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Science 304 (5674): 1147-1150

Copyright © 2004 by the American Association for the Advancement of Science

Autoimmune Disease and Impaired Uptake of Apoptotic Cells in MFG-E8-Deficient Mice

Rikinari Hanayama,1 Masato Tanaka,1,4 Kay Miyasaka,1,5 Katsuyuki Aozasa,2 Masato Koike,3 Yasuo Uchiyama,3 Shigekazu Nagata1,5,6*

Abstract: 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.

1 Department of Genetics, Osaka University Medical School, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan.
2 Department of Pathology, Osaka University Medical School, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan.
3 Department of Cell Biology and Neuroscience, Osaka University Medical School, 2-2 Yamada-oka, Suita, Osaka 565-0871, Japan.
4 Laboratory for Innate Cellular Immunity, RIKEN Research Center for Allergy and Immunology, Yokohama, Kanagawa 230-0045, Japan.
5 Laboratory of Genetics, Integrated Biology Laboratories, Graduate School of Frontier Biosciences, Osaka University, Osaka 565-0871, Japan.
6 Core Research for Evolutional Science and Technology, Japan Science and Technology Corporation, Osaka 565-0871, Japan.

* To whom correspondence should be addressed. E-mail: nagata{at}genetic.med.osaka-u.ac.jp.


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F. Wermeling, Y. Chen, T. Pikkarainen, A. Scheynius, O. Winqvist, S. Izui, J. V. Ravetch, K. Tryggvason, and M. C.I. Karlsson (2007)
J. Exp. Med. 204, 2259-2265
   Abstract »    Full Text »    PDF »
MFG-E8/Lactadherin Promotes Tumor Growth in an Angiogenesis-Dependent Transgenic Mouse Model of Multistage Carcinogenesis.
M. Neutzner, T. Lopez, X. Feng, E. S. Bergmann-Leitner, W. W. Leitner, and M. C. Udey (2007)
Cancer Res. 67, 6777-6785
   Abstract »    Full Text »    PDF »
Proteomics Analysis of Human Coronary Atherosclerotic Plaque: A Feasibility Study of Direct Tissue Proteomics by Liquid Chromatography and Tandem Mass Spectrometry.
C. Bagnato, J. Thumar, V. Mayya, S.-I. Hwang, H. Zebroski, K. P. Claffey, C. Haudenschild, J. K. Eng, D. H. Lundgren, and D. K. Han (2007)
Mol. Cell. Proteomics 6, 1088-1102
   Abstract »    Full Text »    PDF »
Macrophages and Dendritic Cells Use Different Axl/Mertk/Tyro3 Receptors in Clearance of Apoptotic Cells.
H. M. Seitz, T. D. Camenisch, G. Lemke, H. S. Earp, and G. K. Matsushima (2007)
J. Immunol. 178, 5635-5642
   Abstract »    Full Text »    PDF »
Lactadherin Deficiency Leads to Apoptotic Cell Accumulation and Accelerated Atherosclerosis in Mice.
H. Ait-Oufella, K. Kinugawa, J. Zoll, T. Simon, J. Boddaert, S. Heeneman, O. Blanc-Brude, V. Barateau, S. Potteaux, R. Merval, et al. (2007)
Circulation 115, 2168-2177
   Abstract »    Full Text »    PDF »
The EGF repeat and discoidin domain protein, SED1/MFG-E8, is required for mammary gland branching morphogenesis.
M. A. Ensslin and B. D. Shur (2007)
PNAS 104, 2715-2720
   Abstract »    Full Text »    PDF »
Characterization of Galectin-9-Induced Death of Jurkat T Cells.
L.-H. Lu, R. Nakagawa, Y. Kashio, A. Ito, H. Shoji, N. Nishi, M. Hirashima, A. Yamauchi, and T. Nakamura (2007)
J. Biochem. 141, 157-172
   Abstract »    Full Text »    PDF »

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