Complement System & Cytokines Flashcards
A group of linked proteins that assist in immune responses and inflammation.
Complement System
Are complement proteins active or inactive?
Inactive enzymes, activated only when needed
How is the complement system activated?
Step-by-step, cascading, and highly regulated manner
Effector function of the immune system
Process of eliminating pathogens or threats through immune cells and molecules.
Immune cells carry out effector functions?
T cells, B cells, macrophages, and NK cells.
Molecules are involved in immune effector functions?
Antibodies, complement proteins, and cytokines
Cells produce complement proteins
Hepatocytes (main source)
Macrophages & Monocytes
Epithelial cells (genitourinary & GI tract)
3 Biologic Functions of the Complement System
Cytolysis
Opsonization
Activation of Inflammation
Membrane Attack Complex forms pores in pathogens, causing osmotic lysis.
Cytolysis
How does the complement system kill cells
By forming the Membrane Attack Complex (MAC) that disrupts membranes.
Complement proteins (opsonins) tag pathogens for phagocytosis
Opsonization
Which cells have opsonin receptors?
Phagocytes like neutrophils and macrophages.
How is opsonization different from antibodies?
Opsonins are innate; antibodies are adaptive.
How does complement trigger inflammation?
C3a and C5a activate mast cells and attract neutrophils
Stimulate mast cells to release histamine → ↑ inflammation
Anaphylatoxins
How does complement aid B cells?
Enhances B cell response and antibody production
Attracts neutrophils (chemotaxis), boosts local inflammation
C5a
Complement help clear immune complexes
Makes them soluble and easier for phagocytes to remove
Complement system enhances immune defense through
- Cell Lysis
- Opsonization of the Phagocytosis
- Inflammation
- Immune Complex Clearance
Complement proteins in their inactive form
Zymogens (inactive enzymes), activated in a cascade
How does the complement cascade differ from the clotting cascade?
Complement → immune defense; Clotting → fibrin clot formation
What is cascade amplification in complement?
One enzyme activates many others → strong immune response.
Where does complement activation usually occur?
At localized infection or inflammation sites
What triggers the classical complement pathway?
Antigen–antibody complexes
What triggers the alternative pathway?
Direct binding of complement to pathogen surfaces
Why is complement activation tightly regulated?
To prevent damage to normal tissues and avoid unwanted activation
What ensures complement is only active when needed?
Soluble and membrane-bound regulatory proteins.
190 kD disulfide-linked heterodimer (α and β chains).
C5
How is C5 activated?
By either the classical or alternative complement pathway.
C5 activation initiate?
The terminal complement cascade leading to MAC formation.
Forms pores in target cell membranes, causing cytolysis.
Membrane Attack Complex (MAC)
Cleaves C5 → produces C5b
C5 convertase
What binds to C5b first?
C6, then C7 → forms C5b,6,7 complex.
Inserts into the target cell membrane
C5b, 6, and 7
How is the complex stabilized?
C8 binds → forms C5b,6,7,8.
What completes the MAC?
Up to 15 C9 molecules polymerize → form lytic pore.
Complex forms the pore
C5b
C6
C7
C8
C9
What happens if MAC forms on self-tissues?
It damages healthy cells
What does excessive complement activation produce?
Inflammatory mediators (e.g., leukotrienes, prostaglandins).
What are the consequences of excessive inflammation?
Tissue damage, autoimmune diseases, chronic inflammation.
What activates the classical complement pathway?
Binding of C1 to antigen–antibody complexes (IgG or IgM).
Which antibody is more efficient in complement activation?
IgM (pentamer) > IgG (monomer), due to more Fc sites.
Where does C1 bind on the antibody?
Fc region (CH2 domain).
What does the classical pathway primarily require to start?
Antigen–antibody complex
What is the C3 convertase of the classical pathway?
C4b2a
How is the C5 convertase formed in the classical pathway?
C3b binds to C4b2a → forms C4b2a3b.
Main outcome of the classical pathway
Formation of C5 convertase → leads to MAC formation
What type of immunity does the classical pathway support?
