The specific aims of this study is to elucidate the role of immune complexes, complement, immune cells, and genetic factors in patients with rheumatic and related diseases, particularly SLE. The frequency of histocompatibility antigens (HLA) and other genetic markers (complement allotypes, Gm, red cell C3b receptors) in patients, relatives, and normals will be determined in order to better define the genetic susceptibility of individuals to disease. This definition will be expanded and enhanced by determining associations between these genetic markers and the clinical features and immunological abnormalities in these patients. Genetic-disease associations will then be further characterized by defining, at the cellular level, how these genetic factors influence the induction of these immune abnormalities in vitro. Specifically, mononuclear cells from genetically defined individuals will be stimulated with DNA, Sm, RNP, Ro, La, and PWM and specific ANA (i.e., anti-DNA, Sm, RNP, Ro, and La) produced and quantitated by hemolytic plaque assays and enzyme-immunoassay (EIA) in the supernatant. The role of different cells in this system will be defined by removing monocytes and T-cell subsets and reconstituting with cells from autologous or genetically identical/similar (primarily at the Dr loci) patients, relatives, and normals. Using the technique developed for the in vitro production of anti-DNA, we plan to determine whether cells making these antibodies can be selectively killed utilizing complexes of DNA-poly-L-lysine-ricin. Successful elimination of these cells would lead to similar studies in lupus mice to reduce both anti-DNA antibody titer and immunopathology and would prompt similar studies in patients. These studies should improve our understanding of interrelationships among clinical, immunological, cellular, and genetic factors in patients with SLE to provide a better framework for management. Ablation of anti-DNA antibodies may provide a better treatment method in the short-term. In the distant future, correction of genetic abnormalities may be feasible--for now, we must define them.
