Splenic phagocytes promote responses to nucleosomes in (NZB x NZW) F1 mice.
Autoantigen presentation to T cells is crucial for the development of autoimmune disease. However, the mechanisms of autoantigen presentation are poorly understood. In this study, we show that splenic phagocytes play an important role in autoantigen presentation in murine lupus. Nucleosomes are major autoantigens in systemic lupus erythematosus. We found that nucleosome-specific T cells were stimulated dominantly in the spleen, compared with lymph nodes, lung, and thymus. Among splenic APCs, F4/80(+) macrophages and CD11b(+)CD11c(+) dendritic cells were strong stimulators for nucleosome-specific T cells. When splenic phagocytes were depleted in (NZB x NZW) F(1) (NZB/W F(1)) mice, nucleosome presentation in the spleen was dramatically suppressed. Moreover, depletion of splenic phagocytes significantly suppressed anti-nucleosome Ab and anti-dsDNA Ab production. Proteinuria progression was delayed and survival was prolonged in phagocyte-depleted mice. The numbers of autoantibody- secreting cells were decreased in the spleen from phagocyte-depleted mice. Multiple injections of splenic F4/80(+) macrophages, not those of splenic CD11c(+) dendritic cells, induced autoantibody production and proteinuria progression in NZB/W F(1) mice. These results indicate that autoantigen presentation by splenic phagocytes including macrophages significantly contributes to autoantibody production and disease progression in lupus-prone mice.
Okamoto
Akiko
A
Department of Allergy and Rheumatology, Graduate School of Medicine, University of Tokyo, Tokyo, Japan.
Fujio
Keishi
K
van Rooijen
Nico
N
Tsuno
Nelson H
NH
Takahashi
Koki
K
Tsurui
Hiromichi
H
Hirose
Sachiko
S
Elkon
Keith B
KB
Yamamoto
Kazuhiko
K
D000818:Animals; D000974:Antibodies, Antinuclear / Q000276:immunology; D017951:Antigen Presentation / Q000276:immunology*; D001324:Autoantigens / Q000276:immunology*; D039481:CD11b Antigen / Q000276:immunology; D039521:CD11c Antigen / Q000276:immunology; D003713:Dendritic Cells / Q000276:immunology / Q000473:pathology / Q000637:transplantation; D008180:Lupus Erythematosus, Systemic / Q000276:immunology* / Q000473:pathology; D008264:Macrophages / Q000276:immunology* / Q000473:pathology / Q000637:transplantation; D051379:Mice; D009707:Nucleosomes / Q000276:immunology*; D009928:Organ Specificity / Q000276:immunology; D010950:Plasma Cells / Q000276:immunology / Q000473:pathology; D011507:Proteinuria / Q000276:immunology / Q000473:pathology; D013045:Species Specificity; D013154:Spleen / Q000276:immunology* / Q000473:pathology
D000974:Antibodies, Antinuclear; D001324:Autoantigens; D039481:CD11b Antigen; D039521:CD11c Antigen; D009707:Nucleosomes