Initial indications of a red blood cell (RBC) alloimmunization pathway that is interferon-α/β receptor (IFNAR) independent and complement C3 protein dependent have been reported, thus improving our knowledge of RBCs as immunogens and antibody-mediated immune enhancement (AMIE) as a phenomenon in disorders such as hemolytic disease of the fetus and newborn (HDFN).
These findings were based on a study conducted in mice and published in The Journal of Clinical Investigation.
Although immunoglobulins (Igs) are typically considered to be immune effector molecules, it is well recognized that Igs can enhance, in a significant fashion, “primary humoral immunity to soluble or small particulate antigens,” which is known as AMIE. In contrast, the occurrence of HDFN can be dramatically reduced by suppression of maternal alloimmunization via administration of plasma-derived anti-Rhesus D (RhD) immunoglobulin G (IgG) antibodies.
Of note, the administration of anti-RhD IgG to decrease rates of maternal alloimmunization, which is termed antibody-mediated immune suppression (AMIS), was regarded as a groundbreaking clinical development. The utilization of IgG in other settings such as AMIE, however, can exhibit potent immune-stimulatory effects.
It has long been thought that the mechanism of IgG against RBC antigens can lead to AMIE or AMIS, based on its function as a subclass of IgG. The latest improvements in our mechanistic-based knowledge, however, have revealed that RBC alloimmunization necessitates the presence of IFNAR and is inhibited by the existence of complement C3.
Read more about HDFN symptoms and risks
Although IgG2s, IgG2b, and IgG2c dramatically increase the response of antibodies to RBCs that express the human Kell antigen, IgG1 actually suppresses these responses. Recently, it has been shown that the immune properties of RBCs can be differentiated from those of other antigens for a number of reasons:
- RBCs require a spleen
- RBCs need marginal zone (MZ) B cells
- In RBCs, signaling must occur via IFNAR
- In RBCs, suppression takes place via complement C3
- RBCs frequently exhibit a speedy senescence of antibodies,
- RBCs are not able to generate an appreciable antigen-specific primary germinal center (GC) response
In the current analysis, the researchers reported that the opposite occurred with AMIE of an RBC alloantigen. In other words, in this study, IFNAR was not needed for RBC alloimmunization, and the presence of complement C3 led to an enhancement of the response.
Results of the study showed that IgG2c was associated with antigen modulation without any increased complement C3 deposition during AMIE. Further, interferon (IFN) signaling via IFNAR was not necessary for the occurrence of IgG2c-generated AMIE.
The investigators showed that antibody-mediated immune enhancement entails Fc γ receptors and includes the use of complement C3. Additionally, “IgG2c induces consumption of KEL-K2lo RBCs by red pulp macrophages.” They also demonstrated the fact that antibody-facilitated immune enhancement is a process reliant on CD4+ T cells.
Moreover, MZ B cells have been shown to have a role in IgG2c-mediated enhancement. Furthermore, IG2c-generated AMIE is not associated with any significant increase in the presence of germinal center B cells.
An overall model of IgG2c-induced AMIE develops when the current results are combined with observations reported in several prior publications.
“To the best of our knowledge, these findings provide the first evidence of an RBC alloimmunization pathway [that] is IFNAR independent and C3 dependent,” the authors concluded.
