16th February 2024

Complement Disorders

The complement system is an essential part of innate immune response; it plays a vital part in the host’s response to harmful pathogens and altered cells. It comprises more than 30 plasma proteins and forms about 15% of the globular plasma fraction.

The hepatocytes mainly synthesise the complement proteins, but macrophages and monocytes also produce significant amounts. The complement circulates in the plasma in an inactive form.

Both deficiency and overstimulation of complement can be detrimental for the host and are linked to increased predisposition to infections or non-infectious diseases, including autoimmune disease, thrombotic microangiopathy, graft rejection, and cancers.

Complement system activation pathways

Summary

The complement system is activated during pathogen infections and in normal homeostasis. When the system is triggered, a cascade of enzymatic reactions ensues; activated complements transform inactive complements into active components through proteolytic activity.

The complement system can be activated through three main pathways: Classical, Alternative Pathway, and Mannose-binding Lectin (MBL) Pathway.

• The classical pathway:  This pathway is activated by antibody-antigen complex binding to C1q, a part of the C1 complex that contains C1r and C1s. C1s then activates C4 and C2 consequently. Activated C4 and C2 together form C3 convertase.
• The mannan-binding lectin (MBL) pathway: This is very similar to the classical pathway. The MBL protein is similar to C1q. which in turn activates MBL-associated serine proteases, MASP-1 and MASP-2, which stimulate C4 and C2 to form the C3 convertase, C4b2a.
• The alternative pathway:  This third pathway is not activated by protein binding to a pathogen. Instead, it is activated by spontaneous hydrolysis of C3 into C3(H2O), which binds to factor B, allowing it to be cleaved into Ba and Bb. The Bb fragment binds to C3(H2O), forming C3(H20) Bb, the alternative pathway’s C3 convertase. This creates an amplification loop as more C3 is created.

References

• Dunkelberger, J.R. and Song, W.-C. (2009). Complement and its role in innate and adaptive immune responses. Cell Research, [online] 20(1), pp.34–50. Available at: https://www.nature.com/articles/cr2009139/
• A, C., Travers, P., Walport, M. & Shlomchik, M.J. (2010). The complement system and innate immunity. [online] Nih.gov. Available at: https://www.ncbi.nlm.nih.gov/books/NBK27100/
• Merle, N.S., Church, S.E., Fremeaux-Bacchi, V. and Roumenina, L.T. (2015). Complement System Part I. Molecular Mechanisms of Activation and Regulation. Frontiers in Immunology, 6.
• Dr Trynaadh, (2018). Common Complement Deficiencies. [online] WordPress. Available at: https://drtrinadh.wordpress.com/2018/08/01/common-complement-deficiencies/ [Accessed Apr 30 2022].

The terminal pathway

Summary

C3 is the essential complement pathway component; all three activation pathways form the C3 convertase, which converts C3 into C3a and C3b. C3a has anaphylatoxin activity, directly triggering degranulation of mast cells as well as increasing vascular permeability and promoting inflammation. On the other hand, C3b opsonises targets for phagocytosis. Moreover, C3b also acts as a protease by cleaving C5 into C5a and C5b. C5a functions in a similar way to C3a. C5b initiates a cascade of reactions leading to the formation of what is known as the membrane attack complex (MAC) C5b, C6, C7, C8, and C9.

Image Source: Wikimedia Commons (2006). Figure 1.4 Complement activation, Licensed under a creative commons licence. Available for free at: https://upload.wikimedia.org/wikipedia/commons/f/f5/Figure_1.4._Complement_activation.jpg (Accessed: 9 January 2024).

References 

• Dunkelberger, J.R. and Song, W.-C. (2009). Complement and its role in innate and adaptive immune responses. Cell Research, [online] 20(1), pp.34–50. Available at: https://www.nature.com/articles/cr2009139/
• A, C., Travers, P., Walport, M. & Shlomchik, M.J. (2010). The complement system and innate immunity. [online] Nih.gov. Available at: https://www.ncbi.nlm.nih.gov/books/NBK27100/
• Merle, N.S., Church, S.E., Fremeaux-Bacchi, V. and Roumenina, L.T. (2015). Complement System Part I. Molecular Mechanisms of Activation and Regulation. Frontiers in Immunology, 6.
• Dr Trynaadh, (2018). Common Complement Deficiencies. [online] WordPress. Available at: https://drtrinadh.wordpress.com/2018/08/01/common-complement-deficiencies/ [Accessed Apr 30 2022].

