Module 2

Innate Immune Response

Rapid and non-specific

Innate: Immune Barriers

Prevent and slow pathogen entry
Physical, cellular, soluble

Innate: Inflammation

Immediate response

Innate: Pattern-Recognition

Receptors recognize general pattern

Innate: Phagocytosis

Envelop pathogens

Physical Barriers

Structures between inside and outside

Physical: Physical Components

Skin
Mucous membrane: Cover body cavities, specialized structures (cilia)

Physical: Chemical Components

Tears and saliva: Mucous membrane secretions, active antimicrobial substances
Gastric acid: In stomach, destroy pathogens

Cellular Barriers

Innate immune cells

Cellular: Neutrophils

Phagocyte
Circulate blood before entering tissues via diapedesis/extravasation
Recruited by macrophages
1-3 days in tissue

Cellular: Macrophages

Phagocyte
Move in tissues
Repair tissue
APC for T-cells
Phagocytose pathogens to activate
Response to cytokine signalling

Cellular: Dendritic Cells

Phagocyte
Contact with external environment (langerhans)
APC with peptide:MHC complexes for helper T-cells

Cellular: NK Cells

Cytotoxic effector cells
Recognize and destroy abnormal cells
No antigen-specific receptors
Release pore-forming chemicals

Soluble Barriers

Macromolecules mediate response
Inflammation

Soluble: Complement System

30 soluble inactive proteins in blood
Enhance immune function efficiency
Can damage host cell

Complement Activation

Classical, Alternative, Lectin
Direct activation in presence of exogenous pathogens
Indirect activation by pathogen-bound antibodies

Complement Function: Inflammation

Chemotaxis
Bind immune cell complement receptors (mast cells, basophils)
Release chemotactic histamine and cytokines
Attract cells to infection site

Complement Function: Phagocytosis

Opsonization
C3b protein mark pathogen for phagocytosis

Complement Function: Membrane Attack Complex

Create holes in membrane
Cell lysis

Soluble: Cytokines

Small proteins
Immune cell secretions
Chemical communication mediator
Regulate immune processes

Cytokine Function: Autocrine

Most
Affect same cell

Cytokine Function: Paracrine

Most
Affect nearby cells

Cytokine Function: Endocrine

Affect distant cells

Cytokine Function: Specificity and Affinity

Bind specific receptors on target cell

Cytokine Function: Alter Gene Expression

Receptor binding initiate reactions
Gene expression
Cell growth and maturation
Protein production

Cytokine Function: Pro-Inflammatory

Induce inflammation
Most immune cells

Cytokine Function: Anti-Inflammatory

Limit inflammatory response
Some immune cells
Inhibit pro-inflammatory cytokine production
Activate healing immune cells

Inflammation

Biological reaction
Localized tissue response to pathogen invasion
Local and systemic effects

Physical Inflammation

Redness
Heat
Pain
Swelling
Loss of affected area function

Inflammation Purpose

Remove harmful stimuli
Localize and eliminate pathogen
Remove damaged tissue

Inflammation 1: Breach

Injury damages cells
Pathogens breach physical barrier

Inflammation 2: Vasodilation

Increase blood vessel diameter and blood flow
By vasoactive and chemotactic factors secreted by damaged tissue
Activated by immune cells (macrophages, mast cells)

Inflammation 3: Permeabilization

Increase capillary permeability
Vasoconstriction away from area
Exudate (fluid) accumulates at infection site cause edema
Proteins mediate inflammatory response
Pro-inflammatory cytokines (chemokines), complement proteins
Attract cellular barrier cells

Inflammation 4: Extravasation

Chemotactic factors recruit immune cells
Neutrophils arrive first
Margination: Adhere to vessel endothelial walls
Extravasation/Diapedesis: Squeeze from capillary to tissue

Inflammation 5: Phagocytosis

Phagocytes engulf pathogens (Neutrophils, macrophages, dendritic cell)
Induce adaptive response if innate not effective

Pattern Recognition Receptor (PRR)

Immune cell receptors
Recognize repeated molecular patterns
Target specific non-self cells quickly
Innate and adaptive

PRR: Pathogen-Associated Molecular Pattern (PAMP)

Non-specific molecules associated with pathogens
Recognize structure and repeated protein sequences
Quick response to infection

PAMP Ex

Lipopolysaccharide
Peptidoglycan
Flagellum
Viral DNA/RNA

PRR: Damage-Associated Molecular Pattern (DAMP)

Molecules released in necrosis
Body damage
Initiate inflammatory response

DAMP Ex

Abnormal cell structure location
Cell-stress indicator molecules

Toll-Like Receptor (TLR)

PRR family
On plasma/endosomal/lysosomal membranes
Initiate gene transcription for inflammatory cytokines, chemokines, costimulatory molecules
Activate innate cells
Increase phagocytosis and APC

