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

Abstract

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.

Complement C3 and marginal zone B cells promote IgG-mediated enhancement of RBC alloimmunization in mice

“…The IFNAR has emerged as an essential receptor for RBC alloimmunization (both CD4 + T cell dependent and independent), both at baseline and when enhanced by inflammation (viral infection or lupus-like pathology) ( 22 – 25 ). Although characterized mostly in murine systems, viral infection has translated as an independent risk factor for alloimmunization in humans ( 44 ) and an “interferon signature” is associated with human pathologies in which alloimmunization is increased ( 45 – 48 ). In addition, complement C3 has emerged as an inhibitor of RBC alloimmunization ( 26 , 27 ).…”

Retention of functional mitochondria in mature red blood cells from patients with sickle cell disease

“…vaso‐occlusive crisis, steady state, etc.) and alloimmunization status have profound effects on circulating cytokines and interferons 67,68 . It is also possible that the cytokine and/or interferon response required for enhanced alloimmunization occurs locally (e.g.…”

“…and alloimmunization status have profound effects on circulating cytokines and interferons. 67,68 It is also possible that the cytokine and/or interferon response required for enhanced alloimmunization occurs locally (e.g. in secondary lymphoid organ) following clearance of mitochondria-positive RBCs; thus, plasma cytokine and interferon levels may not reflect immune activation in compartments associated with RBC clearance and subsequent initiation of alloantibody production.…”

The Development and Consequences of Red Blood Cell Alloimmunization

“…In addition to distinct features of key immune cells involved in alloantibody production, variation in innate immune signaling may exist between responders and nonresponders. Patients with SCD have higher levels of myxovirus resistance protein 1, a downstream product of type 1 interferon (IFNαβ) activation ( 59 ). Despite this, IFNαβ levels do not appear to segregate responders from nonresponders, although B cells do express more of the activation marker CD86 at baseline among responders than nonresponders ( 59 ).…”