The unresponsiveness of aged mice to polysaccharide antigens is a result of a defect in macrophage function.
A reduction in macrophage (MPhi) function with aging makes mice less responsive to bacterial capsular polysaccharides, such as those present in the pneumococcal polysaccharide vaccine, a model of thymus independent (TI) antigen (Ag). Using trinitrophenol (TNP)-lipopolysaccharide (LPS) and TNP-Ficoll, two other well-studied TI Ag, we studied the mechanistic basis of reduced MPhi function in the aged. We show that aged mice are profoundly hyporesponsive to these TI Ag. As a result of a requirement for MPhi, highly purified B cells from young-adult mice do not respond to TI Ag. When purified, young B cells were immunized with TNP-Ficoll, the antibody production from those cultures reconstituted with MPhi from aged mice was significantly lower than that seen with young MPhi. Consequently, this unresponsiveness can be overcome by a mixture of interleukin (IL)-1beta and IL-6. Upon stimulation with LPS, in comparison with young MPhi, aged MPhi secreted reduced amounts of IL-6, tumor necrosis factor alpha, IL-1beta, and IL-12, cytokines necessary for B cells to respond to TI Ag. LPS also induced aged MPhi to produce an excess of IL-10. Neutralization of IL-10 enhanced the production of proinflamatory cytokines by MPhi upon LPS stimulation and also induced Ab production by aged splenocytes. Thus, the inability of aged MPhi to help the B cell response appears to be caused by an excess of IL-10. As aged MPhi have a reduced number of cells expressing Toll-like receptor 4 and CD14, the imbalance in cytokine production might be partly a result of fewer cells expressing key components of the LPS receptor complex.
Chelvarajan
R Lakshman
RL
Department of Microbiology, Immunology and Molecular Genetics, Sanders Brown Center on Aging, University of Kentucky, Lexington, KY 40536-0230, USA.
Collins
Sarah M
SM
Van Willigen
Juliana M
JM
Bondada
Subbarao
S
D000375:Aging / Q000276:immunology*; D000818:Animals; D001402:B-Lymphocytes / Q000187:drug effects / Q000276:immunology*; D005362:Ficoll; D007249:Inflammation / Q000276:immunology; D016753:Interleukin-10 / Q000378:metabolism; D015850:Interleukin-6 / Q000378:metabolism; D008070:Lipopolysaccharides / Q000276:immunology / Q000494:pharmacology*; D008214:Lymphocytes / Q000187:drug effects / Q000276:immunology*; D008264:Macrophages / Q000276:immunology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D010851:Picrates; D013154:Spleen / Q000187:drug effects / Q000254:growth & development / Q000276:immunology
D015850:Interleukin-6; D008070:Lipopolysaccharides; D010851:Picrates; D016753:Interleukin-10; D005362:Ficoll; C005858:picric acid