Complement and complement cascade

Introduction

The complement system, a key component of the immune system, plays an essential role in the recognition, opsonization (coating with proteins to facilitate phagocytosis), and destruction of foreign substances such as viruses, bacteria, and abnormal cells. This cascade of reactions is collectively known as the complement cascade, which involves a series of proteins that are activated in a stepwise manner, ultimately resulting in the lysis (bursting) of target cells or the promotion of phagocytosis. In this comprehensive course, we will delve into the intricacies of the complement system and the complement cascade, exploring their roles, mechanisms, regulation, and clinical significance.

Chapter 1: Overview of the Complement System

1.1 Structure and Components of the Complement System

• The complement system consists of over 30 proteins, divided into three pathways (classical, alternative, and lectin) and a terminal phase common to all three pathways.

1.2 Activation of the Complement System Pathways

• Classical pathway: activated by antibody-antigen complexes or other molecules on the surface of foreign cells
• Alternative pathway: constitutively active in the fluid and tissues, primed to respond rapidly to microbial surfaces
• Lectin pathway: triggered by mannose-binding lectin (MBL) or ficolins binding to carbohydrates on the surface of microbes

Chapter 2: The Classical Pathway

2.1 Initiation and Amplification Steps

• C1 complex recognition and activation by antibody-antigen complexes
• Formation of the C3 convertase (C4b2a or C4b2a2) and its amplification to generate more C3 convertases

2.2 Terminal Phase and Membrane Attack Complex (MAC) Formation

• C5 convertase formation, leading to the cleavage of C5 into C5a and C5b
• Assembly of the membrane attack complex (MAC), comprising C6, C7, C8, and multiple copies of C9, which insert into the cell membrane of the target and cause its lysis

Chapter 3: The Alternative Pathway

3.1 Initiation and Amplification Steps

• Spontaneous activation of C3 on the surface of microbial cells or activated C3b deposited from the classical pathway can bind to factor B, forming C3bB (also known as C3 convertase).
• Amplification step: the product of the C3 convertase reaction (C3bBb) cleaves more C3, leading to the formation of C3bBb2 and C3bBb3, collectively called properdin-dependent C3 convertases.

3.2 Terminal Phase and MAC Formation

• Similar to the classical pathway, the terminal phase involves the sequential activation of C5, C6, C7, C8, and C9, resulting in MAC formation and lysis of the target cell

Chapter 4: The Lectin Pathway

4.1 Initiation Steps

• Recognition and binding of mannose-binding lectin (MBL) or ficolins to carbohydrate structures on microbial surfaces, leading to the formation of MBL-associated serine proteases (MASPs)
• Activation of C4 and C2 by MASP-1 and MASP-2, respectively, forming C3 convertase (C4b2a or C4b2a2) similar to the classical pathway

4.2 Terminal Phase and MAC Formation

• The terminal phase follows the same steps as in the classical and alternative pathways, leading to MAC formation and lysis of the target cell

Chapter 5: Regulation and Clinical Significance

5.1 Regulation of the Complement System

• Inhibitory proteins such as C1 inhibitor, C4b-binding protein, factor H, and factor I control complement activation by inhibiting or degrading activated complement components

5.2 Clinical Significance and Disorders of the Complement System

• Dysregulation of the complement system can lead to autoimmune diseases (e.g., atypical hemolytic uremic syndrome, systemic lupus erythematosus) or increased susceptibility to infections (e.g., C3 deficiency).

Chapter 6: Conclusion and Future Directions

• The complement system plays a crucial role in innate immunity by recognizing and destroying foreign substances, but dysregulation can lead to autoimmune diseases or increased susceptibility to infection.
• Understanding the intricacies of the complement cascade is essential for developing targeted therapies for various immune-related disorders.