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

• 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.

Ämnesord

MEDICIN OCH HÄLSOVETENSKAP  -- Klinisk medicin -- Reumatologi och inflammation (hsv//swe)

MEDICAL AND HEALTH SCIENCES  -- Clinical Medicine -- Rheumatology and Autoimmunity (hsv//eng)

Nyckelord

Aged

Animals

Antibodies

Monoclonal/immunology

Antibody Specificity

Arthritis

Experimental/*immunology/pathology

Arthritis

Rheumatoid/*immunology/pathology

Autoantibodies/blood/*immunology

Cartilage/*immunology/pathology

Cell Line

Tumor

Chondrosarcoma

Collagen Type II/chemistry/*immunology

Complement C5/immunology

Epitopes/immunology

Extracellular Matrix/immunology/pathology

Female

Humans

Immunoglobulin G/blood/immunology

Male

Mice

Mice

Inbred BALB C

Middle Aged

Protein Structure

Tertiary

Rats

Rats

Inbred Strains

Publikations- och innehållstyp

ref (ämneskategori)

art (ämneskategori)