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

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.

Fig. 1

Functional domains of factor H and main regions in which mutations, polymorphisms or autoantibodies are associated with disease. Factor H is composed of 20 CCP units. Solid lines indicate the regions of factor H that exhibit critical functions such as controlling complement activation, binding to C3b, recognizing host cells, or that have disease-linked polymorphisms (ARMD), mutations (aHUS), or that are recognized by autoantibodies (aHUS) associated with disease. Dotted lines indicate regions where reported binding sites or functions remain uncertain.

Fig. 2

Model illustrating host cell-specific tetramer assembly. Human cells and tissues possess surface-bound polyanionic structures (red structure) including heparan, other glycosaminoglycans and sialic acids many of which are known to interact with factor H (blue). The interactions may induce self assembly (left panel) at the C-terminus region of factor H and result in a higher density of factor H on the surface of host cells that inactivates C3b (yellow structure), through the N-terminal region of factor H. Microbes and other particles generally lack such polyanions (right panel) and these surfaces would not tetramerize factor H resulting in reduced control of the alternative pathway of complement. As a result, alternative pathway activation and C3b amplification would be expected to occur with minimal control on microbes (right panel) while amplification would be inhibited on the host (left panel). The multimeric interactions between the C-terminal region of factor H and C3b/C3d, which may also facilitate dimer/tetramer assembly, are not shown in this model.

Fig. 3

Interaction of factor H with multiple pathogens. The proteins involved in binding are indicated in parentheses. Pathogens that bind factor H but where the interacting domain is unknown are indicated with question marks. Superscripts in bold refer to cited works as follows: Bacteria: 1 (Ben and Klimpel, 2008), 2 (Kim et al., 2009), 3 (Wallich et al., 2005; Rossmann et al., 2007; Kraiczy et al., 2006; Kraiczy et al., 2004; Kraiczy et al., 2001b; Kraiczy et al., 2001a; Hovis et al., 2004; Hartmann et al., 2006; Kraiczy et al., 2003; McDowell et al., 2003), 4 (McDowell et al., 2009; McDowell et al., 2007; McDowell et al., 2005), 5 (Blackmore et al., 1998a; Horstmann et al., 1988; Kotarsky et al., 1998; Sharma and Pangburn, 1997), 6 (Ngampasutadol et al., 2008; Ram et al., 1998a; Shaughnessy et al., 2009), 7 (Shaughnessy et al., 2009; Schneider et al., 2009; Schneider et al., 2006; Madico et al., 2007), 8 (Kunert et al., 2007), 9 (Biedzka-Sarek et al., 2008b; Biedzka-Sarek et al., 2008a; China et al., 1993), 10 (Hallstrom et al., 2008), 11 (Friberg et al., 2008), 12 (Dave et al., 2001; Dave et al., 2004; Duthy et al., 2002; Hammerschmidt et al., 2007; Janulczyk et al., 2000; Neeleman et al., 1999), 13 (Areschoug et al., 2002; Jarva et al., 2004), 14 (Meri et al., 2005; Stevenson et al., 2007; Verma et al., 2006), and 15 (Haupt et al., 2008); Fungi: 16 (Vogl et al., 2008; Behnsen et al., 2008) and 17 (Luo et al., 2009; Meri et al., 2002a; Poltermann et al., 2007); Parasites: 18 (Diaz et al., 1997), 19 (Joiner et al., 1986), 20 (Haapasalo et al., 2009) and 21 (Meri et al., 2002b); Viruses: 22 (Chung et al., 2006) and 23 (Pinter et al., 1995b; Pinter et al., 1995a; Stoiber et al., 1995b; Stoiber et al., 1995a).

Fig. 4

Summary of factor H recognition functions and interactions. Briefly, factor H is essential for fluid phase alternative pathway complement control, as well as for protection of host cells. Normal recognition of cell surfaces is required for effective protection. Thus, mutations and polymorphisms in factor H can result in inadequate protection and disease. Unwanted protection from factor H can result from efficient binding to certain pathogens and cancer cells. Interaction of factor H with other molecules is also shown. Abbreviations: AP, alternative pathway; fH, factor H; MPGN II/DDD, dense deposit disease; ARMD, age-related macular degeneration; aHUS, atypical hemolytic uremic syndrome.