Complement Regulatory Proteins and Related Diseases

Abstract

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.