: CD40, a member of the tumor necrosis factor receptor (TNFR) superfamily, is expressed on the surface of B-cells, activated macrophages, epithelial cells, dendritic cells and a variety of tumor cells. CD40 is activated as a trimer after interaction with its partner, the CD40 ligand (CD40L), which is expressed on the surface of activated CD4+ helper T-cells. Mutations in the CD40L gene are responsible for X-linked hyper-IgM syndrome, a severe inherited human immunodeficiency disease. CD40-CD40L interaction plays an essential role in most of the events of the T-cell-dependent humoral response, including immunoglobulin heavy-chain class switching, antibody affinity maturation, generation and maintenance of memory B-cells, and T-cell activation. However, the molecular mechanisms of CD40 that are involved in these fundamental events in the basic immune response remain to be elucidated. In addition, antibodies specifically blocking the CD40L-CD40 interaction in mouse models can prevent organ rejection after transplantation and can be used to prevent autoimmune diseases such as rheumatoid arthritis, lupus nephritis and encephalomyelitis, as well as to reduce the risk of atherosclerosis. However, these blocking antibodies would also inhibit physiological functions of CD40 in normal immune responses. Our long-term goal is to use CD40 signaling pathways as molecular tools to dissect individual events in the T-cell-dependent humoral response, and to find a way to specifically inhibit CD40-associated diseases without affecting normal immune responses. In this proposal, we will take a genome-wide approach to systematically search for CD40-regulated genes using newly developed DNA microarray technology. We will: 1) investigate signaling and functional specificities between CD40L, LPS and TNF-a; 2) elucidate the molecular mechanisms by which multiple signal transduction pathways control a single CD40-mediated biological event; 3) identify NF-kB subunit specific genes responsible for CD40-mediated cell proliferation and isotype switching.
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