CHPT 4 - new

SUMMARY

• Complement is central to the development of inflammatory reactions and forms one of the major immune defense systems of the body. It serves as a link between the innate and adaptive arms of the immune system.

• Complement activation pathways have evolved to label pathogens for elimination. The key pathways include:

  • Classical Pathway: Links to the adaptive immune system through antibodies ($IgG$ or $IgM$).

  • Alternative Pathway: Provides antibody-independent innate immunity and amplifies the classical pathway through a process called tickover.

  • Lectin Pathway: Similar to the classical pathway but does not require antibodies; instead, it uses mannose-binding lectin (MBL) or ficolins.

• The complement system is rigorously controlled to protect the body from excessive inflammatory responses and self-damage. Key inhibitors include:

  • C1 inhibitor (C1-INH): Controls the classical and lectin pathways by inactivating $C1r$, $C1s$, and $MASPs$.

  • Decay and enzymatic degradation: Proteins like Decay-Accelerating Factor (DAF/CD55) and Factor H regulate C3 and C5 convertase activity.

  • CD59 (Protectin): Inhibits membrane attack complex (MAC) formation on host cells, preventing damage to adjacent healthy cells.

FUNCTIONS OF COMPLEMENT

• Complement has multiple effector functions:

  • Opsonization: Tags pathogens for destruction by coating them with protein fragments like C3b and iC3b, which are recognized by phagocytes.

  • Chemotaxis: Small fragments such as C3a and C5a act as anaphylatoxins, attracting immune cells to sites of infection.

  • Cell Activation: Turns on immune cells (like mast cells and neutrophils) for enhanced function and inflammatory response.

  • Lysis of Target Cells: Destroys infected or abnormal cells directly through the assembly of the membrane attack complex (MAC), which creates pores in cell membranes.

  • Priming of Adaptive Immune Response: Enhances the efficacy of antibodies and promotes B-cell activation through receptors like CR2.

COMPLEMENT DEFICIENCIES

• Deficiencies in complement components illustrate its essential homeostatic roles:

  • Classical Pathway Deficiencies: Lead to impaired clearance of immune complexes and tissue inflammation. Examples include C1, C4, and C2 deficiencies, which often manifest as autoimmune diseases like systemic lupus erythematosus (SLE).

  • Mannan-Binding Lectin (MBL): Deficiency is associated with increased susceptibility to infections, particularly during the "immunological gap" in infants.

  • Alternative Pathway and C3 Deficiencies: Involved in severe bacterial infections (especially encapsulated bacteria) because C3 is central to all pathways.

  • Terminal Pathway Deficiencies: Deficiencies in C5, C6, C7, C8, or C9 specifically precipitate Gram-negative bacterial infections, such as those caused by Neisseria.

  • C1 Inhibitor Deficiency: Results in hereditary angioedema (HAE), a condition of recurrent, localized swelling.

COMPLEMENT AND INFLAMMATION

• The complement system enhances both innate and adaptive immunity through:

  • Triggering and amplifying inflammatory reactions via anaphylatoxins.

  • Attracting phagocytes to the site of infection via chemotaxis.

  • Clearing immune complexes and dead cells (apoptotic debris) to maintain tissue health.

  • Activating cellular processes that lead to the direct killing of microbes.

COMPLEMENT ACTIVATION PATHWAYS

Overview

• Complement activation occurs through three primary pathways that converge at the formation of the C3 convertase:

  1. Classical Pathway — Triggering: Antibody-Antigen complexes.

  2. Lectin Pathway — Triggering: Lectins binding to specific carbohydrates on pathogens.

  3. Alternative Pathway — Triggering: Pathogen surfaces and spontaneous hydrolysis.

Classical Pathway

• Activated by antibody-antigen complexes and requires calcium ions ($Ca^{2+}$).

• Involves the C1 complex, which consists of:

  • C1q: Recognizes the $Fc$ portion of the antibody.

  • C1r & C1s: Enzymatic units that cleave C4 and C2 to form the C3 convertase ($C4b2a$).

Alternative Pathway

• Constantly active at low levels (‘tickover’) and does not require antibodies. It requires magnesium ions ($Mg^{2+}$).

• Initiated by the binding of C3b to Factor B, which is subsequently cleaved by Factor D to generate the C3 convertase, C3bBb.

• Properdin stabilizes this convertase, providing a positive feedback loop to amplify activation.

Lectin Pathway

• Activated by the binding of Mannose-Binding Lectin (MBL) to carbohydrates on pathogen surfaces.

• Involves MASP-1 and MASP-2, which function similarly to C1r and C1s to cleave C4 and C2, creating the same C4b2a convertase used in the classical pathway.

TERMINAL PATHWAY

• All pathways converge on the terminal pathway, which generates the Membrane Attack Complex (MAC) ($C5b-9$).

• The process begins when C5 is cleaved into C5a and C5b.

• C5b recruits C6, C7, C8, and multiple C9 molecules to form a lytic pore in the pathogen's membrane.

Regulation of the Terminal Pathway

• CD59 (Protectin) is the most critical regulator on host cells, inhibiting the final stage of MAC assembly.

• Fluid-phase regulators like S protein (vitronectin) and clusterin prevent the MAC from assembling in the blood or lymph, protecting "bystander" cells.

COMPLEMENT RECEPTORS

• Cells express various Complement Receptors (CR) to mediate biological effects:

  • CR1 (CD35): Binds C3b and C4b; acts as a cofactor for Factor I and promotes phagocytosis.

  • CR2 (CD21): Binds C3d; involved in the activation of B cells.

  • CR3 & CR4: Bind iC3b; important for leukocyte adhesion and migration.

  • C3a and C5a Receptors: Mediate the pro-inflammatory effects of anaphylatoxins.

COMPLEMENT FUNCTIONS IN DISEASE

• While protective, complement can contribute to pathologic processes, including chronic inflammation and autoimmune damage.

COMPLEMENT DEFICIENCIES AND DISEASES

• Genetic deficiencies serve as models to understand immunologic defense and potential treatments:

  • Susceptibility to recurrent infections and susceptibility to autoimmune disease are hallmarks of complement defects.

  • Laboratory Tests: The CH50 assay measures classical pathway activity, while the AH50 assay measures the alternative pathway.

  • Polymorphisms: Variations in Factor H are linked to conditions like age-related macular degeneration (AMD).

FURTHER READING

• Comprehensive references are available for deeper study into the specific molecular mechanisms of each protein component within the immune system's network.