ReviewRegional specialization in the mucosal immune system: what happens in the microcompartments?
Section snippets
Basis of secretory immunity
Active secretory immunity depends on cooperation between mucosal B cells and a 100 kDa transmembrane epithelial glycoprotein called secretory component (SC); its alternative name is polymeric Ig receptor (pIgR) because it mediates the active external transport of dimers and larger polymers of IgA (collectively called pIgA), as well as pentameric IgM (Ref. 1). The B cells responsible for local pIg production are mainly derived from organized mucosa-associated lymphoid tissue (MALT), including
Inductive mucosal immune tissues
Mucosal immune responses are believed to be elicited mainly in the MALT structures, which lack a lymphatic supply of antigens but instead can sample foreign material from epithelial surfaces (Fig. 1a). In mechanistic terms, the best studied mucosal inductive sites are the GALT structures of various experimental animals, including the ileal Peyer's patches and the appendix16, 17. The chief function of GALT is protection of the gut, but its primed effector cells also migrate to other exocrine
Initial mucosal antigen encounter
Live and dead luminal particles are preferentially taken up by MALT through specialized areas of the follicle-associated epithelium (FAE), the so-called M (membrane) cells16, 17. These unique bell-shaped cells (insert in Fig. 1a), which sample antigens unspecifically and by receptor-mediated uptake, can supposedly exert some antigen processing. However, major histocompatibility complex (MHC) class II (HLA-DR) expression is at best faint on human intestinal M cells18, and there is no evidence
Importance of germinal centres for B-cell development
By definition, a Peyer's patch comprises five or more activated B-cell follicles16. Primary intestinal follicles occur early in human fetal life, but secondary follicles that have germinal centres (GCs) depend on antigenic stimulation and do not appear until shortly after birth2. The primary follicles contain recirculating CD19+ CD20+ lymphocytes with a naive phenotype (sIgD+IgM+), both sIg isotypes contributing to the same antigen specificity of the B-cell receptor (BCR). It remains unclear
Isotype switching and J-chain expression
B-cell differentiation usually involves downstream (5′→3′) switching of CH genes61. In addition, the tonsillar GC reaction often induces terminal development of a substantial number of intrafollicular Ig-producing immunocytes (plasmablasts and plasma cells), predominantly with cytoplasmic IgG (55–72%) or IgA (13–18%), the latter isotype being more frequent in children than in adults62. Both of these GC immunocyte classes, and also those producing IgM and IgD, are often associated with J-chain
Mucosal B cells maintain J-chain expression and regionalized homing in IgA deficiency
In selective IgA deficiency, intestinal IgA-producing cells are markedly reduced or completely lacking, whereas IgG and especially IgM immunocytes are substantially increased, constituting 20–35% and 65–75%, respectively2. Conversely, exocrine sites of the upper aerodigestive tract contain 6–70% IgG cells but only 7–25% IgM cells; in this region there is often (but not always) an abundance of IgD immunocytes (25–80%), which usually remain well below 5% in the gut60. Compensation with IgD,
Conclusions
The mucosal immune system is quantitatively the body's most important activated B-cell system. Indeed, mucosal exocrine tissues contain more than 80% of all Ig-producing cells, the major product of which is normally pIgA. Expression of the SC binding site is required by both pIgA and pentameric IgM for their external pIgR-mediated transport, and depends on incorporation of the J chain into the polymer structure. This important function is probably sufficient biological justification for the J
Acknowledgements
Studies in the authors' laboratory are supported by the Norwegian Cancer Society, the Research Council of Norway, Anders Jahres Fund, and Otto Kr. Bruun's Legacy. H.E. Bryne and E.K. Hagen are gratefully acknowledged for excellent assistance with the manuscript, and the technical staff of LIIPAT for invaluable contributions.
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