Complement System

Slide 1 · Complement System

Activation pathways · effector functions · regulation · disease

Dr Abu Suraih Sakhri

MBBS, MD (Pathology)

www.abusuraihsakhri.com

Slide 2 · Learning objectives

By the end of this lecture, students should be able to:

Differentiate the classical, alternative, and lectin pathways by the initiating signal.

Trace C3 and C5 cleavage to their biologically distinct products.

Explain complement-driven inflammation, opsonization, and microbial lysis.

Predict clinical phenotypes from defective complement components or regulators.

Slide 3 · Complement is a plasma-protein defense network

What the term “complement” encompasses

More than 20 proteins circulate or interact with cells as a coordinated system.

Many proteins are present as inactive precursors until an activation trigger appears.

The system participates in host defense and can mediate inflammatory tissue injury.

Slide 4 · Innate and adaptive immunity converge in complement

Innate contribution

Adaptive contribution

Alternative pathway can respond directly to microbial surface molecules.

Lectin pathway detects carbohydrate structures on microbes.

Activation can proceed before a specific antibody response.

Classical pathway recognizes antigen-bound IgM or IgG through C1.

Antibody-directed complement activation focuses effector activity on a target.

The same downstream complement machinery generates inflammatory and antimicrobial effects.

Slide 5 · Complement proteins form a coordinated cascade

Principal components and products

Several components are designated C1 through C9; Additional proteins mediate regulation and pathway initiation.

Proteolytic activation converts selected components into enzymes or biologically active fragments.

Surface-associated fragments and soluble fragments have different destinations and actions.

Slide 6 · Proteolysis drives complement activation

Successive cleavage reactions transmit and amplify the initiating signal.

Inactive precursor

Activation cleavage

Active fragment / enzyme

Cleavage of next component

An enzymatic cascade converts a recognition event into a larger effector response.

Slide 7 · Cascade amplification explains biological potency

Why a small initiating event matters

Activated complement enzymes cleave additional complement proteins.

Repeated proteolysis generates multiple active fragments from an initial trigger.

Regulatory proteins are therefore essential to confine activation to appropriate sites.

Slide 8 · C3 is the central complement component

The critical convergence point

C3 is the most abundant complement component described in the source.

Classical, alternative, and lectin pathways all culminate in its cleavage.

C3-derived fragments connect pathway activation to inflammation and opsonization.

Slide 9 · Complement activation converges on C3

CLASSICAL

Antigen–antibody + C1

ALTERNATIVE

Microbial surface

LECTIN

MBL + microbial mannose

C3 convertase

C3 → C3a + C3b

Slide 10 · Classical pathway: Antigen-bound antibody is the trigger

Recognition of an immune target

IgM or IgG first binds its cognate antigen.

C1 subsequently binds the antigen–antibody complex.

Recognition couples adaptive antibody specificity to complement activation.

Slide 11 · Classical activation requires target-bound antibody

Binding context determines activation

The Robbins description emphasizes IgM or IgG combined with antigen, not antibody alone.

The classical pathway begins with fixation of the C1 complex.

Downstream proteolysis ultimately generates a C3-cleaving enzyme.

Slide 12 · Classical pathway: Sequential activation

The sequence is simplified to the component-level description.

Antigen + IgM/IgG

C1 fixation

C2 / C4 participation

C3 convertase

The classical route uses antibody-dependent recognition to reach C3.

Slide 13 · C1 is the initiating component of the classical pathway

A selective entry point for regulation

C1 engagement follows recognition of antigen-bound IgM or IgG.

Subsequent classical-pathway activation involves C2 and C4.

C1 inhibitor restrains initiation of this pathway.

Slide 14 · C2 and C4 act upstream of C3

Early classical-pathway function

C2 and C4 participate in the sequence that produces a C3-cleaving enzyme.

Deficiency of either component can reduce classical-pathway activity.

The alternative pathway can still control many infections in some affected individuals.

