Aberrant expression of class II (Ia) major histocompatibility complex molecules on many different tissues (synovium, vascular endothelium, proximal tubules, thyroid, islets, brain) is a prominent feature of many """"""""autoimmune"""""""" diseases, although it is not known whether aberrant class II expression is the inciting event or a secondary phenomenon which potentiates the autoimmune destruction process. This proposal is aimed at acquiring a basic understanding of one of the proteins which may be responsible for class II induction in autoimmune connective tissue disease (CTD). We have identified a nuclear factor, NF-IFN-gamma, in nuclear extracts prepared from a macrophage cell line and from normal spleen cells which is inducible upon interferon-gamma (IFN-gamma) treatment. Upon induction, this factor binds to a sequence which is contained within a 30 base pair oligonucleotide located 130 bp upstream of the coding sequence of the mouse E-beta class II gene. We will concentrate our early efforts on the structural characterization of NF-IFN-gamma and its target sequence by obtaining a cDNA clone encoding this protein from a lambda gtll expression library and by preparing antibodies to it. We will use these reagents to examine the function of NF-IFN-gamma. In particular, we will ask whether this nuclear protein plays a significant role in the well-documented induction of class II expression on non-lymphoid tissues in autoimmune disease using lupus nephritis of the MRL/1pr mouse as a model system. Finally, agents will be designed based on our structural analysis of activity in a sequence-specific manner. It is the eventual goal of these studies to selectively manipulate NF-IFN-gamma activity in order to prevent aberrant class II expression and disease progression in autoimmune CTD.