Humoral (antibody-mediated) immunity.
Formation of C3 Convertase
C1 Complex
C4 Activation
C2 Activation
C3 Convertase
Components of the C1 complex
C1q + 2 C1r + 2 C1s.
Role of C1r in the classical pathway
Serine esterase that hydrolyzes ester bonds to activate downstream components
What happens when C4 is activated?
Forms C4b, which covalently binds to the cell surface.
What forms the classical pathway C3 convertase?
C4b + C2a → C4b2a.
What is the function of C3 convertase (C4b2a)?
Cleaves C3 into C3a and C3b.
What is C3b’s key role after C3 cleavage?
Binds to C4b2a to form the C5 convertase.
Classical pathway C5 convertase
C4b2a3b
Formation of C5 Convertase
- C3 Activation
- C4b2a3b Complex
What does the C5 convertase do?
Cleaves C5 → initiates Membrane Attack Complex (MAC) formation.
Made of C4b, C2a, and C3b.
C5 Convertase
What activates the alternative pathway of complement activation?
Activated without antibodies, critical for distinguishing self from foreign microbes
5 proteins are involved in the alternative pathway
Factor B
Factor D
Factor H
Factor I
Properdin.
What does the alternative pathway generate?
Soluble and membrane-bound forms of C3 convertase.
Primary function of the alternative pathway
Cleaves C3, amplifying complement activation.
What molecules initiate the alternative pathway?
C3b and C3(H2O) bind to Factor B.
What happens to Factor B when bound to C3b?
Factor B is cleaved by Factor D into Ba and Bb.
What forms the C3 convertase in the alternative pathway?
C3b + Bb → C3bBb (fluid-phase or membrane-bound).
Stabilizes the C3bBb complex
Properdin
Cleaves C3 into C3a and C3b.
C3 convertase in the alternative pathway
Forms the C5 convertase in the alternative pathway
C3b + C3bBb → C3bBb3b.
Cleaves C5, initiating the formation of the Membrane Attack Complex (MAC).
C5 convertase
What is “tickover” in the alternative pathway?
Spontaneous hydrolysis of C3 to C3(H2O), initiating the cascade even without pathogens.
How is the lectin pathway similar to the classical pathway?
Both activate C4 and C2, continuing the complement cascade.
Carbohydrate-binding proteins that recognize pathogens by binding to polysaccharides
Lectins in Lectin Pathway
3 Pattern Recognition Proteins (PRPs) in Lectin Pathway
Mannan-binding lectin (MBL)
Collectin-11 (CL-11)
Ficolins (1, 2, 3).
Activated by PRPs and cleave C4 and C2 to activate the complement cascade.
MBL-associated serine proteases (MASP-1, MASP-2, MASP-3)
Non-enzymatic proteins are involved in the lectin pathway
MAP1
sMAP
How do lectins initiate the lectin pathway?
Lectins (MBL, Collectins, Ficolins) bind to carbohydrates on pathogens, activating MASPs.
In lectin pathway, cleaves C4 and C2, leading to complement activation.
MASP-2
Activation Requirement: Antigen–Antibody (Ag–Ab) complex (IgM & IgG)
Order of Activation: C1, C4, C2, C3, C5, C6, C7, C8, C9
C3 Convertase: C4b2a
C5 Convertase: C4b2a3b
Classical Pathway
Activation Requirement: Bacterial polysaccharide / IgA binding
Order of Activation: C3, C5, C6, C7, C8, C9 (bypasses C1, C4, and C2)
C3 Convertase: C3bBb
C5 Convertase: C3bBb3b
Alternative Pathway
Activation Requirement: Mannose/mannan sugar in cell wall
Order of Activation: MBL (acts similar to C1q), C4, C2, C3, C5, C6, C7, C8, C9
C3 Convertase: C4b2a
C5 Convertase: C4b2a3b
Lectin Pathway
Goal of complement cascade regulation
To balance activation and inhibition, effectively destroying pathogens while protecting the body’s own cells
Activates the Classical Pathway of the complement system
Antigen-antibody complexes, primarily on cell surfaces.
