The Complement System

Yes, we can provide you with a poster summarizing the entire pathway. For further reading regarding complement function, regulation and its role in disease, we recommend the following review papers: 

Brandwijk Ricardo J. M. G. E. , Michels Marloes A. H. M. , van Rossum Mara , de Nooijer Aline H. , Nilsson Per H. , de Bruin Wieke C. C. , Toonen Erik J. M. ,Pitfalls in complement analysis: A systematic literature review of assessing complement activation, Frontiers in Immunology, Volume 13 – 2022, 2022, 10.3389/fimmu.2022.1007102

Mastellos, D.C., Ricklin, D. & Lambris, J.D. Clinical promise of next-generation complement therapeutics. Nat Rev Drug Discov 18, 707–729 (2019). https://doi.org/10.1038/s41573-019-0031-6

John P. Atkinson, Terry W. Du Clos, Carolyn Mold, Hrishikesh Kulkarni, Dennis Hourcade, Xiaobo Wu, 21 – The Human Complement System: Basic Concepts and Clinical Relevance, Editor(s): Robert R. Rich, Thomas A. Fleisher, William T. Shearer, Harry W. Schroeder, Anthony J. Frew, Cornelia M. Weyand, Clinical Immunology (Fifth Edition), Elsevier, 2019, Pages 299-317.e1, ISBN 9780702068966

Intracellular complement functions as an autonomous regulatory layer that modulates immune cell metabolism, survival, and inflammatory responses, operating inside lysosomes and mitochondria. In contrast, extracellular complement primarily functions in immune surveillance and pathogen elimination via the three pathways in plasma and tissues. A few examples in which intracellular complement differs from extracellular [3]: 

Developing complement inhibitors for clinical use is challenging due to complex pathway crosstalk and activation bypass mechanisms. Non-canonical proteases such as thrombin or kallikrein can cleave C3 or C5 without convertases, allowing bypass activation. This can undermine the efficacy of convertase-targeting therapies [3]. Moreover, functional overlap between pathways enables activation even when one route is blocked. Another challenge lies in the genetic variation in regulatory proteins like factor H and CD46, which can alter disease susceptibility and patient response to therapy. Pathogens further complicate treatment by mimicking host complement regulators, enabling immune evasion. Intracellular complement activity adds complexity and raises questions about how complement inhibitors are expected to work in clinical practice.

Complement dysregulation plays a central role in the development of aHUS and C3 glomerulopathy. In these diseases, uncontrolled alternative pathway activation leads to excessive C3 fragment deposition on host tissue.  This results from mutations or autoantibodies affecting regulators such as factor H, factor I, CD46, or factor H-related proteins. In aHUS, factor H variants often cluster in the C-terminal domains responsible for host-surface recognition.  This impairs regulation on endothelial cells, promoting thrombotic microangiopathy. In contrast, C3 glomerulopathy-associated variants localize to N-terminal domains affecting fluid-phase C3 regulation. The imbalance causes persistent C3b deposition  and complement amplification in the glomerular basement membrane. (The glomerular basement membrane is an extracellular matrix in the kidney.) This drives inflammation, tissue injury, and renal dysfunction. Both diseases reflect distinct but overlapping signatures of alternative pathway dysregulation. Genetic insights from patients have clarified how regulatory defects trigger complement-mediated kidney pathology. [3]

Numerous diseases have been associated with complement system dysfunction. Below is a selection of some widely discussed examples: 

• Kidney-Related Diseases (C3G, Lupus Nephritis, aHUS, MN): Characterized by complement dysregulation, immune complex formation, and inflammation, leading to glomerular damage, renal dysfunction, and progressive kidney disease.
• Hematological Disorders (PNH, AIHA, TMA): Conditions involving red blood cell destruction, thrombotic complications, and hemolytic anemia due to impaired complement regulation and immune system dysfunction.
• Neurological Diseases (Multiple Sclerosis, Alzheimer’s Disease, NMOSD, MMN, ALS, Parkinson’s Disease): Chronic neuroinflammatory and neurodegenerative disorders where complement activation contributes to neuronal damage, demyelination, and disease progression.
• Sepsis, SIRS & Ischemia-Reperfusion Injury (IRI): Dysregulated immune activation leading to systemic inflammation, organ dysfunction, and tissue ischemia, relevant in conditions such as stroke, myocardial infarction, and trauma.
• Systemic Autoimmune Disorders (SLE, TMA-related conditions): Autoantibody formation and complement activation drive widespread inflammation, immune complex deposition, and increased disease severity.
• Oncology & Tumor Progression: Complement activation, particularly TCC formation, plays a role in the tumor microenvironment, influencing immune evasion, chronic inflammation, and cancer progression. Complement inhibitors are being explored as potential therapeutic strategies in oncology.

Because of the large number of complement-mediated diseases and recent advancements in large-scale genomics and proteomic research, interest in the complement system has been revitalized, especially as a promising target for therapeutic intervention. This was demonstrated more than a decade ago by eculizumab (Soliris, Alxion), the first complement-specific drug designed to inhibit the key complement component C5.

Therapeutic strategies can target different levels of the complement pathway to prevent or control excessive activation. A central approach is the use of monoclonal antibodies against C5, such as eculizumab, to prevent C5a and membrane attack complex formation. Compstatin analogues act upstream by inhibiting C3 activation, blocking both opsonization and downstream amplification. To target the alternative pathway specifically, inhibitors of factor B or factor D disrupt its amplification loop. Some therapies interfere with convertase assembly or stability, thereby reducing the generation of effector molecules. C5a receptor (C5aR1) antagonists selectively block inflammatory signaling without affecting upstream complement functions. Complement regulation can also be restored by engineered regulators that mimic the activity of proteins like factor H or CD46. These specific targeted deliveries improve a way to modulate complement activity.

The complement system plays an important role in therapeutic research because of its contribution in immune defense, inflammation, and disease pathology. Malfunction of complement activity contributes to autoimmune diseases, inflammatory disorders, neurodegeneration, cancer, and infectious diseases, making it an interesting target for drug development.