Three non-classical mechanisms for anemic disease of the fetus and newborn, based on maternal anti-Kell, anti-Ge3, anti-M, and anti-Jra cases

Abstract

Maternal alloantibody-mediated hemolytic disease of the fetus and newborn (HDFN) ranges from no or mild symptoms to severe hydrops and intrauterine fetal demise. Hemolytic anti-D-mediated HDFN proceeds via a longknown mechanism, to which three other pathways to fetal/neonatal anemia may be added: (0) Fetal erythrocyte destruction can proceed by extravascular phagocytosis. (1) An apoptotic pathway has been described for anti-Kell, and anti-Ge3. (2) Erythropoietic suppression may arise from altered or deformed erythroblast architecture in anti-M-mediated disease. (3) Clonal escape from erythropoietic suppression is hypothesized to arise from maternal anti-Jr a immune pressure, albeit this requires further elucidation. Alloantibody-mediated anemic disease of the fetus and newborn (ADFN) is a designation we favor for cases when hemolysis or hyperbilirubinemia are not the dominant features, such as those provoked by anti-Kell, anti-Ge3, anti-M, and anti-Jr a .

FcγRIV is required for IgG2c mediated enhancement of RBC alloimmunization

“…In addition to the generalizable advantages of monoclonal antibody therapy (e.g., cost-effective, scalable, high specificity, lot-to-lot consistency), the substantial advances in antibody technology and increased understanding of immune function, now allow antibodies to be engineered to have increased affinity for the neonatal Fc receptor (FcRn), thereby facilitating an extended half-life to make passive immunization more durable. Moreover, antibodies can be engineered to inhibit antibody:FcRn interactions at the maternal-fetal interface, which is especially important for preventing hemolytic disease of the fetus and newborn mediated by alloantibodies to non-D RBC antigens ( 39 , 40 ).…”

Severe fetal anemia caused by anti‐Jra: Burst forming unit‐erythroid colony formation inhibition assay suggesting possible erythroid suppression mechanism

“…11,12 Other antibodies known to cause erythropoietic suppression include anti-K, anti-Ge3, and anti-M via different mechanisms including antibody-mediated apoptosis and alteration of the red cell surface. 24 Our results initiate a mechanistic understanding of anti-Jr a mediated suppression, but confirmation of these findings and further investigations to better elucidate the mechanism are needed. Interestingly, like other case reports, the first child in our case who had possible anti-A and/or anti-Jra mediated HDFN had a positive IgG and C3 DAT.…”

Allo‐anti‐M: Detection peaks around 2 years of age, but may be attenuated by red blood cell transfusion

“…26 Although maternal anti-M IgG titers are often quite low, there is chronic transplacental transfer of maternal IgG into fetal circulation throughout the course of pregnancy, with ongoing cumulative adverse effects. 27 Glycophorin A is expressed on early erythroid precursors and it is believed that anti-M binding may lead to ineffective erythropoiesis and reticulocytopenia similar to that reported for anti-K, 24,27 but with a distinct target molecule. This was demonstrated by Ishida et al who showed a decrease in erythroid colony formation by anti-M in vitro.…”