Immune Regulation of sickle Cell Alloimmunization

Abstract

Red blood cell (RBC) transfusion remains an important treatment for patients with sickle cell disease (SCD) and the majority of patients receive transfusions by adulthood. However, SCD patients are at a high risk of alloimmunization, which can cause life-threatening complications. The high rate of alloimmunization can in part be explained by chronic inflammatory condition in SCD characterized by significant immune and inflammatory activation. Heightened immune effector cell responses and/or impaired regulatory networks are likely to drive alloantibody production in alloimmunized SCD patients. In support of this, altered T cell immunoregulation, known to control antibody responses, have been reported in alloimmunized SCD patients. In addition, stronger follicular help T cell responses that help antibody production by B cells were described in alloimmunized as compared to non-alloimmunized SCD patients. Furthermore, several innate immune abnormalities have been identified in alloimmunized SCD patients, including a compromised anti-inflammatory response against extracellular cell free heme. The data support a model in which alloimmunized SCD patients are unable to switch off their proinflammatory state in response to the ongoing hemolytic state characteristic of SCD, placing this patient subset at a higher risk to develop a strong immune response against allogeneic determinants on transfused RBCs, thus increasing the risk of further alloimmunization. A detailed mechanistic understanding of innate immune abnormalities that can contribute to pathogenic T cell responses in alloimmunized SCD patients will lay the foundation for identification of biomarkers of alloimmunization with the goal that this information will ultimately help guide therapy in these patients.

Keywords: CD83; Follicular helper T cells; NFκB; TIGIT; Tregs; alloimmunization; dendritic cells; heme oxygenase; hemolysis; sickle cell.

Figure 1

TIGIT+ CD4+ T_FH cells are more potent in driving B cell responses, including higher expression levels of costimulatory markers CD40L and ICOS as well increased IL-21 expression levels than CD4 T_FH lacking TIGIT.

Figure 2

In response to heme, TLR-4 signaling inhibits NF-κB and downstream CD83 gene expression in DCs from non-alloimmunized patients, resulting in lower expression of maturation marker (CD83^low). As such, DCs prime naïve T cell to produce lower levels of IFNγ. In contrast, heme driven signaling pathway is defective in DCs from alloimmunized patients, thereby preventing the inhibition of NF-kB and CD83. As a result, primed naïve T cells produce higher levels of IFNγ (IFNγ ^high). We speculate that this pathway represents a mechanism by which enhanced inflammation is induced and/or maintained in alloimmunized patients.