hematopoietic stem cell transplantation or gene therapy, to correct gene defects [1]. SCID phenotypes can be caused by a variety of genetic defects affecting T and or B cell development in humans as well as in mice [3,4]. Common to all SCID phenotypes with B and T cell deficiencies is a defect in proteins controlling the TCR and BCR V(D) J-recombination machinery from germline encoded variable (V), diversity (D) and joining (J) gene segments [5]
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