Deletion of the Mitochondrial Membrane Protein Fam210b Is Associated with the Development of Systemic Lupus Erythematosus.

Abstract

Mitochondrial dysfunction has been increasingly recognized as a trigger for systemic lupus erythematosus (SLE). Recent bioinformatics studies have suggested Fam210b as a significant candidate for the classification and therapeutic targeting of SLE. To experimentally prove the role of Fam210b in SLE, we constructedknockout () mice using the CRISPR-Cas9 method. We found that approximately 15.68% of Fam210bmice spontaneously developed lupus-like autoimmunity, which was characterized by skin ulcerations, splenomegaly, and an increase in anti-double-stranded DNA (anti-dsDNA) IgG antibodies and anti-nuclear antibodies(ANA). Single-cell sequencing showed thatwas mainly expressed in erythroid cells. Critically, the knockout ofresulted in abnormal erythrocyte differentiation and development in the spleens of mice. Concurrently, the spleens exhibited an increased number of CD71erythroid cells, along with elevated levels of reactive oxygen species (ROS) in the erythrocytes. The co-culture of CD71erythroid cells and lymphocytes resulted in lymphocyte activation and promoted dsDNA and IgG production. In summary,knockout leads to a low probability of lupus-like symptoms in mice through the overproduction of ROS in CD71erythroid cells. Thus, Fam210b reduction may serve as a novel key marker that triggers the development of SLE.