Complement System -

Introduction & Pathways/

Functions and Regulation
 The Complement System: A Major Effector of Humoral Immunity

❑ The complement system is a crucial part of the humoral branch of the immune system, playing a vital role in
immune defense.

❑ Discovered in the 1890s, the complement system was first studied by Jules Bordet at the Institut Pasteur in Paris.

Key Historical Discoveries:

•Bordet found that sheep antiserum to Vibrio cholerae lysed the bacteria, but heating the serum destroyed this lytic
activity.
•The activity was restored when fresh serum (without antibodies) was added, revealing two essential components:
• Heat-stable antibodies
• A heat-sensitive factor responsible for lysis (later known as complement)
•Bordet developed a simple hemolysis test using antibody-coated red blood cells.

Further Contributions:

•Paul Ehrlich, working independently in Berlin, coined the term “complement”.

• Defined it as: "The activity of blood serum that completes the action of antibody."
•Subsequent research revealed that the complement system comprises a large, complex group of interacting proteins.
 Functions of the Complement System

Overview of Complement Functions

❑ The complement system now includes over 30 soluble and membrane-bound proteins.
❑ It plays a critical role in both innate and acquired immunity, expanding far beyond its originally recognized
function of antibody-mediated lysis.
❑ Evolutionary studies show its origins in primitive organisms with basic innate immunity, while modern research
demonstrates its influence on adaptive immune processes, such as B-cell regulation.
❑ Complement: A Bridge Between Innate and Acquired Immunity
❑ Complement components function in a highly regulated enzymatic cascade following activation.
❑ These coordinated reactions result in multiple essential immune functions:

Major Functions of the Complement System

❑ Lysis of pathogens such as bacteria, viruses, and host cells (when marked for destruction).
❑ Opsonization: Coating of antigens to enhance phagocytosis by immune cells.
❑ Activation of immune cells through binding to specific complement receptors, leading to:
• Initiation of inflammatory responses
• Secretion of immunoregulatory molecules
❑ Immune clearance: Facilitates removal of antigen-antibody complexes from circulation, depositing them in the
spleen and liver for degradation.
The multiple activities of the complement system. Serum complement proteins and membrane-bound complement receptors partake in a
number of immune activities: lysis of foreign cells by antibody-dependent or antibody-independent pathways; opsonization or uptake of
particulate antigens, including bacteria, by phagocytes; activation of inflammatory responses; and clearance of circulating immune
complexes by cells in the liver and spleen. Soluble complement proteins are schematically indicated by a triangle and receptors by a semi-
circle; no attempt is made to differentiate among individual components of the complement system here.
 Complement Components – Origin, Structure & Activation

Synthesis and Circulation Component Nomenclature

Complement Proteins
↓ → Named by:
Synthesized by: - Numerals: C1 to C9
- Liver hepatocytes (major source) - Letters: e.g., Factor D
- Blood monocytes - Trivial names: e.g., Homologous Restriction Factor
- Tissue macrophages
- Epithelial cells (GI & GU tracts) → Cleavage fragments:
↓ - Smaller = “a” (e.g., C3a) → diffuses to trigger
Make up ~5% of serum globulin fraction inflammation
↓ - Larger = “b” (e.g., C3b) → binds near activation site
Circulate as inactive proenzymes (zymogens) (Note: C2 is an exception: C2a is larger than C2b)
↓
Activated by proteolytic cleavage → removes inhibitory → Enzymatic complexes formed:
fragment → exposes active site - e.g., C4b2a, C3bBb
Three Activation Routes:
┌────────────────────┬───────────
───────────┬─────────────────────┐
│ Classical Pathway │ Alternative Pathway │ Lectin Pathway │
│ Triggered by: │ Triggered by: │ Triggered by: │
│ - Ag-Ab complex │ - Pathogen surfaces │ - MBL binding to │
│ (IgG or IgM) │ (no antibodies) │ mannose residues │
└────────────────────┴───────────
───────────┴─────────────────────┘
↓
C3 convertase formed (e.g., C4b2a or C3bBb)
↓
Cleavage of C3 → C3a + C3b
↓
Formation of C5 convertase
↓
Cleavage of C5 → C5a + C5b
↓
Common Terminal Pathway:
C5b → C6 → C7 → C8 → C9
↓
**Membrane Attack Complex (MAC) Formation**
↓
**Lysis of target cells (bacteria, viruses, infected cells)**
 Classical Pathway – Antigen-Antibody Initiated Activation