Stabilizes the C3b convertase in the Alternative Pathway
Binding to specific cell surfaces.
It binds to C1r and C1s, preventing the classical pathway from starting unless antigen-complexed antibodies are present.
C1 inhibitor (C1INH)
3 Proteins inhibit the formation of C3 and C5 convertases in the Classical Pathway?
C4 Binding Protein (C4bp)
Decay Accelerating Factor (DAF)
Type I Complement Receptor (CR1)
What factor in the alternative pathway inhibits C3 convertase activity through decay-accelerating activity?
Factor H
What factor in the alternative pathway proteolytically cleaves C3b, preventing the formation of the C3 convertase complex (C3bBb).
Factor I
It prevents MAC formation by binding to C8 and C9, inhibiting their incorporation into the membrane
CD59 (Membrane Inhibitor of Reactive Lysis)
This protein regulates the complement system by binding to the soluble C5b, 6, and 7 complex, preventing insertion into the cell membrane.
S Protein (Vitronectin)
In the regulation of the MAC, modulates the activity of MAC, though the exact mechanism remains unknown
SP-40, 40
Small proteins crucial for regulating immune and inflammatory responses, controlling immune cell growth and activity
Cytokines
Role of Cytokines in the Immune system
Cytokines signal the immune system to activate immune cells, increase inflammation, and promote healing
How do cytokines influence immune cell functions?
By binding to specific receptors on target cells, triggering intracellular signaling pathways that affect activation, differentiation, proliferation, and communication.
How do cytokines help coordinate the immune response?
Through signaling, they help the immune system respond to infections, injury, and other immune challenges
Where are cytokines secreted from
Produced by immune cells (e.g., macrophages, T-cells, dendritic cells) in response to infection or inflammation.
How do cytokines bind to target cells?
Cytokines bind to specific receptors on target cells, enabling selective responses.
What happens after cytokine-receptor binding?
Activates signaling pathways (e.g., JAK-STAT, NF-kB), leading to gene expression changes
Effect of pro-inflammatory cytokines
Promotes fever, inflammation, and immune cell recruitment (e.g., IL-1, TNF-α, IL-6).
Suppress excessive immune response to prevent tissue damage (e.g., IL-10, TGF-β).
Anti-inflammatory cytokines
Attract immune cells to infection sites (e.g., CXCL8/IL-8).
Chemokines
These contribute to immune defense by enhancing antiviral and antibacterial responses (e.g., IFN-γ).
Interferons
3 Modes of Cytokine Action
Autocrine
Paracrine
Endocrine
The cytokine acts on the same cell that secretes it.
Example: IL-2 on activated T cells
Autocrine Cytokine
The cytokine affects nearby cells.
Example: IFN-γ activating macrophages
Paracrine Cytokine
The cytokine travels through the bloodstream to act on distant cells.
Example: IL-6 inducing fever via the hypothalamus
Endocrine Cytokine
Process by which immune cells are directed to sites of infection, injury, or inflammation to eliminate pathogens or repair damaged tissues
Immune cell recruitment
Molecular structures found on pathogens (e.g., viral RNA, bacterial DNA) but not human cells. They alert the immune system.
Pathogen-Associated Molecular Patterns (PAMPs)
How do cytokines and chemokines contribute to immune cell recruitment?
Cytokines (e.g., IL-1, TNF-α) and chemokines (e.g., CXCL8/IL-8) create a chemical gradient that attracts circulating immune cells to the infection site
How do cytokines affect endothelial cells during immune cell recruitment?
Cytokines like TNF-α increase the expression of adhesion molecules (e.g., ICAM-1, VCAM-1, P-selectin), making blood vessel walls sticky and allowing immune cells to adhere.
Process where immune cells squeeze between endothelial cells to enter the infected tissue
Diapedesis
What happens during chemotaxis and attack?
