TY - JOUR
T1 - Intenalization of antibodies by endothelial cells via fibronectin implicating a novel mechanism in lupus nephritis
AU - Fujii, Hiroshi
AU - Nakatani, Kimihiko
AU - Arita, Norimasa
AU - Ito, Mitsuko R.
AU - Terada, Miho
AU - Miyazaki, Tatsuhiko
AU - Yoshida, Minako
AU - Ono, Masao
AU - Fujiwara, Takashi
AU - Saiga, Kan
AU - Ota, Toshiyuki
AU - Ohtani, Haruo
AU - Lockwood, Martin
AU - Sasaki, Takeshi
AU - Nose, Masato
N1 - Funding Information:
This study was supported by Grant-in Aid for Scientific Research Funds of the Ministry of Education, Science and Culture of Japan (#08457068 and #11307003) and the Scientist Exchange Program between the Japan Society for the Promotion of Science and the Royal Society. The authors are indebted to Dr. Teruo Watanabe, Dr. Naoto Kobayashi, and Dr. John Bradley for critical discussions and Mr. Alan Brownlee, Ms. Jenny Savidge, and Ms. Yumiko Takei for technical help. We also thank Dr. Herbert M. Schulman for reviewing the manuscript.
PY - 2003/11
Y1 - 2003/11
N2 - Background. One of the crucial events in lupus nephritis is the glomerular deposition of immunoglobulins (Igs), of which pathogenic properties have been proposed mostly to be either type II or type III allergic reactions. Some of IgG3-producing hybridoma clones established from an MRL/MpTn-gld/gld (MRL/gld) lupus mouse generate wire loop-like lesions in glomeruli resembling lupus nephritis when injected into SCID mice. These clones are useful for analyzing the mechanisms of glomerular deposition of antibodies in lupus nephritis at the monoclonal level. Methods. Glomerular lesions of SCID mice injected with the hybridoma clones, 17H8a or 1G3 as control were analyzed by light and electron microscopy. Interaction of the antibodies with human glomerular endothelial cells (HGECs) and human umbilical vein endothelial cells (HUVECs) in vitro was studied by fluorescence microscopy, electron microscopy, and flow cytometry. Results. Both antibodies did not show any antigen specificity for mouse glomeruli. The glomerular lesions generated by 17H8a, but not by 1G3, contained electron-dense deposits not only in subendothelial regions but also in the cytoplasm of endothelial cells, suggesting internalization of the 17H8a antibodies by endothelial cells. In cell culture studies, internalization of only 17H8a antibodies by HGECs and HUVECs was observed, but the antibodies did not have antigen specificity for both types of endothelial cells. The internalization by HUVECs was mediated by actin polymerization, and it was inhibited by RGDS (Arg-Gly-Asp-Ser) tetrapeptide, antihuman fibronectin and antihuman integrin β1 monoclonal antibodies. Conclusion. The interaction between particular antibodies and endothelial cell surface integrins via fibronectin may be involved in their subsequent internalization by endothelial cells leading to antibody deposition in glomeruli. This may be one of the mechanisms of glomerular injury in lupus nephritis.
AB - Background. One of the crucial events in lupus nephritis is the glomerular deposition of immunoglobulins (Igs), of which pathogenic properties have been proposed mostly to be either type II or type III allergic reactions. Some of IgG3-producing hybridoma clones established from an MRL/MpTn-gld/gld (MRL/gld) lupus mouse generate wire loop-like lesions in glomeruli resembling lupus nephritis when injected into SCID mice. These clones are useful for analyzing the mechanisms of glomerular deposition of antibodies in lupus nephritis at the monoclonal level. Methods. Glomerular lesions of SCID mice injected with the hybridoma clones, 17H8a or 1G3 as control were analyzed by light and electron microscopy. Interaction of the antibodies with human glomerular endothelial cells (HGECs) and human umbilical vein endothelial cells (HUVECs) in vitro was studied by fluorescence microscopy, electron microscopy, and flow cytometry. Results. Both antibodies did not show any antigen specificity for mouse glomeruli. The glomerular lesions generated by 17H8a, but not by 1G3, contained electron-dense deposits not only in subendothelial regions but also in the cytoplasm of endothelial cells, suggesting internalization of the 17H8a antibodies by endothelial cells. In cell culture studies, internalization of only 17H8a antibodies by HGECs and HUVECs was observed, but the antibodies did not have antigen specificity for both types of endothelial cells. The internalization by HUVECs was mediated by actin polymerization, and it was inhibited by RGDS (Arg-Gly-Asp-Ser) tetrapeptide, antihuman fibronectin and antihuman integrin β1 monoclonal antibodies. Conclusion. The interaction between particular antibodies and endothelial cell surface integrins via fibronectin may be involved in their subsequent internalization by endothelial cells leading to antibody deposition in glomeruli. This may be one of the mechanisms of glomerular injury in lupus nephritis.
KW - HUVEC
KW - Integrin
KW - Lupus nephritis
KW - MRL mice
KW - Subendothelial deposition
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U2 - 10.1046/j.1523-1755.2003.00252.x
DO - 10.1046/j.1523-1755.2003.00252.x
M3 - Article
C2 - 14531798
AN - SCOPUS:0142249404
SN - 0085-2538
VL - 64
SP - 1662
EP - 1670
JO - Kidney International
JF - Kidney International
IS - 5
ER -