Complement: Deficiency Diseases

Abstract

The complement system is crucial for defence against pathogens, removal of unwanted materials such as dying cells or immune complexes as well as for development of adaptive immune responses. Genetically determined deficiencies of components of the complement system are usually relatively rare, but they result in many severe diseases such as an increased susceptibility to recurrent, severe bacterial infections, autoimmune disorders (systemic lupus erythematosus), glomerulonephritis including dense deposit disease and C3 glomerulonephritis, paroxysmal nocturnal haemoglobinuria or angioedema. In addition, mutations and polymorphisms in complement proteins, particularly complement inhibitors, have been associated with atypical haemolytic uremic syndrome and age‐related macular degeneration. The elucidation of the pathophysiological basis for the different clinical presentations of complement‐deficient individuals has contributed to a better understanding of the physiological role of complement in normal individuals as well as to the development of emerging therapies.

Key Concepts

  • The majority of complement deficiencies are rare but cause severe diseases.
  • Deficiencies of the components of the classical pathway (C1q/r/s, C4 and C2) predispose to bacterial infections and systemic lupus erythematosus.
  • The majority of complement deficiencies predispose to infections either with Neisseria species (deficiency of factor D, factor B, properdin, C5, C6, C7, C8 and C9) or with other encapsulated bacteria (C1q/r/s, mannose‐binding lectin, C2, C4, C3 and factor I).
  • Mutations in C1q/r/s, C2, C4, C3, factor I and factor H can cause glomerulonephritis.
  • Paroxysmal nocturnal haemoglobinuria is caused by deficiency of complement inhibitors CD55 and CD59.
  • Hereditary angioedema is found in patients with low C1‐inhibitor level or dysfunctional C1‐inhibitor.
  • Atypical haemolytic uremic syndrome is mainly associated with mutations and polymorphisms in complement inhibitors.
  • Age‐related macular degeneration is associated with polymorphisms in complement inhibitor factor H.

Keywords: age‐related macular degeneration; angioedema; bacterial infection; complement deficiency; haemolytic uremic syndrome; paroxysmal nocturnal haemoglobinuria; systemic lupus erythematosus

Figure 1. Schematic presentation of complement activation and diseases associated to complement deficiencies. Complement may be activated through the classical pathway (C1q, C1r, C1s, C4 and C2), the lectin pathway (MBL/ficolins, C4 and C2) and the alternative pathway (C3b, FB, FD and properdin (P)), which result in the formation of the C3 convertase C4b2a for the classical and the lectin pathway and C3bBb(P) for the alternative pathway. The activation may then proceed through the terminal pathway (C5, C6, C7, C8 and C9) generating the membrane attack complex (C5b–C9). The activation is governed by regulator molecules of which some are in fluid phase (C1inhibitor, C4BP, FH and FI) and some are membrane bound (DAF, CR1, MCP and CD59). Major associations to disease in cases with deficiencies of the various molecules involved in activation and regulation are given within boxes adjacent to the reaction steps. aHUS, atypical haemolytic uremic syndrome; HAE, hereditary angioedema; SLE, systemic lupus erythematosus and PNH, paroxysmal nocturnal haemoglobinuria.
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Skattum, Lillemor, and Truedsson, Lennart(Nov 2015) Complement: Deficiency Diseases. In: eLS. John Wiley & Sons Ltd, Chichester. http://www.els.net [doi: 10.1002/9780470015902.a0002154.pub3]