Slide 15 · Mechanistic example: Antibody-coated host cell

CLINICAL PATTERN

IgM or IgG binds a surface antigen on a host cell.

Mechanistic interpretation

Classical complement activation can deposit C3-derived opsonins on the cell and promote its recognition by phagocytes; The terminal pathway may also damage the cell membrane.

Slide 16 · Alternative pathway: Microbial surfaces activate complement

Antibody-independent defense

Endotoxin (LPS), complex polysaccharides, and other activating substrates may trigger the pathway.

Classical antigen–antibody binding is not required.

This permits a direct innate response to microbial surface chemistry.

Slide 17 · Alternative pathway uses spontaneous C3 cleavage

Activation begins without an antibody trigger

Spontaneous activation of C3 provides a starting point.

Activation is amplified and stabilized on microbes or other permissive surfaces.

The pathway thereby enriches complement activity where activation can persist.

Slide 18 · Alternative-pathway amplification on microbial surfaces

The scheme shows the conceptual sequence; Detailed factor names are not required here.

Spontaneous C3 activation

Microbial surface support

Amplified C3 cleavage

C3b deposition

Local amplification is the defining feature of the alternative route.

Slide 19 · Alternative activation is not restricted to bacteria

Activating surfaces and substrates

Microbial lipopolysaccharide is one trigger.

Complex polysaccharides and other activating substances can initiate or sustain this route.

Cobra venom is listed as a nonmicrobial activator.

Slide 20 · Classical and alternative pathways differ at initiation

Classical recognition

Alternative recognition

Requires antigen-associated IgM or IgG for its characteristic trigger.

C1 is recruited to the antigen–antibody complex.

C2 and C4 contribute to the classical C3 convertase.

No antigen-bound antibody required.

Spontaneous C3 activation becomes stabilized on permissive substrates.

The route is particularly suited to microbial surface recognition.

Slide 21 · Lectin pathway recognizes microbial carbohydrates

A carbohydrate-dependent trigger

Circulating mannose-binding lectin (MBL) recognizes mannose-containing microbial surface structures.

The recognition event occurs without relying on specific antibody.

Lectin binding activates a protease with homology to C1-associated activation machinery.

Slide 22 · Lectin pathway: Recognition to C3 cleavage

After the initial recognition step, the pathway follows the classical route toward C3.

Microbial mannose

MBL binding

Associated protease activation

Classical-like downstream steps

Its recognition event is distinct; Its downstream activation sequence converges.

Slide 23 · MBL links microbial pattern recognition to complement

Mechanistic interpretation

The lectin pathway detects carbohydrate patterns on a microbial surface.

It does not require antigen-specific IgM or IgG.

MBL defects may increase susceptibility to infection.

Slide 24 · Initiation pathways: A functional comparison

Pathway

Primary trigger

Antibody required?

Classical

Antigen-bound IgM or IgG; C1 fixation

Yes, for the characteristic trigger

Alternative

Microbial surface molecules and other substrates

No

Lectin

MBL recognition of microbial carbohydrate

No

All three converge on generation of C3-cleaving activity.

Slide 25 · C3 convertase is the shared enzymatic checkpoint

Convergence despite distinct initiating signals

All three pathways form an active enzyme termed C3 convertase.

The enzyme splits C3 into C3a and C3b.

Different upstream recognition routes therefore produce overlapping downstream biological effects.

Slide 26 · C3 cleavage creates two functionally different products

C3 convertase cleaves C3

C3a — released into fluid phase

C3b — fixed to nearby surface

C3a promotes inflammation; C3b supports opsonization and further complement activation.

Slide 27 · C3a is a soluble inflammatory mediator

Consequence of C3 cleavage

C3a is released during proteolytic cleavage of C3.

It belongs to the anaphylatoxin family of complement fragments.

Its downstream vascular effects are mediated partly through mast-cell histamine release.

