IL-6 produced by immune complex-activated follicular dendritic cells promotes germinal center reactions, IgG responses and somatic hypermutation.
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 microg 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.
Wu
Yongzhong
Y
Department of Microbiology and Immunology, Virginia Commonwealth University, Richmond, VA 23298, USA.
El Shikh
Mohey Eldin M
ME
El Sayed
Rania M
RM
Best
Al M
AM
Szakal
Andras K
AK
Tew
John G
JG
D000818:Animals; D000936:Antigen-Antibody Complex / Q000378:metabolism; D000941:Antigens / Q000276:immunology; D001402:B-Lymphocytes / Q000276:immunology / Q000378:metabolism*; D002450:Cell Communication; D002454:Cell Differentiation / Q000276:immunology; D020566:Dendritic Cells, Follicular / Q000276:immunology / Q000378:metabolism*; D005260:Female; D018858:Germinal Center / Q000276:immunology*; D007114:Immunization; D007074:Immunoglobulin G / Q000235:genetics / Q000276:immunology* / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000276:immunology / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D027041:Somatic Hypermutation, Immunoglobulin / Q000276:immunology*; D018183:Transplantation Chimera
D000936:Antigen-Antibody Complex; D000941:Antigens; D007074:Immunoglobulin G; D015850:Interleukin-6