C4b-Binding Protein, a Regulatory Component of the Classical Pathway of Complement, Is an Acute-Phase Protein and Is Elevated in Systemic Lupus Erythematosus

Abstract

A radioimmunoassay using monoclonal and polyclonal antihuman C4b-binding protein (C4BP) antibody was developed to quantitate C4BP in serum. Using the assay, the levels of C4BP in healthy individuals, in patients with systemic lupus erythematosus (SLE), and in acute-phase individuals were determined. The levels of C4BP are significantly elevated in individuals with SLE (186%; p = 0.0001) and are even higher in individuals during the acute phase (286%; p = 0.0001). To confirm whether or not individuals were in the acute-phase response, serum C-reactive protein (CRP) levels were assessed. In the acute- phase response, CRP levels were 100-fold elevated over normals, but did not correlate with increases in C4BP (r = -0.031; p = 0.899). In SLE patients, the CRP levels were significantly, but moderately, elevated (5-fold; p = 0.028). The data indicate that C4BP is an acute-phase reactant and is differentially regulated from CRP during the acute-phase response.

Modulation of C4b-Binding Protein Isoforms during the Acute Phase Response Caused by Orthopedic Surgery

“…In previous studies it has been established that C4BP is an acute-phase reactant that increases its plasma concentration 2-to 4-fold [8][9][10]. Conforming to these data, the evolu tion of the C4BP levels in the serial samples from patients who have undergone orthoped ic surgery shows an elevation of the concen tration of total C4BP during the postsurgical acute-phase response ( fig.…”

“…These two activities are performed by two distinct polypeptides of 70 and 45 kDa known as a-and (3-chains, respectively [5], C4BP is present in plasma in various isoforms with different a/(3-composition, a7:(31 (nor mally the major isoform), a7:(30 and a6:|31 [7], C4BP is described as an acute-phase reactant that elevates its concentration in plasma 2-to 4-fold in the acute-phase response [8][9][10], When C4BP is induced, the expression of the C4BPA and C4BPB genes is differentially modulated [11,12], determining changes in the proportion of the C4BP isoforms. Ele vated concentrations of C4BP(3-containing isoforms may result in a lack of free protein S and in an inactivation of the protein C anticoagulatory pathway [13][14][15][16][17][18].…”

The C4b-binding Protein-Protein S Complex Inhibits the Phagocytosis of Apoptotic Cells

“…C4BP also acts as a cofactor to serine protease factor I in the degradation and inactivation of C4b (11) and C3b (12). C4BP is an acute phase protein (13), but only the ␣7␤0 form increases in expression during inflammation (14), ensuring that PS (the ␤-chain ligand) will not be depleted from plasma, which could otherwise lead to severe thrombotic disorders. 1 The abbreviations used are: MBL, mannose binding lectin; CR, complement receptor; C4BP, C4b-binding protein; CCP, complement control protein; HBSS, Hanks' balanced salt solution; PE, phycoerythrin; PS, protein S; EGF, epidermal growth factor; SHBG, sex hormone binding globulin; PBS, phosphate-buffered saline; CFSE, 5-(and 6-)carboxyfluorescein diacetate succinimidyl ester; mAb, monoclonal antibody; ELISA, enzyme-linked immunosorbent assay; SLE, systemic lupus erythematosus.…”

The α-Chains of C4b-binding Protein Mediate Complex Formation with Low Density Lipoprotein Receptor-related Protein

“…The average plasma concentration of C4BP is ϳ260 nM (150 g/ml) (10), although its levels may increase up to 4-fold during inflammation, infection, or tissue damage (11,12). Plasma levels represent a balance between C4BP production and removal.…”

“…In addition, the ␣-chains have been found to contain binding sites for bacterial surface proteins from Streptococcus pyogenes (7) and heparin (8). The heparin interactive site, which overlaps with the C4b interactive site, encompasses a cluster of positively charged amino acids involving Arg residues at positions 39, 64, and 66 (9).The average plasma concentration of C4BP is ϳ260 nM (150 g/ml) (10), although its levels may increase up to 4-fold during inflammation, infection, or tissue damage (11,12). Plasma levels represent a balance between C4BP production and removal.…”