What is the Alternative Pathway?
The
alternative pathway is one of the three pathways that activate the complement system, an essential part of the body's immune response. Unlike the classical and lectin pathways, the alternative pathway can be initiated without the presence of antibodies, making it a crucial component of the innate immune system.
How is the Alternative Pathway Activated?
Activation of the alternative pathway begins with the spontaneous hydrolysis of complement component
C3, leading to the formation of C3(H2O). This molecule can bind to factor B, which is then cleaved by factor D to form the C3 convertase, C3bBb. This enzyme complex can further cleave more C3 molecules, amplifying the response.
Spontaneous hydrolysis of C3 to C3(H2O).
Binding of factor B to C3(H2O), forming C3(H2O)B.
Cleavage of factor B by factor D, forming C3(H2O)Bb, also known as fluid-phase C3 convertase.
C3 convertase cleaves more C3 into C3a and C3b.
C3b binds to pathogen surfaces and to factor B, forming C3bB, which is then cleaved by factor D to form C3bBb, the surface-bound C3 convertase.
Amplification loop: C3bBb cleaves additional C3 molecules, leading to opsonization of pathogens and formation of the membrane attack complex (MAC).
What is the Role of Properdin in the Alternative Pathway?
Properdin is a positive regulator of the alternative pathway. It stabilizes the C3 convertase (C3bBb) on pathogen surfaces, thereby enhancing the pathway's efficiency. Properdin can also bind directly to pathogens, further facilitating the activation of the complement system.
Opsonization: C3b binds to pathogen surfaces, marking them for phagocytosis by immune cells.
Inflammation: C3a and C5a, produced during the pathway's activation, act as anaphylatoxins, attracting immune cells to the site of infection and promoting inflammation.
Cell Lysis: The terminal components of the pathway form the membrane attack complex (MAC), which creates pores in the pathogen's membrane, leading to cell lysis.
Factor H and
Factor I: These proteins inactivate C3b, preventing the formation of C3 convertase.
Decay-Accelerating Factor (DAF): This membrane-bound protein accelerates the decay of C3 convertase, protecting host cells from complement-mediated damage.
Membrane Cofactor Protein (MCP): This protein acts as a cofactor for Factor I, facilitating the inactivation of C3b on host cell surfaces.
Atypical Hemolytic Uremic Syndrome (aHUS): Caused by mutations in regulatory proteins like Factor H or MCP, leading to uncontrolled complement activation.
Age-related Macular Degeneration (AMD): Linked to polymorphisms in the Factor H gene, contributing to chronic inflammation and tissue damage in the retina.
Paroxysmal Nocturnal Hemoglobinuria (PNH): Caused by mutations affecting the synthesis of GPI-anchored proteins, leading to increased complement-mediated lysis of red blood cells.
Conclusion
Understanding the alternative pathway is crucial for comprehending the broader context of the immune system and its role in disease. This pathway's ability to act independently of antibodies makes it a vital first line of defense against infections. However, its regulation is equally important to prevent unintended damage to host tissues. Advances in our knowledge of this pathway continue to pave the way for novel therapeutic approaches in treating complement-mediated diseases.