Initiation of Classical Pathway

•Begins with the formation of antigen-antibody complexes (immune

complexes) or antibody binding to antigens on target cells.
•Only IgM and IgG subclasses (IgG1, IgG2, IgG3) can activate the
classical pathway.
•Inactive components involved: C1, C2, C3, and C4 (present in plasma
as zymogens).
Role of C1 Complex
•C1 complex = C1q + 2 C1r + 2 C1s (C1qr₂s₂), stabilized by Ca²⁺ ions.
•C1q has six collagen-like triple helical arms that bind to Fc region
(CH₂ domain) of antibodies. Structure of the C1 macromolecular complex. (a) Diagram of
C1qr2s2 complex. A C1q molecule consists of 18 polypeptide
•At least 2 Fc sites must bind C1q for stable activation. chains arranged into six triplets, each of which contains one A,
•Pentameric IgM (in "staple" form when bound to antigen) exposes ≥3 one B, and one C chain. Each C1r and C1s monomer contains a
C1q binding sites. catalytic domain with enzymatic activity and an interaction
•IgG has only 1 C1q-binding site → requires ≥2 IgG molecules within domain that facilitates binding with C1q or with each other. (b)
30–40 nm for activation. Electron micrograph of C1q molecule showing stalk and six
globular heads. [Part (b) from H. R. Knobel et al., 1975, Eur. J.
•Thus, 1 IgM can activate complement vs. ~1000 IgG molecules Immunol. 5:78.]
needed on a red cell.
 Hydrolysis of C3 by C3 convertase C4b2a (a) Native C3. (b)
Activated C3 showing site of cleavage by C4b2a resulting in
production of the C3a and C3b fragments. (c) A labile internal
thioester bond in C3 is activated as C3b is formed, allowing the C3b
fragment to bind to free hydroxyl or amino groups (R) on a cell
membrane. Bound C3b exhibits various biological activities,
including binding of C5 and binding to C3b receptors on phagocytic
cells.
Schematic diagram of intermediates in the classical
pathway of complement activation. The completed
membrane attack complex (MAC, bottom right) forms a
large pore in the membrane
 Classical Pathway – Antigen-Antibody Initiated Activation

Initiation of Classical Pathway

•Begins with the formation of antigen-antibody complexes (immune complexes) or antibody binding to
antigens on target cells.
•Only IgM and IgG subclasses (IgG1, IgG2, IgG3) can activate the classical pathway.
•Inactive components involved: C1, C2, C3, and C4 (present in plasma as zymogens).

Role of C1 Complex
•C1 complex = C1q + 2 C1r + 2 C1s (C1qr₂s₂), stabilized by Ca²⁺ ions.
•C1q has six collagen-like triple helical arms that bind to Fc region (CH₂ domain) of antibodies.
•At least 2 Fc sites must bind C1q for stable activation.
•Pentameric IgM (in "staple" form when bound to antigen) exposes ≥3 C1q binding sites.
•IgG has only 1 C1q-binding site → requires ≥2 IgG molecules within 30–40 nm for activation.
•Thus, 1 IgM can activate complement vs. ~1000 IgG molecules needed on a red cell.
 Alternative Pathway – Antibody-Independent Activation

Key Features

❑ Does not require antigen-antibody complex → part of innate immunity.

❑ Major serum proteins involved: C3, Factor B, Factor D, Properdin.
❑ Initiated by foreign surfaces (e.g., bacterial cell walls, yeast, viral envelopes).
❑ Spontaneous hydrolysis of unstable thioester bond in C3 → forms C3a + C3b.
❑ Host cells (with high sialic acid) inactivate C3b rapidly → protects self.
❑ Foreign cells (low sialic acid) retain active C3b → triggers further complement steps.

Formation of C3 Convertase (C3bBb)

❑ Surface-bound C3b binds Factor B → forms C3bB.

