A Case of Germinal Center Formation by CD45RO T and CD20 B Lymphocytes in Rheumatoid Arthritic Subchondral Bone: Proposal for a Two-Compartment Model of Immune-Mediated Disease with Implications for Immunotherapeutic Strategies

In rheumatoid arthritis (RA) disease activity occurring as joint destruction of cartilage and bone is thought to be driven by inflammatory reactions which are initiated by exogenous microbial mechanisms and perpetuated by endogenous autoimmune mechanisms. According to the synovial model of RA, these reactions originate in the adjacent synovial tissues. The following set of observations is presented herein to suggest an alternate model involving subchondral bone. Lymphocytic infiltrates accompanied by immunoglobulin deposits were identified in rheumatoid subchondral bone near areas of cartilage undergoing destruction by local subchondral inflammation. CD45RO T lymphocytes also were identified with these infiltrates as well as with CD20 B lymphocytes in an area of subchondral bone containing a well-organized germinal center. Analysis of extracts of rheumatoid subchondral bone revealed a high incidence of autoantibodies directed against type II collagen, the major protein constituent of cartilaginous tissue. Analysis of IgG subclass and cyanogen bromide peptide specificity revealed a pathogenic subset of these autoantibodies. A passive transfer study utilizing similar antibodies from collagen arthritic animals confirmed that such autoantibodies would have the potential of contributing directly to disease activity observed in rheumatoid subchondral bone. These studies suggest that (i) subchondral bone may be playing an active role in RA as a local site of immune-mediated disease activity and (ii) basic and therapeutic studies aimed at understanding and eventually controlling RA should be diversified to include the study of not only synovial tissue, but also subchondral bone as a local source of the antigenic, cellular, and humoral immune components of joint destruction.