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.


CONCLUSIONS
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.
Nandakumar
Kutty Selva
KS
Lund University, Lund, Sweden. nan@med.lu.se
Bajtner
Estelle
E
Hill
Leigh
L
Böhm
Beate
B
Rowley
Merrill J
MJ
Burkhardt
Harald
H
Holmdahl
Rikard
R
D000368:Aged; D000818:Animals; D000911:Antibodies, Monoclonal / Q000276:immunology; D000918:Antibody Specificity; D001169:Arthritis, Experimental / Q000276:immunology* / Q000473:pathology; D001172:Arthritis, Rheumatoid / Q000276:immunology* / Q000473:pathology; D001323:Autoantibodies / Q000097:blood / Q000276:immunology*; D002356:Cartilage / Q000276:immunology* / Q000473:pathology; D045744:Cell Line, Tumor; D002813:Chondrosarcoma; D024043:Collagen Type II / Q000737:chemistry / Q000276:immunology*; D003182:Complement C5 / Q000276:immunology; D000939:Epitopes / Q000276:immunology; D005109:Extracellular Matrix / Q000276:immunology / Q000473:pathology; D005260:Female; D006801:Humans; D007074:Immunoglobulin G / Q000097:blood / Q000276:immunology; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008875:Middle Aged; D017434:Protein Structure, Tertiary; D051381:Rats; D011919:Rats, Inbred Strains
D000911:Antibodies, Monoclonal; D001323:Autoantibodies; D024043:Collagen Type II; D003182:Complement C5; D000939:Epitopes; D007074:Immunoglobulin G