Autoimmune disease and impaired uptake of apoptotic cells in MFG-E8-deficient mice.
Apoptotic cells expose phosphatidylserine and are swiftly engulfed by macrophages. Milk fat globule epidermal growth factor (EGF) factor 8 (MFG-E8) is a protein that binds to apoptotic cells by recognizing phosphatidylserine and that enhances the engulfment of apoptotic cells by macrophages. We report that tingible body macrophages in the germinal centers of the spleen and lymph nodes strongly express MFG-E8. Many apoptotic lymphocytes were found on the MFG-E8-/- tingible body macrophages, but they were not efficiently engulfed. The MFG-E8-/- mice developed splenomegaly, with the formation of numerous germinal centers, and suffered from glomerulonephritis as a result of autoantibody production. These data demonstrate that MFG-E8 has a critical role in removing apoptotic B cells in the germinal centers and that its failure can lead to autoimmune diseases.
Hanayama
Rikinari
R
Department of Genetics, Osaka University Medical School, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan.
Tanaka
Masato
M
Miyasaka
Kay
K
Aozasa
Katsuyuki
K
Koike
Masato
M
Uchiyama
Yasuo
Y
Nagata
Shigekazu
S
D000818:Animals; D000974:Antibodies, Antinuclear / Q000097:blood; D015703:Antigens, CD / Q000032:analysis; D015214:Antigens, Differentiation, Myelomonocytic / Q000032:analysis; D000954:Antigens, Surface; D017209:Apoptosis; D001323:Autoantibodies / Q000096:biosynthesis / Q000097:blood; D001327:Autoimmune Diseases / Q000276:immunology*; D001402:B-Lymphocytes / Q000276:immunology; D015152:Blotting, Northern; D005260:Female; D018390:Gene Targeting; D018858:Germinal Center / Q000166:cytology / Q000276:immunology / Q000378:metabolism; D005921:Glomerulonephritis / Q000276:immunology*; D020287:In Situ Nick-End Labeling; D008262:Macrophage Activation; D008264:Macrophages / Q000276:immunology / Q000378:metabolism* / Q000648:ultrastructure; D017737:Macrophages, Peritoneal / Q000276:immunology / Q000378:metabolism; D008562:Membrane Glycoproteins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008894:Milk Proteins; D010587:Phagocytosis; D010718:Phosphatidylserines / Q000378:metabolism; D011485:Protein Binding; D013154:Spleen / Q000166:cytology / Q000378:metabolism / Q000473:pathology; D013163:Splenomegaly / Q000473:pathology; D013601:T-Lymphocytes / Q000276:immunology; D000097382:CD68 Molecule
D000974:Antibodies, Antinuclear; D015703:Antigens, CD; D015214:Antigens, Differentiation, Myelomonocytic; D000954:Antigens, Surface; D001323:Autoantibodies; D008562:Membrane Glycoproteins; D008894:Milk Proteins; D010718:Phosphatidylserines; C067980:CD68 antigen, human; D000097382:CD68 Molecule; C490919:Mfge8 protein, mouse