title: Mechanisms of mannose-binding lectin-associated serine proteases-1/3 activation of the alternative pathway of complement.
abstract: Mannose-binding lectin-associated serine proteases-1/3 (MASP-1/3) are essential in activating the alternative pathway (AP) of complement through cleaving pro-factor D (pro-Df) into mature Df. MASP are believed to require binding to mannose binding lectins (MBL) or ficolins (FCN) to carry out their biological activities. Murine sera have been reported to contain MBL-A, MBL-C, and FCN-A, but not FCN-B that exists endogenously in monocytes and is thought not to bind MASP-1. We examined some possible mechanisms whereby MASP-1/3 might activate the AP. Collagen antibody-induced arthritis, a murine model of inflammatory arthritis dependent on the AP, was unchanged in mice lacking MBL-A, MBL-C, and FCN-A (MBL(-/-)/FCN A(-/-) mice) in comparison to wild-type mice. The in vitro induction of the AP by adherent mAb to collagen II was intact using sera from MBL(-/-)/FCN A(-/-) mice. Furthermore, sera from MBL(-/-)/FCN A(-/-) mice lacked pro-Df and possessed only mature Df. Gel filtration of sera from MBL(-/-)/FCN A(-/-) mice showed the presence of MASP-1 protein in fractions containing proteins smaller than the migration of MBL-A and MBL-C in sera from C4(-/-) mice, suggesting possible binding of MASP-1 to an unknown protein. Lastly, we show that FCN-B was present in the sera of MBL(-/-)/FCN A(-/-) mice and that it was bound to MASP-1. We conclude that MASP-1 does not require binding to MBL-A, MBL-C, or FCN-A to activate the AP. MASP-1 may cleave pro-Df into mature Df through binding to FCN-B or to an unknown protein, or may function as an unbound soluble protein.
authors.affiliation: Division of Rheumatology, Departments of Medicine and Immunology, University of Colorado School of Medicine, Aurora, CO 80045, USA.
authors.forename: Nirmal K
authors.initials: NK
authors.lastname: Banda
authors.forename: Minoru
authors.initials: M
authors.lastname: Takahashi
authors.forename: Kazue
authors.initials: K
authors.lastname: Takahashi
authors.forename: Gregory L
authors.initials: GL
authors.lastname: Stahl
authors.forename: Stephanie
authors.initials: S
authors.lastname: Hyatt
authors.forename: Magdalena
authors.initials: M
authors.lastname: Glogowska
authors.forename: Timothy A
authors.initials: TA
authors.lastname: Wiles
authors.forename: Yuichi
authors.initials: Y
authors.lastname: Endo
authors.forename: Teizo
authors.initials: T
authors.lastname: Fujita
authors.forename: V Michael
authors.initials: VM
authors.lastname: Holers
authors.forename: William P
authors.initials: WP
authors.lastname: Arend
mesh_terms: D000818:Animals; D001169:Arthritis, Experimental / Q000378:metabolism*; D015153:Blotting, Western; D011416:Complement Factor D / Q000378:metabolism; D003170:Complement Pathway, Alternative / Q000502:physiology*; D008297:Male; D050606:Mannose-Binding Protein-Associated Serine Proteases / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout
chemical_list: D050606:Mannose-Binding Protein-Associated Serine Proteases; D011416:Complement Factor D