Complement mediated hepatocytes injury in a model of autoantibody induced hepatitis.
Despite multiple reports on autoantibody-initiated complement activation in autoimmune hepatitis (AIH), how does the humoral immunity contribute to the pathogenesis of AIH remained unclear. In this report, by adoptively transferring a polyclonal rabbit anti-OVA antibody into Hep-OVA Tg mice in which OVA is selectively expressed on the surface of hepatocytes, we found that excessive complement activation initiated by the autoantibody overwhelmed the protection of intrinsic cell surface complement regulators, and induced hepatocytes injury both in vitro and in vivo. The anti-OVA antibody induced hepatic injury in Hep-OVA Tg but not WT C57BL/6 mice as assessed by serum ALT levels and liver histopathology. Immunohistochemical analyses showed that after the antibody administration, there was massive complement activation on anti-OVA IgG coated hepatocytes in Hep-OVA Tg mice, but not in WT mice. Consistent with these results, depleting complement by cobra venom factor (CVF) prior to antibody injections protected Hep-OVA Tg mice from anti-OVA IgG induced hepatic injury. In addition, treating Hep-OVA Tg mice with recombinant mouse decay accelerating factor, a native complement inhibitor, protected them from autoantibody induced hepatitis. These results suggest that complement could play a pivotal role in liver specific autoantibody mediated hepatocyte injury in AIH, and that complement inhibitors could be, in principle, developed as novel therapeutics against AIH.
Tu
Zhidan
Z
Department of Pathology, Case Western Reserve University, Cleveland, OH 44106, USA.
Li
Qing
Q
Chou
Hong-Shiue
HS
Hsieh
Ching-Chuang
CC
Meyerson
Howard
H
Peters
Marion G
MG
Bu
Hong
H
Fung
John J
JJ
Qian
Shiguang
S
Lu
Lina
L
Lin
Feng
F
D000276:Adjuvants, Immunologic / Q000494:pharmacology; D000818:Animals; D001323:Autoantibodies / Q000276:immunology*; D018958:CD55 Antigens / Q000378:metabolism / Q000494:pharmacology; D018957:CD59 Antigens / Q000378:metabolism; D003167:Complement Activation / Q000187:drug effects / Q000276:immunology; D003165:Complement System Proteins / Q000378:metabolism*; D004195:Disease Models, Animal; D019693:Hepatitis, Autoimmune / Q000276:immunology* / Q000473:pathology*; D022781:Hepatocytes / Q000276:immunology / Q000473:pathology; D008099:Liver / Q000187:drug effects / Q000276:immunology / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011951:Receptors, Complement / Q000378:metabolism; D017463:Receptors, Complement 3b
D000276:Adjuvants, Immunologic; D001323:Autoantibodies; D018958:CD55 Antigens; D018957:CD59 Antigens; C081470:Cr1l protein, mouse; D011951:Receptors, Complement; D017463:Receptors, Complement 3b; D003165:Complement System Proteins