Type 1 interferons promote allo-antibody responses to RBC transfusion in a lupus mouse model

Abstract

Red blood cell (RBC) transfusion exposes recipients to hundreds of unmatched minor RBC antigens. This exposure can lead to production of alloantibodies that can cause potentially fatal hemolytic events. Prior studies have reported that inflammatory states, including autoimmune disease, in the transfusion recipient can promote alloimmunization. Recent studies reported that pro-inflammatory type 1 interferons (IFNα/β) regulated RBC alloimmunization in multiple mouse transfusion models. Interestingly, patients with systemic lupus erythematosus (SLE) have an increased frequency of alloimmunization and express an IFNα/β gene signature. Thus, we tested the hypothesis that IFNα/β activation in lupus promotes RBC alloimmunization by utilizing the pristane-induced lupus mouse model. Pristane significantly induced serum IFNα and expression of multiple interferon-stimulated genes (ISG) in peritoneal fluid cells, including inflammatory macrophages. Following transfusion with allogeneic RBCs expressing the KEL antigen, pristane-treated WT mice produced significantly elevated levels of anti-KEL IgM and anti-KEL IgG, compared to untreated mice. Pristane-treated mice lacking the IFNα/β receptor (IFNAR1−/−) or IFNα/β-inducing transcription factors (IRF3/7−/−) mice failed to produce ISGs and produced significantly lower levels of anti-KEL IgG compared to WT mice. In conclusion, pristane induction of a lupus-like phenotype promoted alloimmunization to the KEL RBC antigen in an IFNα/β-dependent manner. These results warrant further investigation of the role of IFNα/β in alloimmunization to other RBC antigens and the contribution of IFNα/β responses to the increased frequency of alloimmunization in patients with SLE.