Background Leukocyte immunoglobulin-like receptor A3 (LILRA3) is a secreted protein belongs to LILR family. Our research group previously reported that the functional LILRA3 is a novel genetic risk for multiple autoimmune diseases including systemic lupus erythematosus (SLE). However, the function of LILRA3 in development of lupus is unclear. The bm12 model is a chronic graft-versus-host disease (cGVHD) model characterized by the lupus-like syndrome with cell subtype alteration and autoantibody production. To functionally study the role of LILRA3 in lupus pathogenesis, we constructed the LILRA3 knock-in mice and assessed the clinical manifestation and immune responses in bm12 model.
Methods Human LILRA3 gene (Gene ID: 11026) was inserted into Rosa26 allele in C57BL/6 (B6) mice based on Cas9/sgRNA system. The cGVHD was induced by an intraperitoneal injection of the bm12 donor splenocytes into recipients, either B6 wild-type or knock-in mice. Mice were sacrificed on day 14 and 28. Flow cytometry was used to analyze frequencies of immunocytes from mice splenocytes. Enzyme-linked immunosorbent assay was applied to detect antibodies in serum.
Results Compared with the wild-type mice, the LILRA3 knock-in mice displayed a more severe immune response on both day 14 and day 28 of post induction. Spleen mass were significantly increased in LILRA3 knock-in mice (p<0.001). The proportion of Th2, TFH, germinal center (GC) B, and plasma B cells were increased in knock-in mice (p<0.01), but not Th17 and regulatory T cells. Concentration of serum anti-dsDNA IgG was significantly elevated in knock-in mice (p<0.001).
Conclusions Our data indicate that LILRA3 promotes lupus-like disease probably through the excessive expression of Tfh cells and GC B cells, subsequently help for the induction and maintenance of plasma cell differentiation and autoantibody production.
Funding Source(s): None
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