====== Complement System ======

The complement system is a plasma protein cascade that enhances innate immunity by promoting:

  * Opsonization
  * Inflammation
  * Cell lysis

It links innate and adaptive immunity.

Complement proteins circulate as inactive zymogens and become activated through proteolytic cleavage cascades.

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===== Core Functions =====

  * Opsonization (C3b)
  * Anaphylatoxin production (C3a, C5a)
  * Membrane attack complex (MAC) formation (C5b-9)
  * Immune complex clearance

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===== Pathways of Activation =====

All pathways converge at C3 activation.

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==== 1. Classical Pathway =====

Triggered by:

  * IgG or IgM bound to antigen

Sequence:

  C1 → C4 → C2 → C3 convertase (C4b2a)

Requires antibodies → links adaptive to innate immunity.

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==== 2. Lectin Pathway =====

Triggered by:

  * Mannose-binding lectin (MBL) binding to microbial carbohydrates

Sequence:

  MBL → MASP proteins → C4 + C2 → C3 convertase (C4b2a)

Antibody-independent.

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==== 3. Alternative Pathway =====

Triggered by:

  * Direct pathogen surface activation
  * Spontaneous C3 hydrolysis

Sequence:

  C3 → Factor B → Factor D → C3 convertase (C3bBb)

Provides amplification loop.

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===== Central Convergence =====

All pathways generate:

  C3 convertase → cleaves C3 into:
    * C3a (anaphylatoxin)
    * C3b (opsonin)

C5 convertase then forms → cleaves C5 into:
  * C5a (potent inflammatory mediator)
  * C5b → initiates MAC formation

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===== Membrane Attack Complex (MAC) =====

C5b → C6 → C7 → C8 → C9

C5b-9 forms pore in target membrane → cell lysis

Especially important in Neisseria infections.

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===== Anaphylatoxins =====

  * C3a
  * C5a (most potent)

Effects:

  * Mast cell degranulation
  * Increased vascular permeability
  * Neutrophil chemotaxis

Links to:
  * [[allergy:immunology:type_i_hypersensitivity|Type I Hypersensitivity]]
  * [[immunology:leukocyte_recruitment|Leukocyte Recruitment]]

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===== Complement Regulation =====

Host cells express regulatory proteins to prevent self-damage:

  * CD55 (DAF) – decay accelerating factor
  * CD59 – prevents MAC formation
  * Factor H – regulates alternative pathway

Loss of regulation → autoimmune damage.

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===== Clinical Correlations =====

C3 deficiency:
  * Recurrent pyogenic infections

C5–C9 deficiency:
  * Increased susceptibility to Neisseria

C1 inhibitor deficiency:
  * Hereditary angioedema

Complement overactivation:
  * Atypical hemolytic uremic syndrome
  * Paroxysmal nocturnal hemoglobinuria

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===== Complement Inhibitors =====

Target complement overactivation.

Class page:
  * [[immunology:drug_classes:complement_inhibitors|Complement Inhibitors]]

Key agents:

  * [[immunology:biologics:eculizumab|Eculizumab]] (C5 inhibitor)
  * [[immunology:biologics:ravulizumab|Ravulizumab]] (C5 inhibitor)
  * [[immunology:biologics:pegcetacoplan|Pegcetacoplan]] (C3 inhibitor)
  * [[immunology:biologics:avacopan|Avacopan]] (C5a receptor inhibitor)

Used in:

  * Paroxysmal nocturnal hemoglobinuria
  * Atypical hemolytic uremic syndrome
  * ANCA-associated vasculitis

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===== High-Yield Summary =====

  * Classical pathway requires antibodies.
  * Lectin pathway recognizes microbial sugars.
  * Alternative pathway amplifies activation.
  * All pathways converge at C3.
  * C3b = opsonization.
  * C5a = strongest anaphylatoxin.
  * C5b-9 = membrane attack complex.
  * Complement inhibitors block terminal cascade activation.