C3b-Independent Complement Activation in Ischemia/ReperfusionMesenteric Tissue Injury in Autoimmune Prone (B6.MRL/lpr) Mice

Complement plays a critical role in the development of tissue injury in systemic lupus erythematosus. The B6.MRL/lpr mouse, an autoimmune prone mouse, exhibits accelerated and intensified tissue injury in the ischemia/reperfusion (IR) model. It has been demonstrated in nonautoimmune mice that inhibition of complement attenuates inflammatory tissue injury in IR models. The role of complement is not as clear in the B6.MRL/lpr strain. B6.MRL/lpr-C3 deficient animals are susceptible to injury, but long-term use of C3 inhibitors in B6.MRL/lpr-C3 competent animals restrained the development of nephritis. To clarify the role of complement in the B6.MRL/lpr strain, initial and midpathway inhibitors were evaluated. C1 inhibition attenuated tissue injury, thrombin deposition, and C5a generation in the B6.MRL/lpr strain. Downstream of C1 inhibition of C3 activation by administration of cobra venom factor suppressed IR injury in immune competent mice, but was not as effective in B6.MRL/lpr mice. C3 levels in both strains were decreased after cobra venom factor treatment; however, C5a generation, thrombin deposition, and tissue injury were observed in the B6.MRL/lpr strain. These studies suggest that in the B6.MRL/lpr autoimmune prone strain C1 activation leads to C3-dependent and C3-independent pathways of complement activation.