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ni.1991 Mice carrying a knock-in mutation of Aicda resulting in a defect in somatic hypermutation ha.pdf

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ni.1991 Mice carrying a knock-in mutation of Aicda resulting in a defect in somatic hypermutation ha

264 VOLUME 12 NUMBER 3 MARCH 2011 nature immunology A rt i c l e s The intestinal mucosal surface is the front line of host defense against various pathogens, food antigens and commensal bacteria in the gut1,2. There are at least three layers in the defense system in the intestinal mucosa: the innate immune system the adaptive immune system and the epithelial layer that physically separates microbiota and other contents of the gut from the host body3–6. Immunoglobulin A (IgA) is the main immunoglobulin isotype with a crucial role in the adaptive immune response on the mucosal surface as well as in the gut lumen7–9. IgA is secreted into the gut lumen through the formation of dimers via interaction of the joining (J) chain and its recognition by the polymeric immunoglobulin receptor (pIgR)8–10. Intestinal IgA is produced in the gut-associated lymphoid tissue (GALT), which includes both the organized and unorganized gut lymphoid tissues, represented by Peyer’s patches, mesenteric lymph nodes (MLNs) and isolated lymphoid follicles and by dispersed B lymphocytes in the lamina propria, respectively7–9,11,12. The critical role of secretory IgA in the gut defense against patho- gens has been studied extensively in genetically manipulated ani- mals13–25, including those deficient in the gene encoding IgA (Igh-2), the immunoglobulin J-chain (Igj) or pIgR (Pigr). Although these mice secrete variable amounts of other isotypes, such as IgM and IgG, into the intestinal lumen, all show severe susceptibility to challenge with cholera toxin. In addition, the importance of secretory IgA for the maintenance of commensal bacteria homeostasis has also been well demonstrated by studies of deficiency in activation-induced cyti- dine deaminase (AID)26,27. As AID is essential to both class-switch recombination (CSR) and somatic hypermutation (SHM)28,29, only IgM that has not undergone any SHM is secreted into the gut lumen of AID-deficient mice26. In these mice, con