Abstract
The complement system, composed of the three activation pathways, has both protective and pathogenic roles in the development of systemic lupus erythematosus (or lupus), a prototypic autoimmune disease. The classical pathway contributes to the clearance of immune complexes (ICs) and apoptotic cells, whereas the alternative pathway (AP) exacerbates renal inflammation. The role of the lectin pathway (LP) in lupus has remained largely unknown. Mannose-binding lectin (MBL)-associated serine proteases (MASPs), which are associated with humoral pattern recognition molecules (MBL or ficolins), are the enzymatic constituents of the LP and AP. MASP-1 encoded by the Masp1 gene significantly contributes to the activation of the LP. After the binding of MBL/ficolins to pathogens or self-altered cells, MASP-1 autoactivates first, then activates MASP-2, and both participate in the formation of the LP C3 convertase C4b2a, whereas, MASP-3, the splice variant of the Masp1 gene, is required for the activation of the zymogen of factor D (FD), and finally participates in the formation of the AP C3 convertase C3bBb. To investigate the roles of MASP-1 and MASP-3 in lupus, we generated Masp1 gene knockout lupus-prone MRL/lpr mice (Masp1/3−/− MRL/lpr mice), lacking both MASP-1 and MASP-3, and analyzed their renal disease. As expected, sera from Masp1/3−/− MRL/lpr mice had no or markedly reduced activation of the LP and AP with zymogen forms of complement FD. Compared to their wild-type littermates, the Masp1/3−/− MRL/lpr mice had maintained serum C3 levels, little-to-no albuminuria, as well as significantly reduced glomerular C3 deposition levels and glomerular pathological score. On the other hand, there were no significant differences in the levels of serum anti-dsDNA antibody, circulating ICs, glomerular IgG and MBL/ficolins deposition, renal interstitial pathological score, urea nitrogen, and mortality between the wild-type and Masp1/3−/− MRL/lpr mice. Our data indicate that MASP-1/3 plays essential roles in the development of lupus-like glomerulonephritis in MRL/lpr mice, most likely via activation of the LP and/or AP.
Highlights
The complement system, which consists of over 30 soluble and membrane-bound proteins, plays protective roles in host defense and a role in some immune regulatory functions via activation of the three different initial complement pathways: the classical pathway (CP), lectin pathway (LP), and alternative pathway (AP) [1]
Our group had previously demonstrated that mice deficient for MASP-1/3 had little-to-no activation of both the LP and AP with an inactive form of factor D (FD) in their sera at the C57BL/6 background [8]
Sera from Masp1/3+/+ wild-type MRL/lpr mice had C4 deposition activity on the mannan-coated plates and C3 deposition activity on the zymosan-coated plates in a dose-dependent manner (Figure 1). Both C4 and C3 deposition from the sera of Masp1/3−/− MRL/lpr mice were significantly lower than those in the wild-type MRL/lpr mice. These results indicate that MASP-1 and/or MASP-3 is involved in the activation of the LP and AP in MRL/lpr mice as in C57BL/6 mice
Summary
The complement system, which consists of over 30 soluble and membrane-bound proteins, plays protective roles in host defense and a role in some immune regulatory functions via activation of the three different initial complement pathways: the classical pathway (CP), lectin pathway (LP), and alternative pathway (AP) [1]. Activation of the CP is initiated by the binding of a C1 complex (C1q, C1r, and C1s), in which C1q recognizes IgM or IgG of antigen (Ag)–antibody complexes, followed by the activation of C1r and C1s, subsequently C4 and C2, resulting in the creation of C3 convertase C4b2a [2]. The product, C3(H2O), interacts with factor B (FB), and the subsequent cleavage of FB by the serine protease factor D (FD) This results in the creation of C3 convertase C3(H2O) Bb, which cleaves C3 generating metastable C3b. C3b bound to the host cells is subject to process inactivation by multiple complement-regulatory proteins, present in plasma and on host cell membranes. C3b bound to microorganisms is subject to process a chain reaction-like amplification loop that can bind large numbers of C3b molecules on the cell surface after the initial C3b binding. Uncontrolled activation of the AP is associated with multiple inflammatory diseases, such as systemic lupus erythematosus (SLE or lupus)
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