Generation of Mucosal IgA in Organized Follicular Structures

The GALT, which is the main site for generation of mucosal immune responses, is generally divided into two compartments: inductive sites, represented by organized follicular structures, and effector sites, represented by diffuse tissue of the intestinal LP (Brandtzaeg et al. 1999; Fagarasan and Honjo 2003). The major inductive sites in the small intestine are PP and solitary follicles that are scattered throughout the intestine, called isolated lymphoid follicles (ILF) (Hamada et al. 2002), which develop before and after birth, respectively. Their organization requires multiple interactions between inducer cells of hematopoietic origin and organizer mesenchymal cells (Nishikawa et al. 2003). Among the key events absolutely necessary for PP and ILF formation is the expression of LTa102 on CD3-CD4+IL-7R+ inducer cells on stimulation through IL-7R and its interaction with LT0R+ organizer cells (Honda et al. 2001; Lorenz et al. 2003; McDonald et al. 2005; Yoshida et al. 2002). Sev eral feedback loops necessary for PP and ILF formation involve chemokines and adhesion molecules such as CXCR5-CXCL13 and CXCR5-induced a401-VCAM-1 interactions (Finke et al. 2002).

Cellular studies suggested that bone marrow-derived precursors for IgA+ plasma cells are mainly generated in the PP (Cebra and Shroff 1994; Tseng 1981,1984), and a clonal relationship between IgA+ B cells in the PP and IgA plasma cells in the (LP has been demonstrated (Dunn-Walters et al., 1997; Stoel et al., 2005).

It is generally accepted that IgA B cell development depends on the antigenic stimulation and induction of GC, a microenvironment that allows strong interactions between B cells, antigens trapped on follicular dendritic cells (FDC) and local CD4 T cells, that facilitate B cell proliferation, class switch recombination (CSR) and somatic hypermutation (SHM) and affinity maturation which are necessary for efficient humoral responses (Butcher et al. 1982; Strobel et al. 2005; Weinstein and Cebra 1991).

Indeed, neonatal mice or germ-free mice are almost completely devoid of IgA+ B cells in gut. However, gut IgA+ B cells are detected after bacterial colonization, around the peak of the GC reaction in PP, and these IgAs commonly have specificities against molecules such as phosphocholine, p2-1 fructosyl and p galactosyl groups associated with bacteria present in the intestine (Cebra 1999).

In conventionally reared mice, PP as well as ILF, which are induced to develop by bacterial stimulation (see later discussion), continuously exhibit GC and contain the highest proportion of actively dividing IgA+ B cells as compared with GC from spleen or peripheral lymph nodes, in which the predominant switched isotype is IgG (Cebra 1999).

The IgA+ B cells in PP or ILF are generated by in situ switching of IgM+ B cells after antigenic stimulation. This is demonstrated by the presence of large amounts of AID, the master molecule for CSR and SHM (Muramatsu et al. 2000), in IgM+ B cells from PP (Fagarasan et al., 2001). Furthermore, footprints for recent switching can be detected in PP IgA+ B cells. These are short-lived transcripts, known as a circle-transcripts (aCT), which are initiated from the Ia promoter located in the circular DNA that is looped out during IgA switching (Fagarasan et al. 2001; Kinoshita et al. 2001). This preferential switching to IgA in PP led to the proposal that PP GC are intrinsically different from other GC, most likely because of the constant antigenic stimulation, the presence of special regulatory T cells and dendritic cells (DC) that through costimulatory molecules (CD40-CD40L, CD80/CD86-CD28) and Th2 cytokines would promote efficient switching to IgA (Cebra and Shroff 1994; Lycke 1998).

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