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H. Schonewille et al.
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AB
Figure 1. Non-inherited maternal antigens (NIMA) and anti-IPA (inherited paternal antigens) immunity. A. The X-/- child (= “mother” in cohort) encounters X as NIMA during pregnancy and nursing from her heterozygous X-/+ mother (=”grandmother”), resulting in immunity or regu- lation against the X-antigen. B. During her (=”mother”) pregnancy of a X-/+ child this can determine whether she will form antibodies against the fetal X-IPA. C. During her (=”mother”) pregnancy of a X-/+ child she re-encounters X as a fetal (f) -IPA.
implies extended exposure to soluble and cellular maternal antigens and, in addition, extracellular vescicles (EVs) which can exert several immune effects. EVs are derived from a variety of cells including RBC, and several clinically relevant Rhesus, Kell, Duffy and Kidd blood group anti- gens are expressed.29,30 Erythrocyte derived EVs have immunomodulating properties.31 Up to 6 months after delivery, human colostrum and breast milk contains exo- somes capable of increasing Foxp3+CD4+CD25+ allospecif- ic T regulator cells in vitro.19 In the postnatal period, when the newborn is developing immunity against environmen- tal threats, prolonged exposure to the maternal antigens may be perceived as auto-antigens requiring regulation. Moreover, oral exposure to antigens and antigen-antibody complexes was reported to induce regulation in neonates as well as in adults.32,33 In D-sensitized women pregnant of a subsequent D-positive child, oral administration of D- antigen inhibited an expected boost in anti-D titer.34 Finally, breast milk provides an additional source of viable maternal cells that may increase maternal
microchimerism, which is considered a driving force of
regulation leading to maintenance of tolerance for NIMAs.18,35,36
A different history of maternal BF may explain the dis- crepancy of finding a grandmother effect in various stud- ies. Until manufactured baby milk became available, BF was part of our immunological education. Several, also cultural aspects, such as wealth and women’s emancipa- tion, often replaced BF by cow milk. This may however have consequences that are still unknown. Another aspect of BF is the transmission of maternal cells which seem to play a role in immunity against malignant diseases in the child as shown by Amatay and colleagues, based on a meta-analysis suggesting that BF may strengthen anti- leukemic immunity in progeny.37
Our observations on the effect of oral exposure to NIMAs by BF may not just explain the historical contro- versies regarding the grandmother theory. Why only a minority of individuals form RBC alloantibodies after pregnancy and/or blood transfusions (responders), while
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haematologica | 2019; 104(2)