Bidirectional transcytosis of IgG by the rat neonatal Fc receptor expressed in a rat kidney cell line: a system to study protein transport across epithelia

McCarthy, Kevin M.; Yoong, Yinlee; Simister, Neil E.

doi:10.1242/jcs.113.7.1277

Cited by 129 publications

(11 citation statements)

References 67 publications

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“…In contrast, all FcRn‐mediated transport of IgG (transcytosis in both directions and recycling from both the apical and basolateral surfaces) are inhibited by nocodazole when IgG is internalized at either acidic or basic pH (Table II), suggesting that all forms of FcRn‐mediated transport of IgG require intact microtubules. These results are consistent with those obtained for FcRn‐mediated trans cytosis in inner medullary collecting duct (IMCD) cells (McCarthy et al ., 2000). However, only basolateral to apical transcytosis of an FcγRII/FcRn chimeric protein expressed in MDCK cells was inhibited by nocodazole (Stefaner et al ., 1999), which may reflect a different mechanism for transcytosis in the apical to basolateral direction when the FcRn ectodomain is absent.…”

Section: Resultssupporting

confidence: 92%

“…We also found that the use of serum containing bovine IgG induced a similar redistribution of FcRn (data not shown). Redistribution of FcRn caused by transport of bovine IgG in serum could account in part for the predominance of basolateral surface expression over apical surface expression seen for rat FcRn expressed in IMCD cells (McCarthy et al ., 2000).…”

Section: Discussionmentioning

confidence: 99%

“…This result, when combined with the similar distributions of FcRn and FcRn–GFP (Figure 2A and B), demonstrates that GFP fluorescence can be used to reliably report the location of FcRn. Consistent with previous studies (Praetor et al ., 1999; McCarthy et al ., 2000), we find FcRn‐mediated IgG transport in both the apical to basolateral and basolateral to apical directions. However, apical to basolateral transport is more efficient in both the FcRn‐ and FcRn–GFP‐expressing cells, with ∼4‐ to 5‐fold more IgG transported in this direction as compared with the opposite direction (Table II).…”

Section: Discussionmentioning

confidence: 99%

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IgG transcytosis and recycling by FcRn expressed in MDCK cells reveals ligand-induced redistribution

Ramalingam

2002

The EMBO Journal

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The neonatal Fc receptor (FcRn) transports IgG across epithelial cells and recycles serum IgG. FcRn binds IgG at the acidic pH of endosomes and releases IgG at the basic pH of blood. We expressed rat FcRn in polarized MDCK cells and demonstrated that it functions in transcytosis and recycling of IgG. In the absence of IgG, FcRn is distributed predominantly apically, but redistributes to basolateral locations upon IgG addition, indicating that ligand binding induces a signal that stimulates transcytosis. FcRn transcytoses IgG more ef®ciently in the apical to basolateral than the reverse direction when IgG is internalized by receptor-mediated endocytosis at acidic pH or by¯uid phase endocytosis at basic pH. The PI 3-kinase inhibitor wortmannin disrupts basolateral recycling and transcytosis in both directions, but only minimally reduces apical recycling. Confocal imaging and quantitative IgG transport studies demonstrate that apically-internalized IgG recycles to the apical surface mainly from wortmannin-insensitive apical early endosomes, whereas FcRn±IgG complexes that transcytose to the basolateral surface pass through downstream Rab11-positive apical recycling endosomes and transferrin-positive common endosomal compartments.

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Section: Resultssupporting

confidence: 92%

Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

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IgG transcytosis and recycling by FcRn expressed in MDCK cells reveals ligand-induced redistribution

Ramalingam

2002

The EMBO Journal

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“…In other cells, such as epithelial cells lining mucosal interfaces, FcRn mediates IgG transcytosis, thereby participating in immune surveillance and host defense. Extensive evidence for a FcRn-dependent IgG transcytosis pathway has been gathered from in vitro studies in various polarized cell lines (e.g., refs − ). This pathway was also documented in vivo in mice, and was shown to be efficient in the female genital epithelium as well as the respiratory epithelium of the lung barrier. , …”

Section: Macromolecular Transport In the Central Nervous System Acros...mentioning

confidence: 99%

Physiology of Blood–Brain Interfaces in Relation to Brain Disposition of Small Compounds and Macromolecules

