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Gut IgA Class Switch Recombination in the Absence of CD40 Does Not Occur in the Lamina Propria and Is Independent of Germinal Centers¹

Department of Microbiology and Immunology, Mucosal Immunobiology and Vaccine Research Center, Institute of Biomedicine, Göteborg University, Göteborg, Sweden

Conflicting findings have recently been presented as to the sites and sources of B cells that undergo class switch recombination (CSR) to IgA in the gut. In this study we provide compelling evidence in CD40^–/– mice demonstrating that IgA CSR can be independent of CD40 signaling and germinal center formation and does not occur in the gut lamina propria (LP) itself. We found that CD40^–/– mice had near normal levels of gut total IgA despite lacking germinal centers and completely failing to raise specific responses against the T cell-dependent Ags cholera toxin and keyhole limpet hemocyanin. The Peyer’s patches in CD40^–/– mice expressed unexpectedly high levels of activation-induced cytidine deaminase mRNA and germline transcripts, but few postswitch circular DNA transcripts, arguing against significant IgA CSR. Moreover and more surprisingly, wild-type mice exhibited no to low IgA CSR in mesenteric lymph nodes or isolated lymphoid follicles. Importantly, both strains failed to demonstrate any of the molecular markers for IgA CSR in the gut LP itself. Whereas all of the classical sites for IgA CSR in the GALT in CD40^–/– mice appeared severely compromised for IgA CSR, B cells in the peritoneal cavity demonstrated the expression of activation-induced cytidine deaminase mRNA comparable to that of wild-type mice. However, peritoneal cavity B cells in both strains expressed intermediate levels of the germinal center marker GL7 and exhibited no germline transcripts, and only three of 51 mice analyzed showed the presence of postswitch circular DNA transcripts. Taken together, these findings strongly argue for alternative inductive sites for gut IgA CSR against T cell-independent Ags outside of the GALT and the nonorganized LP.

The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ This study was supported by the Swedish Research Council, the Swedish Cancer Foundation, the Sahlgrenska University Hospital Foundation, the Swedish Foundation for Strategic Research, the Mucosal Immunobiology and Vaccine Center, and European Union Grants QLK2-CT-2001-01702, QLK2-CT-199-00228, and LSHP-CT- 2003-503240.

² M.B. and N.Y.L. share senior authorship.

³ Address correspondence and reprint requests to Dr. Nils Lycke, Department of Microbiology and Immunology, University of Göteborg, 405 30 Göteborg, Sweden. E-mail address: nils.lycke{at}microbio.gu.se

⁴ Abbreviations used in this paper: LP, lamina propria; AID, activation-induced cytidine deaminase; APRIL, a proliferation-inducing ligand; BAFF, B cell-activating factor; CSR, class switch recombination; CT, cholera toxin; DC, dendritic cell; GC, germinal center; ILF, isolated lymphoid follicle; KLH, keyhole limpet hemocyanin; MLN, mesenteric lymph node; PerC, peritoneal cavity; PP, Peyer’s patch; SFC, spot forming cell; SHM, somatic hypermutation; TD, T cell dependent; TI, T cell independent; WT, wild type.

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