Slide 28 · C3b becomes fixed at the activation site

Complement is spatially organized

C3b becomes covalently attached to a nearby cell or molecular surface.

Surface attachment facilitates its function as an opsonin.

Additional deposited C3b participates in formation of C5-cleaving activity.

Slide 29 · Surface-bound C3b links recognition and effector action

One fragment contributes to two tasks

It marks a microbial surface for complement-receptor-bearing phagocytes.

It contributes to assembly of the downstream C5 convertase.

These actions connect microbial recognition to clearance and terminal activation.

Slide 30 · C5 convertase forms after additional C3b deposition

The shared downstream route builds upon prior C3 activation.

C3 cleavage

Surface C3b accumulation

Additional C3b association

C5 convertase

C5 activation depends on successful upstream complement activity.

Slide 31 · C5 cleavage generates an inflammatory and a terminal fragment

C5 convertase cleaves C5

C5a — inflammatory / chemotactic

C5b — initiates terminal assembly

C5a is released; C5b remains associated with the target surface.

Slide 32 · C5a is a potent inflammatory output

The C5 cleavage product acts on leukocytes and vessels

C5a is one of the complement anaphylatoxins.

It recruits neutrophils and several other leukocyte populations.

It also enhances the lipoxygenase pathway of arachidonic acid metabolism in neutrophils and monocytes.

Slide 33 · Terminal complement assembly builds the membrane attack complex

Late complement components assemble after cleavage of C5.

C5b deposition

C6–C8 association

Multiple C9 molecules

Membrane attack complex

The membrane attack complex (MAC) is the principal direct lytic effector.

Slide 34 · Membrane attack complex: Disruption of membrane integrity

Terminal assembly

C5b

C6–C8

Multiple C9

Permeability ↑

C5b–C9 pore (schematic)

Water / ion entry → osmotic lysis

Slide 35 · Membrane attack results in osmotic cell injury

Physical consequence of terminal complement activation

The MAC renders target membranes permeable to water and ions.

Loss of membrane integrity disturbs osmotic balance.

The resulting osmotic injury may lyse susceptible target cells.

Slide 36 · Terminal complement is especially important against Neisseria

Microbial susceptibility differs by cell-envelope properties

Killing bacteria with relatively thin cell walls, particularly Neisseria.

Deficiency of terminal components impairs membrane attack complex assembly.

The clinical consequence is susceptibility to recurrent meningococcal or gonococcal infection.

Slide 37 · One cascade, three distinct effector functions

Complement activation

C3a / C5a

Inflammation

C3b / iC3b

Opsonization

C5b–C9

Membrane lysis

Distinct cleavage products mediate different biological outcomes.

Slide 38 · Inflammation is a major complement function

Generation of inflammatory cleavage products

C5a, C3a, and to a lesser extent C4a act as anaphylatoxins.

These fragments promote mast-cell mediator release.

Complement links innate recognition to vascular and cellular inflammation.

Slide 39 · Anaphylatoxins: Relative functions

Fragment

Principal teaching function

Additional note

C5a

Inflammation and leukocyte chemotaxis

Enhances lipoxygenase pathway

C3a

Inflammatory vascular effects

Acts as an anaphylatoxin

C4a

Weaker anaphylatoxin effect

Less prominent than C3a/C5a

Slide 40 · Anaphylatoxins alter microvascular function

The vascular response helps plasma proteins and leukocytes reach an inflamed site.

C3a / C5a generation

Mast-cell histamine release

Vasodilation

Vascular permeability ↑

Inflammatory fragments act through mediator release; They are not simply pores.

Slide 41 · C5a is a leukocyte chemoattractant

Cell types explicitly named by Robbins

Neutrophils are recruited toward an inflammatory focus.

Monocytes, eosinophils, and basophils also respond to C5a.

The chemotactic effect complements C5a-mediated changes in vascular permeability.

Slide 42 · C5a amplifies mediator production in leukocytes

The source links C5a to arachidonic-acid-derived mediator production.

