Alternative pathway of the complement system

Under normal physiological conditions, the alternative pathway (AP) takes precedence over the classical and lectin pathways. It operates at a basal level, leading to the hydrolysis of C3 into C3b. When encountering foreign biological or artificial surfaces such as carbohydrates, lipids, proteins, gas bubbles, etc., this pathway is spontaneously initiated. This continuous activation of C3, known as “tick over,” results in the production of modest quantities of C3b. If required, this process can be amplified.

Steps / Mechanism / Process of Alternative pathway of the complement system

The alternative pathway is one of the three pathways that make up the complement system, a crucial part of the immune system responsible for enhancing the body’s ability to clear pathogens. The alternative pathway is unique in that it can be activated without prior immune recognition.

Steps involved in the alternative pathway of the complement system:

  • Continuous C3 Hydrolysis (Tick Over):

Under normal physiological conditions, a small fraction of C3 in the bloodstream undergoes spontaneous hydrolysis. This results in the formation of C3(H2O), which is an activated form of C3.

  • Binding of Factor B:

Factor B, another protein present in the blood, binds to C3(H2O). This binding causes a conformational change in Factor B, exposing a binding site for Factor D.

  • Activation of Factor D:

Factor D, a serine protease, recognizes and cleaves Factor B that is bound to C3(H2O). This cleavage results in the formation of two fragments: Ba and Bb. Bb remains bound to C3(H2O) as a complex known as C3(H2O)Bb, which is a C3 convertase.

  • Amplification of the C3 Convertase:

C3(H2O)Bb, the C3 convertase, is capable of cleaving additional C3 molecules into C3a and C3b. This amplifies the activation of C3 and initiates the downstream events of the complement cascade.

  • Opsonization by C3b:

C3b, the larger fragment produced from the cleavage of C3, can covalently bind to surfaces of pathogens or foreign particles. This process, known as opsonization, marks the target for phagocytosis by immune cells.

  • Formation of C5 Convertase:

C3b can also bind to C3 convertase (C3(H2O)Bb), creating a more potent enzyme known as C5 convertase (C3bBbC3b). This complex can cleave C5 into C5a and C5b.

  • Assembly of Membrane Attack Complex (MAC):

C5b initiates the formation of the MAC, a structure that can create pores in the membranes of pathogens. C5b associates with C6, C7, C8, and multiple molecules of C9, resulting in the formation of a channel-like structure in the membrane.

  • Cell Lysis and Pathogen Destruction:

The MAC creates pores in the membrane of the target pathogen. These pores disrupt the osmotic balance and can lead to cell lysis, ultimately destroying the pathogen.

Regulators of the Alternative Pathway

The alternative pathway of the complement system is tightly regulated to prevent excessive activation and potential harm to host cells. Several proteins act as regulators of the alternative pathway. These regulators work in concert to maintain a delicate balance between complement activation for immune defense and protection of host cells from unintended damage. Their coordinated actions help prevent excessive complement activation, which could potentially lead to autoimmune reactions or tissue injury. Here are the key regulators:

  • Factor H:

Factor H is a soluble plasma protein that plays a critical role in regulating the alternative pathway. It acts as a cofactor for Factor I, allowing Factor I to cleave C3b into its inactive form, iC3b. Additionally, Factor H competes with Factor B for binding to C3b, preventing the formation of the C3 convertase (C3bBb).

  • Factor I:

Factor I is a soluble enzyme that cleaves C3b into iC3b, which is incapable of participating in further complement activation. Factor I requires a cofactor, such as Factor H or membrane-bound complement receptor 1 (CR1), to exert its proteolytic activity.

  • Membrane-Bound Complement Receptor 1 (CR1):

CR1 is a membrane-bound protein found on the surface of cells, including erythrocytes. It serves as a cofactor for Factor I, enhancing its ability to cleave C3b into iC3b. By doing so, CR1 helps in the regulation of complement activation on host cell surfaces.

  • Membrane Cofactor Protein (MCP):

Also known as CD46, MCP is a membrane-bound protein expressed on the surface of host cells. It acts as a cofactor for Factor I, accelerating the degradation of C3b into iC3b.

  • Decay-Accelerating Factor (DAF or CD55):

DAF is a membrane-bound protein that prevents the assembly of the C3 convertase on host cell surfaces. It achieves this by accelerating the dissociation of C3bBb, thereby inhibiting further complement activation.

  • Complement Receptor 1 (CR1 or CD35):

CR1 is a membrane-bound protein expressed on various immune cells. It serves as both a receptor for C3b/C4b-coated immune complexes and a cofactor for Factor I, enhancing the cleavage of C3b into iC3b.

  • Protectin (CD59):

CD59 is a membrane-bound protein that inhibits the formation of the membrane attack complex (MAC) by preventing the polymerization of C9. It is particularly important for protecting host cells from damage during complement activation.

Applications / Significance of Alternative pathway

  • Immune Defense Against Infections:

The alternative pathway provides a rapid and powerful means of activating the complement system, even in the absence of specific immune recognition. It enhances the body’s ability to clear pathogens by opsonization, phagocytosis, and the formation of the membrane attack complex (MAC) for direct lysis of microbes.

  • Inflammatory Response:

Activation of the alternative pathway leads to the release of anaphylatoxins, including C3a and C5a, which promote inflammation. These molecules recruit immune cells to the site of infection, increase vascular permeability, and facilitate the immune response.

  • Opsonization:

C3b, a product of the alternative pathway, coats the surface of pathogens, enhancing their recognition and uptake by phagocytic cells like macrophages and neutrophils. This process accelerates the clearance of pathogens from the body.

  • Clearance of Immune Complexes:

The alternative pathway participates in the clearance of immune complexes formed during the immune response. It helps in the removal of antigen-antibody complexes from circulation, reducing the risk of autoimmune reactions.

  • ComplementMediated Cytotoxicity (CMC):

The alternative pathway can contribute to complement-mediated cytotoxicity, which is utilized in immunotherapy and targeted therapy for certain diseases, such as cancer. Antibodies can activate the complement system to destroy cancer cells.

  • Microbial Pathogenesis Studies:

Understanding the mechanisms of complement activation, including the alternative pathway, is crucial for studying microbial pathogenesis. It provides insights into how pathogens evade or exploit the immune system.

  • Drug Development and Therapeutics:

Targeting specific components or regulators of the alternative pathway can be explored for therapeutic interventions. For example, developing complement inhibitors may have applications in treating complement-mediated diseases.

  • Research Tool in Immunology:

The study of the alternative pathway serves as a valuable tool in immunological research. It helps elucidate the intricate interactions between the immune system and various pathogens.

  • Clinical Diagnostics:

Assessing complement activity, including the alternative pathway, can be important in diagnosing and monitoring certain immune-related disorders, such as complement deficiencies and autoimmune diseases.

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