Complement System Pathways

• The complement system originated in organisms with rudimentary immune systems.
• It can be activated by both antibodies and components of the innate immunity.
• The complement system circulates in the blood serum, acting as a form of circulating immunity.
• Complement activation occurs through three pathways, ultimately leading to inflammation and immune clearance.
• Complement components make up 5% of blood serum by weight.
• The three complement pathways converge to form the membrane attack complex (MAC).

Complement Pathways: Activation and Function

• Focus should be placed on the requirements for activation and the unique function for each complement fragment for each pathway.

Alternative Pathway

• Activated by the spontaneous hydrolysis of C3.
• C3b fragment attaches to foreign microbes.
• Factor B and factor D, which are soluble proteins, help form C3 convertase.
• C3 convertase is an enzyme that creates more C3 and forms C5 convertase.
• The purpose of C5 convertase is to attach C5b to the surface of microbes and form the MAC.

Lectin Pathway

• Mannose-binding lectin (MBL) activates the lectin complement pathway.
• MBL is an acute phase protein that increases during inflammation.
• MBL binds to mannose residues on glycoproteins or carbohydrates (sugars) on the surface of microbes.
• Human cells are protected because they have sialic acid residues covering their sugar groups, preventing MBL recognition.
• After MBL binds, MBL-associated proteases MASP-1 and MASP-2 bind to MBL, causing cleavage and activation of C4 and C2.
• C3 convertase is then formed, leading to C5 convertase and culminating in the MAC.

Classical Pathway

• Formation of an antigen-antibody complex induces a conformational change in the Fc portion of the IgM molecule.
• This creates a binding site for C1 on the surface of a microbe, activating the classical pathway.
• The antibody-C1 complex cleaves C4 and C2, leading to the formation of C3 and C5 convertase.
• This consequently leads to the formation of the MAC.

Pathway Convergence and Overlap

• The three complement pathways are interconnected and do not operate independently.
• The classical and lectin pathways have considerable overlap in activation.
• All three pathways converge by forming C3 and C5 convertase, which leads to the MAC and cell lysis.

Pathway Initiation

• Classical Pathway: Initiated by the binding of complement component C1 to antigen-antibody complexes, specifically the Fc region of IgM or IgG antibodies bound to antigens.

• Lectin Pathway: Initiated by pattern recognition molecules (mannose-binding lectin, ficolins) binding to carbohydrate patterns on the surface of pathogens.

• Alternative Pathway: Initiated by the spontaneous hydrolysis of C3, leading to the formation of C3(H2O).

Sequence Differences and Similarities Between Pathways

• Classical Pathway:

• Activation of C1 leads to the cleavage of C4 and C2, forming the classical pathway C3 convertase (C4b2a).

• The classical pathway C3 convertase cleaves C3 into C3a and C3b.

• Lectin Pathway:

• Activation leads to the cleavage of C4 and C2, forming the lectin pathway C3 convertase (C4b2a).

• The lectin pathway C3 convertase cleaves C3 into C3a and C3b.

• Alternative Pathway:

• Initiated by the spontaneous hydrolysis of C3, leading to the formation of C3(H2O).

• Properdin stabilizes the C3 convertase (C3bBb) formed by the association of C3(H2O) with factor B.

• Shared Steps:

• All pathways converge at the formation of the C5 convertase (C4b2a3b or C3bBb3b), which cleaves C5 into C5a and C5b.

• C5b initiates the assembly of the MAC, leading to the formation of a pore on the pathogen surface.

Consequences of Pathway Dysfunction

• Classical Pathway Dysfunction:

• Leads to impaired clearance of immune complexes.

• Reduces opsonization of pathogens, leading to decreased phagocytosis.

• Decreases formation of the membrane attack complex (MAC), affecting direct lysis of pathogens.

• Example: Systemic Lupus Erythematosus (SLE), is associated with dysfunction in the classical pathway, leading to impaired clearance of immune complexes.

• Lectin Pathway Dysfunction:

• Leads to impaired recognition and opsonization of certain pathogens, especially those with carbohydrate patterns recognized by lectins.

• Results in reduced activation of the downstream complement cascade.

• Example: Mannose-Binding Lectin (MBL) Deficiency, is associated with increased susceptibility to infections, particularly those caused by bacteria with mannose-rich surfaces.

• Alternative Pathway Dysfunction:

• Leads to impaired amplification of the complement cascade.

• Reduces opsonization and phagocytosis of pathogens.

• Decreases formation of the MAC and causes compromised direct lysis of pathogens.

• Example: Atypical Hemolytic Uremic Syndrome (aHUS), is associated with dysregulation of the alternative pathway, leading to excessive complement activation.

• General Consequences of Complement Dysfunction:

• Increases susceptibility to infections due to the compromised ability to clear pathogens.

• Autoimmune Disorders may develop due to dysregulation in complement activation, as seen in SLE.

• Inflammatory Conditions can arise from excessive or insufficient inflammation due to dysfunctional complement activation.

• Impaired Immune Surveillance results from dysfunctional complement pathways affecting the immune system's ability to eliminate abnormal cells, pathogens, and immune complexes.

Importance of Specific Complement Fragments

• Each complement fragment has a specific role.
• Understanding each role is important for understanding complement regulation and disorders.
• These disorders originate from the absence or dysfunction of specific complement fragments.
• The complement fragments generated by the liver are particularly important.
• These fragments are essential not only for forming the MAC but also for developing an effective inflammatory response.
• The development of an effective inflammatory response is essential for bridging the innate and adaptive immune responses.

Key Complement Functions

• C3b facilitates phagocytosis and opsonization.
• Certain fragments are needed for the formation of the MAC.
• Early complement deficiencies of C1 through C4 increase the risk of recurrent respiratory tract infections.
• Deficiencies of terminal complement fragments involved in MAC formation increase the risk of Neisseria meningitis and related bacterial infections.

Additional Roles of Complement Fragments

• C3b acts as an opsonin, aiding immune cells in phagocytizing debris.
• C5a and C3a act as chemotaxins, which recruit neutrophils, eosinophils, monocytes, and macrophages to the site of inflammation.
• C5a and C3a are also anaphylatoxins, which help basophils and mast cells degranulate, releasing pro-inflammatory molecules like histamine and heparin.
  • This can cause smooth muscle contraction, bronchiole constriction, and increased vascular permeability.

Consequences of Complement Deficiencies

• Deficiencies in C1, C2, C3, and C4, which are involved in removing antigen-antibody complexes, can result in a lupus-like illness, chronic renal disease, and repeated infections.
• Deficiencies in C5, C6, C7, or C8 lead to repeated Neisseria infections and a higher risk of developing gonorrhea or meningitis.
• Deficiencies in C9 appear to have no significant problems because C5, C6, C7, and C8 can lyse bacteria on their own. C9 is just enhancement.