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International Immunology Advance Access originally published online on May 21, 2009
International Immunology 2009 21(6):745-756; doi:10.1093/intimm/dxp041
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© The Japanese Society for Immunology. 2009. All rights reserved. For permissions, please e-mail: journals.permissions@oxfordjournals.org

IL-6 produced by immune complex-activated follicular dendritic cells promotes germinal center reactions, IgG responses and somatic hypermutation

Yongzhong Wu1,*, Mohey Eldin M. El Shikh1,*, Rania M. El Sayed1, Al M. Best2, Andras K. Szakal3 and John G. Tew1

1 Department of Microbiology and Immunology
2 Department of Biostatistics
3 Department of Anatomy and Neurobiology and Immunology Group, Virginia Commonwealth University, Richmond, VA 23298, USA

Correspondence to: J. G. Tew; E-mail: tew{at}vcu.edu

Reports that follicular dendritic cells (FDCs) produce IL-6 prompted the hypotheses that immune complexes (ICs) induce FDCs to produce IL-6 and that FDC–IL-6 promotes germinal center (GC) reactions, somatic hypermutation (SHM) and IgG production. FDCs were activated in vitro by addition of ICs and FDC–IL-6 production was determined. Wild-type (WT) and IL-6 knockout (KO) mice, as well as chimeras with WT and IL-6 KO cells, were immunized with (4-hydroxy-3-nitrophenyl)-acetyl (NP)–chicken gamma globulin (CGG) and used to study anti-(4-hydroxy-3-iodo-5-nitrophenyl) acetyl (NIP) responses, GC formation and SHM in the VH186.2 gene segment in Ig-gamma. FDC–IL-6 increased when FDCs encountered ICs. At low immunogen dose, 1 µg NP–CGG per mouse, the IgG anti-NIP response in IL-6 KO mice was low and immunohistochemistry revealed a reduction in both the number and size of GCs. The physiological relevance of FDC–IL-6 was apparent in the chimeric mice where total splenocytes from WT mice were unable to provide the IL-6 needed for normal IgG and GC responses in IL-6 KO animals with IL-6-defective FDCs. Moreover, the rate of mutation decreased from 18 to 8.9 mutations per 1000 bases (P < 0.001) in WT versus IL-6 KO mice. Addition of anti-IL-6 to GC reactions in vitro reduced antibody levels and SHM from 3.5 to 0.65 mutations per 1000 bases (P < 0.02). Thus, the absence of FDC–IL-6 correlated with a reduction in SHM that coincided with the reduction in GCs and specific anti-NIP. This is the first study to document that ICs induce FDC–IL-6 and that FDC-derived IL-6 is physiologically relevant in generating optimal GC reactions, SHM and IgG levels.

Keywords: B cell differentiation, germinal center reactions in vitro, IL-6 KO, immune complexes, VH186.2

* These authors contributed equally to this study.

Transmitting editor: T. F. Tedder

Received 11 June 2008, accepted 9 April 2009.


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