Type 1 interferons promote anti-RBC antibody responses in interferon-dependent lupus mice

Abstract Red blood cell (RBC) transfusion can induce anti-RBC antibodies that promote hemolytic events. Patients with systemic lupus erythematosus (SLE) have an increased frequency of RBC alloimmunization, and two-thirds of patients express a type 1 interferon (IFNα/β) gene signature. We previously reported that IFNα/β induces RBC alloimmunization in the IFNα/β-dependent pristane lupus mouse model. However, it is unclear whether the lupus-like phenotype or IFNα/β directly promoted alloimmunization. Thus, we examined alloantibody responses in MRL/lpr mice, which have an IFNα/β-independent lupus-like phenotype. MRL/lpr mice produced anti-dsDNA lupus antibodies. However, unlike pristane-treated WT mice, IFNα/β-stimulated genes (ISGs) were not elevated in MRL/lpr mice. After transfusion with allogeneic RBCs, untreated WT and MRL/lpr mice produced minimal levels of anti-RBC antibodies, compared to elevated levels produced by pristane-treated WT mice. To determine whether IFNα/β can induce alloimmunization in MRL/lpr mice, WT and MRL/lpr mice were treated with recombinant IFNα (rIFNα) or the IFNα/β stimulus, poly(I:C), prior to transfusion. While rIFNa and poly(I:C) induced RBC alloimmunization in WT mice, they failed to induce alloimmunization in MRL/lpr mice. Thus, MRL/lpr mice are resistant to IFNα/β-induced alloimmunization due to a currently explored mechanism. These findings also illustrate that allogeneic transfusion induces alloimmunization in an IFNα/β-dependent lupus model, but not in an IFNα/β-independent model. Thus, the lupus-like phenotype is not sufficient to induce alloimmunization. Collectively, these findings warrant investigation of the role of IFNα/β in RBC alloimmunization in patients with SLE. NIH (R01 HL165169-01); NIH (R03 HL158637-01); NIH (K08 HL141446-03)