FIGURES AND TABLES
FROM:
The immune geography of IgA induction and function
A J Macpherson, K D McCoy, F-E Johansen and P Brandtzaeg
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Figure 1.
IgA structure and class switch recombination (CSR). (a) The intron–exon structure of the constant 
heavy-chain (CH) gene. Each exon encodes a separate domain (C1, C2, C3). The hinge (H) region is encoded at the 5' end of the C2 exon and the 18-amino-acid extension at the C-terminal end of secreted IgA is encoded at the 3' end of the C3 exon (tail piece available for J-chain combination). The transmembrane and cytoplasmic tail sequences are encoded by the M exon located 3' of the C3 exon. The shaded box represents 3'-untranslated RNA. (b) Three-dimensional model of monomeric human IgA2 showing wide separation of antigen-binding sites at the top (reproduced with permission from ref. 128). (c) Following V(D)J recombination, synthesis of the 
heavy chain and subsequent association with a light chain, an IgM molecule is expressed on the surface of the B cell. CSR to IgA (shown for the mouse) is preceded by the production of an germline transcript (not shown), which is formed following transcription through the initiation (I) exon, the intronic switch (S) region, and the C exons. Transcription is initiated from cytokine-inducible promoters upstream of the I exon. Processing of this primary transcript generates the germline transcript and a spliced out S-region transcript. The spliced out S-region stably associates with the template DNA strand of the S-region, forming a stable RNA–DNA hybrid. The displaced G-rich single-stranded DNA is thought to be the substrate for the enzyme activation-induced cytidine deaminase (AID). DNA double-strand breaks at the S-region and DNA repair result in joining of the S and S regions yielding the rearranged IgA heavy chain constant region and the excised intervening DNA, depicted as a DNA switch circle, which represents a short-lasting sign of local CSR. E upstream of the S region indicates the intronic enhancer. Gene elements depicted are not to scale.
Figure 2.
Costimulatory signals for class switch recombination (CSR) to IgA. BAFF and APRIL are expressed by dendritic cells, monocytes, and human colonic epithelial cells (following Toll-like receptor signaling, not shown), whereas APRIL can also be secreted by macrophages and activated T cells. These cytokines bind to their receptors, BAFF-R, TACI, or BCMA, which are all expressed by B cells. APRIL, A proliferation-inducing ligand; BAFF, B-cell activating factor of the TNF family; BCMA, B-cell maturation antigen; TACI, transmembrane activator and CAML interactor.
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Figure 3.
B-cell homing to mucosal and peripheral tissues is mediated by specific combinations of chemokine receptors and adhesion molecules. Newly developed B cells express specific chemokine receptors that mediate responsiveness to chemokine ligands expressed in secondary lymphoid tissues, bone marrow (BM), and mucosal effector sites. Within secondary lymphoid tissues, B cells encounter specific antigen leading to their activation and differentiation. In general, activation of B cells and differentiation to mucosal IgA antibody-secreting cells (plasmablasts and plasma cells) induce upregulation of CCR10 and expression of 4
1 integrin, which mediate attraction to CCL28 and VCAM-1, respectively. Expression of VCAM-1 in effector sites is indicated, although the expression of vascular adhesion molecules (like VCAM-1) at various effector sites is not yet systematically worked out. Differentiation of IgA plasmablasts within small intestinal lymphoid tissues additionally induces upregulation of CCR9 and 47 and directs homing back to the small intestine, which expresses CCL25 and MAdCAM-1. In contrast, differentiation to IgG plasmablasts of systemic type leads to upregulation of CXCR3, allowing responsiveness to CXCL9 and CXCL10 and migration to inflamed mucosal and non-mucosal tissues. Homing to the bone marrow is mediated through CXCR4, which is expressed on all types of plasmablasts, as well as CCR10. Memory B cells (not shown) retain expression of CCR7, CXCR5, and CXCR4 to allow their recirculation through lymphoid tissues. Retained expression of CCR7 and CD62L on effector B cells from tonsils/NALT may explain their joint tropism for organized lymphoid tissue and the upper aerodigestive tract (not shown). Specific chemokine–chemokine receptor pairs are indicated by corresponding colored text; specific integrin–ligand pairs are depicted by gray and yellow boxes. Bold text indicates the molecule is expressed on lymphocytes; text in italics indicates expression on endothelial or stromal cells. BALT, bronchus-associated lymphoid tissue; CCL, CC-chemokine ligand; CCR, CC-chemokine receptor; CXC-chemokine ligand; CXCL, VCAM-1, vascular cell-adhesion molecule-1; CXCR, CXC-chemokine receptor; MAdCAM-1, mucosal addressin cell-adhesion molecule-1; MLN, mesenteric lymph nodes; NALT, nasopharynx-associated lymphoid tissue; PP, Peyer's patches; PLN, peripheral lymph nodes.