TLR Functions

Recognize PAMPs/DAMPs
Induce signalling to activate T-cells

TLR 1: Sense Infection

Recognize PAMPs/DAMPs
Phagocyte engulf pathogen

TLR 2: APC

Present pathogen on peptide:MHC complex

TLR 3: Costimulatory Molecule Production

Increase APC strength and stability

TLR 4: Bind T-Cell

Immunocompetent naive T cell binds peptide:MHC complex
Through antigen-specific TCR
Activate T-cell
Initiate adaptive response

Phagocytosis

Type of endocytosis
Cell take material from environment
Membrane forms vacuole
Defense after immune barrier

Phagocytosis Induction

PAMP recognition by PRR
Pathogen opsonization

Phagocyte: Neutrophil

First arrival cell
Early phagocytosis
Rapid pathogen elimination
Initiate inflammation

Phagocyte: Macrophage

Monocytes from blood to tissue
Most efficient
Release cytokines to stimulate inflammation
Recruit immune cells

Phagocyte: Dendritic Cell

Recognize microbes
Most efficient APC

Phagocytosis 1: Attachment

Pathogen attaches to pseudopodia (membrane evaginations)

Phagocytosis 2: Ingestion

Phagosome formation
Vacuole from cell membrane contain ingested pathogen

Phagocytosis 3: Fusion

Phagosome fuse with lysosome
Form phagolysosome
Release lysosomal enzymes to degrade material

Phagocytosis 4: Digestion

Lysosomal enzymes destroy and digest pathogen

Phagocytosis 5: Release

Exocytose digestion products
Vacuole membrane fuse with cell membrane

Adaptive Immune System

Second line of defense
Longer initiation time
Activate after innate evasion

Adaptive: Specificity

Recognize specific pathogen epitopes
Unique elimination reactions

Adaptive: Diversity

Different immune cells specific to antigen

Adaptive: B-Cells

Humoral
B-cell receptor (BCR) on surface
Plasmocyte: Effector produce antibodies
Memory: Express BCR

Adaptive: T-Cell

Cell-mediated
T-cell receptor (TCR) on surface
Helper (CD4+): Effector activate adaptive response
Cytotoxic (CD8+): Effector kill infected cells
Memory: Express TCR and CD4/CD8

Adaptive Activation

APC present antigen to naive CD4+ T-cell
Differentiation depend on antigen
TH1: Induce cell-mediated immunity
TH2: Induce humoral immunity

Humoral Immunity

B-cells
Antibody-mediated response

Humoral 1: B-Cell Activation

TH2 cells induce B-cell differentiation into plasmocytes

Humoral 2: Antibody Production

Produced by plasmocytes
Antigen-specific

Cell-Mediated Immunity

T-cells
Cytotoxic-mediated response

Cytotoxic 1: CD8+ Activation

TH1 cells induce T-cell differentiation into cytotoxic T-cells

Cell-Mediated 2: Antigen Elimination

Cytotoxic T-cells recognize and eliminate antigens with MHC class I complex

Immunoglobulins

Antibodies
Y-shaped proteins
Highly specific
Recognize 1 epitope
Produced by B-cells

Surface Antibodies

Bound to B-cell membrane
Part of BCR

Soluble Antibodies

Secreted by plasmocytes
Circulate in blood

Immunoglobulin Function

Humoral immunity
Eliminate pathogens

Immunoglobulin Function: Neutralization

Neutralize pathogen biological effect

Immunoglobulin Function: Opsonization

Mark for phagocytosis

Immunoglobulin Function: Complement Activation

Induce MAC formation and opsonization

Immunoglobulin Function: Effector Cell Activation

Bind antigen
Allow immune cell recognition and effector activation

Immunoglobulin Structure

2 heterodimeric proteins
Held by disulfide bonds

Immunoglobulin Structure: 2 Light Chains

Protein subunit
Part of main antigen-binding region

Immunoglobulin Structure: 2 Heavy Chains

Protein subunit
Structure majority
Part of antigen-binding region
Form Fc region

Immunoglobulin Structure: 2 Antigen Binding Regions

Diverse
Specific

Immunoglobulin Structure: 1 Fc Region

Fragment crystallizable
Constant in class
Fc receptors interact with immune cell surface receptors

Immunoglobulin Classes

By heavy chain type in Fc domain
Different immune response type or stage
In serum

IgM

Pentamer
First antibody formed
Non-specific
Systemic
Activate complement
Amplify inflammatory and adaptive response

IgG

Monomer
Specific
Systemic
Coat pathogens for phagocytosis and immune cell recruitment
Cross placental barrier

IgA

Dimer
In secretions and mucosal membranes
First line of defense

IgE

Monomer
Allergic reactions
Immunity against parasites

IgD

Monomer
On mature B-cells
For B-cell development

Passive Immunity

Develop after receiving antibodies from external source
Time limited