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

Abstract

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.

On the Perplexingly Low Rate of Transport of IgG2 across the Human Placenta

“…We recently reported that these effects are attributable to a single amino acid difference between IgG3 and the other subclasses. While IgG1, IgG2 and IgG4 have a histidine at position 435, a key amino acid responsible for the pH-dependent binding to FcRn, most IgG3 allotypes have an arginine at this position, causing them to lose competition for recycling and transcytosis [18], [20]. IgG3 allotypes which express a histidine at this position have equal half-life to that of IgG1, and are transported equally well across the placenta [18], [20].…”

“…For IgG2, however, these FcRn-mediated transcytosis and recycling functions seem to diverge [18], [29]. Although IgG1, IgG2 and IgG4 share all known contact residues with FcRn, and FcRn is known to mediate both IgG transcytosis and extend IgG serum persistence in a very similar manner, IgG2 crosses the human placenta with a markedly lower efficiency, with trans-placental transport more closely matching that of IgG3.…”

“…IgG1, IgG4 and H435-containing allotypes of IgG3) typically exceeds maternal levels. Thus the transport of IgG2 is much less efficient and is in fact comparable to that of R435-containing IgG3 [17], [18]. Since FcRn is thought to play a very similar key role in both of these processes, the reason for this discrepancy remains unclear.…”

Targeting FcRn for the modulation of antibody dynamics

“…The important contribution of His435 to FcRn interactions raises the question as to how these substitutions might affect binding. Studies in which His435 in human IgG1 was mutated to Arg, and reciprocally, Arg435 in human IgG3 mutated to His, demonstrate that the His-containing antibodies have higher affinities for FcRn at pH 6.0, longer in vivo half-lives and improved transport across the placental barrier (Einarsdottir et al, 2014; Kim et al, 1999; Stapleton et al, 2011). Consistent with the pKa of the Arg side chain, Arg-containing allotypes of IgG3 retain significant binding to FcRn at near neutral pH, which also contributes to the lower activity in functions dependent on FcRn-mediated transport.…”

Errors in data interpretation from genetic variation of human analytes

“…responses to vaccination, autoantibodies (9)(10)(11)(12), alloimmunization to transfusion and transplantation antigens (13,14), and maternal alloantibodies against fetal and paternal antigens (15)(16)(17). In addition, IgG subclass deficiency is among the more common immunodeficiencies in pediatric populations, resulting in increased rates of particular infections (18,19).…”