Autoantibodies to T cell costimulatory molecules in systemic autoimmune diseases

To determine whether antilymphocyte Abs to T cell costimulatory molecules a re generated in patients with autoimmune diseases and, if they exist, to cl arify the mechanism of their production and pathological roles, we investig ated the presence of autoantibodies to CTLA-4 (CD152), CD28, B7-1 (CD80), a nd B7-2 (CD86) in serum samples obtained from patients with various autoimm une diseases and from normal subjects using recombinant fusion proteins. In ELISAs, anti-CD28, anti-B7-1, and anti-B7-2 Abs were rarely seen, whereas anti-CTLA-4 Abs were detected in 8.2% of the patients with systemic lupus e rythematosus, 18.8% of those with rheumatoid arthritis, 3.1% of those with systemic sclerosis, 31.8% of those with Behcet's disease, 13.3% of those wi th Sjogren's syndrome, and 0% of healthy donors. This reactivity was confir med by immunoblotting, More importantly, the purified anti-CTLA-4 Abs react ed with CTLA-4 expressed on P815 cells by how cytometry. In addition, rye f ound at least three epitopes on the CTLA-4 molecule. Furthermore, among the patients with Behcet's disease, uveitis was seen significantly less freque ntly in the anti-CTLA-4 Ab-positive patients. Taken collectively, these dat a indicate that anti-CTLA-4 autoantibodies are generated in systemic autoim mune diseases by an Ag-driven mechanism and may modulate the immune respons e in vivo by binding to CTLA-4 on T cells.