C5a signaling

Neutrophils / monocytes

Lipoxygenase pathway

Additional inflammatory mediators

Complement can amplify inflammation beyond its initial cleavage products.

Slide 43 · Complement-driven inflammation has a cost

Host defense and tissue injury share pathways

Greater vascular permeability and leukocyte recruitment are advantageous during microbial defense.

The same mechanisms can cause injury when activation occurs on host cells or in host tissues.

Complement regulation must protect cells without abolishing microbial defense.

Slide 44 · Opsonization is the second major complement function

Surface fragments help phagocytes recognize targets

C3b deposits on microbial surfaces.

Inactive C3b (iC3b), a cleavage product of C3b, also functions as an opsonin.

Neutrophils and macrophages express receptors for complement fragments.

Slide 45 · Complement opsonization leads to ingestion of microbes

The surface tag recruits the phagocytic machinery without itself causing lysis.

Microbial surface

C3b / iC3b deposition

Complement-receptor binding

Phagocytosis

Opsonization improves recognition; Ingestion and destruction occur in phagocytes.

Slide 46 · IC3b retains an opsonic role after C3b cleavage

Inactivation does not mean loss of all function

C3b can be cleaved to inactive C3b (iC3b).

Both C3b and iC3b as opsonins.

Complement-fragment receptors allow phagocytes to recognize coated microbes.

Slide 47 · Complement opsonization differs from antibody Fc recognition

Complement recognition

Antibody recognition

C3-derived fragments decorate target surfaces.

Neutrophils and macrophages bind complement fragments through their receptors.

Surface coating increases phagocytic recognition.

IgG-coated cells can bind Fc receptors on phagocytes.

Antigen-bound IgM or IgG can trigger classical complement activation.

Fc-receptor and complement-receptor pathways can act together.

Slide 48 · Opsonization and lysis are different complement outcomes

Opsonization

Direct lysis

C3b and iC3b tag a surface.

Requires contact with a complement-receptor-bearing phagocyte.

Promotes cellular uptake and intracellular destruction.

C5b–C9 forms a membrane attack complex.

Changes target-membrane permeability.

Can induce osmotic rupture without phagocytic ingestion.

Slide 49 · Host cells require protection from complement

Regulation prevents self-injury

Complement can deposit activated fragments on healthy as well as microbial surfaces.

Host cells express regulators that limit formation or persistence of active fragments.

Circulating regulators provide additional restraint of complement activation.

Slide 50 · Regulatory proteins interrupt complement at different stages

Complement control mechanisms

Block initiation

Destabilize convertases

Remove deposited fragments

Block membrane attack

Distinct checkpoints protect normal cells against excessive complement injury.

Slide 51 · C1 inhibitor controls classical-pathway initiation

Early control point

C1 inhibitor (C1 INH) blocks activation of the classical pathway’s first component.

It prevents unrestricted activation at the initiation stage.

An inherited deficiency is associated with hereditary angioedema.

Slide 52 · Hereditary angioedema illustrates loss of protease control

Mechanism of tissue swelling

C1 INH also regulates factor XII and the kallikrein system, not only complement.

Deficiency permits unregulated kallikrein activity and production of vasoactive peptides, including bradykinin.

The clinical phenotype is episodic edema involving skin and mucosal surfaces.

Slide 53 · Clinical correlation: Hereditary angioedema

CLINICAL PATTERN

An individual experiences recurrent episodes of swelling of the skin and mucosal surfaces; Some episodes affect the larynx or gastrointestinal tract.

Mechanistic interpretation

Loss of C1 inhibitor permits dysregulated protease activity involving the kallikrein pathway. The important risk is potentially life-threatening laryngeal edema.

Slide 54 · CD55 prevents formation of C3 convertases

Decay-accelerating factor (DAF)

CD55 is also known as decay-accelerating factor.

It is attached to the cell membrane by a glycosylphosphatidylinositol (GPI) anchor.