❑ Factor D cleaves bound Factor B → releases Ba, forms C3bBb.
❑ C3bBb = C3 convertase (unstable, 5-min half-life).
❑ Properdin binds and stabilizes C3bBb → increases half-life to ~30 minutes.
Hydrolysis of C3 by C3 convertase C4b2a (a) Native C3. (b) Activated C3 showing site of cleavage by C4b2a
resulting in production of the C3a and C3b fragments. (c) A labile internal thioester bond in C3 is activated as
C3b is formed, allowing the C3b fragment to bind to free hydroxyl or amino groups (R) on a cell membrane.
Bound C3b exhibits various biological activities, including binding of C5 and binding to C3b receptors on
phagocytic cells.
Alternative Pathway – Amplification & C5 Convertase Formation

Amplification Mechanism

✓ Once C3bBb (C3 convertase) is formed and stabilized by Properdin, it becomes enzymatically active.
✓ This active convertase cleaves multiple native C3 molecules into C3a and C3b.
✓ Newly generated C3b binds to the pathogen surface → recruits more Factor B → more C3bBb is formed.
✓ This forms a positive feedback loop, leading to rapid amplification of the response.
✓ In less than 5 minutes, over 2 million C3b molecules may be deposited on a single microbial surface.

C5 Convertase Formation

✓ When an additional C3b binds to C3bBb, the complex becomes C3bBb3b.

✓ This trimolecular complex acts as C5 convertase in the alternative pathway.

C5 Cleavage and Downstream Effects

✓ C3b component of C5 convertase binds C5 and brings it into the enzyme's proximity.
✓ The Bb component then cleaves C5 into:
• C5a: A potent anaphylatoxin and chemoattractant → promotes inflammation and recruits immune cells.
• C5b: Initiates assembly of the Membrane Attack Complex (MAC) by sequentially binding C6, C7, C8, and multiple
C9.
Schematic diagram of intermediates in the formation of bound C5b by the
alternative pathway of complement activation. The C3bBb complex is stabilized
by binding of properdin. Conversion of bound C5b to the membrane-attack
complex occurs by the same sequence of reactions as in the classical pathway
Lectin Pathway – Antibody-Independent but Classical-Like

Initiation of the Lectin Pathway

•The Lectin pathway is activated without antibody, making it part of the innate immune system.
•It begins when mannose-binding lectin (MBL) binds to mannose residues on microbial surfaces.
•MBL is a soluble pattern recognition receptor and an acute-phase protein produced during inflammation.

Microorganisms Targeted

•MBL binds to mannose-rich glycans on pathogens such as:

• Salmonella, Listeria, Neisseria
• Fungi: Cryptococcus neoformans, Candida albicans

MBL-MASP Complex Formation

•Once MBL binds to the pathogen, it associates with MBL-associated serine proteases (MASPs):
• MASP-1 and MASP-2
•These serine proteases are structurally and functionally similar to C1r and C1s of the classical pathway.
Activation of C4 and C2

•The MBL–MASP complex cleaves:

• C4 → C4a + C4b
• C2 → C2a + C2b

•C4b binds to the microbial surface and recruits C2a, forming the C4b2a complex.

•This complex is the C3 convertase, just like in the classical pathway.

C5 Convertase and Terminal Events

•When an additional C3b joins the C3 convertase, it becomes C4b2a3b — the C5 convertase.
•This initiates the terminal pathway leading to:

• C5 cleavage into C5a (anaphylatoxin) and C5b

• Formation of the Membrane Attack Complex (MAC)
Innate Immune Significance
•The lectin pathway bridges innate and adaptive immunity by mimicking classical pathway mechanisms without
requiring antibodies.
•It plays a crucial first-line defense role, especially in early infection.
Overview of the complement activation
pathways. The classical pathway is initiated
when C1 binds to antigen-antibody
complexes. The alternative pathway is
initiated by binding of spontaneously
generated C3b to activating surfaces such as
microbial cell walls. The lectin pathway is
initiated by binding of the serum protein
MBL to the surface of a pathogen. All three
pathways generate C3 and C5 convertases
and bound C5b, which is converted into a
membrane-attack complex (MAC) by a
common sequence of terminal reactions.
Hydrolysis of C3 is the major amplification
step in all pathways, generating large
amounts of C3b, which forms part of C5
convertase. C3b also can diffuse away from
the activating surface and bind to immune
complexes or foreign cell surfaces, where it
functions as an opsonin.
 Convergence of Complement Pathways – Formation of Membrane Attack Complex (MAC)

Common Endpoint of Classical, Lectin & Alternative Pathways

•All three complement pathways lead to the production of an active C5 convertase.

•C5 convertase cleaves C5 → C5a + C5b.

• C5a: Potent anaphylatoxin, diffuses away to induce inflammation.
• C5b: Binds to the target cell membrane, initiating the terminal complement cascade.

