Complement Regulatory Proteins and Related Diseases

Abstract

Many regulatory proteins exist to prevent excessive complement activation and to protect our cells and tissues from inappropriate damage. The classical and lectin pathways are inhibited by C1 inhibitor (C1 INH) and C4b‐binding protein (C4bp). Deficiencies in C1 INH predispose to hereditary angiooedema (HAE). Factor H(FH) is the main inhibitor of the alternative pathway amplification cascade. Mutations and polymorphisms in FH predispose to meningococcal infections, dense deposit disease (also called membranoproliferative glomerulonephritis type II), partial lipodystrophy, atypical haemolytic uraemic syndrome (aHUS) and age‐related macular degeneration. aHUS can also be the consequence of mutations in factor I (C4b/C3b inactivator) or membrane cofactor protein (CD46). Two other membrane regulators, decay‐accelerating factor (CD55) and protectin (CD59), have glycosylphosphatidylinositol (GPI)‐anchors, whose acquired deficiency from bone marrow‐derived cells can lead to paroxysmal nocturnal haemoglobinuria (PNH). Cell damage and vascular thromboses are characteristic for PNH and aHUS.

Key Concepts:

  • Several complement inhibitors are needed because the complement system has a strong potential to cause inflammation and tissue damage.

  • The default of the complement system – in the absence of regulators – is to become activated and stay in a state of activation.

  • The alternative pathway factor H can discriminate between activators (nonhost) and nonactivators (host) to prevent attack against viable endogenous cells and structures.

  • Loss of complement inhibitor function usually predisposes to a spectrum of distinct diseases.

  • The diseases are characterised by ‘innate autoreactivity’, that is, attack against endogenous cells and tissues.

  • Anaemia, thrombocytopenia and endothelial cell damage are common features and lead, in severe cases, to thrombotic microangiopathy.

  • Inability to control complement activation may also lead to secondary complement deficiency and increased susceptibility to infections.

  • Complement regulators have cross‐inhibitory activity to kinin (C1INH) and coagulation (FH) systems. Loss of function thus predisposes, for example, to bradykinin formation (in HAE) and thrombosis (aHUS).

  • Initiation of complement dysregulation‐related diseases and disease attacks usually requires triggering factors (e.g. infection, trauma, medication and stress).

  • The emergence of therapeutic complement inhibitors and replacement therapy helps in controlling excessive disease‐related complement activation.

Keywords: C1 inhibitor; factor H; MCP; CD59; age‐related macular degeneration; atypical haemolytic uraemic syndrome; glomerulonephritis; hereditary angiooedema

Figure 1.

An overview of complement activation, regulation and diseases caused by deficiencies of complement regulator proteins. The C1r and C1s are serine esterases that are inhibited by the plasma protein C1 inhibitor (C1 INH). C1 INH also inhibits analogous MBL‐associated serine protease, MASP‐2. Activity of the classical pathway C3/C5 convertase, C4b2a, is inhibited by the plasma factor C4b‐binding protein (C4bp). The activity of the alternative pathway C3/C5 convertase, C3bBb, can be enhanced by the only known physiological positive complement regulator, properdin (P). The self‐amplifying process of the AP is inhibited by multiple regulator molecules described in Figure . The five terminal plasma glycoproteins (C5, C6, C7, C8 and C9) bind sequentially to each other to generate the cytolytic membrane attack complex (MAC). Soluble regulators S‐protein and clusterin keep forming terminal C complexes in the fluid phase. On human cell membranes the main inhibitor of MAC is CD59 (protectin). Consequences of major complement regulator deficiencies are indicated by broken arrows. aHUS, atypical haemolytic uraemic syndrome; AMD, age‐related macular degeneration; DDD, dense deposit disease; HAE, hereditary angiooedema and PNH, paroxysmal nocturnal haemoglobinuria.

Figure 2.

Structure of C‐terminal FH domains 19–20 in complex with two copies of C3d. CCP domains are composed of antiparallel beta strands. Both CCP domains carry binding sites for C3d. CCP domain 20 has also important recognition sites for polyanionic surfaces (not shown). The data (2XQW) were obtained from pdb protein databank and the image was produced by Jmol Version 12.2.15 (Kajander et al., ).

Figure 3.

Regulators of the classical (CP) and alternative (AP) pathways of complement. Membrane regulators include decay‐accelerating factor (DAF; CD55), complement receptor type 1 (CR1; CD35), complement receptor of the immunoglobulin superfamily (CRIg) and membrane cofactor protein (MCP; CD46). Soluble regulators include C1 inhibitor (C1 INH), C4b‐binding protein (C4bp) and FH (H).

Figure 4.

Inhibition of the MAC of complement by protectin (CD59). By binding to the C5b‐8 complex at the C8α chain (a) and C9 (b); CD59 inhibits C9 incorporation and polymerisation in the MAC.

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Meri, Seppo, and Jarva, Hanna(Jun 2013) Complement Regulatory Proteins and Related Diseases. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0001434.pub3]