Abstract
The neonatal receptor, FcRn, mediates both serum half–life extension as well as active transport of maternal IgG to the fetus during pregnancy. Therefore, transport efficiency and half-life go hand-in-hand. However, while the half-life of the human IgG2 subclass is comparable to IgG1, the placental transport of IgG2 is not, with the neonatal IgG1 levels generally exceeding maternal levels at birth, but not for IgG2. We hypothesized that the unique short-hinged structure of IgG2, which enables its κ-, but not λ-isotype to form at least three different structural isoforms, might be a contributing factor to these differences. To investigate whether there was any preference for either light chain, we measured placental transport of IgG subclasses as well as κ/λ-light chain isotypes of IgG1 and IgG2 in 27 matched mother-child pairs. We also studied the half-life of IgG1 and IgG2 light chain isotypes in mice, as well as that of synthesized IgG2 structural isotypes κA and κB. In order to investigate serum clearance of IgG1 and IgG2 light-chain isotypes in humans, we quantified the relative proportions of IgG1 and IgG2 light chains in hypogammaglobulinemia patients four weeks after IVIg infusion and compared to the original IVIg isotype composition. None of our results indicate any light chain preference in either of the FcRn mediated mechanisms; half-life extension or maternal transport.
Highlights
Immunoglobulin G (IgG) forms the backbone of our circulating, adaptive immune system
Due to the shortness of the IgG2 hinge, which causes the F(ab)2 to be relatively close to the Fc as well as the distinct structural isoforms of IgG2, we hypothesized that the low placental transport of IgG2 may be attributable to a single structural isoform, unique to IgG2k, interacting differently with FcRn, possibly affecting its half-life as well. For this reason we studied the trans-placental transport of IgG2l and IgG2k in humans and their half-life in mice and humans, both of which are FcRn-ascribed functions, and tested whether the unique structural isoforms of IgG2k could explain the low efficiency of IgG2 transport
FcRn mediates IgG- transcytosis and recycling, both of which are compromised for IgG3, with reduced serum persistence and placental transport
Summary
Immunoglobulin G (IgG) forms the backbone of our circulating, adaptive immune system. The fully assembled IgG molecule consists of two identical 50 kDa heavy chains (c1, c2, c3 or c4 subclasses), and two identical 23 kDa light chains forming a heterodimer (one heavy chain and one light chain) that further assemble into dimers. The assembled molecule is Y shaped, with the light chains and the N-terminal parts of the heavy chains (CH1 and VH domains) in tight association, forming the two Fab arms (Fragment antigen binding), and the C-terminal CH2 and CH3 domains forming the Fc-tail. Length and flexibility of the hinge region varies extensively amongst the IgG subclasses influencing the relative orientation and movement of the Fab arms and Fc tail of the IgG antibody [1]. IgG2 has a 12 amino acid hinge region and contains a rigid poly-proline double helix, stabilized by four inter-heavy chain disulfide bridges. IgG3 has the longest hinge region, about 4 times as long as IgG1, and the greatest flexibility, while the IgG4 hinge contains 12 amino acids yielding an intermediate flexibility compared to IgG1 and IgG2 [2]
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