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.
RBC transfusion can lead to the production of alloantibodies against RBC antigens. RBC alloimmunization can result in hemolytic events and severely limit the availability of compatible RBCs. Patients with sickle cell disease (SCD) have the highest rate of alloimmunization, compared to any other disease population. However, mechanisms underlying this increased frequency are poorly understood. Inflammation in the recipient has been shown to promote alloimmunization in mice and humans. In mouse transfusion models, type 1 interferons (IFNα/β) and interferon-stimulated genes (ISGs) have been shown to promote alloimmunization. Given the chronic inflammatory state in patients with SCD, we hypothesized that SCD patients may also have an IFNα/β gene signature that may contribute to the increased frequency of alloimmunization. To test this hypothesis, we measured the expression of multiple ISGs, including myxovirus resistance protein 1 (MxA) and Siglec-1 by whole blood immunoassay and flow cytometry, respectively. MxA and Siglec-1 levels were significantly elevated in SCD patients, compared to transfused controls. We then determined the degree to which ISG expression correlated with alloimmunization frequency by linear regression. There was a trend toward elevated MxA expression in patients with 1 or more alloantibodies. Patients with 2 or more alloantibodies had significantly elevated MxA compared to non-alloimmunized transfused patients. These findings suggest the presence of an IFNα/β gene signature in patients with SCD and warrant further investigation of the contribution of IFNα/β pathways toward the profoundly elevated frequency of RBC alloimmunization in patients with SCD.
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