Essential Role for the Lectin Pathway in Collagen Antibody−Induced Arthritis Revealed through Use of Adenovirus Programming Complement Inhibitor MAp44 This information is current as Expression of September 26, 2021. Nirmal K. Banda, Gaurav Mehta, Troels R. Kjaer, Minoru Takahashi, Jerome Schaack, Thomas E. Morrison, Steffen Thiel, William P. Arend and V. Michael Holers J Immunol 2014; 193:2455-2468; Prepublished online 28 Downloaded from July 2014; doi: 10.4049/jimmunol.1400752 http://www.jimmunol.org/content/193/5/2455 http://www.jimmunol.org/ Supplementary http://www.jimmunol.org/content/suppl/2014/07/26/jimmunol.140075 Material 2.DCSupplemental References This article cites 62 articles, 30 of which you can access for free at: http://www.jimmunol.org/content/193/5/2455.full#ref-list-1 by guest on September 26, 2021 Why The JI? Submit online. • Rapid Reviews! 30 days* from submission to initial decision • No Triage! Every submission reviewed by practicing scientists • Fast Publication! 4 weeks from acceptance to publication *average Subscription Information about subscribing to The Journal of Immunology is online at: http://jimmunol.org/subscription Permissions Submit copyright permission requests at: http://www.aai.org/About/Publications/JI/copyright.html Email Alerts Receive free email-alerts when new articles cite this article. Sign up at: http://jimmunol.org/alerts The Journal of Immunology is published twice each month by The American Association of Immunologists, Inc., 1451 Rockville Pike, Suite 650, Rockville, MD 20852 Copyright © 2014 by The American Association of Immunologists, Inc. All rights reserved. Print ISSN: 0022-1767 Online ISSN: 1550-6606. The Journal of Immunology Essential Role for the Lectin Pathway in Collagen Antibody– Induced Arthritis Revealed through Use of Adenovirus Programming Complement Inhibitor MAp44 Expression Nirmal K. Banda,* Gaurav Mehta,* Troels R. Kjaer,† Minoru Takahashi,‡ Jerome Schaack,x Thomas E. Morrison,x Steffen Thiel,† William P. Arend,* and V. Michael Holers* 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 Downloaded from 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 http://www.jimmunol.org/ 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. The Journal of Immunology, 2014, 193: 2455–2468. heumatoid arthritis (RA) is a complex autoimmune dis- The complement system is a central part of the innate immune ease with genetic and environmental components, affect- system and has been found to play a major role in the development by guest on September 26, 2021 R ing ∼1% of the population worldwide (1). Autoantibodies, of inflammation and tissue damage in CAIA and other animal especially as constituents of immune complexes (ICs), play a cen- models of inflammatory arthritis (4–7). Activation of the com- tral role in triggering inflammation in this disease (2, 3). In this plement system is thought to contribute to inflammation and tis- study, we examined the pathophysiology of RA using a mouse sue damage in human RA, especially in early disease (8–10). ICs model of collagen Ab–induced arthritis (CAIA), where ICs are containing Abs of the IgG isotype are found in the cartilage and formed in the joint between anti–collagen type II (CII) mAbs and synovium of the joints of patients with RA, and these ICs have CII, one of the major matrix proteins of the articular cartilage. been implicated in induction of local tissue damage through ac- tivation of the complement system (11–13). The complement system can be activated by three pathways: *Division of Rheumatology, Department of Medicine, University of Colorado School the classical pathway (CP), the lectin pathway (LP), and the alter- of Medicine, Aurora, CO 80045; †Department of Biomedicine, Aarhus University, DK-8000 Aarhus C, Denmark; ‡Department of Immunology, Fukushima Medical native pathway (AP). IgG Abs in arthritis-related IC in human x University School of Medicine, Fukushima 960-1295, Japan; and Department of RA have previously been shown to activate both the CP and AP of Microbiology, University of Colorado School of Medicine, Aurora, CO 80045 the complement system (14–16). In CAIA, using pathway-specific Received for publication March 21, 2014. Accepted