Its protective action reduces persistence or formation of C3-cleaving activity on host surfaces.

Slide 55 · CD59 prevents membrane attack complex assembly

Terminal protection of host cells

CD59 is a GPI-anchored complement regulatory protein.

Its main action is to inhibit formation of the membrane attack complex.

Together, CD55 and CD59 act at distinct levels of the cascade.

Slide 56 · Complement regulation: Site and mechanism

Regulator

Primary control point

Consequence of loss

C1 INH

Initiation / regulated proteases

Hereditary angioedema

CD55 (DAF)

C3 convertases

Excess C3 activation on affected cells

CD59

Membrane attack complex

Complement-mediated cell lysis

Factor H

Alternative pathway C3b and convertases

Complement-associated vascular injury

Slide 57 · GPI anchoring localizes CD55 and CD59 to cell membranes

Why one biosynthetic defect affects two inhibitors

Both CD55 and CD59 are attached to the plasma membrane by GPI anchors.

An acquired defect in GPI-anchor synthesis can remove multiple surface protective proteins.

The resulting loss of restraint makes vulnerable cells susceptible to complement-mediated injury.

Slide 58 · Clinical correlation: Paroxysmal nocturnal hemoglobinuria

CLINICAL PATTERN

An acquired cellular defect eliminates normal GPI-anchored protective proteins, including CD55 and CD59, from affected erythrocytes.

Mechanistic interpretation

The red cell loses convertase and terminal-pathway protection and becomes susceptible to complement-mediated hemolysis.

Slide 59 · Factor H restrains the alternative pathway

Circulating control of deposited complement

Factor H is a circulating glycoprotein that limits the alternative complement pathway.

It promotes cleavage and inactivation of C3b.

It also promotes turnover of C3 convertases, thereby reducing amplification.

Slide 60 · Factor H deficiency can damage glomerular endothelium

A mechanistic sequence described for atypical hemolytic uremic syndrome.

Defective alternative-pathway control

Excess complement deposition

Glomerular endothelial injury

Platelet-rich thrombi

Regulatory failure may produce thrombotic microangiopathic injury.

Slide 61 · Clinical correlation: Atypical hemolytic uremic syndrome

CLINICAL PATTERN

Inherited abnormalities of Factor H or interacting complement regulatory proteins impair control of alternative-pathway activation.

Mechanistic interpretation

Uncontrolled complement deposition in glomerular vessels can injure endothelium and favor platelet-rich thrombus formation.

Slide 62 · Factor H variants are also linked to retinal degeneration

A distinct consequence of complement dysregulation

An association between Factor H gene polymorphisms and age-related macular degeneration.

The association implicates complement regulation in a disease outside acute infection.

The source describes a genetic association; It does not provide a quantitative individual risk estimate.

Slide 63 · Complement activation can injure host tissue

Immune complexes and surface-reactive antibodies

Antibodies or antigen–antibody complexes may accumulate on host cells and tissues.

Complement activated at those sites contributes to inflammation, opsonization, and tissue injury.

The protective cascade becomes pathogenic when its effector mechanisms target self.

Slide 64 · Early classical-component deficiency may associate with autoimmunity

Deficiencies of C1q, C2, and C4

C2 deficiency is described as the most common complement-protein deficiency.

Early classical-pathway deficiencies can predispose to infection, but some individuals have no symptoms.

Deficiency of C1q, C2, or C4 may present prominently with systemic lupus erythematosus.

Slide 65 · C3 deficiency compromises multiple complement effects

A shared-pathway failure

C3 is required for the convergent downstream responses of all three pathways.

Deficiency may cause serious, recurrent pyogenic infection.

Robbins also describes increased immune complex–mediated glomerulonephritis.

Slide 66 · Alternative-pathway deficiencies increase infection risk

Properdin and factor D

Deficiencies affecting properdin or factor D are described as rare.

Loss of alternative-pathway function is associated with recurrent pyogenic infections.

