Complement Inhibitor C4b-Binding Protein Interacts Directly with Small Glycoproteins of the Extracellular Matrix

被引:40
作者
Happonen, Kaisa E. [1 ]
Sjoeberg, Andreas P. [1 ]
Moergelin, Matthias [3 ]
Heinegard, Dick [2 ]
Blom, Anna M. [1 ]
机构
[1] Lund Univ, Malmo Univ Hosp, Wallenberg Lab, Dept Lab Med, S-20502 Malmo, Sweden
[2] Lund Univ, Biomed Ctr, Dept Expt Med Sci, Lund, Sweden
[3] Lund Univ, Biomed Ctr, Dept Med Informat, Lund, Sweden
基金
瑞典研究理事会; 美国国家卫生研究院;
关键词
C-REACTIVE PROTEIN; KERATAN SULFATE PROTEOGLYCAN; COLLAGEN-INDUCED ARTHRITIS; RICH REPEAT PROTEINS; ALPHA-CHAIN; CLASSICAL PATHWAY; FACTOR-H; RHEUMATOID-ARTHRITIS; ELECTRON-MICROSCOPY; CONNECTIVE TISSUES;
D O I
10.4049/jimmunol.182.3.1518
中图分类号
R392 [医学免疫学]; Q939.91 [免疫学];
学科分类号
100102 ;
摘要
Components derived from cartilage have been suggested to maintain the inflammation in joints in arthritis. Small leucinerich repeat proteins (SLRPs) are structural components of cartilage important in organizing the meshwork of extracellular matrix components. It has recently been shown that the SLRP fibromodulin interacts with complement initiator C1q, leading to complement activation. The complement response is limited since fibromodulin also interacts with the complement inhibitor factor H. We have now found that osteoadherin, chondroadherin, fibromodulin, and proline arginine-rich end leucine-rich repeat protein bind to the complement inhibitor C4b-binding protein (C4BP). Using direct binding assays with C4BP fragments and C4BP mutants lacking individual domains in combination with electron microscopy, we have demonstrated that mainly the central core of C4BP mediated binding to SLRPs. Binding of SLRPs to C4BP did not affect its ability to inhibit complement. Osteoadherin, fibromodulin, and chondroadherin, which bind C1q and activate complement, were found to cause significantly higher C9 deposition in C4BP-depleted serum compared with Igs, indicating that the level of complement activation initiated by SLRPs is regulated by simultaneous binding to C4BP. A similar dual binding of C1q and complement inhibitors was observed previously for other endogenous ligands (amyloid, prions, C-reactive protein, and apoptotic cells) but not for exogenous activators (bacteria-bound Igs). These interactions can be significant during inflammatory joint diseases, such as rheumatoid arthritis, where cartilage is degraded, and cartilage components are released into synovial fluid, where they can interact with factors of the complement system. The Journal of Immunology, 2009, 182: 1518-1525.
引用
收藏
页码:1518 / 1525
页数:8
相关论文
共 45 条
[1]   Alternative complement pathway activation is essential for inflammation and joint destruction in the passive transfer model of collagen-induced arthritis [J].
Banda, Nirmal K. ;
Thurman, Joshua M. ;
Kraus, Damian ;
Wood, Allyson ;
Carroll, Michael C. ;
Arend, William P. ;
Holers, V. Michael .
JOURNAL OF IMMUNOLOGY, 2006, 177 (03) :1904-1912
[2]   THIOCYANATE GOLD - SMALL (2-3 NM) COLLOIDAL GOLD FOR AFFINITY CYTOCHEMICAL LABELING IN ELECTRON-MICROSCOPY [J].
BASCHONG, W ;
LUCOCQ, JM ;
ROTH, J .
HISTOCHEMISTRY, 1985, 83 (05) :409-411
[3]   THE PRIMARY STRUCTURE OF A BASIC LEUCINE-RICH REPEAT PROTEIN, PRELP, FOUND IN CONNECTIVE TISSUES [J].
BENGTSSON, E ;
NEAME, PJ ;
HEINEGARD, D ;
SOMMARIN, Y .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1995, 270 (43) :25639-25644
[4]   FIBRONECTIN BINDS TO THE CLQ COMPONENT OF COMPLEMENT [J].
BING, DH ;
ALMEDA, S ;
ISLIKER, H ;
LAHAV, J ;
HYNES, RO .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA-BIOLOGICAL SCIENCES, 1982, 79 (13) :4198-4201
[5]  
Blom AM, 2004, ARCH IMMUNOL THER EX, V52, P83
[6]   CCP1-4 of the C4b-binding protein α-chain are required for factor I mediated cleavage of complement factor C3b [J].
Blom, AM ;
Kask, L ;
Dahlbäck, B .
MOLECULAR IMMUNOLOGY, 2003, 39 (10) :547-556
[7]   A cluster of positively charged amino acids in the C4BP α-chain is crucial for C4b binding and factor I cofactor function [J].
Blom, AM ;
Webb, J ;
Villoutreix, BO ;
Dahlbäck, B .
JOURNAL OF BIOLOGICAL CHEMISTRY, 1999, 274 (27) :19237-19245
[8]   Structural requirements for the complement regulatory activities of C4BP [J].
Blom, AM ;
Kask, L ;
Dahlbäck, B .
JOURNAL OF BIOLOGICAL CHEMISTRY, 2001, 276 (29) :27136-27144
[9]   THE C1Q SUBUNIT OF THE 1ST COMPONENT OF COMPLEMENT BINDS TO LAMININ - A MECHANISM FOR THE DEPOSITION AND RETENTION OF IMMUNE-COMPLEXES IN BASEMENT-MEMBRANE [J].
BOHNSACK, JF ;
TENNER, AJ ;
LAURIE, GW ;
KLEINMAN, HK ;
MARTIN, GR ;
BROWN, EJ .
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA, 1985, 82 (11) :3824-3828
[10]  
BRODEUR JP, 1991, ARTHRITIS RHEUM, V34, P1531