Type I IFN Is Necessary and Sufficient for Inflammation-Induced Red Blood Cell Alloimmunization in Mice

Abstract

During RBC transfusion, production of alloantibodies against RBC non-ABO Ags can cause hemolytic transfusion reactions and limit availability of compatible blood products, resulting in anemia-associated morbidity and mortality. Multiple studies have established that certain inflammatory disorders and inflammatory stimuli promote alloimmune responses to RBC Ags. However, the molecular mechanisms underlying these findings are poorly understood. Type I IFNs (IFN-α/β) are induced in inflammatory conditions associated with increased alloimmunization. By developing a new transgenic murine model, we demonstrate that signaling through the IFN-α/β receptor is required for inflammation-induced alloimmunization. Additionally, mitochondrial antiviral signaling protein—mediated signaling through cytosolic pattern recognition receptors was required for polyinosinic-polycytidylic acid—induced IFN-α/β production and alloimmunization. We further report that IFN-α, in the absence of an adjuvant, is sufficient to induce RBC alloimmunization. These findings raise the possibility that patients with IFN-α/β—mediated conditions, including autoimmunity and viral infections, may have an increased risk of RBC alloimmunization and may benefit from personalized transfusion protocols and/or targeted therapies.

Red blood cell alloimmunization is associated with lower expression of FcγR1 on monocyte subsets in patients with sickle cell disease

“…CD64 expression is typically observed in response to IFNγ stimulation of monocytes, and recent in vitro data has shown that IFNα/β suppresses IFNγ responses in macrophages, leading to CD64 downregulation . Although we did not find differences in measured IFNγ levels between responders and non‐responders, our findings in sickle cell patients may be consistent with recent work from our laboratory showing that IFNα/β impacts the ability of a murine transfusion recipient to form RBC alloantibodies to the KEL human blood group antigen expressed on murine RBCs . Taken together, these data suggest that alloimmunized patients with SCD may have higher IFNα/β levels that prevent IFNγ from leading to the same increase in CD64 expression as would be seen in the absence of IFNα/β.…”

“…Recently, studies in an animal model related IFNα/β and RBC alloimmunization, with exogenous IFNα/β increasing the likelihood of a transfusion recipient becoming alloimmunized. Further, recipients lacking type 1 IFN receptors failed to become alloimmunized . Other cytokine genes also have been shown to be more prevalent in alloimmunized patients with SCD compared to non‐alloimmunized patients …”

Risk factors for red blood cell alloimmunization in the Recipient Epidemiology and Donor Evaluation Study (REDS‐III) database

“…Multiple studies have also described a close association between RBC alloantibodies and RBC autoantibodies (Dhawan et al , ; Nickel et al , ). Animal studies (Gibb et al , ,b) suggest that a potential unifying hypothesis for the connection between some types of autoimmunity (Crow, ) and alloimmunization may involve type 1 interferon signalling.…”

Identification of genetic biomarkers for alloimmunization in sickle cell disease

“…IFNs are critical for host defence against viruses and the literature suggests that they are important mediators of autoimmune disease (Niewold, ). Interestingly, Gibb et al (,) found that type 1 IFNs are necessary to promote alloimmunization in mice. As the SNP we tested is an intergenic variant, its role in influencing the ability of IFN receptor to sense type 1 IFNs is unknown.…”