Among women with systemic lupus erythematosus (SLE) who express an IFNα/β gene signature, an elevated risk for the development of hemolytic disease of the fetus and newborn (HDFN) that can lead to red blood cell (RBC) alloimmunization is possible, according to findings from a study conducted in mouse models and published in the journal Frontiers in Immunology.
When patients undergo allogeneic red blood cell (RBC) transfusions, they are exposed to both ABO and non-ABO antigens, including Duffy, Kell, and Kidd antigens. In fact, both transfused patients and RBC donors usually are not matched for antigens besides ABO and Rhesus D (RhD), thus exposing them to as many as 340 non-ABO alloantigens and elevating their risk for RBC alloantibody production. This, in turn, can be associated with HDFN in pregnancy, transfusion reactions, and renal allograft rejection in the setting of transplantation.
The results of prior analyses have revealed that the occurrence of RBC alloimmunization increases in individuals with autoimmune disorders and during times of an inflammatory response. Nonetheless, the mechanisms that affect alloimmune responses among patients with autoimmune disease remain to be elucidated.
It has been well recognized that more than 50% of adults with SLE generate type 1 interferons (IFNα/β) express IFNα/β-stimulated gene signatures. Recognizing that the extent to which the IFNα/β response or the SLE-like phenotype promotes RBC alloimmunization remains unclear, the researchers sought to assess the involvement of IFNα/β inflammation in RBC alloimmune responses in the context of SLE.
Read more about HDFN symptoms and risks
To examine the theory that that IFNα/β stimulates RBC alloimmune responses in SLE, the investigators studied alloimmune responses in IFNα/β-independent (MRL-lpr) and IFNα/β-dependent (pristane) SLE mouse models. They used C57BL/6 mice and MRL-lpr mice to perform their analyses. Although prior research has shown that C57BL/6 induces an RBC alloimmune response in the pristane mouse model, which leads to development of an SLE-like phenotype that depends on IFNα/β signaling, clarification is needed regarding whether IFNα/β or the SLE-like phenotype produces alloimmunization in models of SLE.
Results of the current study demonstrated that although pristane therapy significantly generated IFN-stimulated genes, MRL-lpr mice induced significantly lower levels that were similar to those observed in untreated wild-type (WT) mice. Transfusing murine RBCs that exhibit the KEL antigen is associated with the production of anti-KEL immunoglobulin G (IgG) by pristane-treated WT mice.
Study findings showed that MRL-lpr mice, in contrast, were responsible for generating minimal levels of IgG. In fact, the treatment of MRL-lpr mice with recombinant IFNα boosted alloimmunization to a significant degree.
Taken together, these findings demonstrate that an SLE-like phenotype in preclinical models is not sufficient to generate the production of RBC alloantibodies. Thus, IFNα/β gene signatures may be responsible for the RBC alloimmune responses that have been observed in mouse models of SLE.
“If these findings are extended to alternate [preclinical] models and clinical studies, patients with SLE who express an IFNα/β gene signature may have an increased risk of developing RBC alloantibodies and may benefit from [the use of] more personalized transfusion procedures,” the authors concluded.