for publication June 28, 2014. functional deficiencies of the complement system developed through This work was supported by National Institutes of Health Grant AR051749 (to V.M.H.) gene targeting and inactivation of specific pathway components, it and a grant from the Lundbeck Foundation (to T.R.K. and S.T.). was previously concluded that the AP alone is both necessary and Address correspondence and reprint requests to: Dr. Nirmal K. Banda and Dr. V. Michael Holers, Division of Rheumatology B115, University of Colorado sufficient for the development of CAIA through its role in both the School of Medicine, 1775 Aurora Court, Aurora, CO 80045. E-mail addresses: initiation process and amplification loop (4). The lack of a role for [email protected] (N.K.B.) and [email protected] (V.M.H.) the LP was inferred using MBL-A/C and C4 deficient mice (4, 6, The online version of this article contains supplemental material. 17), and for the CP using C4- and C1q-deficient mice (4, 17), where Abbreviations used in this article: Ad, adenovirus; AP, alternative pathway; CAIA, disease was largely unchanged. collagen antibody–induced arthritis; CAR, Coxsackie-adenovirus receptor; CDA, clinical disease activity; CIA, collagen-induced arthritis; CII, collagen type II; CP, The CP is initiated by C1q binding to Ab in an IC, leading to classical pathway; FB, factor B; FD, factor D; HD, higher dose; IC, immune com- activation of C1r and C1s and to the subsequent formation of the plex; IHS, immunohistochemical staining; LD, lower dose; LP, lectin pathway; Map44, MBL-associated protein of 44 kDA; MASP-1, MBL-associated serine pro- CP C3 convertase, C4b2b. The LP is initiated when members of tease-1; MASP-2, MBL-associated serine protease-2; MASP-3, MBL-associated ser- a family of pattern recognition molecules designated the collectins, ine protease-3; MBL, mannose-binding lectin; RGD, Arg-Gly-Asp; RRV, Ross River whose members are mannose-binding lectin (MBL), ficolins (the virus; RT, rheumatoid arthritis; WT, wild type. three in humans are designated H, L, and M), and Collectin-11 (also Copyright Ó 2014 by The American Association of Immunologists, Inc. 0022-1767/14/$16.00 termed CL-K1) bind, along with MBL-associated serine proteases www.jimmunol.org/cgi/doi/10.4049/jimmunol.1400752 2456 LECTIN PATHWAY IN INFLAMMATORY ARTHRITIS (MASP-1, MASP-2, and MASP-3), to arrays of specific mono- has not previously been shown to have an essential role in CAIA, saccharides or modified carbohydrates present on the surface of we hypothesized that ficolin-A or -B or Collectin-11 mediate the microorganisms and other target surfaces and molecules. Notably, recognition of ligands independently of MBL-A/C. In addition, in humans one MBL is found, whereas in mice two, MBL-A and direct MASP-mediated cleavage of C3 (39) could have allowed C3 MBL-C, are present; in addition, two ficolins (Ficolin-A and activation and engagement of the amplification loop even in the Ficolin-B) are found in mice along with Collectin-11 (18–21). This absence of MBL-A/C or C4. The use of MAp44 as an endogenous process leads to the formation of the shared CP/LP C3 convertase, inhibitor of all of the MASPs, because of its interference with the C4b2b, through the activities of MASP-2 (22) in a manner that interactions between the recognition molecules and MASPs, should requires initial engagement of MASP-1 (23, 24). The AP is initiated allow a more complete impairment of the LP and better assessment by spontaneous turnover of C3 with transient formation of hydro- of its role in the development of CAIA. lyzed C3 (H2O), followed by binding of factor B (FB) with cleav- In this study, we examined the effect of replication defective age by factor D (FD) and generation of the AP initiation C3 convertase adenovirus (Ad) serotype 5 vectors containing the human C3(H2O)Bb (25). Cleavage of C3 also exposes a short-lived thio- (AdhMAp44) or mouse (AdmMAp44) genes on the initiation of ester in C3b that covalently attaches to amine and carboxyl groups CAIA. Using this approach, our study provides strong support for on target surfaces (25). Following formation of C3b through any of a key role of the LP in the initiation and pathogenesis of CAIA.