Sequential Assembly of the MAC

•C5b is labile and must bind C6 within 2 minutes to remain active.

•C5b6 complex forms the initial platform for MAC assembly.
•Binding of C7 induces a hydrophilic-to-amphiphilic structural transition:
• Exposes hydrophobic regions allowing membrane insertion.
• The resulting C5b67 complex embeds into the target cell membrane if available.
• If no membrane is present (e.g., immune complex in fluid), it may insert into nearby healthy cells, causing
innocent-bystander lysis.

Pathological Consequences
•Innocent-bystander lysis can cause collateral damage to host cells.
•Regulatory proteins usually prevent this; deficiency can lead to hemolytic disorders.
 Completion of MAC and Cell Lysis

Final Steps in MAC Assembly

•C8 binds to membrane-anchored C5b67, undergoing a conformational change:

• Exposes its own hydrophobic regions and inserts into the membrane.
• C5b678 complex forms a small pore (~10 Å):
• Enough to lyse red blood cells, but not nucleated cells.

Polymerization of C9 – MAC Completion

•C9, a perforin-like protein, binds to C5b678 and polymerizes.

•10–17 C9 molecules form a ring-like structure around the complex.
•During polymerization, C9 also inserts into the membrane.
•Final MAC structure:
• Tubular pore (70–100 Å in diameter).
• Core: C5b678, surrounded by poly-C9 ring.

Biological Effect of MAC

•The pore disrupts osmotic balance:
• Influx of water, efflux of ions and solutes.
•Results in target cell lysis and death.
 Overview of Complement Regulation – Importance and General Mechanisms

Need for Regulation

•Complement components can potentially damage host cells as well as pathogens, necessitating tight regulatory
control.
•Regulatory mechanisms ensure that complement activation is restricted to target surfaces.

General Regulatory Strategies

•Many complement proteins are highly labile and undergo spontaneous inactivation unless stabilized by
interaction with specific partners.

•Regulatory proteins intervene at multiple stages to prevent inappropriate complement activation on host tissues.
Example: C1 Inhibitor (C1Inh)

•C1Inh binds to and inactivates C1r2s2, detaching it from C1q, thereby halting the classical pathway before C4
and C2 activation.
Regulation of the complement system by regulatory proteins
(black).
Regulation of C3 Convertases in Classical and Alternative Pathways

Major Amplification Step: C3 Convertase Formation

•All three pathways amplify complement activity through C3 convertases:
• Classical/Lectin: C4b2a
• Alternative: C3bBb
•Uncontrolled C3b production risks opsonization or MAC formation on healthy host cells.
Intrinsic Control of C3b Activity
•C3b becomes hydrolyzed within 40 nm if it fails to bind, losing its activity.
•This spatial limitation helps protect nearby host cells.
Regulators of Complement Activation (RCA)
•RCA proteins are encoded on chromosome 1 and contain conserved short consensus repeats (SCRs).
•They function by:
• Preventing convertase formation
• Disassembling active convertases
• Facilitating cleavage by Factor I
Classical Pathway Regulation
•Soluble C4b-binding protein (C4bBP), membrane-bound CR1, and MCP:
• Bind C4b and block C2a association.
• Recruit Factor I to cleave C4b → C4d (bound) + C4c (soluble).
Alternative Pathway Regulation
•CR1, MCP, or Factor H bind to C3b, blocking Factor B binding.
• Factor I cleaves C3b → iC3b + C3f, and further to C3c + C3dg.
Additional Regulatory Proteins and Control of MAC Formation

Dissociation of Active Convertases

•C4bBP, CR1, Factor H, and Decay-Accelerating Factor (DAF/CD55):

• Promote decay (dissociation) of active C3 convertases by removing enzymatic subunits:
• C2a from C4b2a
• Bb from C3bBb
• After dissociation, Factor I inactivates remaining C4b or C3b on the cell surface.

MAC Regulation – Preventing Innocent Bystander Lysis

•Released C5b67 complexes can insert into membranes of healthy cells.
• S protein binds C5b67 → induces hydrophilic transition, blocking membrane insertion.