The phenotype reflects weakened antibody-independent complement defense.

Slide 67 · MBL deficiency weakens lectin-pathway initiation

A recognition defect rather than terminal lysis defect

Inherited deficiency or defective MBL impairs the lectin pathway’s recognition event.

The textbook associates this abnormality with increased susceptibility to infection.

This differs mechanistically from deficiency of terminal C5–C9 components.

Slide 68 · Terminal-component deficiency preferentially predisposes to Neisseria

Loss of membrane attack

C5, C6, C7, C8, and C9 are required for MAC formation.

Deficiency is associated with recurrent Neisseria infections.

Classical and alternative upstream activation may remain possible despite ineffective terminal lysis.

Slide 69 · Complement defects predict characteristic clinical patterns

Affected component

Primary mechanism

Illustrative clinical phenotype

C1q / C2 / C4

Impaired early classical pathway

Infection ± SLE

C3

Loss of major shared effector functions

Recurrent severe pyogenic infection

Factor D / properdin

Alternative-pathway defect

Recurrent pyogenic infection

C5–C9

Deficient membrane attack complex

Recurrent Neisseria infection

C1 INH / CD55 / CD59 / Factor H

Loss of complement regulation

Angioedema / PNH / complement-associated vascular injury

Slide 70 · Complement inhibition targets the cascade itself

A therapeutic principle stated in the source

Inhibitors of complement C5 activation are approved for several complement-mediated disorders.

Inhibitors of C3 activation have also entered approved clinical use.

The clinical rationale is to block pathological complement effects while recognizing its host-defense function.

Slide 71 · Clinical reasoning: Recurrent Neisseria infections

CLINICAL PATTERN

A patient has repeated meningococcal or gonococcal infections without an explanation based on leukocyte dysfunction.

Mechanistic interpretation

Consider deficiency of late complement components: C5–C9-dependent membrane attack is particularly important against Neisseria.

Slide 72 · Clinical reasoning: Severe recurrent pyogenic infection

CLINICAL PATTERN

A patient has recurrent serious pyogenic bacterial infections together with evidence of immune complex–related glomerular injury.

Mechanistic interpretation

A shared complement-component defect such as C3 deficiency can impair opsonization and multiple complement functions.

Slide 73 · Pathogenic complement: Too little versus too much

SOLUBLE / INFLAMMATORY

Complement component deficiency

Inadequate opsonization / lysis

Susceptibility to infection

MEMBRANE / CELL-ASSOCIATED

Regulator deficiency

Excess activation on host structures

Tissue or vascular injury

Clinical phenotypes depend on where the cascade is impaired.

Slide 74 · Synthesis: Four mechanistic checkpoints

Follow the biological logic rather than memorizing isolated proteins

Recognition: Classical, alternative, or lectin trigger.

Amplification: Generation of C3 convertase and C3 cleavage.

Effector action: Inflammation, C3b/iC3b opsonization, or C5b–C9 lysis.

Regulation: Initiation, convertase, and terminal controls prevent host injury.

Slide 75 · Mechanism-based revision questions

Question

Mechanism-based answer

Why do three pathways produce overlapping effects?

All form C3 convertase.

Which C3 product marks target surfaces?

C3b; iC3b retains opsonic activity.

Which complement product recruits leukocytes?

C5a (especially important).

What causes osmotic membrane injury?

C5b–C9 membrane attack complex.

Why does GPI-anchor loss favor hemolysis?

Affected red cells lose CD55 and CD59 protection.

Slide 76 · References and source boundaries

Primary textbook

Robbins, Cotran & Kumar: Pathologic Basis of Disease. 11th ed. 2026.

Chapter 3: Inflammation and Repair — “Complement System,” pp. 81–82.

Chapter 6: Diseases of the Immune System — complement deficiencies; antibody-mediated cellular injury.

Original explanatory diagrams were constructed from the supplied textbook material. No source figure or specimen was reproduced.