H435-containing immunoglobulin G3 allotypes are transported efficiently across the human placenta: implications for alloantibody-mediated diseases of the newborn.

Abstract

The neonatal receptor (FcRn) extends the half-life of human immunoglobulin (Ig)G and transports it across the placenta, providing the newborn with humoral immunity. Of the four subclasses, IgG3 stands out with strong effector functions, short half-life (7 days vs. 21 days for other subclasses), and poor placental transport. We recently described how a single-amino-acid polymorphism at Position 435 in IgG3 is sufficient to explain the short half-life of R435-containing IgG3 and demonstrated that H435-IgG3 has a normal half-life of 21 days. Here, we investigated whether the R435 also explains the relatively poor placental transport of IgG3.

Sera were collected from paired mothers and newborns at birth. The study included six mothers expressing R435-IgG diagnosed with fetal and neonatal alloimmune thrombocytopenia and treated with intravenous immune globulin (IVIG; containing H435-IgG3, also known as G3m16 or G3m(s,t) allotype), as well as 33 paired samples of both G3m16(-) and G3m16(+) mothers. Placental IgG transport was estimated by comparing cord and maternal concentrations of IgG subclass and G3m16 allotype.

The placental transport of naturally occurring H435-IgG3 allotypes was significantly more efficient than that of other R435-IgG3 allotypes and was comparable to IgG1 transport.

We demonstrate that the poor maternal-fetal transport of IgG3 is only true for most individuals of western populations where the G3m16 is not common. In G3m16(+) individuals, expressing H435-containing IgG3, IgG3 transport is similar to IgG1, which may give rise to enhanced complications in pregnancy-associated alloimmune disease in ethnic communities where this naturally occurring H435 containing IgG3 allotype is more frequent.