Homologous Restriction – Protection Against Cross-Species Lysis

•Host cells express:
• Homologous Restriction Factor (HRF)
• Membrane Inhibitor of Reactive Lysis (MIRL/CD59)
•These proteins bind to C8, preventing poly-C9 assembly and MAC completion.
•They are effective only with complement from the same species, which poses challenges in xenotransplantation.
Inactivation of bound C4b and C3b by regulatory proteins of the complement system. (a) In the classical pathway,
C4bBP (C4b-binding protein), CR1 (complement receptor type 1), or MCP (membrane cofactor protein) bind to
C4b and act as cofactors for factor I–mediated cleavage of C4b. (b) In the alternative pathway, factor H, CR1, or
MCP bind to Ccb and act as cofactors for factor I–mediated cleavage of C4b. Free diffusible fragments are shown
in dark shades; membrane bound components in light shades.
Biological Consequences of Complement Activation – Part 1

•Complement Activation Amplifies Humoral Immune Response

The complement system enhances the humoral immune response by promoting inflammation, opsonization, and lysis of
pathogens, making it an effective line of defense.

•Membrane Attack Complex (MAC) Induces Cell Lysis

MAC can lyse a wide variety of cells including gram-negative bacteria, viruses, parasites, erythrocytes, and nucleated cells
by forming pores in their membranes.

•Complement Receptors Mediate Immune Functions

Complement fragments bind to specific complement receptors on various immune cells, facilitating phagocytosis,
inflammation, and regulation of complement activity by degrading active fragments
•.
•Complement in Antiviral Defense
Most enveloped viruses (e.g., herpesviruses, orthomyxoviruses, retroviruses) are susceptible to MAC-induced lysis since
their membranes are derived from host cells and can be targeted by the complement system.

•Role in Innate and Adaptive Immunity

The alternative and lectin pathways function without the need for antibodies and provide rapid, non-specific protection,
while the classical pathway adds specificity via antibody-dependent activation.
Biological Consequences of Complement Activation – Part 2

•Resistance Mechanisms in Pathogens

Some gram-negative bacteria like E. coli, Salmonella, and Neisseria gonorrhoeae develop resistance by expressing long
LPS side chains or membrane proteins that prevent MAC insertion.

•Gram-Positive Bacteria are Generally Resistant to Lysis

The thick peptidoglycan wall in gram-positive bacteria like Streptococcus pneumoniae blocks MAC insertion. Even when
complement is activated, bacterial capsules hinder opsonization by interfering with C3b-CR1 interactions on phagocytes.

•Pathogens Mimic Regulatory Proteins

Many bacteria, viruses, fungi, and protozoa produce proteins that mimic host regulatory proteins (C4bBP, CR1, DAF),
thereby interrupting complement activation on their surfaces.

•Evasion by Nucleated Cells and Cancer Cells

Lysis of nucleated cells requires multiple MACs. Many cells, including cancer cells, can endocytose and remove the
MAC before significant damage occurs, reducing the efficacy of antibody-complement based cancer therapies.

•Immune Complex Clearance and Inflammatory Response

Complement activation facilitates the clearance of immune complexes and enhances inflammation via anaphylatoxins
like C3a and C5a, although some pathogens neutralize this by inactivating these fragments.
Complement Cleavage Products in Inflammation and Opsonization

•Anaphylatoxins Mediate Inflammation

Cleavage fragments such as C3a, C4a, and C5a (anaphylatoxins) bind to receptors on mast cells and basophils, inducing
degranulation and releasing histamine and other mediators of inflammation.
•Physiological Effects of Anaphylatoxins
These fragments also cause smooth muscle contraction and increase vascular permeability, allowing antibody and phagocyte
infiltration at the site of infection.
•Regulation of Anaphylatoxins by Carboxypeptidase N
Carboxypeptidase N inactivates anaphylatoxins by cleaving terminal Arg residues, producing des-Arg forms—completely
inactivating C3a and C4a, while des-Arg C5a retains limited activity.
•Leukocyte Activation and Chemotaxis
C3a, C5a, and C5b67 promote monocyte and neutrophil adhesion to endothelium, transmigration, and migration to the site of
infection; C5a is especially potent in picomolar concentrations.
•Opsonization via C3b and C4b
C3b is the principal opsonin, facilitating phagocytosis by coating antigens and immune complexes. C4b and iC3b also contribute
to opsonization.
•Complement Receptors Aid Phagocytosis
Phagocytes express receptors (CR1, CR3, CR4) that bind C3b, iC3b, and C4b. Binding of C3b-coated antigens to CR1 enhances
phagocytosis, especially after C5a-induced upregulation of CR1 on phagocytes.
•C3b as an Immunologic Adjuvant
C3b, when coupled with antigens, acts as an adjuvant by directing antigens to phagocytes, facilitating processing, and accelerating
the specific antibody response.
(a) Schematic representation of the roles of C3b and antibody in opsonization. (b) Electron micrograph of EpsteinBarr
virus coated with antibody and C3b and bound to the Fc and C3b receptor (CR1) on a B lymphocyte. [Part (b) from
N. R. Cooper and G. R. Nemerow, 1986, in Immunobiology of the Complement System, Academic Press.]
Complement System and Viral Neutralization

