Type 1 IFN signaling critically regulates influenza‐induced alloimmunization to transfused KEL RBCs in a murine model

Liu, Dong; Gibb, David R.; Escamilla-Rivera, V.; Liu, Jingchun; Santhanakrishnan, Manjula; Shi, Zhang; Xu, Lan; Eisenbarth, Stephanie C.; Hendrickson, Jeanne E.

doi:10.1111/trf.15482

Cited by 14 publications

(22 citation statements)

References 34 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Leuko-reduced K1 RBCs were transfused into WT mice treated without or with pristane 2, 14, or 48 days prior to transfusion, and anti-KEL IgM and IgG antibody levels were measured by flow cytometric crossmatch. Consistent with prior studies (29,37), transfused untreated mice produced low levels of anti-KEL IgM, and produced nearly undetectable levels of anti-KEL IgG. Transfusion 2 days after pristane treatment did not induce elevated alloantibody production, compared to untreated mice.…”

Section: Induction Of Anti-kel Alloimmunization In Pristane-induced Lsupporting

confidence: 87%

“…Thus, we utilized the well described pristane-induced lupus model, in which IFNα/β production and signaling have been shown to promote autoantibody production and subsequent renal pathology ( 41 ). While transient inflammation induced by viral stimuli has previously been shown to promote RBC alloimmunization ( 27 – 29 ), it was unclear whether chronic inflammation in autoimmune models would also induce alloimmunization. Further, in addition to IFNα, pristane induces production of numerous NFκB-induced cytokines, including IL-6, IL-1b, and TNFα, which contribute to other manifestations of lupus.…”

Section: Discussionmentioning

confidence: 99%

“…Prior studies using K1 mice indicate that inflammation at the time of transfusion influences alloimmunization (29,37). Thus, given the elevated alloantibody responses and clearance in pristane-induced lupus mice, we examined markers of inflammation at the time of transfusion.…”

Section: Pristane-induced Inflammation In the Peri-transfusion Periodmentioning

confidence: 99%

“…Co-transfusion with CpG DNA or pre-treatment with polyinosinic:polycytidylic acid [poly(I:C)], a mimetic of viral double stranded RNA, has been shown to induce alloimmunization to a human RBC antigen expressed on mouse RBCs ( 25 – 27 ). Accordingly, polyoma and influenza viral infections in mice enhance the alloimmune response to transfused RBCs ( 28 , 29 ). Prior studies have also shown that transfusion of pro-inflammatory stored RBCs induces alloimmunization ( 30 – 32 ).…”

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Type 1 Interferon Gene Signature Promotes RBC Alloimmunization in a Lupus Mouse Model

et al. 2020

Self Cite

View full text Add to dashboard Cite

Red blood cell (RBC) transfusion exposes recipients to hundreds of unmatched minor RBC antigens. This exposure can lead to production of alloantibodies that promote clinically significant hemolytic events. Multiple studies have reported an increased frequency of RBC alloimmunization in patients with autoimmunity. However, cellular and molecular mechanisms that underlie autoimmunity-induced alloimmunization have not been reported. Patients with systemic lupus erythematosus (SLE) have a high frequency of alloimmunization and express a type 1 interferon (IFNα/β) gene signature. Thus, we utilized the pristane-induced lupus mouse model to test the hypothesis that inflammation in lupus promotes RBC alloimmunization, and to examine the potential role of IFNα/β. Intraperitoneal injection of pristane, a hydrocarbon oil, led to autoantibody production, glomerulonephritis, and pulmonary hemorrhage in wild type (WT) mice. Pristane treatment significantly induced serum IFNα and expression of multiple interferon-stimulated genes (ISGs) in peripheral blood and peritoneal fluid cells, including inflammatory macrophages. Following transfusion with allogeneic RBCs expressing the KEL glycoprotein, pristane-treated WT mice produced significantly elevated levels of anti-KEL IgM and anti-KEL IgG, compared to untreated mice. Pristane induced comparable levels of inflammatory cells and cytokines in mice lacking the IFNα/β receptor (IFNAR1 −/−) or the IFNα/β-inducing transcriptions factors (IRF3/7 −/−), compared to WT mice. However, pristane-treated IFNAR1 −/− and IRF3/7 −/− mice failed to produce ISGs and produced significantly lower levels of transfusion-induced anti-KEL IgG, compared to WT mice. Thus, pristane induction of a lupus-like phenotype promoted alloimmunization to the KEL RBC antigen in an IFNα/β-dependent manner. To our knowledge, this is the first examination of molecular mechanisms contributing to RBC alloimmunization in a model of autoimmunity. These results warrant further investigation of the role of IFNα/β in alloimmunization to other RBC antigens and the contribution of the IFNα/β gene signature to the elevated frequency of alloimmunization in patients with SLE.

