Multiple studies in genetically manipulated mice, however, revealed a poor correlation between the presence of GC, organized follicular structures such as PP and IgA plasma cells in the LP, implying the existence of multiple, intricate pathways for IgA B cell development in gut. For example, fully functional, somatically mutated gut IgA against T-dependent antigens does not necessarily require the presence of GC. CD28-/- mice that lack GC and have an impaired systemic response show normal mucosal IgA responses to a T-de-pendent antigen (Gardby et al. 2003). This would imply that T cell activation by the B7-CD28 signaling pathway that is essential for serum IgA (and IgG) responses can be complemented by an alternative, mucosa-specific, and GC-independent mechanism.
Peritoneal B1 cells, which are known to be unable to migrate to GC in PP, generate large amounts of gut IgA, at least in mice (Fagarasan and Honjo 2000; Fagarasan et al. 2000; Kroese et al. 1989). Unlike the IgA generated in the PP, IgA production by B1 cells appears to be independent of T cell help, and functionally the Bl-derived IgAs appear to be fully capable of preventing systemic invasion of intestinal bacteria (Fagarasan and Honjo 2000; Macpherson et al. 2000).
Furthermore, mice deficient for inhibitor of bHLH transcription factor (Id2), retinoic acid-related orphan receptor (ROR) yt-/- mice, or bone marrow (BM)-reconstituted LTa-/- or TNF-LTa-/- mice, which lack PP, mesenteric lymph nodes (MLN), or any other gut follicular structures including ILF, do have IgA plasma cells in the intestine, although their number varies depending on the mouse background and rearing conditions. These observations clearly indicate that gut IgAs can be also generated outside GC or gut organized fol-licular structures (Eberl and Littman 2004; Kang et al. 2002; Ryffel et al. 1998).
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