Identification and function of neonatal Fc receptor in mammary gland of lactating mice

Abstract

In addition to its proposed function in regulating serum IgG levels, the MHC class I-related neonatal Fc receptor (FcRn) is known to play a role in IgG transfer across rodent yolk sac and neonatal intestine. In contrast to humans, for which transplacental transfer of IgG appears to be the only mechanism of maternal IgG delivery, the transmission of IgG in mice occurs both antenatally (yolk sac) and neonatally (transport from mother's milk across intestinal epithelial cells). In the current study, a possible role for FcRn in regulating IgG transfer into milk has been investigated. FcRn has been shown to be present in functional form in the mammary gland of lactating mice, and is localized to the epithelial cells of the acini. Analysis of the transfer of Fc fragments and IgG which have different affinities for FcRn indicate that, unexpectedly, these proteins are transferred in inverse correlation with their binding affinity for FcRn. Thus, in the lactating mammary gland FcRn appears to play a role in recycling IgG in a mode that may have relevance to FcRn trafficking during the maintenance of constant serum IgG levels.

Over‐expression of the bovine FcRn in the mammary gland results in increased IgG levels in both milk and serum of transgenic mice

“…It thus seems that over-expression of bFcRn leads to retention of IgG in serum rather than accumulation of IgG in milk. This result is in accordance with a previous observation that IgG subclasses are transferred with an inverse correlation to their binding affinity for FcRn in mice, 9 as an enhanced FcRn expression obviously increases the chance for IgG to bind to the FcRn.…”

“…5 In the mouse mammary gland, FcRn appears to play a role in recycling IgG to maintain constant serum IgG levels during lactation. 9 As discussed above, the increase in endogenous murine IgG levels could also be because the serum IgG is prevented from being secreted into milk more effectively because of the over-expression of the bFcRn. To validate this notion, we further investigated the clearance of human IgG in these transgenic mice and clearly showed that the human IgG was prevented from being secreted more effectively and/or degraded more slowly in transgenic mice than in controls.…”

“…5 In rodents, maternal antibodies are transported to their offspring both antenatally and neonatally. 4,8,9 A pivotal molecule responsible for the transfer of maternal IgG is neonatal Fc receptor (FcRn), which was first identified in the small intestine of neonatal rats where it mediates uptake of IgG from milk. 10 FcRn is a major histocompatibility complex class I related molecule consisting of an a-chain and b2-microglobulin and its major roles are to protect both IgG and albumin from catabolism and so extend their half-lives 3,11,12 in addition to transporting IgG through multiple mucosal barriers.…”

“…15,18,19 However, the data obtained from rodent models supports the notion either that FcRn was not involved in IgG transfer from serum to milk or that transport of IgG was in an inverse correlation with their binding affinity to FcRn. 9,13 In 1995, Israel et al measured the milk IgG level in mid-lactation of b2-microglobulin gene (b2m) knockout mice. They revealed no obvious difference between b2m-deficient and heterozygous mice, 13 suggesting that FcRn may not transport IgG back from blood to the mammary gland.…”

“…Another study also showed that FcRn could be identified in the epithelial cells of the acini in the mammary glands of lactating mice, and that the FcRn may function as a recycling receptor rather than a transport receptor. 9 The postulated function of FcRn in ruminants to transport IgG from serum to milk so far relies only on indirect evidence obtained by studies on FcRn messenger RNA (mRNA) expression and protein distribution in the mammary gland around parturition. 15,16,18,20 To address this question, we have generated a transgenic mouse model in which bovine FcRn (bFcRn) is over-expressed in the lactating mammary gland.…”