show abstract

Section: Induction Of Anti-kel Alloimmunization In Pristane-induced Lsupporting

confidence: 87%

Section: Discussionmentioning

confidence: 99%

Section: Pristane-induced Inflammation In the Peri-transfusion Periodmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Type 1 Interferon Gene Signature Promotes RBC Alloimmunization in a Lupus Mouse Model

et al. 2020

Self Cite

View full text Add to dashboard Cite

show abstract

“…Thus, IFNα/β plays a critical role in the way that poly (I:C) enhances alloimmunization in the murine models studied to date. Recently, recipient influenza infection has also been shown to exert a similar effect as poly (I:C) on RBC alloantibody induction in a murine model ( 66 ) and recipient treatment with exogenous type 1 IFN (IFNα) has been shown to have a similar adjuvant effect as poly (I:C) treatment ( 51 ).…”

Section: Inflammation and Rbc Alloantibody Induction In Murine Modelsmentioning

confidence: 99%

Red blood cell alloimmunization and sickle cell disease: a narrative review on antibody induction

Hendrickson¹

2020

Ann Blood

Self Cite

View full text Add to dashboard Cite

The high prevalence of red blood cell (RBC) alloantibodies in people with sickle cell disease (SCD) cannot be debated. Why people with SCD are so likely to form RBC alloantibodies, however, remains poorly understood. Over the past decade, a better understanding of non-ABO blood group antigen variants has emerged; RH genetic diversity and the role this diversity plays in RBC alloimmunization is discussed elsewhere. Outside of antigen variants, the immune systems of people with SCD are known to be different than those of people without SCD. Some of these differences are due to effects of free heme, whereas others are impacted by hyposplenism. Descriptive studies of differences in white blood cell (WBC) subsets, platelet counts and function, and complement activation between people with SCD and race-matched controls exist. Studies comparing the immune systems of alloimmunized people with SCD to non-alloimmunized people with SCD to race-matched controls without SCD have uncovered differences in T-cell subsets, monocytes, Fcγ receptor polymorphisms, and responses to free heme. Studies in murine models have documented the role that recipient inflammation plays in RBC alloantibody formation, with human studies reporting a similar association. Murine studies have also reported the importance of type 1 interferon (IFNα/β), known to play a pivotal role in autoimmunity, in RBC alloantibody formation. The goal of this manuscript is to review existing data on factors influencing RBC alloantibody induction in people with SCD with a focus on inflammation and other immune system considerations, from the bench to the bedside.

show abstract

Altered type 1 interferon responses in alloimmunized and nonalloimmunized patients with sickle cell disease

Madany

Lee

Halprin

et al. 2021

eJHaem

Self Cite

View full text Add to dashboard Cite

Patients with sickle cell disease (SCD) have a high prevalence of RBC alloimmunization.However, underlying mechanisms are poorly understood. Given that proinflammatory type 1 interferons (IFNα/β) and interferon stimulated genes (ISGs) promote alloimmunization in mice, we hypothesized that IFNα/β may contribute to the increased frequency of alloimmunization in patients with SCD. To investigate this, expression of ISGs in blood leukocytes and peripheral blood mononuclear cells (PBMCs) of previously transfused SCD patients with or without alloimmunization and race-matched healthy controls were quantified, and IFNα/β gene scores were calculated. IFNα/β gene scores of SCD leukocytes and plasma cytokines were elevated, compared to controls (gene score, p < 0.01). Upon stimulation with IFNβ, isolated PBMCs from patients with SCD had elevated ISGs and IFNα/β gene scores (p < 0.05), compared to stimulated PBMCs from controls. However, IFNβ-stimulated and unstimulated ISG expression did not significantly differ between alloimmunized and non-alloimmunized patients. These findings indicate that patients with SCD express an IFNα/β gene signature, and larger studies are needed to fully determine its role in alloimmunization. Further, illustration of altered IFNα/β responses in SCD has potential implications for IFNα/β-mediated viral immunity, responses to IFNα/β-based therapies, and other sequelae of SCD.

show abstract

Type 1 IFN signaling critically regulates influenza‐induced alloimmunization to transfused KEL RBCs in a murine model

Cited by 14 publications

References 34 publications

Type 1 Interferon Gene Signature Promotes RBC Alloimmunization in a Lupus Mouse Model

Type 1 Interferon Gene Signature Promotes RBC Alloimmunization in a Lupus Mouse Model

Red blood cell alloimmunization and sickle cell disease: a narrative review on antibody induction

Altered type 1 interferon responses in alloimmunized and nonalloimmunized patients with sickle cell disease

Contact Info

Product

Resources

About