2013

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The brain develops and functions within a strictly controlled environment resulting from the coordinated action of different cellular interfaces located between the blood and the extracellular fluids of the brain, which include the interstitial fluid and the cerebrospinal fluid (CSF). As a correlate, the delivery of pharmacologically active molecules and especially macromolecules to the brain is challenged by the barrier properties of these interfaces. Blood-brain interfaces comprise both the blood-brain barrier located at the endothelium of the brain microvessels and the blood-CSF barrier located at the epithelium of the choroid plexuses. Although both barriers develop extensive surface areas of exchange between the blood and the neuropil or the CSF, the molecular fluxes across these interfaces are tightly regulated. Cerebral microvessels acquire a barrier phenotype early during cerebral vasculogenesis under the influence of the Wnt/β-catenin pathway, and of recruited pericytes. Later in development, astrocytes also play a role in blood-brain barrier maintenance. The tight choroid plexus epithelium develops very early during embryogenesis. It is specified by various signaling molecules from the embryonic dorsal midline, such as bone morphogenic proteins, and grows under the influence of Sonic hedgehog protein. Tight junctions at each barrier comprise a distinctive set of claudins from the pore-forming and tightening categories that determine their respective paracellular barrier characteristics. Vesicular traffic is limited in the cerebral endothelium and abundant in the choroidal epithelium, yet without evidence of active fluid phase transcytosis. Inorganic ion transport is highly regulated across the barriers. Small organic compounds such as nutrients, micronutrients and hormones are transported into the brain by specific solute carriers. Other bioactive metabolites, lipophilic toxic xenobiotics or pharmacological agents are restrained from accumulating in the brain by several ATP-binding cassette efflux transporters, multispecific solute carriers, and detoxifying enzymes. These various molecular effectors differently distribute between the two barriers. Receptor-mediated endocytotic and transcytotic mechanisms are active in the barriers. They enable brain penetration of selected polypeptides and proteins, or inversely macromolecule efflux as it is the case for immnoglobulins G. An additional mechanism specific to the BCSFB mediates the transport of selected plasma proteins from blood into CSF in the developing brain. All these mechanisms could be explored and manipulated to improve macromolecule delivery to the brain.

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“…The expression of FcRn was found at the brain microvasculature and choroid plexus epithelium [ 60 ]. It has been shown that FcRn transports IgG across cellular barriers between mother and offspring [ 61 ]. Similarly, FcRn in the BBB may facilitate the transfer of MS plasma IgG antibodies into CNS.…”

Section: Discussionmentioning

confidence: 99%

Multiple sclerosis plasma IgG aggregates induce complement-dependent neuronal apoptosis

et al. 2023

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Grey matter pathology is central to the progression of multiple sclerosis (MS). We discovered that MS plasma immunoglobulin G (IgG) antibodies, mainly IgG1, form large aggregates (>100 nm) which are retained in the flow-through after binding to Protein A. Utilizing an annexin V live-cell apoptosis detection assay, we demonstrated six times higher levels of neuronal apoptosis induced by MS plasma IgG aggregates (n = 190, from two cohorts) compared to other neurological disorders (n = 116) and healthy donors (n = 44). MS IgG aggregate-mediated, complement-dependent neuronal apoptosis was evaluated in multiple model systems including primary human neurons, primary human astrocytes, neuroblastoma SH-SY5Y cells, and newborn mouse brain slices. Immunocytochemistry revealed the co-deposition of IgG, early and late complement activation products (C1q, C3b, and membrane attack complex C5b9), as well as active caspase 3 in treated neuronal cells. Furthermore, we found that MS plasma cytotoxic antibodies are not present in Protein G flow-through, nor in the paired plasma. The neuronal apoptosis can be inhibited by IgG depletion, disruption of IgG aggregates, pan-caspase inhibitor, and is completely abolished by digestion with IgG-cleaving enzyme IdeS. Transmission electron microscopy and nanoparticle tracking analysis revealed the sizes of MS IgG aggregates are greater than 100 nm. Our data support the pathological role of MS IgG antibodies and corroborate their connection to complement activation and axonal damage, suggesting that apoptosis may be a mechanism of neurodegeneration in MS.

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Bidirectional transcytosis of IgG by the rat neonatal Fc receptor expressed in a rat kidney cell line: a system to study protein transport across epithelia

Cited by 129 publications

References 67 publications

IgG transcytosis and recycling by FcRn expressed in MDCK cells reveals ligand-induced redistribution

IgG transcytosis and recycling by FcRn expressed in MDCK cells reveals ligand-induced redistribution

Physiology of Blood–Brain Interfaces in Relation to Brain Disposition of Small Compounds and Macromolecules

Multiple sclerosis plasma IgG aggregates induce complement-dependent neuronal apoptosis

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