Abstract
Milk fat globule‐EGF factor 8 (MFG‐E8) promotes the phagocytosis of apoptotic cells by serving as a bridging molecule between apoptotic cells and phagocytes. Many apoptotic cells are left unengulfed in the germinal centers of the spleen of MFG‐E8^−/−^ mice, which develop a human systemic lupus erythematosus (SLE)‐like autoimmune disease. Here, we analyzed the MFG‐E8 gene in human SLE patients, and found in two out of 322 female patients a heterozygous intronic mutation, which caused a cryptic exon from intron 6 to be included in the transcript. The cryptic exon contained a premature termination codon, generating a C‐terminally truncated MFG‐E8 protein. The mutant MFG‐E8 was aberrantly glycosylated and sialylated, but bound to phosphatidylserine and enhanced the phagocytosis of apoptotic cells. When intravenously injected into mice, the mutant MFG‐E8 was sustained longer in the blood circulation than wild‐type MFG‐E8. Repeated administrations of the mutant MFG‐E8 protein induced the production of autoantibodies, such as anti‐cardiolipin and anti‐nuclear antibodies, at a lower dose than that required for the wild‐type protein. These results suggested that the intronic mutation in the human MFG‐E8 gene can lead to the development of SLE.