C4b-binding protein (C4BP) inhibits development of experimental arthritis in mice

Abstract

Objectives:To assess the human complement inhibitor C4b-binding protein (C4BP) for treatment of arthritis.Methods:We have used two mouse models of rheumatoid arthritis (RA) to assess the therapeutic effect of C4BP on different phases of arthritis, the collagen antibody-induced arthritis (CAIA), an acute antibody-induced disease and the collagen-induced arthritis (CIA), which carries the full complexity of arthritis.Results:Purified human C4BP injected intraperitoneally alleviated CAIA significantly in a manner similar to cobra venom factor that depletes complement due to massive activation. Furthermore, C4BP was injected before and after the disease development into CIA mice. In the former case, the disease onset was delayed and in the latter, the severity of the disease was reduced in animals treated with C4BP. However, C4BP did not affect the anti-CII antibody synthesis. C4BP present in mouse sera decreased activity of the classical but not the alternative pathway of the complement system when these were assessed in a fluid phase. However, C4BP was efficiently inhibiting the alternative pathway when present on the activating surface. Taken together, the disease ameliorating effect of C4BP appears to be related to inhibition of both pathways of complement.Conclusions:Although human C4BP was cleared relatively fast from the circulation and was only moderately affecting complement activity, its effect on the disease severity was substantial, suggesting that minor alterations in complement activity can have significant therapeutic value in RA.

The α7β0 Isoform of the Complement Regulator C4b-Binding Protein Induces a Semimature, Anti-Inflammatory State in Dendritic Cells

“…injection of human C4BP induced a low level of complement inhibition, it was able to significantly inhibit the development of experimental arthritis in mice (15). Thus, our study could provide a possible mechanism explaining the in vivo effect of C4BP(b 2 ) regulating autoim- …”

“…It has been recently reported that i.p. administration of human C4BP was able to inhibit the development of autoimmune arthritis in mice, although it was only moderately affecting complement activity (15). This suggests that other mechanisms might be involved in the anti-inflammatory activity of C4BP.…”

“…1A, left) plus the minor C4BP a 6 b 1 isoforms (both in complex with ProS) purified from pooled human plasma, as previously described (6). In this study, the C4BP (b 2 ) isoform refers to both: 1) the polymeric recombinant full-length C4BP a 6 b 0 , expressed in HEK293 cells (CRL-1573; American Type Culture Collection, Manassas, VA) and purified by affinity chromatography from an Affi-Gel column (Bio-Rad, Hercules, CA) coupled with mAb MK104 against the CCP1 domain of the C4BP a-chain (23); and 2) human plasma C4BP a 7 b 0 , analogously purified by affinity chromatography after C4BP(b + )-ProS removal by BaCl 2 precipitation (6,15) (Fig. 1A, center and right, respectively).…”

PRELP Protein Inhibits the Formation of the Complement Membrane Attack Complex

“…In RA, complement activation is triggered by immune complexes, apoptotic/ necrotic cells, and released cartilage components, which results in further activation of components of both the innate and adaptive immune system due to the interaction of complement activation products and their receptors on target cells. A number of studies have demonstrated beneficial effects of complement inhibition at the level of C3-convertase (20) or C5a generation (21,22) in murine models of RA. Formation of MAC has FIGURE 5.…”

Emerging roles of serine proteinases in tissue turnover in arthritis

“…Deposited autoantibodies, immune complexes, apoptotic cells, and necrotic cells can activate this cascade, leading to the release of proinflammatory activators, recruitment of inflammatory cells (Figure 1), and formation of membrane attack complexes. The levels of complement activation components are elevated in the synovial fluid, synovium, and cartilage of patients with arthritis (19)(20)(21)(22)(23), and targeted deletion/inhibition reduces disease severity in murine arthritis models (7,24,25). These previous studies have led to the development of therapeutic approaches targeting complement components for the treatment of RA (for review, see ref.…”