Complement System: Pathways, Functions, and Clinical Implications in Immunity

Primary role of the complement system

Enhances antibody-mediated and innate immunity

Major functions of complement

Opsonization, cell lysis, inflammation, immune complex clearance

Complement activation style

Protein cascade

Three functional units of complement

Recognition, amplification, membrane attack

Recognition unit function

Detects immune complexes or pathogen surfaces

Amplification unit function

Generates C3 convertase and large amounts of C3b

Membrane attack unit function

Forms MAC (C5b-C9) causing cell lysis

Classical pathway activation trigger

Antigen-antibody complexes (IgG or IgM)

Classical pathway sequence

C1 → C4 → C2 → C3 convertase (C4b2a) → C5 → C6-C9

Alternative pathway activation trigger

Microbial surfaces; no antibody required

Alternative pathway sequence

C3 → Factor B → Factor D → C3 convertase (C3bBb) → C5 → C6-C9

Central complement component

C3

C3 cleavage products

C3a and C3b

C3a function

Anaphylatoxin; increases inflammation and vascular permeability

C3b function

Major opsonin; enhances phagocytosis; forms C5 convertase

Role of C3b in immunity

Opsonization and immune complex clearance

C1 function

Initiates classical pathway

C2 and C4 function

Form classical C3 convertase

C5a function

Strong chemotaxis and inflammation

C5b-C9 function

Membrane Attack Complex (cell lysis)

Factor B and Factor D function

Activate alternative pathway

Properdin function

Stabilizes alternative C3 convertase

Biological effects of complement activation

Cell lysis, opsonization, inflammation, chemotaxis

C1 inhibitor (C1-INH) function

Blocks C1 activation

Factor H function

Inhibits C3b in alternative pathway

Factor I function

Cleaves C3b and C4b

DAF (CD55) function

Prevents C3 convertase formation on cell membranes

CD59 function

Blocks MAC formation

Low C3 and C4 associated with

SLE and immune complex disease

C3 deficiency clinical consequence

Severe recurrent pyogenic bacterial infections

C5-C9 deficiency clinical consequence

Recurrent Neisseria infections

C1-INH deficiency causes

Hereditary angioedema

Hereditary angioedema

Severe edema without urticaria

Complement proteins as reactants

Acute-phase reactants

Conditions with elevated complement

Acute inflammation, infection, trauma, pregnancy

Low CH50 indicates

Classical pathway deficiency

Low AH50 indicates

Alternative pathway deficiency

Normal CH50 with low AH50

Alternative pathway component defect

Normal AH50 with low CH50

Classical pathway component defect

Low C1-INH lab result

Hereditary angioedema

Low C5-C9 lab result

Recurrent Neisseria infections

Main purpose of complement

Opsonization, inflammation, and cell lysis

Central complement protein

C3

Most important opsonin

C3b

Consequence of C3 deficiency

Severe recurrent pyogenic bacterial infections

Classical pathway trigger

Antigen-antibody complexes (IgG or IgM)

Alternative pathway trigger

Microbial surfaces; no antibody required

Classical pathway key sequence

C1 → C4 → C2 → C3 convertase (C4b2a)

Alternative pathway key sequence

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

Function of C3a

Anaphylatoxin causing inflammation

Function of C5a

Strong chemotaxis and inflammation

MAC components

C5b-C9

Function of MAC

Direct cell lysis

Complement components causing inflammation

C3a and C5a

Complement component for chemotaxis

C5a

Complement regulator on cell membranes

DAF (CD55)

Function of CD59

Blocks MAC formation

Function of Factor I

Cleaves C3b and C4b

Function of Factor H

Inhibits alternative pathway

C1 inhibitor deficiency causes

Hereditary angioedema

Hereditary angioedema

Severe edema without urticaria

Complement deficiency linked to Neisseria

C5-C9 deficiency

Low C3 and C4 indicates

SLE or immune complex disease

Complement levels in acute inflammation

Increased

CH50 test evaluates

Classical pathway

AH50 test evaluates

Alternative pathway

Low CH50 with normal AH50

Classical pathway defect

Normal CH50 with low AH50

Alternative pathway defect

Why IgM strongly activates complement

Pentamer structure binds C1 efficiently

Most efficient complement activator

IgM

Key exam rule

C3b = opsonization; C5-C9 = lysis