Contrasting roles of complement activation and its regulation in membranous nephropathy.
The complement system is involved in defense against microorganisms, the processing of immune complexes and apoptotic debris, and the development of an appropriate immune response. Along with these physiologic effects, complement activation has the potential to result in tissue pathology. To limit this, various complement regulatory proteins (CRP) are present on host cells, including the glomerular podocyte. Experimental data from the Heymann nephritis (HN) rat model of human membranous nephropathy (MN) have shown that IgG antibodies in subepithelial immune deposits initiate complement activation and C5b-9-mediated damage of the overlying podocyte. Although IgG can activate the classical pathway, there also is evidence that alternative pathway activation occurs in MN, which could occur because of absent, dysfunctional, or inhibited podocyte CRP. Related to this are experimental data in HN showing the presence of antibodies that bind and inhibit podocyte CRP; although such antibodies have not been documented in human MN, a decrease in CR1 quantity on the podocyte has been observed. A s a result of a relative lack of CRP and the exposure of activating complement proteins to tubular cells, alternative complement pathway activation and C5b-9-mediated tubular injury can occur in MN and other proteinuric diseases. Overall, in a disease such as MN, the balance between complement regulation and activation is tipped toward its being activated. Therefore, a number of therapeutic approaches have been developed to counteract this, including recombinant forms of endogenous CRP and complement-inhibitory monoclonal antibodies. There is good reason to be optimistic that approaches to block complement activation will become viable therapy for human MN in the future.
Cunningham
Patrick N
PN
Section of Nephrology, The University of Chicago, AMB-S523, MC 5100, 5841 South Maryland Avenue, Chicago, IL 60637, USA.
Quigg
Richard J
RJ
D000818:Animals; D002097:C-Reactive Protein / Q000037:antagonists & inhibitors / Q000276:immunology; D003167:Complement Activation / Q000276:immunology*; D015433:Glomerulonephritis, Membranous / Q000276:immunology* / Q000473:pathology* / Q000628:therapy; D006801:Humans
D002097:C-Reactive Protein