? Rheumatoid arthritis (IRA) is a chronic, inflammatory disorder affecting nearly 1% of the adult population. Despite effective therapies, it causes enormous physical disability and financial cost. Although autoimmune T and B lymphocytes are clearly part of the pathogenesis of RA, the innate immune system has become a focus of intense interest, in part due to the success of treatments that target cytokine products of Synovial macrophages and fibroblasts. Such therapies are not effective in all patients, however. Apoptosis Inhibitor expressed in Macrophages (AIM), a member of the Scavenger Receptor Cysteine Rich superfamily, has recently been shown to be a potent inducer of inflammatory cytokines in mouse macrophages and dendritic cells, in addition to its ability to block apoptosis in monocytic and lymphocytic cells.
Human AIM i s about 80% identical to mouse AIM, yet has distinct structural features. The objective of this exploratory/developmental project is to determine whether human AIM is also a potent stimulator of human cells, and can inhibit their apoptosis.
Two specific aims will be investigated: 1. Determine the expression of human AIM protein by monocytic cells derived from tissue and peripheral blood 2. Determine the ability of human AIM to induce cytokine and inflammatory mediator release from human cells, and to inhibit apoptosis AIM will be quantified in serum from patients and controls, as well as in synovial fluid.
AIM -expressing cells in RA synovial tissue will be characterized. Recombinant human AIM will be tested for its ability to stimulate moncytic cells from blood and synovial tissue to release inflammatory mediators, and to block apoptosis caused by Fas ligation or growth factor withdrawal. If successful, these studies will identify AIM as a novel target for therapies in autoimmune and inflammatory disease. ? ?
