THE ROLE OF COMPLEMENT SYSTEM IN DISEASE AND HEALTH

The complement system is a part of the immune system that plays a vital role in protecting the body against invading pathogens, such as bacteria, viruses, and fungi. It is a complex system of proteins that work together to help eliminate pathogens from the body. The complement system consists of more than 30 proteins, which are activated in a specific order to create a cascade of chemical reactions that help to destroy pathogens.

 

Activation of the complement system

The activation of the complement system involves a cascade of reactions that ultimately lead to the destruction of pathogens, recruitment of immune cells, and modulation of the inflammatory response.

The activation of the complement system can occur through three different pathways: the classical pathway, the lectin pathway, and the alternative pathway. Each pathway is triggered by distinct molecular patterns associated with pathogens or damaged host cells.

1. Classical Pathway:
The classical pathway is primarily initiated by the binding of antibodies to antigens on the surface of pathogens. When antibodies recognize and bind to these antigens, they undergo a conformational change that exposes a binding site for C1q, a component of the complement system. C1q then binds to the antibody-antigen complex, leading to the activation of C1r and C1s proteases. Activated C1s cleaves C4 and C2 proteins into smaller fragments (C4a, C4b, C2a, and C2b). The resulting fragments assemble into a complex called the C3 convertase (C4b2a), which cleaves C3 into C3a and C3b. The generation of C3b marks an important step in complement activation as it allows for further amplification and progression of the cascade.

2. Lectin Pathway:
The lectin pathway is initiated by pattern recognition molecules called mannose-binding lectins (MBLs) or ficolins. These molecules can recognize specific carbohydrate patterns present on the surface of pathogens. Upon binding to these patterns, MBLs or ficolins associate with MBL-associated serine proteases (MASPs), leading to their activation. Activated MASPs then cleave C4 and C2 proteins, similar to the classical pathway, resulting in the formation of the C3 convertase (C4b2a) and subsequent cleavage of C3 into C3a and C3b.

3. Alternative Pathway:
The alternative pathway is unique as it can be spontaneously activated in the absence of antibodies or lectins. It relies on the continuous low-level hydrolysis of C3 in the plasma. This results in the generation of C3b, which can bind to nearby surfaces, including pathogens or host cells. Properdin, a regulatory protein, stabilizes the binding of C3b to these surfaces and allows for the formation of the alternative pathway C3 convertase (C3bBb). The alternative pathway C3 convertase cleaves additional C3 molecules into C3a and C3b, amplifying the complement cascade.

Regardless of the pathway through which complement activation occurs, the generation of C3b is a critical step. Once formed, C3b can bind covalently to pathogens or damaged host cells, marking them for destruction by phagocytic cells such as macrophages and neutrophils. Additionally, C3b can bind to complement receptors on immune cells, promoting their recruitment to the site of infection or inflammation.

The activation of the complement system also leads to the formation of membrane attack complexes (MACs). MACs are formed when multiple complement proteins assemble on the surface of pathogens or host cells. These complexes create pores in the cell membrane, causing osmotic lysis and ultimately leading to cell death.

In summary, the activation of the complement system involves a series of intricate molecular interactions that occur through three different pathways: classical, lectin, and alternative. These pathways converge at the generation of C3 convertases and subsequent production of C3b. The activation of complement serves as an essential defense mechanism, aiding in the elimination of pathogens and the modulation of immune responses.

 

The regulation of the complement system

The regulation of the complement system is a tightly controlled process that involves several mechanisms to ensure that it is activated only when necessary and that it does not cause harm to the body’s own tissues. Here are some of the key mechanisms of regulation:

1. Inhibitors: The complement system has several inhibitors that can bind to and inhibit the activity of complement proteins, preventing the complement cascade from being activated. These inhibitors include factors such as C1 esterase, factor H, and Crry.

2. Regulatory proteins: The complement system also has several regulatory proteins that can modulate its activity. These proteins include factors such as C3bB, C4BP, and factor P. These proteins can bind to complement proteins and prevent their activation, or they can bind to pathogens and enhance their recognition by the immune system.

3. Receptor-mediated regulation: The complement system can also be regulated by receptors on the surface of immune cells. These receptors, such as CR1 and CR3, can bind to complement proteins and prevent their activation, or they can bind to pathogens and enhance their recognition by the immune system.

4. Cellular regulation: The complement system can also be regulated by cellular mechanisms. For example, immune cells can produce cytokines that either stimulate or inhibit the activity of the complement system.

Overall, the regulation of the complement system is a complex process that involves multiple mechanisms to ensure that it is activated only when necessary and that it does not cause harm to the body’s own tissues.

 

The Complement System: Biological Effects

The complement system has several biological effects on the body, including:

• Opsonization: Opsonization is the process by which the complement system coats pathogens with antibodies, making them more easily recognizable and phagocytosed by immune cells such as neutrophils and macrophages. This helps to remove pathogens from the body more efficiently.
• Activation of Immune Cells: The complement system can activate immune cells such as neutrophils and macrophages, which then release enzymes and reactive oxygen species to kill pathogens. This activation also triggers the production of cytokines, which are signaling molecules that help to coordinate the immune response.
• Inflammation: The complement system can cause inflammation by attracting immune cells to the site of infection and promoting the release of chemical mediators that cause swelling and pain. While inflammation can be beneficial in the short term, chronic inflammation can lead to tissue damage and diseases such as arthritis and atherosclerosis.
• Clearance of Dead Cells and Debris: The complement system helps to clear dead cells and debris from the body by marking them for destruction by immune cells. This is important for maintaining tissue health and preventing infection.

