title: Essential role for the lectin pathway in collagen antibody-induced arthritis revealed through use of adenovirus programming complement inhibitor MAp44 expression.
abstract: Previous studies using mannose-binding lectin (MBL) and complement C4-deficient mice have suggested that the lectin pathway (LP) is not required for the development of inflammatory arthritis in the collagen Ab-induced arthritis (CAIA) model. MBL, ficolins and collectin-11 are key LP pattern recognition molecules that associate with three serine proteases-MASP-1, MASP-2, and MASP-3-and with two MBL-associated proteins designated sMAP and MBL-associated protein of 44kDA (MAp44). Recent studies have shown that MAp44, an alternatively spliced product of the MASP-1/3 gene, is a competitive inhibitor of the binding of the recognition molecules to all three MASPs. In these studies, we examined the effect of treatment of mice with adenovirus (Ad) programmed to express human MAp44 (AdhMAp44) on the development of CAIA. AdhMAp44 and Ad programming GFP (AdGFP) expression were injected i.p. in C57BL/6 wild type mice prior to the induction of CAIA. AdhMAp44 significantly reduced the clinical disease activity (CDA) score by 81% compared with mice injected with AdGFP. Similarly, histopathologic injury scores for inflammation, pannus, cartilage and bone damage, as well as C3 deposition in the cartilage and synovium, were significantly reduced by AdhMAp44 pretreatment. Mice treated with AdmMAp44, programming expression of mouse MAp44, also showed significantly decreased CDA score and histopathologic injury scores. In addition, administration of AdhMAp44 significantly diminished the severity of Ross River virus-induced arthritis, an LP-dependent model. Our study provides conclusive evidence that an intact complement LP is essential to initiate CAIA, and that MAp44 may be an appropriate treatment for inflammatory arthritis.
authors: Division of Rheumatology, Department of Medicine, University of Colorado School of Medicine, Aurora, CO 80045; Nirmal.Banda@ucdenver.edu Michael.Holers@ucdenver.edu.
authors: Nirmal K
authors: NK
authors: Banda
authors: Division of Rheumatology, Department of Medicine, University of Colorado School of Medicine, Aurora, CO 80045;
authors: Gaurav
authors: G
authors: Mehta
authors: Department of Biomedicine, Aarhus University, DK-8000 Aarhus C, Denmark;
authors: Troels R
authors: TR
authors: Kjaer
authors: Department of Immunology, Fukushima Medical University School of Medicine, Fukushima 960-1295, Japan; and.
authors: Minoru
authors: M
authors: Takahashi
authors: Department of Microbiology, University of Colorado School of Medicine, Aurora, CO 80045.
authors: Jerome
authors: J
authors: Schaack
authors: Department of Microbiology, University of Colorado School of Medicine, Aurora, CO 80045.
authors: Thomas E
authors: TE
authors: Morrison
authors: Department of Biomedicine, Aarhus University, DK-8000 Aarhus C, Denmark;
authors: Steffen
authors: S
authors: Thiel
authors: Division of Rheumatology, Department of Medicine, University of Colorado School of Medicine, Aurora, CO 80045;
authors: William P
authors: WP
authors: Arend
authors: Division of Rheumatology, Department of Medicine, University of Colorado School of Medicine, Aurora, CO 80045; Nirmal.Banda@ucdenver.edu Michael.Holers@ucdenver.edu.
authors: V Michael
authors: VM
authors: Holers
mesh_terms: D000256:Adenoviridae; D018354:Alphavirus Infections / Q000235:genetics / Q000276:immunology / Q000473:pathology; D017398:Alternative Splicing / Q000235:genetics / Q000276:immunology; D000818:Animals; D001169:Arthritis, Experimental / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D003176:Complement C3 / Q000235:genetics / Q000276:immunology*; D037582:Complement Pathway, Mannose-Binding Lectin / Q000235:genetics / Q000276:immunology*; D006801:Humans; D050606:Mannose-Binding Protein-Associated Serine Proteases / Q000235:genetics / Q000276:immunology*; D051379:Mice; D018345:Mice, Knockout; D012398:Ross River virus / Q000276:immunology; D014161:Transduction, Genetic
chemical_list: D003176:Complement C3; C577328:MASP-1 protein, mouse; D050606:Mannose-Binding Protein-Associated Serine Proteases