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Coinhibitory Molecules in Autoimmune Diseases

DOI: 10.1155/2012/269756

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Coinhibitory molecules such as CTLA-4, PD-1 and BTLA negatively regulate immune responses. Multiple studies indicate that the deficiency or mutation of coinhibitory molecules leads to the development of autoimmune diseases in mice and humans, indicating that the negative signals from coinhibitory molecules are crucial for the prevention of autoimmunity. In some conditions, the administration of decoy coinhibitory receptors (e.g., CTLA-4?Ig) or mAb against coinhibitory molecules suppresses the responses of self-reactive T cells in autoimmune diseases. Therefore, modulation of coinhibitory signals seems to be an attractive approach to induce tolerance in autoimmune diseases in humans where the disease-inducing self-antigens are not known. Particularly, administration of CTLA-4?Ig has shown great promise in animal models of autoimmune diseases and has been gaining increasing attention in clinical investigation in several autoimmune diseases in humans. 1. Introduction The immune system has developed multiple mechanisms to prevent harmful activation of immune cells. One such mechanism is the balance between costimulatory and coinhibitory signals delivered to T cells. The B7-1 (CD80)/B7-2 (CD86)-CTLA-4 pathway is the best-characterized inhibitory pathway for T-cell activation [1–3]. Another inhibitory pathway involves programmed death-1 (PD-1), which interacts with PD-L1 (B7-H1) and PD-L2 (B7-DC) and negatively regulates T cell activation [1, 3, 4]. B and T lymphocyte attenuator (BTLA), the third coinhibitory molecule for T-cell activation, is a cell surface molecule with similarities to CTLA-4 and PD-1 [5]. The ligand for BTLA is herpesvirus-entry mediator (HVEM), a TNF receptor family protein, and the ligation of BTLA with HVEM attenuates T-cell activation [6–9]. Since these inhibitory coreceptors inhibit proliferation and cytokine production of T cells in vitro and in vivo, they are thought to play important roles in maintaining immunological homeostasis and tolerance [10–12]. Autoimmune diseases occur because of a failure of the immune system to maintain nonresponsiveness or tolerance to self-antigens. Accumulating evidence indicates that coinhibitory molecules are key in the prevention of autoimmune diseases, because a defect or a functional mutation in these molecules promotes autoimmunity and polymorphisms of these genes are associated with genetic susceptibility to autoimmune diseases in humans. Once an autoimmune disease developed, whether it is organ specific or nonorgan specific, in most cases corticosteroids and/or immunosuppressants are used for

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