Separation of Self From Non-Self in the Complement System: A Role for Membrane Cofactor Protein and Decay Accelerating Factor

2010

Molecular Immunology

366

357

The complement system is an essential component of the innate immune system that participates in elimination of pathogens and altered host cells and comprises an essential link between the innate and adaptive immune system. Soluble and membrane-bound complement regulators protect cells and tissues from unintended complement-mediated injury. Complement factor H is a soluble complement regulator essential for controlling the alternative pathway in blood and on cell surfaces. Normal recognition of self cell markers (i.e. polyanions) and C3b/C3d fragments is necessary for factor H function. Inadequate recognition of host cell surfaces by factor H due to mutations and polymorphisms have been associated with complement-mediated tissue damage and disease. On the other hand, unwanted recognition of pathogens and altered self cells (i.e. cancer) by factor H is used as an immune evasion strategy. This review will focus on the current knowledge related to these versatile recognition properties of factor H.

Section: Introductionmentioning

confidence: 99%

Complement control protein factor H: The good, the bad, and the inadequate

Ferreira

Pangburn

2010

Molecular Immunology

366

357

“…Tissue bound C3b can then catalyze further complement activation through the CAP, unless the reaction is effectively controlled by complement regulatory proteins (CRPs). Tickover permits the rapid elimination of pathogens that do not bear CRPs, and expression of CRPs can be regarded as a recognition mechanism by which the CAP distinguishes healthy host cells from injured cells and invasive pathogens (3). However, continual initiation of the CAP renders host cells critically dependent upon control of CAP activation by CRPs to prevent spontaneous complement mediated injury.…”

Section: Introductionmentioning

confidence: 99%

Binding of factor H to tubular epithelial cells limits interstitial complement activation in ischemic injury

Renner

Ferreira

et al. 2011

Kidney International

Factor H is a regulator of the alternative pathway of complement. Genetic studies have revealed that patients with factor H mutations are at increased risk for several types of renal disease. Pathogenic activation of the alternative pathway in acquired diseases, such as ischemic acute kidney injury, also suggests that non-mutated factor H also has a limited ability to control the alternative pathway in the kidney. In the current study we examined the ability of circulating factor H to control alternative pathway activation on renal tubular epithelial cells. We found that an absolute deficiency of factor H prevented complement activation on the cells after ischemia/reperfusion, likely because of consumption of alternative pathway proteins in the fluid phase. In contrast, when the fluid phase regulation by factor H was retained but the interaction of factor H with cell surfaces was blocked, complement activation after renal ischemia/reperfusion increased. Finally, a recombinant form of factor H that is specifically targeted to sites of C3 deposition was found to reduce complement activation in the tubulointerstitium after I/R. These studies demonstrate that native factor H provides critical regulation of the alternative pathway in the renal tubulointerstitium after injury, but that this protection is incomplete. An inhibitor that targeted recombinant factor H to the tissue surface prevented alternative pathway activation and attenuated renal injury after I/R.

“…Most host cells and tissues are protected by a family of membrane-bound and soluble proteins structurally related to the soluble protein factor H (reviewed in (1–3)). Activation of this arm of the human innate immune system occurs spontaneously (4, 5) on surfaces lacking these protective proteins and this process proceeds without reliance on target-specific recognition by the adaptive immune system.…”

Section: Introductionmentioning

confidence: 99%

Polyanion-Induced Self-Association of Complement Factor H

Pangburn

Rawal

The Journal of Immunology

et al. 2009

Factor H is the primary soluble regulator of activation of the alternative pathway of complement. It prevents activation of complement on host cells and tissues upon association with C3b and surface polyanions such as sialic acids, heparin, and other glycosaminoglycans. Here we show that interaction with polyanions causes self-association forming tetramers of the 155,000 Da glycosylated protein. Monomeric human factor H is an extended flexible protein that exhibits an apparent size of 330,000 Da, relative to globular standards, during gel filtration chromatography in the absence of polyanions. In the presence of dextran sulfate (5000 Da) or heparin an intermediate species of apparent m.w. 700,000 and a limit species of m.w. 1,400,000 were observed by gel filtration. Sedimentation equilibrium analysis by analytical ultracentrifugation indicated a monomer Mr of 163,000 in the absence of polyanions and a Mr of 607,000, corresponding to a tetramer, in the presence of less than a 2-fold molar excess of dextran sulfate. Increasing concentrations of dextran sulfate increased binding of factor H to zymosan-C3b 4.5-fold. This result was accompanied by an increase in both the decay accelerating and cofactor activity of factor H on these cells. An expressed fragment encompassing the C-terminal polyanion binding site (complement control protein domains 18–20) also exhibited polyanion-induced self-association, suggesting that the C-terminal ends of factor H mediate self-association. The results suggest that recognition of polyanionic markers on host cells and tissues by factor H, and the resulting regulation of complement activation, may involve formation of dimers and tetramers of factor H.