Complement disorders

Complement disorders can be broadly classified into acquired and inherited disorders.

Acquired complement deficiencies

This is the most common cause of complement deficiencies. Acquired deficiencies of complement proteins are seen in diseases with widespread activation of the complement system, leading to increased complement consumption. Immunological processes, such as SLE, hypocomplementemia glomerulonephritis, sepsis, and certain viral infections, can lead to acquired deficiencies. Specific non-immunological processes can similarly cause acquired complement disorders, such as severe malnutrition.

The following table illustrates complement consumption and deficiency in kidney diseases (Primary and part of systemic diseases). The percentage of patients with low C3 levels is also shown in brackets.

Table adapted from Thurman J. M. (2015). Complement in kidney disease: core curriculum 2015. American journal of kidney diseases: the official journal of the National Kidney Foundation, 65(1), 156–168. https://doi.org/10.1053/j.ajkd.2014.06.035

Inherited complement deficiencies

Deficiency of the classical pathway proteins

C1, C2, C3, and C4 increase predisposition to develop autoimmune disease and infections.

C1q deficiency is associated with the development of SLE (90% of affected cases develop SLE), which usually manifests at an earlier age compared to the usual SLE cohort and tends to be less responsive to steroids.

C2 is the most common complement deficiency among the classical pathway components and leads to increased tendencies to develop sepsis in secondary encapsulated organisms.

C3 deficiency is the rarest and is linked to an increased risk of bacterial infection and immunocomplex-mediated diseases.

C4a is associated with SLE, and C4b is linked to invasive bacterial infections

Deficiency of the alternative pathway proteins

Factor B or D deficiency is associated with an increased risk of severe infections, particularly Neisseria.

C3 deficiency is associated with severe pyogenic infection in early infancy life.

Deficiency of the MBL pathway proteins

This is very common but mostly asymptomatic.

Deficiency of the terminal pathway proteins

Deficiency of any of the proteins involved in the terminal pathway (C5-C9) leads to an inability to form MAC and increases susceptibility to Neisseria infections. Usually presents with severe recurrent infection by Neisseria gonorrhoeae or Neisseria meningitidis.

Regulation of the complement pathway

The classical pathway is controlled by a C1 esterase inhibitor (C1 INH), which binds C1r or C1s, deactivating the C1 complex. C1 INH has another job outside the complement pathway regulation by controlling the level of bradykinin, and deficiency of C1 INH leads to increased vascular permeability because of high levels of bradykinin, as seen in hereditary angioedema. Plasma-driven C1 INH is a recognised treatment for hereditary angioedema. Other inhibitors of C1q include chondroitin-4 sulfate proteoglycan and Calreticulin.

Inhibitors of the mannan-binding lectin (MBL) pathway are MASP-3, MAp44, and MAp19 proteins; they are very similar to MASP1 and MASP2 and have a high ability to bind MBL.

References

• Dunkelberger, J.R. and Song, W.-C. (2009). Complement and its role in innate and adaptive immune responses. Cell Research, [online] 20(1), pp.34–50. Available at: https://www.nature.com/articles/cr2009139/
• A, C., Travers, P., Walport, M. & Shlomchik, M.J. (2010). The complement system and innate immunity. [online] Nih.gov. Available at: https://www.ncbi.nlm.nih.gov/books/NBK27100/
• Merle, N.S., Church, S.E., Fremeaux-Bacchi, V. and Roumenina, L.T. (2015). Complement System Part I. Molecular Mechanisms of Activation and Regulation. Frontiers in Immunology, 6.
• Dr Trynaadh, (2018). Common Complement Deficiencies. [online] WordPress. Available at: https://drtrinadh.wordpress.com/2018/08/01/common-complement-deficiencies/ [Accessed Apr 30 2022].