Introduction
The complement system is one of immunity’s oldest defense mechanisms (discovered in the 1890s). It consists of various soluble blood proteins or membrane-associated proteins. Activation of complement leads to a cascade of events (known as complement activation pathways), resulting in potent immune proteins that elicit physiological responses against pathogens.
The complement system has been considered a simple killing cascade aimed at the pathogens infecting the host. However, it is an intricate immune surveillance pathway because it plays a role in homeostasis (a self-regulating process to maintain balance), inflammation, and defense against pathogens. Further, it is becoming increasingly evident that complement also plays a role in adaptive immunity (immune response formed after the attack of pathogens) involving T (a type of WBC that attacks specific foreign particles) and B cells (a type of WBC that produces antibodies) and maintaining immunologic memory against pathogenic re-invasion.
What Is the General Role of Complement System in Immune Defense?
1. Direct Killing: Pathogens are attacked by the complement system, which results in their direct killing. However, the killing depends on the membrane composition of the pathogens, such as bacteria. Further, activation of the final complement pathway results in the membrane-attack complex (MAC) formation. MAC forms large and wide pores in the target pathogen’s membrane. However, most pathogens can repair MAC-induced damage and resist complement killing by MAC, such as Gram-positive bacteria (bacteria that give positive results in the Gram stain test, for example, Staphylococcus). It is because they have a very thick cell wall that MAC cannot penetrate. On the other hand, some Gram-negative bacteria (bacteria that give negative results in the Gram stain test, for example, E. coli) are sensitive to complement killing.
2. Opsonization and Phagocytosis: The primary role of the complement system in pathogen elimination is indirect. Opsonization is the deposition of complement fragments on the surface of pathogens to allow their recognition, ingestion, and destruction by cells such as neutrophils, monocytes, and macrophages (all are types of white blood cells, WBCs, involved in immunity). However, complement opsonization allows their elimination before an adaptive immune response and the appearance of antibodies (immune proteins).
Phagocytosis leads to the elimination of pathogens by engulfing them. As a result, microorganisms are killed by toxic reactive oxygen species (ROS), free radicals, and microbicidal (microorganism-killing) components (lysozyme and proteases). Finally, the complement system also aids in the apoptosis (cell death) of phagocytic cells, which leads to the resolution of infection and inflammation.
What Is the Role of the Complement System in Innate Immune Defense?
Various defense mechanisms exist to protect from pathogen invasion in humans. However, the complement system is a vital element of innate immunity that also aids in rapid pathogen recognition and elimination.
- Role of Complement Proteins: C3a and C5a (fragments produced as part of the complement system activation) play a critical role in the modulation of immune system activity. They contribute to inflammation by activating immune cells. They also stimulate inflammation by inducing an oxidative burst in macrophages, eosinophils, and neutrophils. Moreover, C3a and C5a cause vasodilation (blood vessel dilation) through histamine (a compound involved in local immune response) production by basophils and mast cells (both are types of immune cells). Thus, it suggests their anti-inflammatory role in acute inflammation.
What Is the Role of the Complement System in Adaptive Immune Defense?
Research has shown that the complement system plays a role in inflammation and adaptive immunity.
1. The Complement System and B Cells: Various studies demonstrate the relationship between the complement system and B cells. C3 (a complement protein) plays a pertinent role in antibody generation by B cells. Also, C3 is vital for the induction and maintenance of memory- B cells (to remember the pathogen in the future).
2. The Complement System and T Cells: During an infection, the complement system controls T cell proliferation and differentiation. During inflammation, C3a and C5a can bind their corresponding receptors on the T cells leading to the production of (cytokines) inflammatory mediators.
Hence, these points depict the importance of the complement system in a successful immune response. Also, this cascade should be considered a factor mediating innate immunity and inflammation and a potent regulator of adaptive immunity.
What Are the Disorders Related to Defects in the Complement System?
1. Hemolytic Uremic Syndrome: Hemolytic uremic syndrome (HUS) leads to inflammation of small blood vessels of the kidney due to excess complement system activation. The primary cause is a mutated factor H gene that leads to increased blood vessel damage with resultant fibrin (a protein that causes blood clotting) deposition.
2. Hereditary Angioedema: Hereditary angioedema (HAE) is a rare, life-threatening disorder characterized by sudden, repeated, and self-limiting episodes of swelling of the face, extremities, trunk, genitals, or respiratory tract. It is caused by low levels or a dysfunctional complement protein C1-inhibitor (C1-INH). Swelling in the respiratory tract is the most grave clinical feature that may lead to airway obstruction and death.
3. Paroxysmal Nocturnal Hemoglobinuria: Paroxysmal nocturnal hemoglobinuria (PNH) is an uncommon entity due to mutation in complement system proteins. It presents with hemolytic anemia (anemia due to increased destruction of red blood cells, RBCs), hemoglobinuria (hemoglobin excretion in urine), and symptoms including fatigue and dyspnea (shortness of breath). The complications are primarily due to hemolysis (RBC destruction), thrombosis (blood clots), and bone marrow failure. WBCs are also susceptible to destruction, and tissue factors (a protein that triggers blood clotting) released from the damaged WBCs may contribute to thrombosis in PNH patients.
4. Systemic Lupus Erythematosus: Complement system deficiencies predispose to systemic lupus erythematosus (SLE). SLE is characterized by fever, rash, glomerulonephritis (a kidney disease), and hemolytic anemia in some individuals. Defective particular complement proteins can result in impaired immune complex clearance and their consequent deposition in various organs (especially in the kidney and arteries) and autoimmunity (due to defective self-recognition by B and T cells).
5. Bacterial Infections: Deficiency in various complement system proteins can also lead to recurrent bacterial infections. Further, defective complement system proteins are associated with increased susceptibility to meningitis (bacterial infection of the brain membranes).
Conclusion
To conclude, various studies have demonstrated that complement takes part in almost every step of the immune reaction and deserves a pivotal role in immunological research. Unfortunately, there is a lack of integrity in complement proteins' nomenclature and the enzymatic cascade. As a result, it renders the complement system one of the most complicated parts of immunology avoided by scientists.
