Expression and function of inducible co-stimulator in patients with systemic lupus erythematosus: possible involvement in excessive interferon-γ and anti-double-stranded DNA antibody production

Systemic lupus erythematosus (SLE), a prototype autoimmune disease, is characterized by activation of lymphocytes and the presence of various types of autoantibodies in peripheral blood. These autoantibodies are considered to form immune complexes with their corresponding autoantigens and to mediate tissue and organ damage [1]. Recent investigations suggest that collaboration between autoantibody-producing B cells and antigen-specific T-helper (Th) cells is important to the production of these pathogenic autoantibodies [2].The fate of T cells, after they encounter specific antigens, is modulated by co-stimulatory signals, which are required for both lymphocyte activation and the development of adaptive immunity (for review [3-6]). In general, activation of T cells requires two signals: one from a T cell receptor and the other from co-stimulatory molecules such as CD28 and tumour necrosis factor family members [3,7]. The inducible co-stimulator (ICOS; also known as AILIM [activation-inducible lymphocyte immunomediatory molecule]) was identified in 1999 as a membrane glycoprotein that is expressed on the surface of activated T cells and that shares several structural and functional similarities with CD28 [8-10]. Like CD28, ICOS has potent co-stimulatory effects on proliferation of T cells and production of cytokines [8-12]. ICOS is also important for germinal centre formation, clonal expansion of T cells, antibody production, and class switching in response to various antigens [13,14]. CD28 and cytotoxic T lymphocyte associated antigen 4 use the MYPPPY motif in their extracellular domains to bind to their ligands, namely B7.1 and B7.2. ICOS does not possess this motif, and so B7.1 and B7.2 are not among its ligands [9]. Subsequently, it was shown that a B7-like molecule, termed B7-related protein-1 (B7RP-1) (also referred to as B7-H2, GL50 and LICOS), binds to ICOS [9,15-21]. B7RP-1 shares 20% identity with B7.1/B7.2 [9] and is constitutively expressed on B cells and