Essential Role of Complement Mannose-Binding Lectin-Associated Serine Proteases-1/3 in the Murine Collagen Antibody-Induced Model of Inflammatory Arthritis

Abstract

Gene-targeted mice deficient in the complement mannose-binding lectin-associated serine protease-1 and -3 (MASP1/3−/−) express only the zymogen of factor D (pro-factor D [pro-Df]), a necessary component of the alternative pathway (AP). We used the murine collagen Ab-induced arthritis (CAIA) model, in which the AP is unique among complement pathways in being both necessary and sufficient for disease induction, to determine whether MASP-1/3 are required in vivo for the development of tissue injury. Disease activity scores, complement C3 tissue deposition in the joint, and histopathologic injury scores were markedly decreased in MASP1/3−/− as compared with wild-type (WT) mice. MASP-1 protein was immunochemically localized to synovial cells of knees of WT mice with arthritis. Pro-Df was present in both synovial cells and chondrocytes of knees of WT and MASP1/3−/− mice without arthritis, with increased amounts present in synovial cells of WT mice with CAIA. No conversion of pro-Df to mature Df was detectable in the serum of MASP1/3−/− mice during the evolution of CAIA. C3 activation and deposition as well as C5a generation induced in vitro by adherent anti-type II collagen mAbs were absent using sera from MASP1/3−/− mice under conditions in which only the AP was active. The addition of human Df fully reconstituted in vitro C3 activation and C5a generation using sera from MASP1/3−/− mice. Our studies demonstrate for the first time, to our knowledge, the absolute requirement for the activity of MASP-1 protein in autoimmune-associated inflammatory tissue injury in vivo through activation of the AP of complement by cleavage of pro-Df to mature Df.

Essential Role for the Lectin Pathway in Collagen Antibody–Induced Arthritis Revealed through Use of Adenovirus Programming Complement Inhibitor MAp44 Expression

“…CAIA was induced in WT mice using a cocktail of 5 mAbs to bovine CII (Arthritomab-CIA, Chondrex) suspended in sterile PBS as previously described (4, 17, 38). WT mice were injected i.p.…”

“…S2A). Clinical disease activity (CDA) was examined daily until day 10 by observers blinded to the treatment as per our previously published studies (4, 17, 38). …”

“…Previously, studies in mice deficient in different components of the complement system have shown that the AP is both necessary and sufficient to mediate CAIA as neither the LP nor the CP appear to be required (4, 17). Additionally, mice lacking MASP-1, MASP-3 and MAp44 ( MASP-1/3 −/− ) were shown to be resistant to CAIA (38), which was considered to be likely because they lacked mature FD and a functional AP (30). Although the AP may initiate and amplify CAIA, the LP (and CP) may also function to initiate the disease process.…”

Lessons learned from mice deficient in lectin complement pathway molecules

“…Since MASP-1 and MASP-3 are crucial for AP activation via FD activation, it was examined whether the expression of MASP-1/3 is essential for the development of CAIA (Banda et al, 2010). In the report, it was shown that Masp1/3 −/− mice are highly resistant to CAIA as evidenced by a significant decrease compared to WT mice (Banda et al, 2010). This evidence strongly supports that MASP-1 and MASP-3 are required for the AP activation in vivo.…”

Insidious pathogen-mimicking properties of nanoparticles in triggering the lectin pathway of the complement system

“…MASP1 is also able to cleave C3 directly, which results in activation of the alternative pathway (27). Others, based on a knockout mouse model, have also proposed a role for MASP1 and MASP3 in directly activating the alternative pathway factor D as well as limited factor B cleavage by MASP3 (28)(29)(30). However, there are ongoing debates on these findings (31,32).…”