Elsevier

Molecular Immunology

Volume 47, Issue 13, August 2010, Pages 2187-2197
Molecular Immunology

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

https://doi.org/10.1016/j.molimm.2010.05.007Get rights and content

Abstract

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.

Introduction

The complement system is the major non-cellular component of the innate immune system. It efficiently protects the host from pathogenic microorganisms, contributes to immune complex regulation, and represents an important link between the innate and specific immune system. Complement comprises a group of more than 30 proteins, which participate in a cascade-like activation process, serve as control proteins or act as cellular receptors. Activation of the central component C3 may occur through three different pathways: the classical, the lectin and the alternative pathway. Each of these pathways leads to direct killing, to marking of the target with ligands (C3b, iC3b, and C3d) for receptors of the cellular innate immune system (CD35, CD21, CR3, etc.) and to numerous cellular and humoral responses from systems of acquired immunity (Carroll, 1998, Fearon and Locksley, 1996, Fearon, 1997).

The alternative pathway represents a true safeguard system of the human host and, unlike the classical and lectin pathways that require specific recognition molecules for initiation (C1q or MBL/ficolins, respectively), the alternative pathway is triggered spontaneously and everywhere in an organism. The system is initiated in the fluid phase by the spontaneous hydrolysis of the thioester bond in C3 that allows the generation of a fluid phase initiating protease (C3(H2O)Bb) with the ability to digest C3, generating C3b fragments. These C3b fragments possess a labile thioester group, allowing it to bind covalently to any nearby membranes with exposed amino or hydroxyl groups. Bound C3b can now bind factor B, which is then cleaved by factor D, generating the membrane-bound C3 convertase. This convertase has the ability to greatly amplify the deposition of C3b on the surface of a cell (Muller-Eberhard and Gotze, 1972, Pangburn, 1998, Rother, 1998). Importantly, although deposition of C3b occurs on all cells exposed to activated complement (i.e. pathogenic microorganisms as well as our own host cells), it does not result in continued activation on all surfaces. To prevent unintended injury by our own activated complement, our organism uses a complex set of plasma proteins (factor H, factor I, C4bp, C1 inhibitor) and cell-bound regulators (DAF, CR1, CD59, MCP, and CRIg) (Atkinson et al., 1991, Kim and Song, 2006, Kirkitadze and Barlow, 2001, Liszewski et al., 1996, Morgan and Harris, 1999, Wiesmann et al., 2006) to restrict complement at critical stages of the cascade reaction. This review will focus on the versatile properties of soluble complement control protein factor H.

Section snippets

Recognition molecules used by the alternative pathway to identify host

The alternative pathway uses three recognition molecules to identify the host or targets: factor H, properdin, and C3b. Properdin, first identified in 1959 (Lepow et al., 1959) and known to be a stabilizer of the central enzyme in alternative pathway amplification (Muller-Eberhard, 1988), was recently proposed to be a pattern recognition molecule with the ability to initiate complement activation (Kemper et al., 2008, Kemper et al., 2009, Spitzer et al., 2007, Xu et al., 2008). The

Normal recognition of cells by factor H

The factor H gene is located in the regulators of complement activation (RCA) gene cluster on human chromosome 1(Rodriguez de et al., 1985, Vik et al., 1990). Ripoche et al. (1988) deduced the amino acid sequence from three overlapping cDNA clones. In addition to the 150-kD factor H protein, a second gene product, a 43-kD factor H-like molecule (FHL-1), has been identified in human plasma (Schwaeble et al., 1987). There are also a number of factor H-related (FHR) molecules, reviewed elsewhere (

Conclusions

Factor H is a versatile and essential molecule for control of the alternative pathway of complement. Fig. 4 summarizes the main points discussed in this review and emphasizes the extraordinary ability of factor H to recognize, bind to and protect cells undergoing physiological processes, cells and tissues undergoing complement-mediated damage, and even pathogenic cells that have learned to use this protection as an immune evasion strategy. Thus, further studies aimed at deciphering the fine

Disclosure

MKP is an officer of and has a financial interest in Complement Technology, Inc. (www.ComplementTech.com), a supplier of complement reagents.

Acknowledgments

The authors thank all the collaborators we have the privilege to work with, whose work was cited herein. The authors acknowledge the support from American Heart Association Grant 0735101N (V.P.F.), National Institutes of Health Grant 1P30HL101317-01 (V.P.F.), and National Institutes of Health Grant DK-35081 (M.K.P.).

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