CD11c-Cre driven deletion ofreveals the effect of somatic mosaicism in a mouse model of SLE.

Abstract

The pathogenesis of systemic lupus erythematosus (SLE) is caused by a complex mix of genetic factors that lead to dysregulation of the immune response. Mild susceptibility or resistance factors can tilt the scale towards or against pathology. Here, we present evidence for thegene as a lupus protective factor in conditions of haploinsufficiency or mosaicism. We targetedexpression in mice deficient in, a well characterized mouse model of SLE. As is the case in human SLE, hyperresponsive B cells and dendritic cells (DCs) are causal factors at various stages of disease in-deficient mice (). Sinceis essential for the generation of cDC1s, we used conditional deletion with various known DC-targeting Cre systems to delete. All conditional systems tested to deletereduced the titer of antinuclear antibodies and abrogated kidney pathology inmice. In addition to the expected effect ofdeletion in cDC1s, we unexpectedly found that mosaic deletion ofalso occurred in B cells and other immune cells. Using mixed bone marrow chimeras we determined that the aborted disease inandmice could be attributed to the inability of B cells with partial reduction of IRF8 to produce autoantibodies. Therefore, these results reveal IRF8 as a susceptibility factor of SLE even in cases of mild changes of expression levels and mosaic somatic deletion of the gene in B cells.