Abstract
The neonatal Fc receptor (FcRn) regulates IgG and albumin homeostasis, mediates maternal IgG transport, takes an active role in phagocytosis, and delivers antigen for presentation. We have previously shown that overexpression of FcRn in transgenic mice significantly improves the humoral immune response. Because rabbits are an important source of polyclonal and monoclonal antibodies, adaptation of our FcRn overexpression technology in this species would bring significant advantages. We cloned the full length cDNA of the rabbit FcRn alpha-chain and found that it is similar to its orthologous analyzed so far. The rabbit FcRn - IgG contact residues are highly conserved, and based on this we predicted pH dependent interaction, which we confirmed by analyzing the pH dependent binding of FcRn to rabbit IgG using yolk sac lysates of rabbit fetuses by Western blot. Using immunohistochemistry, we detected strong FcRn staining in the endodermal cells of the rabbit yolk sac membrane, while the placental trophoblast cells and amnion showed no FcRn staining. Then, using BAC transgenesis we generated transgenic rabbits carrying and overexpressing a 110 kb rabbit genomic fragment encoding the FcRn. These transgenic rabbits – having one extra copy of the FcRn when hemizygous and two extra copies when homozygous - showed improved IgG protection and an augmented humoral immune response when immunized with a variety of different antigens. Our results in these transgenic rabbits demonstrate an increased immune response, similar to what we described in mice, indicating that FcRn overexpression brings significant advantages for the production of polyclonal and monoclonal antibodies.
Highlights
Maintenance of antibody (Ab) levels requires continuous secretion of immunoglobulin (Ig) by plasma cells and protection from degradation
At about the same time, it was shown that 7S c-globulin (IgG) is the fraction of Ig that was protected by such a mechanism [3]; a few years later, it was shown that IgG mediates maternal immune transport in mammals [4,5]
Several publications have shown that FcRn plays major roles in Ag-IgG immune-complex phagocytosis by neutrophils [15], in antigen presentation of IgG immune complexes by professional antigen presenting cells [16,17,18,19] and in generating antigen specific antibodies [18]
Summary
Maintenance of antibody (Ab) levels requires continuous secretion of immunoglobulin (Ig) by plasma cells and protection from degradation. IgG is a class of Abs that is unique to mammals. It is the most abundant Ab in serum and is passively transferred to mammalian offspring. In 1958, Brambell described a saturable receptor that mediates the transport of maternal gamma-globulin to the fetus [1]; he inferred the presence of a similar or identical receptor that protected gamma-globulin from catabolism to make it the longest surviving of all plasma proteins [2]. At about the same time, it was shown that 7S c-globulin (IgG) is the fraction of Ig that was protected by such a mechanism [3]; a few years later, it was shown that IgG mediates maternal immune transport in mammals [4,5]
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