In conclusion, the complement system has several biological effects on the body that help to protect it against invading pathogens and maintain tissue health. These effects include opsonization, activation of immune cells, inflammation, and clearance of dead cells and debris.

 

Clinical aspects of the complement system

The clinical aspects of the complement system encompass various disorders and diseases that arise from deficiencies, dysregulation, or overactivation of the complement components.

Deficiencies in complement components can lead to an increased susceptibility to infections, particularly those caused by encapsulated bacteria. One of the most well-known complement deficiencies is deficiency in C1q, which is associated with an increased risk of developing systemic lupus erythematosus (SLE). Deficiencies in other components such as C2, C3, C4, or terminal complement components (C5-C9) can also result in recurrent infections, especially with Neisseria species.

Dysregulation of the complement system can lead to autoimmune diseases. For example, excessive activation of the complement system has been implicated in the pathogenesis of diseases like SLE, rheumatoid arthritis (RA), and atypical hemolytic uremic syndrome (aHUS). In these conditions, the uncontrolled activation of complement can cause tissue damage and inflammation. On the other hand, deficiencies or mutations in complement regulatory proteins can result in uncontrolled activation of the complement system and contribute to diseases such as age-related macular degeneration (AMD) and paroxysmal nocturnal hemoglobinuria (PNH).

Complement-mediated diseases are a group of disorders characterized by abnormal deposition of complement components within tissues. These include conditions like membranoproliferative glomerulonephritis (MPGN), dense deposit disease (DDD), and C3 glomerulopathy. In these diseases, dysregulation or mutations in complement regulatory proteins lead to excessive activation and deposition of complement components within the glomeruli of the kidneys, resulting in inflammation and damage.

Hereditary angioedema (HAE) is a rare genetic disorder caused by deficiencies or dysfunction of C1 inhibitor, a key regulator of the complement system. HAE is characterized by recurrent episodes of swelling in various body parts, including the face, extremities, gastrointestinal tract, and airways. These episodes can be life-threatening if they involve the airway and lead to asphyxiation. Treatment options for HAE include replacement therapy with C1 inhibitor or medications that inhibit bradykinin, a potent mediator of angioedema.

Complement activation in inflammatory diseases is another important clinical aspect. In conditions such as sepsis, ischemia-reperfusion injury, or acute respiratory distress syndrome (ARDS), excessive complement activation can contribute to tissue damage and exacerbate the inflammatory response. Targeting complement components or inhibiting complement activation pathways has emerged as a potential therapeutic strategy in these inflammatory disorders.

In summary, the clinical aspect of the complement system encompasses deficiencies, dysregulation, and overactivation of complement components. These can lead to increased susceptibility to infections, autoimmune diseases, complement-mediated diseases, hereditary angioedema, and contribute to the pathogenesis of various inflammatory disorders.

 

Overview of the role of complement system in disease and health

The complement system is an integral part of the immune system and plays a crucial role in maintaining both disease and health. It is a complex network of proteins that work together to defend the body against pathogens, clear immune complexes, and regulate inflammation. The complement system consists of over 30 proteins that are produced by various cells in the body, including liver hepatocytes, macrophages, and epithelial cells.

One of the primary functions of the complement system is to recognize and eliminate foreign invaders such as bacteria, viruses, and fungi. This process, known as opsonization, involves the binding of complement proteins to the surface of pathogens, marking them for destruction by phagocytic cells such as neutrophils and macrophages. Additionally, the complement system can directly lyse certain pathogens through the formation of membrane attack complexes (MACs), which create pores in the pathogen’s membrane leading to cell death.

In addition to its role in host defense, the complement system also contributes to immune regulation and inflammation. Activation of the complement cascade can lead to the release of various inflammatory mediators such as cytokines and chemotactic factors. These molecules attract immune cells to the site of infection or injury, promoting an inflammatory response that helps contain and eliminate pathogens. However, dysregulation of the complement system can also lead to excessive inflammation and tissue damage, contributing to the pathogenesis of various diseases.

Several diseases have been associated with abnormalities in the complement system. For example, deficiencies or mutations in certain complement proteins can increase susceptibility to infections. One well-known example is deficiency in C3 or C5 components, which predisposes individuals to recurrent bacterial infections. On the other hand, excessive activation of the complement system has been implicated in autoimmune diseases such as systemic lupus erythematosus (SLE) and rheumatoid arthritis (RA). In these conditions, autoantibodies can form immune complexes that activate the complement system, leading to tissue damage and chronic inflammation.

Furthermore, the complement system has been implicated in various other diseases, including neurodegenerative disorders, cardiovascular diseases, and cancer. In neurodegenerative diseases like Alzheimer’s disease, complement proteins have been found to accumulate in affected brain regions and contribute to neuronal damage. In cardiovascular diseases such as atherosclerosis, complement activation can promote inflammation within blood vessels, leading to plaque formation and progression of the disease. Additionally, the complement system has been shown to play a role in tumor growth and metastasis by modulating immune responses and promoting angiogenesis.

In terms of health maintenance, the complement system also contributes to tissue homeostasis and repair. It helps clear apoptotic cells and cellular debris, preventing their accumulation and potential autoimmune responses. Moreover, the complement system is involved in tissue regeneration and wound healing processes by promoting cell migration and proliferation.

In conclusion, the complement system plays a multifaceted role in both disease and health. It is essential for host defense against pathogens, immune regulation, inflammation, tissue homeostasis, and repair. Dysregulation of the complement system can contribute to the pathogenesis of various diseases, including infections, autoimmune disorders, neurodegenerative diseases, cardiovascular diseases, and cancer. Understanding the intricate mechanisms of complement activation and regulation is crucial for developing targeted therapies for these conditions.