Anti-CD69 autoantibodies cross-react with low density lipoprotein receptor-related protein 2 in systemic autoimmune diseases

We investigated whether autoantibodies to CD69, one of the earliest markers of lymphocyte activation, exist in the sera of patients with systemic auto immune disease. Serum samples were obtained from patients with rheumatoid a rthritis (RA), systemic lupus erythematosus, and Behcet's disease, and were tested for the presence of anti-CD69 autoantibodies by ELISA and Western b lotting using rCD69 fusion proteins. IgG-type autoantibodies to CD69 were d etected in the sera of 38.3% of the PA patients, 14.5% of the systemic lupu s erythematosus patients, and 4.0% of the patients with Behcet's disease. A mong those with RA, the anti-CD69 autoantibody-positive patients had a high er serum level of rheumatoid factors and a more accelerated erythrocyte sed imentation rate than the anti-CD69 autoantibody-negative patients. Further, the predominant epitope on the CD69 molecule to which most of the anti-CD6 9 autoantibody-positive serum samples exclusively reacted, was mapped at th e C terminus of CD69. Of interest, this epitope is homologous to a stretch of amino acids in the protein sequence of low-density lipoprotein receptor- related protein 2 (LRP2), which is a receptor for multiple ligands includin g beta -very low density lipoprotein and is also an autoantigen responsible for Heymann nephritis in rats. The anti-CD69 autoantibody cross-reacted to LRP2 through the homologous amino acid sequence. To our knowledge, this is the first evidence of the existence of anti-CD69 autoantibodies. This auto antibody may modulate the function of CD69- and LRP2-expressing cells.