Regulatory B‐cell compartment in transfused alloimmunized and non‐alloimmunized patients with sickle cell disease

Abstract

Transfusion therapy is a life-sustaining treatment for patients with sickle cell disease (SCD), but can cause serious complications including alloimmunization. We previously reported diminished regulatory T cells (Tregs) and skewed Th2 responses in alloimmunized SCD patients. We hypothesized that the B cell regulatory (Breg) compartment, which controls Treg and Th differentiation, may also be compromised in allosensitized SCD patients. Phenotypically, we did not find differences in the frequency or numbers of CD24hiCD38hi and CD24hiCD27+ B cell subsets, both previously identified as human Bregs, between alloimmunized and non-alloimmunized SCD patients on regular transfusions. However, at the functional level, CD19+ B cells from alloimmunized SCD patients expressed lower levels of IL-10 following stimulation as compared with non-alloimmunized patients (p<0.05), and had reduced ability in inhibiting autologous CD14+ monocyte TNF-α expression (p<0.05). These findings suggest that Bregs from alloimmunized and non-alloimmunized SCD patients differ in their ability to produce IL-10 and dampen monocyte activation, all consistent with an altered immunoregulatory state in alloimmunized SCD patients.

Red blood cell alloimmunization is influenced by recipient inflammatory state at time of transfusion in patients with sickle cell disease

“…Bao et al (2011) described differences in regulatory T cell (Tregs) subsets of SCD patients receiving regular blood transfusions with alloantibodies compared to those without, specifically a reduction in Treg activity, an increase toward T-helper cell type 2 (Th2) responses and lower serum levels of interleukin (IL) 10 in the alloimmunized group of patients. The same group (Bao et al, 2013) also presented data suggesting that regulatory B cells (Bregs) from alloimmunized and non-alloimmunized SCD patients differ in their ability to produce IL10 upon stimulation and dampen monocyte activation despite comparable frequencies of Bregs (CD19 + CD24 hi CD38 hi and CD24 hi CD27 + subsets) supporting an altered immunoregulatory state in alloimmunized SCD patients. Investigations of cytokine levels during acute SCD-related complications have shown increased neutrophil chemotaxis, monocyte phagocytosis and levels of IL6 and TNF during VOC (Graido-Gonzalez et al, 1998;Pathare et al, 2004).…”

The sickle cell mouse lung: proinflammatory and primed for allergic inflammation

“…However, there is some evidence that Tregs in SCD display an altered phenotype and may have reduced immunosuppressive capacity, although the latter remains debated 46,47 . Of particular note, alloimmunization associated with frequent blood transfusion, a mainstay of treatment of SCD, may produce dysfunction in both Tregs 46 and regulatory B cells (Bregs) 48 . We and others have shown that Tregs 32,49,50 and Bregs 30,31,51 play important roles in the regulation of allergy and asthma.…”

Factors Influencing RBC Alloimmunization: Lessons Learned from Murine Models

“…Regulatory T cells are known to suppress the activation and effector functions of many different cell types, in many different situations. The group of Yazdanbakhsh have explored this scenario with respect to RBC antigens in mice and humans, with the conclusion that certain phenotypes of regulatory T cells and B cells may influence responses to transfused RBC antigens [90,91,98,99]. Another group, however, failed to find functional differences in regulatory T cells in alloimmunized or non-alloimmunized humans with sickle cell disease [104].…”

“…However, there is much debate surrounding the reasons for the high rates of RBC alloimmunization [15,87,88], with potential factors including transfusion burden, RBC phenotypic differences between donors and recipients, and RBC genotypic variants in the sickle patients themselves. Sickle cell-associated vascular disease and chronic inflammation [89], as well as immune dysregulation [90,91], may also potentially contribute to the high rates of RBC alloimmunization in patients with sickle cell disease.…”