IMMUNOREGULATORY MECHANISMS IN THE RHEUMATIC DISEASES

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The objective has been to characterized immunoregulatory abnormalities in patients with connective tissue diseases. Our studies originally focused on a subset of human blood lymphocytes with high density Fc receptors for IgG which we called "L cells." These lymphocytes are part of a larger population characterized by a unique morphological appearance and which react with monoclonal antibodies which recognize the Type III complement receptor (CR3). We plan to separate L cells and other CR3+ lymphocyte subsets, determine their relationship with T cells and determine their regulatory effects on B cell activity in patients with Systemic Lupus Erythematosus. We have recently observed that lymphocytes from patients with both active and inactive SLE have an impaired capacity to produce interleukin 2 in vitro. Moreover, these patients have spontaneously activated T8+ lymphocytes that inhibit IL-2 production. We plan to determine whether this is an inherited, primary immunologic defect in SLE or whether it is a secondary manifestation of the disease. This will be accomplished by a study of Twins with SLE. Our last objective is to determine the relationship of the IL-2 defect and B lymphocyte hyperactivity in SLE. This will be accomplished by determining the effects of interleukin 2 on lymphocytes which regulate the production of B cell growth factors and which have direct effects on B cell functions. We will determine whether CR3+ lymphocytes are involved in these regulatory circuits. These studies should lead to a better understanding of pathogenetic mechanisms in patients with the connective tissue diseases.