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.

• Authors: Nirmal K Banda, Minoru Takahashi, Brandt Levitt, Magdalena Glogowska, Jessica Nicholas, Kazue Takahashi, Gregory L Stahl, Teizo Fujita, William P Arend, V Michael Holers
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 185 Issue 9 Pg. 5598-606 (Nov 01 2010) ISSN: 1550-6606 [Electronic] United States
• PMID: 20870940 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Mannose-Binding Protein-Associated Serine Proteases
• Complement Factor D

Topics

• Animals
• Arthritis, Experimental (immunology, metabolism, pathology)
• Blotting, Western
• Complement Factor D (immunology, metabolism)
• Complement Pathway, Alternative (immunology)
• Female
• Humans
• Immunohistochemistry
• Male
• Mannose-Binding Protein-Associated Serine Proteases (immunology, metabolism)
• Mice
• Mice, Inbred C57BL
• Mice, Knockout
• Polymerase Chain Reaction