IL-6 produced by immune complex-activated follicular dendritic cells promotes germinal center reactions, IgG responses and somatic hypermutation
| Autor: | Mohey Eldin M. El Shikh, Al M. Best, Rania M. El Sayed, Yongzhong Wu, Andras K. Szakal, John G. Tew |
|---|---|
| Rok vydání: | 2009 |
| Předmět: |
Immunogen
Immunology Somatic hypermutation Antigen-Antibody Complex Cell Communication Immunoglobulin G Mice Immune system Antigen Animals Immunology and Allergy Antigens Mice Knockout B-Lymphocytes Transplantation Chimera biology Follicular dendritic cells Interleukin-6 Germinal center Cell Differentiation General Medicine Germinal Center Molecular biology Immune complex Mice Inbred C57BL biology.protein Female Immunization Somatic Hypermutation Immunoglobulin Original Research Papers Dendritic Cells Follicular |
| Zdroj: | International Immunology. 21:745-756 |
| ISSN: | 1460-2377 0953-8178 |
| Popis: | 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. |
| Databáze: | OpenAIRE |
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