The complement system, as the name implies, complements the activities of the immune system and plays a critical role in host defense against infections. It is an intricate network of small proteins produced by the liver and circulating in the blood plasma and within tissues. In response to specific triggers, these proteins interact in a series of cascading reactions leading to a diverse range of immunological and inflammatory processes (Ricklin, D., Hajishengallis, G., Yang, K., & Lambris, J. D., 2010).

The complement system can be activated via three primary pathways: the classical pathway, the lectin pathway, and the alternative pathway. Each pathway is triggered differently, but all culminate in a common terminal pathway (Walport, M. J., 2001).

The classical pathway is initiated by the binding of C1q, the first component of the classical pathway, to antibodies (IgG or IgM) that are bound to antigens. This pathway primarily coordinates with the adaptive immune response (Carroll, M. C., & Isenman, D. E., 2012).

The lectin pathway is triggered by the binding of mannose-binding lectin (MBL) or ficolins to specific sugar residues on the surface of pathogens (Garred, P., Genster, N., Pilely, K., Bayarri-Olmos, R., Rosbjerg, A., Ma, Y. J., & Skjoedt, M. O., 2016).

The alternative pathway is unique as it is continually active at a low level. It is amplified when complement proteins bind to the surface of pathogens. This pathway is crucial in the initial innate immune response before the classical or lectin pathways are activated (Fearon, D. T., 2014).

The sequential activation of these pathways leads to the formation of a C3 convertase, an enzyme that cleaves the central complement protein, C3, into C3a and C3b. This process marks the convergence of the three pathways and the beginning of the terminal pathway.

The binding of C3b to C3 convertase forms C5 convertase, which cleaves C5 into C5a and C5b. C5b initiates the assembly of the terminal complement complex or membrane attack complex (MAC), composed of C5b, C6, C7, C8, and multiple units of C9. The MAC forms a pore in the membrane of the targeted cell, leading to osmotic lysis and cell death (Morgan, B. P., 2016).

Additionally, complement activation generates potent proinflammatory molecules like C3a and C5a (anaphylatoxins), which recruit and activate immune cells, enhance vascular permeability, and stimulate inflammation. C3b and its derivatives opsonize pathogens, enhancing their recognition and phagocytosis by immune cells (Ricklin, D., et al., 2010).

While the complement system is crucial for immune defense, uncontrolled activation can harm host tissues. Therefore, it is tightly regulated by numerous fluid-phase and cell-bound regulators. Dysregulation or genetic deficiencies in the complement system or its regulators can lead to various pathological conditions, including autoimmune diseases, inflammatory disorders, and susceptibility to infections (Reis, E. S., Mastellos, D. C., Hajishengallis, G., & Lambris, J. D., 2019).

The complement system is a crucial arm of the innate immune system, offering rapid and potent responses to infections. It coordinates with both the innate and adaptive immune systems to remove pathogens and stimulate inflammation, playing a central role in immune defense.

References:

Ricklin, D., Hajishengallis, G., Yang, K., & Lambris, J. D. (2010). Complement: a key system for immune surveillance and homeostasis. Nature Immunology, 11(9), 785-797.
Walport, M. J. (2001). Complement. First of two parts. The New England journal of medicine, 344(14), 1058-1066.
Carroll, M. C., & Isenman, D. E. (2012). Regulation of humoral immunity by complement. Immunity, 37(2), 199-207.
Garred, P., Genster, N., Pilely, K., Bayarri-Olmos, R., Rosbjerg, A., Ma, Y. J., & Skjoedt, M. O. (2016). A journey through the lectin pathway of complement—MBL and beyond. Immunological Reviews, 274(1), 74-97.
Fearon, D. T. (2014). Activation of the alternative complement pathway. In The Complement System (pp. 89-103). Springer, New York, NY.
Morgan, B. P. (2016). The membrane attack complex as an inflammatory trigger. Immunobiology, 221(6), 747-751.
Reis, E. S., Mastellos, D. C., Hajishengallis, G., & Lambris, J. D. (2019). New insights into the immune functions of complement. Nature Reviews Immunology, 19(8), 503-516.

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