The Complement System: Classical, Lectin, and Alternative Pathways

Summary

This video script discusses the complement system, an essential part of the innate immune system. It begins with a historical perspective, highlighting key discoveries by Jules Bordet and Paul Ehrlich, then dives into how the complement system operates. The complement system involves a cascade of proteins that activate each other to protect the body from pathogens. The video explains the three activation pathways—classical, lectin, and alternative—and their role in pathogen destruction, including opsonization and the membrane attack complex. It also covers regulation mechanisms to prevent harm to host cells.

Takeaways

• 🔍 The complement system is a crucial part of the innate immune system, providing defense mechanisms against pathogens.
• 📚 Historically, the complement system was named by Paul Ehrlich in 1899 for its role in 'complementing' the heat-stable aspect of immunity, later identified as antibodies.
• 🌐 Complement proteins are ancient, with homologs found across various species, indicating their evolutionary significance.
• 🧬 Complement proteins circulate in the blood as inactive enzymes called zymogens, requiring activation to perform their functions.
• 🔗 The complement system is activated through three pathways: classical, lectin, and alternative, each converging at the cleavage of C3.
• 🔑 The classical pathway begins with C1, which binds to antibodies or pathogens, initiating a cascade of events leading to C3 convertase formation.
• 🍬 The lectin pathway involves lectins like MBL and ficolins that bind to specific carbohydrate groups on pathogens, activating MASP proteases and converging at C3 convertase formation.
• 🔄 The alternative pathway utilizes a C3 convertase consisting of C3b bound to Factor B, representing an amplification loop for complement activation.
• 🛡️ C3b plays a dual role in immune defense: opsonization to mark pathogens for phagocytosis and formation of C5 convertase for downstream complement activation.
• 💥 The terminal complement proteins assemble into the membrane attack complex (MAC), which forms pores in pathogen membranes, causing lysis.
• ⚖️ Regulation of the complement system is vital to prevent overreaction and damage to host cells, involving both intrinsic mechanisms of the proteins and specific regulatory proteins.

Q & A

What is the complement system, and what role does it play in the immune system?

The complement system is a component of the innate immune system made up of several proteins that circulate in the blood. It helps the immune system fight infections by promoting pathogen killing, enhancing phagocytosis, and forming the membrane attack complex to lyse pathogens.

What historical discovery led to the identification of the complement system?

In the late 17th century, scientists noticed that blood from animals could kill bacteria in vitro, but heating the blood removed this ability. In the 1890s, Jules Bordet proposed two components in the blood: a heat-stable component (later identified as antibodies) and a heat-labile component, which Paul Ehrlich named 'complement.'

How do complement proteins become activated?

Complement proteins are usually inactive zymogens that require biochemical changes to become enzymatically active. Activation begins when one complement protein is cleaved, which then activates the next protein in a sequential 'molecular domino effect.'

What are the three pathways of complement activation, and how do they differ?

The three pathways of complement activation are the classical, lectin, and alternative pathways. The classical pathway is triggered by antibody binding to a pathogen, the lectin pathway is activated by carbohydrate-binding lectins, and the alternative pathway is activated by spontaneous hydrolysis of C3 or pathogen-bound C3b.

How does the classical pathway of complement activation work?

The classical pathway begins with the binding of the C1 complex (C1q, C1r, C1s) to antibodies or bacterial surfaces. C1r and C1s are activated and cleave C4 and C2 to form the C3 convertase (C4b2a), which cleaves C3, leading to further immune responses.

What role do C3a and C3b play in the complement system?

C3a is an anaphylatoxin that recruits neutrophils and other immune cells to the site of infection. C3b binds to pathogen surfaces, marking them for phagocytosis (opsonization) and can also form the C5 convertase, which leads to the formation of the membrane attack complex.

What is the membrane attack complex, and how does it destroy pathogens?

The membrane attack complex (MAC) forms when C5b binds with C6, C7, C8, and C9 proteins to create a pore in the pathogen's membrane. This pore allows water and solutes to enter, causing the pathogen to lyse and die.

How does the body regulate the complement system to prevent damage to host cells?

The complement system is regulated by several mechanisms, including the inactivation of complement proteins when not bound to pathogens, zymogen activation, and regulatory proteins like C1 inhibitor, decay-accelerating factor, and protectin, which prevent excessive complement activation and damage to host cells.

What are anaphylatoxins, and what is their role in the immune response?

Anaphylatoxins, such as C3a and C5a, are small cleavage products of complement proteins that induce smooth muscle contraction, increase vascular permeability, and recruit immune cells to infection sites. However, excessive levels can lead to anaphylactic shock.

What is the evolutionary significance of the complement system?

The complement system is evolutionarily ancient, with homologs found in invertebrates like starfish and sea urchins. The alternative pathway is likely the oldest, with the classical pathway evolving later, as it depends on antibodies, which are only present in jawed vertebrates.