✓ Complement neutralizes viruses via classical, alternative, or lectin pathways.

✓ Antibody-coated viruses form immune complexes that trigger the classical pathway.
✓ Some viruses (e.g., retroviruses, EBV, rubella) can activate complement without antibodies.
✓ C3b promotes viral aggregation, reducing the number of infectious particles.
✓ Antibody and complement coat viral surfaces, blocking host cell attachment.
✓ Coated viruses are taken up by phagocytes via Fc or CR1 receptors, leading to destruction.
✓ MAC lyses enveloped viruses by disrupting their membranes and nucleocapsids.
Complement System in Clearance of Immune Complexes

✓ The complement system helps remove immune complexes

from circulation to prevent tissue damage.
✓ In systemic lupus erythematosus (SLE), excessive immune Clearance of circulating
immune complexes by
complexes cause damage via complement-mediated lysis and
reaction with receptors for
hypersensitivity. complement products on
✓ Paradoxically, deficiencies in C1, C2, C4, and CR1 erythrocytes and removal of
increase the risk of SLE—about 90% of people lacking C4 these complexes by receptors
on macrophages in the liver
develop SLE. and spleen. Because
✓ These deficiencies impair solubilization and clearance of erythrocytes have fewer
immune complexes, allowing them to deposit in tissues. receptors than macrophages,
the latter can strip the
✓ C3b coats soluble immune complexes, facilitating their complexes from the
binding to CR1 receptors on erythrocytes. erythrocytes as they pass
✓ Though erythrocytes express fewer CR1 molecules than through the liver or spleen.
granulocytes, their high number (~1000:1 ratio) makes them Deficiency in this process can
lead to renal damage due to
primary carriers of immune complexes. accumulation of immune
✓ Red blood cells transport these complexes to the liver and complexes.
spleen, where they are removed and phagocytosed.
✓ In SLE, low C3b levels and reduced CR1 expression on
erythrocytes hinder immune complex clearance, worsening
the disease.
Complement Deficiencies and Their Clinical Implications
❑ Genetic deficiencies have been reported for nearly every complement component, each leading to distinct
clinical outcomes.

❑ Homozygous deficiencies in early classical pathway components (C1q, C1r, C1s, C4, C2) result in increased
susceptibility to immune complex diseases such as SLE, glomerulonephritis, and vasculitis.

❑ These deficiencies impair C3b generation, which is critical for immune complex solubilization and
clearance.

❑ Patients also suffer recurrent infections with pyogenic bacteria (e.g., Streptococcus, Staphylococcus) due to
ineffective opsonization, despite these bacteria being resistant to MAC lysis.

❑ C3 deficiency causes the most severe symptoms, including frequent bacterial infections and immune-
complex diseases, reflecting its central role in all complement pathways and MAC formation.

❑ Deficiencies in factor D and properdin (alternative pathway components) are linked primarily to Neisseria
infections, but not to immune-complex diseases.
❑ MAC component deficiencies (C5-C9) lead to recurrent meningococcal and gonococcal infections
(Neisseria spp.), but do not typically cause immune complex diseases, suggesting sufficient C3b is
still produced.

❑ C9 deficiency is usually asymptomatic, indicating that the full MAC may not always be essential for
complement-mediated protection.

❑ C1 inhibitor (C1Inh) deficiency, an autosomal dominant disorder (~1 in 1000 prevalence), results in
hereditary angioedema (HAE), causing localized swelling in skin, bowel, or airways, sometimes
triggered by trauma.

❑ C1Inh deficiency leads to uncontrolled C1 activation, causing excessive C4 and C2 cleavage and
inflammatory edema.

❑ Knockout mouse models and human deficiency cases have helped clarify individual roles of
complement proteins in immunity, offering critical insights into complement biology.