An immune response (?autoimmune) may trigger the synovitis of rheumatoid arthritis (RA). In several experimental systems helper T cells are sensitized when antigens are presented on accessory dendritic cells (DC), sizable numbers of which are present in synovial exudates. To characterize T cells that could contribute to the immune response in RA, we will clone T cells from the joints and determine if they exhibit the DR4 restriction that is characteristic of the disease. To enrich for such lymphocytes, that is to separate disease-specific from nonspecific T cells, we will take advantage of the observation that DC aggregate the CD4 cells that they stimulate, and that DC-T cell clusters are prominent in cultures of RA synovial mononuclear cells. We will look for disease-associated antigens in joint fluid and lining, plasma, and on DC. The effector limb of RA synovitis is likely to be influenced by such monocyte products as interleukin-1, tumor necrosis factor, arachidonic acid metabolites, and reactive oxygen intermediates. Assays for these products are ongoing in this program. The assays will be used to compare the secretory products of synovial monocytes and DC, and to determine if function is constitutive in RA or requires defined inducing stimuli. As stimuli, we will test lipopolysaccharide, immune complexes, and clusters of interacting DC and T lymphocytes. Recent evidence indicates that macrophages and DC may harbour human immunodeficiency virus (HIV). Techniques will be developed to enrich these cells from normal skin and lymph node, and to follow the movement and differentiation of human epidermal Langerhans cells (LC) in organ culture. We will then evaluate if a) DC and LC function are altered in AIDS and b) if DC and LC from AIDS patients harbor HIV. To test if a productive HIV infection can be activated during the APC-helper T cell interaction, or if infected APC fuse with CD4 cells, we will coculture AIDS APC and normal T cells and isolate clusters of APC and blast transformed CD4 lymphocytes. We will also assess if normal macrophages, DC and LC can be infected with exogenous HIV. Given the capacity of DC to interact and stimulate unprimed CD4 cells, DC infection and malfunction could be significant in the pathogenesis of AIDS.
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