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Vol. 273, Issue 3, 1551-1561, January 16, 1998

Arthritis-related B Cell Epitopes in Collagen II Are Conformation-dependent and Sterically Privileged in Accessible Sites of Cartilage Collagen Fibrils

Stefan Schulte^§, Christine Unger^§, John A. Mo^¶, Olaf Wendler^§, Eva Bauer^§, Svenja Frischholz^§, Klaus von der Mark^§, Joachim R. Kalden, Rikard Holmdahl^¶, and Harald Burkhardt^§

From the  Department of Internal Medicine III, Institute of Clinical Immunology and the ^§ Institute of Experimental Medicine, University of Erlangen-Nürnberg, D-91054 Erlangen, Germany, and the ^¶ Section for Medical Inflammation Research, Department of Cell and Molecular Biology, Lund University, S-221 00 Lund, Sweden

In collagen-induced arthritis, a murine autoimmune model for rheumatoid arthritis, immunization with native but not heat-denatured cartilage-specific collagen type II (CII) induces a B cell response that largely contributes to arthritogenicity. Previously, we have shown that monoclonal antibodies established from arthritis prone DBA/1 mice require the triple-helical conformation of their epitopes for antigen recognition. Here, we present a novel approach to characterize arthritis-related conformational epitopes by preparing a panel of 130 chimeric collagen X/CII molecules. The insertion of a series of CII cassettes into the triple-helical recombinant collagen X allowed for the first time the identification of five triple-helical immunodominant domains of 5-11 amino acid length, to which 75% of 36 monoclonal antibodies bound. A consensus motif, "R G hydrophobic," was found in all immunodominant epitopes. The antibodies were encoded by a certain combination of V-genes in germline configuration, indicating a role of the consensus motif in V-gene selection. The immunodominant domains are spread over the entire monomeric CII molecule with no apparent order; however, a highly organized arrangement became apparent when the CII molecules were displayed in the quarter-staggered assembly within a fibril. This discrete epitope organization most likely reflects structural constraints that restrict the exposure of CII epitopes on the surface of heterotypically assembled cartilage fibrils. Thus, our data suggest a preimmune B cell selection process that is biased by the accessibility of CII determinants in the intact cartilage tissue.

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