Alternative complement pathway activation is essential for inflammation and joint destruction in the passive transfer model of collagen-induced arthritis

被引:119
作者
Banda, Nirmal K.
Thurman, Joshua M.
Kraus, Damian
Wood, Allyson
Carroll, Michael C.
Arend, William P.
Holers, V. Michael
机构
[1] Univ Colorado, Hlth Sci Ctr, Div Rheumatol, Dept Med, Denver, CO 80262 USA
[2] Univ Colorado, Hlth Sci Ctr, Div Nephrol & Hypertens, Denver, CO 80262 USA
[3] Harvard Univ, Sch Med, CBR Inst Biomed Res, Boston, MA 02115 USA
[4] Harvard Univ, Sch Med, Dept Pediat, Boston, MA 02115 USA
关键词
INNATE IMMUNE-SYSTEM; RHEUMATOID-ARTHRITIS; RENAL-DISEASE; PROGRESSION; INHIBITION; DEFICIENCY; INITIATION; PREVENTS; ANTIBODY; SITES;
D O I
10.4049/jimmunol.177.3.1904
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Activation of each complement initiation pathway (classical, alternative, and lectin) can lead to the generation of bioactive fragments with resulting inflammation in target organs. The objective of the current study was to determine the role of specific complement activation pathways in the pathogenesis of experimental anti-type II collagen mAb-passive transfer arthritis. C57BL/6 mice were used that were genetically deficient in either the alternative pathway protein factor B (Bf(-/-)) or in the classical pathway component C4 (C4(-/-)). Clinical disease activity was markedly decreased in Bf(-/-) compared with wild-type (WT) mice (0.5 +/- 0.22 (n = 6) in Bf(-/-) vs 8.83 +/- 0.41 (n = 6) in WT mice (p < 0.0001)). Disease activity scores were not different between C4(-/-) and WT mice. Analyses of joints showed that C3 deposition, inflammation, parmus, cartilage, and bone damage scores were all significantly less in Bf(-/-) as compared with WT mice. There were significant decreases in mRNA levels of C3, C4, CR2, CR3, C3aR, and C5aR in the knees of Bf(-/-) as compared with C4(-/-) and WT mice with arthritis; mRNA levels for complement regulatory proteins did not differ between the three strains. These results indicate that the alternative pathway is absolutely required for the induction of arthritis following injection of anti-collagen Abs. The mechanisms by which these target organ-specific mAbs bypass the requirements for engagement of the classical pathway remain to be defined but do not appear to involve a lack of alternative pathway regulatory proteins.
引用
收藏
页码:1904 / 1912
页数:9
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