The long-term aims of this proposal are to i) define the molecular mechanisms underlying the aberrant expression of the cytokine interleukin 1(IL-1) observed in macrophages derived from prediseased mice from several of the major murine models of autoimmunity; and ii) to determine the role such IL-1 underexpression (and the molecular abnormalities underlying it) plays in the overall function of the autoimmune macrophage. It is hypothesized that the basis for this abnormality may be a protein mutation within a signal transduction pathway shared by the cytokines interleukin 4 and insulin-like growth factor 1. It is further suggested that this mutation provides a predisposing genetic background upon which other as yet unidentified factors (both genetic and environmental) may act to initiate autoimmunity. Based upon the fact that differences in IL-1 expression can be abrogated by the use of a protein synthesis inhibitor, it appears that a major contribution to the defect occurs through the differential induction of protein factor(s) between normal and autoimmune- prone mice. We will use differential display of messenger RNA (a recently described and more efficient means of separating and cloning differentially expressed messenger RNA) to identify the specific gene(s) whose differential expression contributes to the underexpression of IL-1 as well as other abnormalities noted in autoimmune macrophages. In addition, we will characterize fully the range of macrophage abnormalities attributable to abnormal signal transduction occurring as a result of this protein mutation. Because the basic events leading to the development of autoimmunity can best be determined by studying antoimmune-prone mice before the onset of overt disease, all lupus-prone mice in these studies will be used well before the development of autoimmune signs. The existence of an abnormality in macrophages from prediseased autoimmune- prone mice may have implications for antigen presentation by these macrophages and hence the maintenance of self-tolerance. Thus, a second specific aim of this proposal is to determine the effects of this abnormality on the presentation of antigen by macrophages from prediseased autoimmune-prone mice. A very simple experimental system will be used, in which the processing and presentation of specific antigens by macrophages are assessed via the response of helper T lymphocyte clones specific for the antigen. Current therapies for SLE are limited in that they oppose the effector pathways of established disease. Understanding of the fundamental abnormalities predisposing to autoimmunity should lead to more effective therapies that present and/or interrupt the development and maintenance of autoimmunity.
Showing the most recent 10 out of 12 publications
