The hematopoietic compartment is sufficient for lupus development resulting from the POLB-Y265C mutation

Abstract

Systemic lupus erythematosus is a chronic disease characterized by autoantibodies, renal and cutaneous disease, and immune complex formation. Emerging evidence suggests that aberrant DNA repair is an underlying mechanism of lupus development. We previously showed that the POLBY265C/C mutation, which results in development of an aberrant immune repertoire, leads to lupus-like disease in mice. To address whether the hematopoietic compartment is sufficient for lupus development, we transplanted bone marrow cells from POLBY265C/C and POLB+/+ into wild-type congenic mice. Only mice transplanted with the POLBY265C/C bone marrow develop high levels of antinuclear antibodies and renal disease. In conclusion, we show that the hematopoietic compartment harvested from the POLBY265C/C mice is sufficient for development of autoimmune disease.

Mouse models to explore the biological and organismic role of DNA polymerase beta

“…Consistent with the role for this Polβ mutant as part of the BER pathway, the severity of the lupus symptoms observed in the Polb Y265C KI mouse is diminished after KO of the upstream BER initiating enzymes Ogg1 and Neil1 (Paluri et al 2021). Interestingly, the autoimmune phenotype exhibited by thePolb Y265C mouse model only requires implantation of the bone marrow isolated from thePolb Y265C KI mouse, suggesting a role for the hematopoietic compartment in disease onset due to the Polβ mutation (Rahim et al 2022). This same mouse model (Polb Y265C ), when crossed with a mouse model for Fragile X Syndrome, also supports a role for Polβ in triplet repeat expansion (Lokanga et al 2015).…”

Mouse models to explore the biological and organismic role of DNA polymerase beta

“…Consistent with the role of this Polβ mutant as part of the BER pathway, the severity of the lupus symptoms observed in the Polb Y265C KI mouse is diminished after KO of the upstream BER initiating enzymes Ogg1 and Neil1 (Paluri et al, 2021). Interestingly, the autoimmune phenotype exhibited by the Polb Y265C mouse model only requires implantation of the bone marrow isolated from the Polb Y265C KI mouse, suggesting a role for the hematopoietic compartment in disease onset due to the Polβ mutation (Rahim et al, 2022). This same mouse model ( Polb Y265C ), when crossed with a mouse model for Fragile X Syndrome, also supports a role for Polβ in triplet repeat expansion (Lokanga et al, 2015).…”