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J Immunol. 2017 Sep 1;199(5):1835-1845. doi: 10.4049/jimmunol.1700119. Epub 2017 Jul 24.

Deconstructing the Lectin Pathway in the Pathogenesis of Experimental Inflammatory Arthritis: Essential Role of the Lectin Ficolin B and Mannose-Binding Protein-Associated Serine Protease 2.

Author information

1
Division of Rheumatology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045; nirmal.banda@ucdenver.edu.
2
Division of Rheumatology, Department of Medicine, University of Colorado Anschutz Medical Campus, Aurora, CO 80045.
3
Skaggs School of Pharmacy, University of Colorado Anschutz Medical Campus, Aurora, CO 80045.
4
Department of Immunology, Fukushima Medical University, Fukushima, Hikarigaoka, Japan 960-1295; and.
5
Medical Research Council Centre for Transplantation, Division of Transplantation Immunology and Mucosal Biology, King's College London, Strand, London SE19 RT, United Kingdom.

Abstract

Complement plays an important role in the pathogenesis of rheumatoid arthritis. Although the alternative pathway (AP) is known to play a key pathogenic role in models of rheumatoid arthritis, the importance of the lectin pathway (LP) pattern recognition molecules such as ficolin (FCN) A, FCN B, and collectin (CL)-11, as well as the activating enzyme mannose-binding lectin-associated serine protease-2 (MASP-2), are less well understood. We show in this article that FCN A-/- and CL-11-/- mice are fully susceptible to collagen Ab-induced arthritis (CAIA). In contrast, FCN B-/- and MASP-2-/-/sMAp-/- mice are substantially protected, with clinical disease activity decreased significantly (p < 0.05) by 47 and 70%, respectively. Histopathology scores, C3, factor D, FCN B deposition, and infiltration of synovial macrophages and neutrophils were similarly decreased in FCN B-/- and MASP-2-/-/sMAp-/- mice. Our data support that FCN B plays an important role in the development of CAIA, likely through ligand recognition in the joint and MASP activation, and that MASP-2 also contributes to the development of CAIA, likely in a C4-independent manner. Decreased AP activity in the sera from FCN B-/- and MASP-2-/-/sMAp-/- mice with arthritis on adherent anti-collagen Abs also support the hypothesis that pathogenic Abs, as well as additional inflammation-related ligands, are recognized by the LP and operate in vivo to activate complement. Finally, we also speculate that the residual disease seen in our studies is driven by the AP and/or the C2/C4 bypass pathway via the direct cleavage of C3 through an LP-dependent mechanism.

PMID:
28739878
PMCID:
PMC5568486
DOI:
10.4049/jimmunol.1700119
[Indexed for MEDLINE]
Free PMC Article

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