The membrane attack complex of complement (MAC or MC5b-9) destroys cells by forming channels through cell membranes. Using a monoclonal antibody to a neoantigen of C9 on MC5b-9 as well as immunohistochemical techniques, the MAC has been demonstrated in kidney tissue from human patients with glomerulonephritic and non-nephritic disease. In glomerulonephritis the MAC was present in immune deposits; in all varieties of progressive renal diseases it was deposited in the mesangium, along tubular basement membranes, and regions undergoing sclerosis. A role for the MAC in glomerulonephritis and in progressive renal disease irrespective of etiology is suggested.
The first aim of this research is to study the functional role of the terminal components C5-C9 in animal models of immune complex nephritis using either congenic strains of C5 deficient mice or an inhibitor of C5 activation.
A second aim i s to study the role of the MC5b-9 in progressive renal injury. Using immunohistochemical techniques a correlation will be made between MAC deposition and the development of sclerosis. The effects of deposition of preformed MAC in the mesangium of normal and diseased kidneys will be explored. The monoclonal antibody to a neoantigen of C9 also recognizes the noncytolytic fluid phase form of the attack complex (SC5b-9). In a radioimmunoassay, SC5b-9 levels in serum have been demonstrated to be an excellent marker of disease activity in systemic lupus nephritis (SLE).
The third aim i s to investigate the relationship of SC5b-9 to renal disease. SC5b-9 levels will be measured in human patients with active glomerulonephritis and correlated with therapy in SLE nephritis. Since SC5b-9 has been found in serum, the question of whether C5b-9 in kidney is formed by local activation of MC5b-9 or deposition of SC5b-9 after systemic activation will be investigated.
The final aim of this proposal is to explore in tissue culture the effect of C5b-9 on glomerular mesangial cells and fibroblast proliferation and collagen production. These functional, immunohistochemical, radioimmunoassay, and tissue culture studies will elucidate the role of the membrane attack complex in the pathogenesis of glomerulonephritis and other renal disease.
| Dalmasso, A P; Falk, R J; Raij, L (1989) The pathobiology of the terminal complement complexes. Complement Inflamm 6:36-48 |
| Falk, R J; Jennette, J C (1988) Anti-neutrophil cytoplasmic autoantibodies with specificity for myeloperoxidase in patients with systemic vasculitis and idiopathic necrotizing and crescentic glomerulonephritis. N Engl J Med 318:1651-7 |
| Jennette, J C; Tidwell, R R; Geratz, J D et al. (1987) Amelioration of immune complex-mediated glomerulonephritis by synthetic protease inhibitors. Am J Pathol 127:499-506 |
