Mutation of POLB Causes Lupus in Mice

•Mutation of POLB leads to lupus in mice•Mutation of Pol B results in short CDR3 regions during VDJ recombination in B cells•Large numbers of mutations in variable regions lead to SLE•Mutation of DNA repair genes may lead to SLE

SummaryA replication study of a previous genome-wide association study (GWAS) suggested that a SNP linked to the POLB gene is associated with systemic lupus erythematosus (SLE). This SNP is correlated with decreased expression of Pol β, a key enzyme in the base excision repair (BER) pathway. To determine whether decreased Pol β activity results in SLE, we constructed a mouse model of POLB that encodes an enzyme with slow DNA polymerase activity. We show that mice expressing this hypomorphic POLB allele develop an autoimmune pathology that strongly resembles SLE. Of note, the mutant mice have shorter immunoglobulin heavy-chain junctions and somatic hypermutation is dramatically increased. These results demonstrate that decreased Pol β activity during the generation of immune diversity leads to lupus-like disease in mice, and suggest that decreased expression of Pol β in humans is an underlying cause of SLE.

Graphical AbstractFigure optionsDownload full-size imageDownload as PowerPoint slide