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Published online before print February 26, 2008

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© by The Society for Leukocyte Biology
Journal of Leukocyte Biology, doi:10.1189/jlb.1107730

Received for publication November 6, 2007.
Revised January 31, 2008.
Accepted for publication January 31, 2008.

Article

Milk fat globule EGF factor 8 in the serum of human patients of systemic lupus erythematosus

Hiroshi Yamaguchi ^*, Junichi Takagi , Takako Miyamae , Shumpei Yokota , Takashi Fujimoto ^||, Shinobu Nakamura ^||, Shiro Ohshima ^¶#, Tetsuji Naka ^¶**, and Shigekazu Nagata ^*@

*Department of Medical Chemistry, Graduate School of Medicine, Kyoto University, Kyoto, Japan; Departments of Genetics and ^¶Molecular Medicine, Graduate School of Medicine, and Laboratory of Protein Synthesis and Expression, Institute for Protein Research, Osaka University, Osaka, Japan; Department of Pediatrics, Yokohama City University School of Medicine, Yokohama, Japan; ^||Department of General Medicine, Nara Medical University, Nara, Japan; ^#Department of and Rheumatology and Clinical Research, National Hospital Organization Osaka Minami Medical Center, Osaka, Japan; **Laboratory for Immune Signal, National Insutitute of Biomedical Innovation, Osaka, Japan; and Solution Oriented Research for Science and Technology, Japan Science and Technology Corporation, Kyoto, Japan

^@ To whom correspondence should be addressed. E-mail: snagata{at}mfour.med.kyoto-u.ac.jp.

	Abstract

Mouse milk fat globule epidermal growth factor 8 (MFG-E8), which is secreted by a subset of activated macrophages, binds to apoptotic cells by recognizing phosphatidylserine and promotes their engulfment. Many apoptotic cells are left unengulfed in the germinal centers of the spleen in MFG-E8^-/- mice, and these mice develop an autoimmune disease resembling human systemic lupus erythematosus (hSLE). Here, we report that hMFG-E8 bound to phosphatidylserine and an integrin _v3 complex. Increasing concentrations of MFG-E8 generated a bell-shaped response curve for the efficiency of phagocytosis. That is, in NIH3T3 and MFG-E8^-/- thioglycollate-elicited peritoneal macrophages that do not express MFG-E8, hMFG-E8 enhanced engulfment at low concentrations but inhibited it at high concentrations. On the other hand, hMFG-E8 dose-dependently inhibited the engulfment of apoptotic cells by MFG-E8^+/+ thioglycollate-elicited peritoneal macrophages, indicating that an excess of MFG-E8 has an inverse effect on the engulfment of apoptotic cells. To investigate the role of MFG-E8 in human disease, we generated two mAb against MFG-E8 and screened human blood samples for MFG-E8 using an ELISA. We found that some childhood-onset and adult SLE patients carried a significant level of MFG-E8 in their blood samples. These results suggested that the aberrant expression of MFG-E8 is involved in the pathoetiology of some cases of hSLE.

Key Words: apoptosis • clinical immunology • macrophages • autoimmunity • integrin