A Comprehensive Review of the Complement System: Molecular Mechanisms, Regulatory Networks, and Therapeutic Applications

Authors

  • Abouelhag H. A. Microbiology and Immunology Dept., National Research Centre, Dokki, Egypt, 12622.

DOI:

https://doi.org/10.33687/ricosbiol.03.09.77

Keywords:

Complement System, Innate Immunity, Classical Pathway, Alternative Pathway, Lectin Pathway, Membrane Attack Complex, Complement Regulators, C3 Convertase, Therapeutic Inhibition, Autoimmune Diseases

Abstract

The complement system represents a sophisticated immune surveillance network that bridges innate and adaptive immunity through a cascade of proteolytic reactions. Comprising over 50 proteins, this system provides first-line defense against pathogens, clears immune complexes, and maintains tissue homeostasis. However, dysregulated complement activation contributes significantly to the pathogenesis of autoimmune disorders, thrombotic microangiopathies, and inflammatory diseases. This review offers a comprehensive examination of the complement system's molecular architecture, focusing on the intricate mechanisms of its three activation pathways and their convergence on common effector functions. We detail the critical regulatory networks that maintain complement homeostasis and prevent host tissue damage. The review systematically analyzes the pathological consequences of complement dysregulation across various disease states and discusses the revolutionary advances in complement-targeted therapeutics. Finally, we explore emerging research directions and the future landscape of complement-based diagnostics and treatments, providing insights into the evolving understanding of this complex biological system.

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Author Biography

  • Abouelhag H. A., Microbiology and Immunology Dept., National Research Centre, Dokki, Egypt, 12622.

    Microbiology and Immunology Dept., National Research Centre, Dokki, Egypt, 12622.

References

Anderson, D. H., Radeke, M. J., Gallo, N. B., Chapin, E. A., Johnson, P. T., Curletti, C. R., Hancox, L. S., Hu, J., Ebright, J. N., Malek, G., Hauser, M. A., Rickman, C. B., Bok, D., Hageman, G. S., and Johnson, L. V. (2019). The pivotal role of the complement system in aging and age-related macular degeneration: hypothesis re-visited. Progress in Retinal and Eye Research, 69, 1-29.

Bajic, G., Degn, S. E., Thiel, S., and Andersen, G. R. (2015). Complement activation, regulation, and molecular basis for complement-related diseases. The EMBO Journal, 34(22), 2735-2757.

Bohlson, S. S., Garred, P., Kemper, C., and Tenner, A. J. (2019). Complement nomenclature—deconvoluted. Frontiers in Immunology, 10, 1308.

Garred, P., Genster, N., Pilely, K., Bayarri-Olmos, R., Rosbjerg, A., Ma, Y. J., and Skjoedt, M. O. (2016). A journey through the lectin pathway of complement—MBL and beyond. Immunological Reviews, 274(1), 74-97.

Hillmen, P., Szer, J., Weitz, I., Röth, A., Höchsmann, B., Panse, J., and Usuki, K. (2021). Pegcetacoplan versus eculizumab in paroxysmal nocturnal hemoglobinuria. New England Journal of Medicine, 384(11), 1028-1037.

Hourcade, D. E., Mitchell, L. M., and Medof, M. E. (2019). The role of properdin in the assembly of the alternative pathway C3 convertases of complement. Journal of Biological Chemistry, 294(40), 14524-14535.

Klos, A., Wende, E., Wareham, K. J., and Monk, P. N. (2013). International Union of Basic and Clinical Pharmacology. LXXXVII. Complement peptide C5a, C4a, and C3a receptors. Pharmacological Reviews, 65(1), 500-543.

Leffler, J., Bengtsson, A. A., and Blom, A. M. (2014). The complement system in systemic lupus erythematosus: an update. Annals of the Rheumatic Diseases, 73(9), 1601-1606.

Liszewski, M. K., Elvington, M., Kulkarni, H. S., and Atkinson, J. P. (2017). Complement's hidden arsenal: new insights and novel functions inside the cell. Molecular Immunology, 84, 2-9.

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, 262.

Morgan, B. P. (2018). Complement in the pathogenesis of Alzheimer's disease. Seminars in Immunopathology, 40(1), 113-124.

Muller-Eberhard, H. J. (1986). The membrane attack complex of complement. Annual Review of Immunology, 4(1), 503-528.

Noris, M., and Remuzzi, G. (2013). Overview of complement activation and regulation. Seminars in Nephrology, 33(6), 479-492.

Reis, E. S., Mastellos, D. C., Hajishengallis, G., and Lambris, J. D. (2019). New insights into the immune functions of complement. Nature Reviews Immunology, 19(8), 503-516.

Ricklin, D., Reis, E. S., and Lambris, J. D. (2016). Complement in disease: a defence system turning offensive. Nature Reviews Nephrology, 12(7), 383-401.

Risitano, A. M., Marotta, S., Ricci, P., Marano, L., and Frieri, C. (2022). Complement as a target in COVID-19? Nature Reviews Immunology, 22(2), 125-126.

Rodríguez de Córdoba, S., Hidalgo, M. S., and Pinto, S. (2019). The complement system in the pathophysiology of pregnancy and in systemic autoimmune rheumatic diseases during pregnancy. Frontiers in Immunology, 10, 2954.

Ricos Biology Journal Vol. 3, No. 9

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Published

23-09-2025

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How to Cite

A Comprehensive Review of the Complement System: Molecular Mechanisms, Regulatory Networks, and Therapeutic Applications. (2025). Ricos Biology, 3(9), 32-39. https://doi.org/10.33687/ricosbiol.03.09.77

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