GLOMERULAR IMMUNE DEPOSIT FORMATION IN SLE

Systemic Lupus Erythematosus (SLE) nephritis is considered to be the
prototype of human disease mediated by pathogenic immune complexes.
However, neither the participating immune reactants nor the mechanisms of
glomerular immune deposit formation (GIDF) in this disorder are completely
understood. The reasons why certain individuals get severe nephritis and
others with elevated circulating autoantibody and immune complex levels do
not is enigmatic. Furthermore, the long-term effect of various treatment
regiment in such patients is of debatable benefit. The overall objective
of the proposed research is to develop an understanding of the events
leading to GIDF and subsequent injury in SLE. Ultimately through this
understanding, a rational approach to alter these events can be planned.
The specific aims of this proposal are to identify and characterize the
immune reactants involved in SLE nephritis and determine the mechanism(s)
of GIDF in SLE. These studies will utilize MRL-lpr/lpr mice, an autoimmune
strain that develops an accelerated form of SLE associated with severe
glomerulonephritis and the production of anti-DNA antibodies, and an
existing library of immune reagents derived from these animals, including
monoclonal anti-DNA antibodies, anti-immunoglobulins and anti-idiotypic
antibodies. The characterization of nephritogenic antibodies in murine SLE
will involve a detailed analysis of the immunoglobulins eluted from
MRL-lpr/lpr kidneys including definition of their ligand binding
properties, charge, subclass, idiotypic repertoire, as well as
anti-idiotypic and anti-immunoglobulin activity. The mechanism(s) of GIDF
will be analyzed using nucleic acid antigens and autoantibodies, including
immunoglobulins eluted from nephritic kidneys and monoclonal antibodies
that share idiotypes with these eluted immunoglobulins. The capacity of
each of these immune reagents to localize within the glomerulus and then
initiate IDF will be studied in vitro by direct binding studies of
radiolabeled reagent to isolated normal glomeruli, and in vivo by
measurement of glomerular binding after passive administration of
radiolabeled immune reactants to normal mice. The precise localization of
these reagents will be further detailed by autoradiography,
immunofluorescence and electron microscopy.