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Immunoglobulin transport across polarized epithelial cells

Nature Reviews Molecular Cell Biology volume 3, pages 944–956 (2002)Cite this article

Key Points

  • Transcytosis is a transport mechanism through which proteins are internalized from one surface of an epithelial cell and then delivered to the other. Transcytosis is an important mechanism used by epithelial cells to maintain surface polarity. Receptor-mediated transcytosis was first described for the immunoglobulins.

  • Transport of IgA and IgM is mediated through the polymeric immunoglobulin receptor pIgR, and involve very similar mechanisms. pIgR binds to its ligand on the basolateral surface of epithelial cells. En route or at the apical surface, pIgR is proteolytically cleaved and the extracellular binding domain of the receptor, bound to IgA, is released into the mucosal secretions. This cleaved extracellular domain of the receptor is known as the secretory component (SC).

  • Secreted IgA, together with the SC, is known as secretory IgA (sIgA), which is important for neutralizing extracellular pathogens. pIgR–dIgA complexes are important in intracellular virus neutralization and the clearing of antigens from the lamina propria.

  • Transport of IgG is mediated through FcRn, and binding takes place either at the cell surface or in endosomes. Transport is pH dependent and can occur in both the apical-to-basolateral and basolateral-to-apical direction.

  • IgG is also important in neutralizing pathogens. In addition, FcRn is important in regulating IgG catabolism and FcRn–IgG complexes might have an important function in immune activation and tolerance.

  • Receptor-mediated transcytosis involves transport through multiple endocytic compartments, although the exact number and identity of these compartments is still being defined.

  • Transcytosis of pIgR and FcRn is highly regulated. pIgR-mediated transport involves the cytoskeleton, multiple Rab GTPases and a number of signalling cascades, some of which depend on ligand binding. The regulation of FcRn-dependent transport might involve the cytoskeleton and signal transduction pathways.

Abstract

IgA, IgG and IgM are transported across epithelial cells in a receptor-mediated process known as transcytosis. In addition to neutralizing pathogens in the lumen of the gastrointestinal, respiratory and urogenital tracts, these antibody–receptor complexes are now known to mediate intracellular neutralization of pathogens and might also be important in immune activation and tolerance. Recent studies on the intracellular transport pathways of antibody–receptor complexes and antibody-stimulated receptor-mediated transcytosis are providing new insight into the nature and regulation of endocytic pathways.

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Figure 1: Domain structure of pIgR and FcRn.
Figure 2: Functions of dIgA/sIgA and pIgR.
Figure 3: Functions of IgG and FcRn.
Figure 4: Transcytotic pathway of pIgR–dIgA.
Figure 5: Transcytotic pathways of FcRn–IgG.
Figure 6: Model for ligand-stimulated transcytosis of pIgR–dIgA.

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Acknowledgements

We apologize to our colleagues for omitting references in this review because of space limitations. We would like to thank R. Hughey, O. Weisz and S. Truschel for their helpful comments and discussion. This work was supported by a grant to G.A. from the National Institutes of Health.

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Authors and Affiliations

  1. Renal Electrolyte Division of the Departments of Medicine, Laboratory of Epithelial Cell Biology, Cell Biology and Physiology, University of Pittsburgh, Pittsburgh, 15261, Pennsylvania, USA

    Raul Rojas & Gerard Apodaca

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  1. Raul Rojas
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  2. Gerard Apodaca
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Correspondence to Gerard Apodaca.

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DATABASES

LocusLink

Cdc42

cellubrevin

EEA1

erythropoietin

FcRn

p115

phospholipase Cγ

pIgR

PKCɛ

protein kinase C

Rab11

Rab17

Rab25

Rab3b

Rac1

RhoA

SNAP-25

Tf

Glossary

MUCOSA

The outermost layer of tissue that lines the surfaces of the gut, respiratory tract and urogenital tract. It consists of a surface epithelium, the lamina propria and might also include smooth muscle.

TIGHT JUNCTION

A circumferential ring at the apex of epithelial cells that seals adjacent cells to one another. The tight junction prevents the mixing of proteins and lipids between the apical and basolateral plasma membrane domains, and regulates solute and ion flux between adjacent epithelial cells.

T LYMPHOCYTES

Cells that are involved in cell-mediated immunity. They are agents of the body's immune system and can differentiate into killer, helper and suppressor T cells. T-helper cells assist in the stimulation of B lymphocytes to produce antibodies.

TRANSCYTOSIS

Transport of macromolecules across polarized epithelial cells, involving uptake at one cell surface and delivery — through a series of intermediate endocytic compartments — to the opposite plasma-membrane domain.

B LYMPHOCYTES

Involved in the production of antibodies against invading agents. They differentiate into plasma cells that synthesize and secrete a specific antibody.

LAMINA PROPRIA

Layer of connective tissue underlying the basal lamina of the epithelium. It might contain smooth-muscle cells, lymphoid tissue, fibroblasts and extracellular matrix.

ANTIGEN

Any foreign substance that is capable of inducing an immune response.

COLOSTRUM

A yellowish fluid produced by the mammary gland that precedes the production of milk and is rich in antibodies and nutrients.

YOLK SAC

A membranous sac that is attached to the embryo and has a function in nutrient transport. In rats and mice, IgG is transported across this structure. In primates, IgG is transported across the chorioallantoic placenta.

ENTEROCYTES

Mature cells of the intestinal epithelium, the primary function of which is the absorption of substances from the lumen and delivery to the circulatory system. In the small intestine, enterocytes are found both in crypts and on the surface of the villi.

Rabs

The largest family of monomeric small GTP-binding proteins. Rab proteins are distributed in distinct intracellular compartments where they function in the tethering/docking of vesicles to their target compartment, leading to membrane fusion. In addition, Rab proteins have been implicated in cargo selection, vesicle budding and organelle motility.

TRANSFERRIN

An iron storage protein that is found in mammalian serum. Transferrin receptors on the cell surface bind transferrin as part of the transport route of iron into cells. In many epithelial cells, the trafficking of transferrin bound to its receptor has been used to define the basolateral-recycling pathway.

ACTIN COMET

Actin tail at one end of an endosome that propels the organelle inwards. First described for the intracellular movement of Listeria.

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Rojas, R., Apodaca, G. Immunoglobulin transport across polarized epithelial cells. Nat Rev Mol Cell Biol 3, 944–956 (2002). https://doi.org/10.1038/nrm972

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