Evidence is sought supporting the concept that the glomerular deposits which are basic to the pathogenesis of membranoproliferative glomerulonephritis type III (MPGN III) are composed of the amplification C3-C5 convertase, C3b, Bb, or a derivative of this convertase. It is hypothesized that while this convertase may be present in the glomeruli in other glomerulonephritides of immune origin, it is virtually the sole constituent of the deposits in MPGN III. Evidence for this concept derives first, from studies of seven patients with Marder's syndrome. In this syndrome, a gene is producing an abnormal C3 which, as C3b, has a low affinity binding site for factor H. Amplification C3-C5 convertase containing this variant C3b is abnormally stable. The syndrome is associated in two patients with MPGN III and two others have glomerular deposits characteristic of """"""""pre"""""""" MPGN III. Their deposits contain only the proteins which would be associated with the amplification C3-C5 convertase; there is no evidence for immune complexes. Secondly, others have demonstrated C3 covertase immunohistologically in frozen sections of glomeruli in MPGN. Thirdly, we have found glomeruli in glomerulonephritis to contain the B antigenic determinant of C3, a determinant found on C3b deposited by its labile binding site but not on other C3 fragments. Further, glomerular deposits in MPGN III out Marder's syndrome have a composition compatible with C3-C5 convertase, a complement profile which gives no evidence of a classical pathway activation and, inthe four so far tested, we have evidence for a circulating slowly reacting, stable C3 convertase different from the at in Marder's syndrome. Thus, both in the presence and absence of Marder's syndrome, MPGN III can be produced by glomerular deposits containing only the proteins of C3-C5 amplification convertase and present evidence indicates a relatively stable convertase is circulating.
The aims of the present proposal are (1) to investigate in detail the nature of the stable convertase we have found in the serum of patients with MPGN III, (2) to gain further evidence by immunohistoloic and autoradiographic techniques for functional glomerular convertase or for a surface with the characteristics of an alternative pathway activator in the glomeruli in MPGN III, (3) to determine whether the B antigenic determinant of C3 is present in the glomeruli on native C3 or on convalently bound C3b and (4) to measure in patient's serum, complexes containing properdin and C3 which would be the product of fluid phase C3 activation.
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| Clardy, C W; Forristal, J; Strife, C F et al. (1989) Serum terminal complement component levels in hypocomplementemic glomerulonephritides. Clin Immunol Immunopathol 50:307-20 |
