Generation of C5a in the absence of C3: a new complement activation pathway.
Complement-mediated tissue injury in humans occurs upon deposition of immune complexes, such as in autoimmune diseases and acute respiratory distress syndrome. Acute lung inflammatory injury in wild-type and C3-/- mice after deposition of IgG immune complexes was of equivalent intensity and was C5a dependent, but injury was greatly attenuated in Hc-/- mice (Hc encodes C5). Injury in lungs of C3-/- mice and C5a levels in bronchoalveolar lavage (BAL) fluids from these mice were greatly reduced in the presence of antithrombin III (ATIII) or hirudin but were not reduced in similarly treated C3+/+ mice. Plasma from C3-/- mice contained threefold higher levels of thrombin activity compared to plasma from C3+/+ mice. There were higher levels of F2 mRNA (encoding prothrombin) as well as prothrombin and thrombin protein in liver of C3-/- mice compared to C3+/+ mice. A potent solid-phase C5 convertase was generated using plasma from either C3+/+ or C3-/- mice. Human C5 incubated with thrombin generated C5a that was biologically active. These data suggest that, in the genetic absence of C3, thrombin substitutes for the C3-dependent C5 convertase. This linkage between the complement and coagulation pathways may represent a new pathway of complement activation.
Huber-Lang
Markus
M
Department of Traumatology, Hand and Reconstructive Surgery, University of Ulm Medical School, Steinhoevelstrasse 9, D-89075 Ulm, Germany.
Sarma
J Vidya
JV
Zetoune
Firas S
FS
Rittirsch
Daniel
D
Neff
Thomas A
TA
McGuire
Stephanie R
SR
Lambris
John D
JD
Warner
Roscoe L
RL
Flierl
Michael A
MA
Hoesel
Laszlo M
LM
Gebhard
Florian
F
Younger
John G
JG
Drouin
Scott M
SM
Wetsel
Rick A
RA
Ward
Peter A
PA
D000818:Animals; D000936:Antigen-Antibody Complex; D001992:Bronchoalveolar Lavage Fluid / Q000737:chemistry / Q000166:cytology; D003167:Complement Activation / Q000502:physiology*; D003176:Complement C3 / Q000235:genetics / Q000276:immunology*; D015936:Complement C5a / Q000235:genetics / Q000276:immunology*; D006801:Humans; D007074:Immunoglobulin G / Q000276:immunology; D008099:Liver / Q000166:cytology / Q000378:metabolism; D008168:Lung / Q000276:immunology / Q000473:pathology; D055370:Lung Injury; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011516:Prothrombin / Q000235:genetics / Q000378:metabolism; D013917:Thrombin / Q000378:metabolism
D000936:Antigen-Antibody Complex; D003176:Complement C3; D007074:Immunoglobulin G; D015936:Complement C5a; D011516:Prothrombin; D013917:Thrombin