Arthritogenic antibodies specific for a major type II collagen triple‐helical epitope bind and destabilize cartilage independent of inflammation

Abstract

Objective. To investigate the significance and pathogenic potential of a highly conserved major type II collagen triple-helical epitope-specific antibody (U1; amino acids 494-504) in vivo and in vitro in patients with early rheumatoid arthritis (RA) and in experimental animal models of collagen-induced arthritis (CIA).Methods. U1-specific antibodies in sera from patients with early RA (with or without joint erosions) were analyzed. Disease progression in the CIA models in mice and rats with anti-U1 antibodies was compared. The pathogenicity of binding of monoclonal antibodies (mAb) UL1 and CIIF4 to the U1 epitope and the F4 epitope (aa 926-936), respectively, was compared in vivo and on chondrocyte cultures and preformed cartilage in vitro, using Fourier transform infrared microspectroscopy analysis. In addition, UL1-induced proteoglycan depletion in vivo in the presence and absence of the complement factor C5 was analyzed.Results. Increased levels of U1 antibodies were observed in patients with early RA, especially in association with joint erosions. A significant correlation of U1-specific antibodies with disease progression was found in rats and mice with CIA. UL1 mAb induced, whereas CIIF4 mAb inhibited, the progression of arthritis. Similarly, UL1, but not CIIF4, impaired matrix synthesis on chondrocyte cultures and adversely affected preformed cartilage. Furthermore, UL1 induced significant proteoglycan depletion in vivo 3 days after injection, even in the absence of C5.Conclusion. Antibody epitope specificity contributes significantly to the development of arthritis, and the early pathogenic events operate independent of inflammation both in vitro and in vivo.

Experimental Arthritis Triggers Periodontal Disease in Mice: Involvement of TNF-α and the Oral Microbiota

“…Collagen I is one of the major components of periodontal tissues (31) and, it was shown, mainly for RA, that Abs binding to self-Ags can initiate an inflammatory reaction in tissues, possibly through the release of tissue-degrading enzymes (32) and cytokines (33) by the infiltrating cells (34). In this study, the production of proinflammatory cytokines, such as TNF-a and IL-17, was enhanced by cells of AIA mice when stimulated by collagen I.…”

Characterization of the anticollagen antibody response in a new model of chronic polyarthritis

“…Anti-CII antibodies are believed to be arthritogenic in murine CIA; in fact, transfer of serum containing these antibodies can induce arthritis in healthy animals (16,18,21). Bovine or rat CII used to immunize animals in the CIA model elicits an antibody response specific for CII.…”

“…Bovine or rat CII used to immunize animals in the CIA model elicits an antibody response specific for CII. These antibodies against foreign collagen are believed to cross-react with self collagen and become pathogenic (21,33). In the model of arthritis developed in this study, we demonstrated the breach of self tolerance toward collagen and the production of anti-CII and anti-U1 antibodies.…”

“…Anti-U1 antibodies have been detected in patients with early RA, especially those with erosive arthritis (21). They are also correlated with disease progression in murine CIA, and the injection of a monoclonal antibody directed against U1 induced both cartilage damage (21) and the relapse of arthritis in mice with chronic arthritis (20). Of interest, monoclonal antibody anti-U1 reacted with the intact cartilage matrix in vivo, demonstrating its accessibility by immunoglobulins (23).…”

“…Synthesis of recombinant triple helical peptides and use of monoclonal antibodies have allowed the identification of predominant collagen epitopes and their relevance to disease (20). Some of these epitopes are arthritogenic in murine CIA (21,22), while others are shared between human and murine RA, such as C1 and U1 epitopes (20,23). However, an important limitation of the CIA model is that the collagen response and the disease are stimulated by exogenously injected collagen, whereas human RA is characterized by a spontaneous breach of self tolerance.…”