Immune cells follow the chemokine gradient to the infection site and either engulf pathogens (phagocytosis) or release toxic molecules to kill infected cells
Protein hormones that mediate the effector phases of both natural and specific immunity.
Cytokines
Primary sources of cytokines
Mainly macrophages (natural immunity) and activated T lymphocytes (specific immunity).
General properties of cytokines
- Produced during immune response
- Short-lived secretion
- Pleiotropism and redundancy
- Influence other cytokines
- Bind specific receptors
- Regulate mRNA/protein synthesis
- Act as growth factors
Pleiotropism in cytokines
Cytokines have multiple effects on different cell types
How do cytokines affect immune responses?
Amplify responses by influencing other cytokines and inducing new protein synthesis.
Role of cytokines in natural immunity
Produced by mononuclear phagocytes to aid in innate immune responses
How do cytokines regulate lymphocyte activation?
Control activation, growth, and differentiation of lymphocytes, especially in T-cell responses
How do cytokines regulate immune-mediated inflammation?
Activate non-specific inflammatory cells, playing a key role in inflammation.
Role of cytokines in leukocyte growth
Promote growth and differentiation of immature leukocytes.
Excessive cytokine release leading to hyperactive immune responses, causing inflammation and tissue damage, e.g., in COVID-19.
Cytokine Storm
In innatural immunity, this is a antiviral, antiproliferative, increases class I MHC expression, and activates NK cells.
Type 1 interferon
Pomote leukocyte chemotaxis and activation
Chemokines in natural immunity
Activates neutrophils, endothelial cells (inflammation, coagulation), hypothalamus (fever), and liver (acute phase reactants).
Tumor necrosis factor (TNF)
Acts as a costimulator for thymocytes and mature B cells and induces acute phase reactants (fibrinogen) in the liver.
Interleukin-6 (IL-6)
Cytokines that mediate Natural Immunity
Type 1: Interferon
Chemokine
Tumor Necrosis Factor
Interleukin-6
T cells: Stimulates growth and cytokine production
NK cells: Stimulates growth and activation
B cells: Stimulates growth and antibody synthesis
Interleukin-2 (IL-2)
B cells: Induces isotype switching to IgE
T cells: Stimulates growth
Macrophages: Inhibits activation
Interleukin-4 (IL-4)
Inhibits T cell activation and proliferation
Transforming Growth Factor-Beta (TGF-β)
Cytokines that regulate lymphocyte activation, growth, and differentiation
Interleukin-2
Interleukin-4
Transforming Growth Factor-Beta
Pluripotent Stem (Ancestral stem cell): Activation
C-Kit Ligand (bone marrow)
Immature progenitor: Stimulates growth and differentiation to all cell lines
Interleukin-3 (IL-3)
Committed progenitor: Differentiation to mononuclear phagocytes
Macrophage Colony-Stimulating Factor (Macrophage–CSF)
Committed progenitor: Differentiation to granulocytes
Granulocyte Colony-Stimulating Factor (Granulocyte–CSF)
Cytokines that mediate Hematopoiesis
C–Kit Ligand (bone marrow)
Interleukin–3
(T cell)
Macrophage–CSF (Macrophage)
Granulocyte–CSF (Macrophage)
Eosinophil: Activation
B cell: Growth and activation
Interleukin-5 (IL-5)
Macrophage: Inhibition (anti-inflammatory effect)
Interleukin-10 (IL-10)
Macrophage & NK cell: Activation
Gamma Interferon
Cytokines that regulate immune-mediated inflammation
Gamma interferon
Interleukin-5
Interleukin-10
Binds bacterial cell walls (lecithin)
Activates classical complement pathway
Key marker for inflammation/infection
C-Reactive Protein (CRP)
What stimulates the liver to produce acute phase proteins?
Cytokines during infection or inflammation
4 other acute phase proteins and their functions
α1-antitrypsin: Inhibits proteases
α2-macroglobulin: Inhibits proteases (esp. in inflammation)
Serum Amyloid A: Inflammatory response & tissue repair
Fibrinogen: Clotting & wound healing
