Abstract
Factor H-related (FHR) proteins consist of varying number of complement control protein domains that display various degrees of sequence identity to respective domains of the alternative pathway complement inhibitor factor H (FH). While such FHR proteins are described in several species, only human FHRs were functionally investigated. Their biological role is still poorly understood and in part controversial. Recent studies on some of the human FHRs strongly suggest a role for FHRs in enhancing complement activation via competing with FH for binding to certain ligands and surfaces. The aim of the current study was the functional characterization of a murine FHR, FHR-B. To this end, FHR-B was expressed in recombinant form. Recombinant FHR-B bound to human C3b and was able to compete with human FH for C3b binding. FHR-B supported the assembly of functionally active C3bBb alternative pathway C3 convertase via its interaction with C3b. This activity was confirmed by demonstrating C3 activation in murine serum. In addition, FHR-B bound to murine pentraxin 3 (PTX3), and this interaction resulted in murine C3 fragment deposition due to enhanced complement activation in mouse serum. FHR-B also induced C3 deposition on C-reactive protein, the extracellular matrix (ECM) extract Matrigel, and endothelial cell-derived ECM when exposed to mouse serum. Moreover, mouse C3 deposition was strongly enhanced on necrotic Jurkat T cells and the mouse B cell line A20 by FHR-B. FHR-B also induced lysis of sheep erythrocytes when incubated in mouse serum with FHR-B added in excess. Altogether, these data demonstrate that, similar to human FHR-1 and FHR-5, mouse FHR-B modulates complement activity by promoting complement activation via interaction with C3b and via competition with murine FH.
Highlights
The proper balance between enhancement and inhibition of complement activation is important to maintain the physiological functions of complement and prevent pathological complement activation and complement-mediated diseases [1]
Factor H-related-B from serum and FHR-B expressed in yeast were shown to bind weakly to human C3b [9]
FHR-B was immobilized in microplate wells and, after blocking, incubated with recombinant mouse pentraxin 3 (PTX3). We found that this conserved pentraxin interacts with FHR-B, as well as with human C1q, used as a positive control, but it did not bind to bovine serum albumin (BSA), which was used as a negative control (Figure 5A)
Summary
The proper balance between enhancement and inhibition of complement activation is important to maintain the physiological functions of complement and prevent pathological complement activation and complement-mediated diseases [1]. Early, studies assessed the direct complement regulatory roles of FHRs, and some activities in the regulation of C3 or C5 convertases [15,16,17,18], inhibition of the terminal pathway by FHR-1 [19], and synergistic enhancement of the cofactor activity of FH by FHR-3 and FHR-4 [15] were reported. FHR-1, FHR-4, and FHR-5 were shown to promote alternative pathway activation by binding C3b and allowing formation of the C3bBb alternative pathway C3 convertase enzyme [23, 24, 26], FHR-5 via interaction with properdin [27]. FHR-1 was shown to modulate activation of human neutrophils in the context of interaction of neutrophils with the human-pathogenic yeast Candida albicans [28], and, by binding C3d, FHR-3 to inhibit C3d-mediated co-activation of B cells [29]
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