Department of Pathology and Laboratory Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, United States.
Kao Autoimmunity Institute, Cedars-Sinai Medical Center, Los Angeles, CA, United States.
Front Immunol. 2024 Jan 15;14:1304086. doi: 10.3389/fimmu.2023.1304086. eCollection 2023.
During transfusion of red blood cells (RBCs), recipients are exposed to both ABO and non-ABO 'minor' antigens. RBC donor units and recipient RBCs are not routinely matched for non-ABO antigens. Thus, recipients are exposed to many RBC alloantigens that can lead to RBC alloantibody production and subsequent clinically significant hemolysis. RBC alloantibodies also significantly limit the provision of compatible RBC units for recipients. Prior studies indicate that the frequency of RBC alloimmunization is increased during inflammatory responses and in patients with autoimmune diseases. Still, mechanisms contributing to alloimmune responses in patients with autoimmunity are not well understood. More than half of adult patients with systemic lupus erythematosus (SLE) produce type 1 interferons (IFNα/β) and express IFNα/β stimulated genes (ISGs). Previously, we reported that IFNα/β promote RBC alloimmune responses in the pristane mouse model, which develops a lupus-like phenotype that is dependent on IFNα/β signaling. However, it is unclear whether IFNα/β or the lupus-like phenotype induces alloimmunization in lupus models. Therefore, we tested the hypothesis that IFNα/β promotes RBC alloimmune responses in lupus by examining alloimmune responses in IFNα/β-independent (MRL-) and IFNα/β-dependent (pristane) lupus models. Whereas pristane treatment significantly induced interferon-stimulated genes (ISGs), MRL- mice produced significantly lower levels that were comparable to levels in untreated WT mice. Transfusion of murine RBCs that express the KEL antigen led to anti-KEL IgG production by pristane-treated WT mice. However, MRL- mice produced minimal levels of anti-KEL IgG. Treatment of MRL-lpr mice with recombinant IFNα significantly enhanced alloimmunization. Collectively, results indicate that a lupus-like phenotype in pre-clinical models is not sufficient to induce RBC alloantibody production, and IFNα/β gene signatures may be responsible for RBC alloimmune responses in lupus mouse models. If these findings are extended to alternate pre-clinical 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 more personalized transfusion protocols.
在输注红细胞（RBC）期间，受体会暴露于 ABO 和非 ABO“次要”抗原。RBC 供体单位和受者 RBC 通常不针对非 ABO 抗原进行匹配。因此，受者会接触到许多 RBC 同种异体抗原，这些抗原可能导致 RBC 同种异体抗体的产生，并随后导致临床显著的溶血。RBC 同种异体抗体也严重限制了受者可获得相容的 RBC 单位。先前的研究表明，在炎症反应和自身免疫性疾病患者中，RBC 同种免疫的频率增加。尽管如此，导致自身免疫患者发生同种免疫反应的机制仍未得到很好的理解。超过一半的系统性红斑狼疮（SLE）成年患者产生 1 型干扰素（IFNα/β）并表达 IFNα/β 刺激基因（ISGs）。先前，我们报道 IFNα/β 在 pristane 小鼠模型中促进 RBC 同种免疫反应，该模型发展为依赖于 IFNα/β 信号的狼疮样表型。然而，尚不清楚 IFNα/β 或狼疮样表型是否在狼疮模型中诱导同种免疫。因此，我们通过检查 IFNα/β 非依赖性（MRL-）和 IFNα/β 依赖性（ pristane）狼疮模型中的同种免疫反应来检验 IFNα/β 促进 RBC 同种免疫反应的假设。尽管 pristane 处理显著诱导干扰素刺激基因（ISGs），但 MRL-小鼠产生的水平明显较低，与未处理的 WT 小鼠相当。输注表达 KEL 抗原的鼠 RBC 导致 pristane 处理的 WT 小鼠产生抗-KEL IgG。然而，MRL-小鼠产生的抗-KEL IgG 水平极低。用重组 IFNα 治疗 MRL-lpr 小鼠显著增强同种免疫。总的来说，结果表明，临床前模型中的狼疮样表型不足以诱导 RBC 同种异体抗体的产生，IFNα/β 基因特征可能是狼疮小鼠模型中 RBC 同种免疫反应的原因。如果这些发现扩展到替代临床前模型和临床研究，表达 IFNα/β 基因特征的 SLE 患者可能有更高的风险发展 RBC 同种异体抗体，并且可能受益于更个性化的输血方案。
