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.

[1]  刘金明,et al.  IL-13受体α2降低血吸虫病肉芽肿的炎症反应并延长宿主存活时间[英]/Mentink-Kane MM,Cheever AW，Thompson RW，et al//Proc Natl Acad Sci U S A , 2005 .

[2]  S. Nagata,et al.  Expression of milk fat globule epidermal growth factor 8 in immature dendritic cells for engulfment of apoptotic cells , 2004, European journal of immunology.

[3]  S. Nagata,et al.  Expression of Developmental Endothelial Locus-1 in a Subset of Macrophages for Engulfment of Apoptotic Cells1 , 2004, The Journal of Immunology.

[4]  H. Yoshida,et al.  Impaired thymic development in mouse embryos deficient in apoptotic DNA degradation , 2003, Nature Immunology.

[5]  John Savill,et al.  A blast from the past: clearance of apoptotic cells regulates immune responses , 2002, Nature Reviews Immunology.

[6]  Keiko Miwa,et al.  Identification of a factor that links apoptotic cells to phagocytes , 2002, Nature.

[7]  A. Ridley,et al.  Phosphatidylserine (PS) induces PS receptor–mediated macropinocytosis and promotes clearance of apoptotic cells , 2001, The Journal of cell biology.

[8]  R. Scott,et al.  Phagocytosis and clearance of apoptotic cells is mediated by MER , 2001, Nature.

[9]  M. Hengartner.  Apoptosis Corralling the Corpses , 2001, Cell.

[10]  John Savill,et al.  Corpse clearance defines the meaning of cell death , 2000, Nature.

[11]  Siamon Gordon,et al.  Apoptotic Thymocyte Clearance in Scavenger Receptor Class A-Deficient Mice Is Apparently Normal , 2000, The Journal of Immunology.

[12]  N. Aoki,et al.  Lactation-dependent expression of an mRNA splice variant with an exon for a multiply O-glycosylated domain of mouse milk fat globule glycoprotein MFG-E8. , 1999, Biochemical and biophysical research communications.

[13]  D. Mevorach,et al.  Systemic Exposure to Irradiated Apoptotic Cells Induces Autoantibody Production , 1998, The Journal of experimental medicine.

[14]  M. Raff,et al.  Programmed Cell Death in Animal Development , 1997, Cell.

[15]  J. Sprent,et al.  T-cell apoptosis detected in situ during positive and negative selection in the thymus , 1994, Nature.

[16]  C. Abrass,et al.  Circulating immune complexes in renal injury. , 1992, Seminars in nephrology.

[17]  V. Fadok,et al.  Exposure of phosphatidylserine on the surface of apoptotic lymphocytes triggers specific recognition and removal by macrophages. , 1992, Journal of immunology.

[18]  S. Gordon,et al.  Macrosialin, a macrophage-restricted membrane sialoprotein differentially glycosylated in response to inflammatory stimuli [published erratum appears in J Exp Med 1992 Jan 1;175(1):309] , 1991, The Journal of experimental medicine.

[19]  J. P. Smith,et al.  Kinetics of the tingible body macrophage response in mouse germinal center development and its depression with age , 1991, The Anatomical record.

[20]  A. Bui,et al.  cDNA cloning of a mouse mammary epithelial cell surface protein reveals the existence of epidermal growth factor-like domains linked to factor VIII-like sequences. , 1990, Proceedings of the National Academy of Sciences of the United States of America.

[21]  G. Kraal,et al.  Marginal metallophilic cells of the mouse spleen identified by a monoclonal antibody. , 1986, Immunology.

[22]  R. van Furth,et al.  Effect of thioglycolate on phagocytic and microbicidal activities of peritoneal macrophages , 1984, Infection and immunity.

[23]  I. Baumann,et al.  Impaired uptake of apoptotic cells into tingible body macrophages in germinal centers of patients with systemic lupus erythematosus. , 2002, Arthritis and rheumatism.

[24]  S. Gordon,et al.  Membrane molecules as differentiation antigens of murine macrophages. , 1998, Advances in immunology.

[25]  J. Hooker.  The botany of the Antarctic voyage of H.M. discovery ships Erebus and Terror in the Years 1839-1843 under the command of Captain Sir James Clark Ross , 1843 .