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Protection of the classical and alternative complement pathway C3 convertases, stabilized by nephritic factors, from
Insights
Nephritic factors (C4Nef and C3Nef) stabilize complement C3 convertases, bypassing regulatory proteins. This stabilization may impact immune complex processing in patients with nephritic factors.
Area of Science:
- Immunology
- Complement System Biology
Background:
- The classical (C4b,2a) and alternative (C3b,Bb) complement pathways are tightly regulated.
- Key regulators include intrinsic enzyme lability, decay factors (C4bp, H), cleavage enzyme (I), and complement receptor 1 (CR1).
Purpose of the Study:
- To investigate how nephritic factors (C4Nef, C3Nef) affect the regulation of complement C3 convertases.
- To determine if C4Nef and C3Nef can bypass normal regulatory mechanisms, including CR1 inhibition.
Main Methods:
- Studied the binding of C4Nef to classical C3 convertase (C4b,2a) and C3Nef to alternative C3 convertase (C3b,Bb).
- Assessed the ability of CR1 to decay stabilized convertases compared to unstabilized ones.
- Evaluated CR1's effect on cell lysis mediated by C4b,2a(C4Nef).
Main Results:
- C4Nef binding stabilized C4b,2a against CR1-mediated decay significantly more than unstabilized convertases.
- CR1 inhibited lysis of C4b,2a(C4Nef)-bearing cells by targeting C5 interaction.
- C3Nef stabilized C3b,Bb, offering protection against CR1-mediated decay.
Conclusions:
- C4Nef and C3Nef effectively bypass multiple regulatory mechanisms of complement C3 convertases.
- Stabilization of convertases by nephritic factors may alter immune complex processing in vivo, particularly in patients with these factors.
Abstract:
Formation and function of the classical (C4b,2a) and alternative (C3b,Bb) complement pathway C3 convertases are regulated by the intrinsic lability of the enzymes, extrinsic decay by C4bp and H, cleavage of C4b and C3b by I, and by the inhibitory action of the C3b receptor molecule (CR1). Binding of C4 nephritic factor (C4Nef) to C4b and of C3 nephritic factor (C3Nef) to C3b stabilizes the C3 convertases and bypasses inactivation by C4bp, H and/or I. In the present study, binding of C4Nef to the classical C3 convertase was found to prevent decay of C4b,2a by inputs of CR1 that were at least 15 times the amount of CR1 which inactivated 50% unstabilized classical pathway C3 convertase sites in 2.5 min. CR1 could however inhibit lysis of C4b,2a(C4Nef)-bearing cells in a dose-dependent manner. The latter inhibitory effect was directed at the interaction of C5 with the C5 convertase, most likely at C5 binding to cell-bound C3b. In an analogous manner to C4Nef in the classical pathway, stabilization of alternative pathway C3b,Bb convertase sites by C3Nef resulted in a relative protection of C3 convertase sites from decay by CR1. Thus, C4Nef and C3Nef can bypass all mechanisms susceptible to regulate function of the classical and alternative pathway C3 convertases. Because CR1 is essential for degradation of C3b bound to immune complexes in whole blood, stabilization of C4b,2a and C3b,Bb by C4Nef and C3Nef may alter in vivo processing of immune complexes in patients with nephritic factors.