Pathogenic complement activation in collagen antibody-induced arthritis in mice requires amplification by the alternative pathway.
Immune complex-induced inflammation can be mediated by the classical pathway of complement. However, using mice genetically deficient in factor B or C4, we have shown that the collagen Ab-induced model of arthritis requires the alternative pathway of complement and is not dependent on the classical pathway. We now demonstrate that collagen Ab-induced arthritis is not altered in mice genetically deficient in either C1q or mannose-binding lectins A and C, or in both C1q and mannose-binding lectins. These in vivo results prove the ability of the alternative pathway to carry out pathologic complement activation in the combined absence of intact classical and lectin pathways. C3 activation was also examined in vitro by adherent collagen-anti-collagen immune complexes using sera from normal or complement-deficient mice. These results confirm the ability of the alternative pathway to mediate immune complex-induced C3 activation when C4 or C1q, or both C1q and mannose-binding lectins, are absent. However, when all three activation pathways of complement are intact, initiation by immune complexes occurs primarily by the classical pathway. These results indicate that the alternative pathway amplification loop, with its ability to greatly enhance C3 activation, is necessary to mediate inflammatory arthritis induced by adherent immune complexes.
Banda
Nirmal K
NK
Division of Rheumatology B115, University of Colorado at Denver and Health Sciences Center, Aurora, CO 80045, USA.
Takahashi
Kazue
K
Wood
Allyson K
AK
Holers
V Michael
VM
Arend
William P
WP
D000818:Animals; D000911:Antibodies, Monoclonal / Q000008:administration & dosage*; D000936:Antigen-Antibody Complex / Q000378:metabolism / Q000502:physiology; D001169:Arthritis, Experimental / Q000235:genetics / Q000276:immunology* / Q000378:metabolism*; D002118:Calcium / Q000172:deficiency / Q000378:metabolism; D002413:Cations, Divalent / Q000378:metabolism; D024043:Collagen Type II / Q000276:immunology*; D015922:Complement C1q / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D003176:Complement C3 / Q000172:deficiency / Q000235:genetics / Q000378:metabolism; D003170:Complement Pathway, Alternative / Q000235:genetics / Q000276:immunology*; D005260:Female; D007106:Immune Sera / Q000235:genetics / Q000502:physiology; D008297:Male; D037601:Mannose-Binding Lectin / Q000097:blood / Q000172:deficiency / Q000235:genetics; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D011485:Protein Binding / Q000235:genetics / Q000276:immunology; D015054:Zymosan / Q000494:pharmacology