Anti-RhD antibody therapy modulates human natural killer cell function

Abstract

Anti-RhD antibodies are widely used in clinical practice to prevent immunization against RhD, principally in hemolytic disease of the fetus and newborn. Intriguingly, this disease is induced by production of the very same antibodies when an RhD negative woman is pregnant with an RhD positive fetus. Despite over five decades of use, the mechanism of this treatment is, surprisingly, still unclear. Here we show that anti-RhD antibodies induce human natural killer (NK) cell degranulation. Mechanistically, we demonstrate that NK cell degranulation is mediated by binding of the Fc segment of anti-RhD antibodies to CD16, the main Fcγ receptor expressed on NK cells. We found that this CD16 activation is dependent upon glycosylation of the anti-RhD antibodies. Furthermore, we show that anti-RhD antibodies induce NK cell degranulation in vivo in patients who receive this treatment prophylactically. Finally, we demonstrate that the anti-RhD drug KamRho enhances the killing of dendritic cells. We suggest that this killing leads to reduced activation of adaptive immunity and may therefore affect the production of anti-RhD antibodies.

N‐glycan profiling alterations of serum and immunoglobulin G in immune thrombocytopenia

“…The Fc portion of IgG has a uniquely conserved glycosylation site at asparagine 297 (Asn297). The exact composition of the attached N‐glycan affects IgG‐mediated effector functions such as antibody‐dependent cell‐mediated cytotoxicity (ADCC), complement‐dependent cytotoxicity (CDC), and antibody‐dependent cellular phagocytosis (ADCP) through modification of the IgG Fc binding affinity for Fcγ receptors (FcγRs) and complement protein C1q complex 1‐5 . Glycosylation of IgG Fc is critical for modulating the pro‐inflammatory and anti‐inflammatory activities of IgG and may contribute to autoimmune and inflammatory diseases.…”

“…The exact composition of the attached N‐glycan affects IgG‐mediated effector functions such as antibody‐dependent cell‐mediated cytotoxicity (ADCC), complement‐dependent cytotoxicity (CDC), and antibody‐dependent cellular phagocytosis (ADCP) through modification of the IgG Fc binding affinity for Fcγ receptors (FcγRs) and complement protein C1q complex. 1 , 2 , 3 , 4 , 5 Glycosylation of IgG Fc is critical for modulating the pro‐inflammatory and anti‐inflammatory activities of IgG and may contribute to autoimmune and inflammatory diseases. It has been reported that a variety of autoimmune and inflammatory diseases such as autoimmune hemolytic anemia, systemic lupus erythematosus, inflammatory bowel disease, and rheumatoid arthritis have skewed IgG glycosylation pattern, 6 , 7 , 8 , 9 and in some diseases, the skewed IgG glycosylation is associated with disease severity and treatment response.…”

Immunomodulation of Antibody Glycosylation through the Placental Transfer

“…In RhD HDFN immunization, anti-RhD antibodies enhance the NK cell activation, thereby promoting immune suppression by eliminating DCs and, as a result, preventing B cells from producing anti-RhD antibodies. Removed glycosylation from anti-RhD antibodies, such as core fucosylation, abolishes their ability to induce NK cell degranulation, indicating that anti-RhD antibodies activate NK cells via glycosylation-dependent Fc segments [118].…”