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Introduction to the Immune Response
The central problem dealt with by the immune system is invasion by microbial pathogens
The main task of the immune system is to distinguish self from non-self
It must not attack and destroy self, but must eliminate:
1. Whole organisms (bacteria and fungi)
2. Intracellular pathogens (viruses)
Innate VS Acquired Immunity
Innate immunity
Natural immunity, very old in evolution
Anatomic barriers:
skin- epidermis has keratin, low pH, prevents bacterial growth
mucous membranes- trap organisms
Physiologic barriers:
Temperature, pH, oxygen tension, soluble factors
Soluble factors include:
lysosyme- found in mucous, cleaves bacterial peptidoglycans
interferons- antiviral effects, produced by infected cells
complement- series of proteins, form a cascade on exposure to
sialic acid, lead to bacterial lysis
Endocytosis/Phagocytosis
Endocytosis (all cells) delivers macromolecules to endosomes
Phagocytosis (monocytes, macrophages, neutrophils)
engulfs particles/organisms via receptors, degrades them in lysosomes
the receptor for this binds lipopolysaccharides on bacteria.
Inflammatory Response
Vasodilation- increase in blood vessel diameter
increase in capillary permeability, exudate released
influx of phagocytic cells
Margination- adherence to capillary wall
Extravasation- exit from capillary
Chemotaxis-migration towards area of inflammation
Soluble mediators involved in inflammation
Acute phase proteins- released by liver,bind polysaccharides, initiate complement cascade
Histamine- released following injury, stimulate vasodilation
Kinins- released following injury, stimulate vasodilation, stimulate pain receptors in skin
Receptors involved in innate immunity
Discriminate between pathogens and self
Use germline-encoded receptors that recognize patterns
Toll-like receptors (TLR)
Binding of these receptors activates the innate cell
Examples of TLRs and their ligands
TLR-2- Certain bacterial lipoproteins and glycolipids
TLR-4- LPS, found in membranes of Gram- bacteria
TLR-5- Flagellin, a protein found in flagella
TLR-6- Certain bacterial lipoproteins and glycolipids
TLR-9- unmethylated CpG dinucleotides (found in bacteria)
Acquired Immunity
(Adaptive, Specific)
Characterized by more rapid, stronger memory response (anamnestic)
First appears in evolution in cartelagenous fishes
Can detect subtle changes in proteins, carbohydrates, and lipids
This response is specific
It must detect self versus non-self
It must differentiate different forms of non-self
Antigen (Ag)- the molecule or structure against which the immune response is directed
The immune response only sees bio-organic molecules
The antigenic universe is incredibly diverse
This diversity must be overcome by the immune response
Genetic change (mutation)
Can rapidly alter Ags on pathogens (AIDS virus has 1-3 mutations per progeny)
The antigenic universe is constantly changing
B and T cells: bear receptors for antigens, that distinguish self from non-self
These receptors/cells help remove Ag from the body
B cell receptor- antibody (Ab)
Abs can be found on the cell surface or in secreted forms
T cell receptor (TCR)
Only found on the T cell surface
Binds Ag on the surface of other cells
Robert Koch- discovered antibody responses
Injected animals with bacteria or toxins.
A transferable substance in blood protected against challenge
Theories of Ab formation
Instructional: Ag helps determine specificity of Ab molecule
Selective: Ag selects pre-made Ab
Side Chain Theory- Paul Ehrlich (~ 1900)
Agent (Ag) binds to side-chain receptor
Results in release of receptor
Induces production and release of more side-chain receptor
Repertoire of Ab exists independently of Ag
Ag selects particular side chain it reacts with
Karl Landsteiner (1930’s-40’s)
Made synthetic organic molecules
All induced Ab resposes
Too much diversity! Cast doubt on selective theories
Linus Pauling (1930’s-40’s)
Selected Abs were “blanks”, influenced by Ag to generate diversity
Failed to explain memory or self recognition
Clonal Selection Theory
Burnett (1950s)
Only certain cells make Ab
Every one of these cells makes a different Ab
Each cell produces Abs of a single specificity
Ab is displayed on cell surface
Specificity of Ab is generated randomly
Any cell making self-reactive Abs is eliminated
Cells reacting to antigen proliferate (clonal expansion)
Some cells become Ab producers (plasma cells)
Other cells become long-lived (memory cells)
Generation of Diversity
1. Multiple genes encoding different proteins with different specificities
2. Multiple gene segments which can differentially combine
3. Different junctional joining of gene segments, changing triplet codons
4. Somatic mutation events
Orchestration of the Immune Response
Immune system cells are generated from bone marrow stem cells
Primary lymphoid tissues:
Bone marrow- Generates B cells, macrophages, dendritic cells, granulocytes
Thymus- Generates T cells
Cells from primary lymphoid tissues usually move to secondary tissues
Spleen, lymph nodes, tonsils, etc.
Effector functions generally occur in secondary lymphoid tissues
Cells Critical to Immune Response
Antigen presenting cells (APC)
Macrophages, dendritic cells (DC)
Trap Ag, process Ag, present it on the cell surface
Ag presented in context of major histocompatability molecules (MHC)
Also can express soluble proteins (cytokines) to activate cells
Part of the innate immune system, but activate acquired immunity
Effector Cells
B cells- Make and secrete Ab
Bind and remove (neutralize) Ag
Help phagocytes engulf Ag (opsonization)
Ab binding Ag can activate complement cascade, causing lysis of bacteria
T cells- react to Ag on the cell surface (associated with MHC molecules)
CD4 T cells- respond to Ag by secreting cytokines, help other cells
CD8 T cells- kill cells expressing Ag on their surface (with MHC)
Stops spread of viruses
Can kill tumor cells
Anatomy of the Immune System
The cells and organs of the immune system are connected by blood and lymph
Communication is achieved by surface interactions and via cytokines
The immune response has two basic aspects:
Antigen elimination
Inflammation
Altered vascular permeability
Edema
Erythema
Fever
Cells of the Immune System
Granulocytes
Neutrophils (PMNs)
50-60% of circulating white cells
Phagocytic
FcR
Short lived
Mast Cells/Basophils/Eosinophils
Highly granular
Granules contain mediators
FcR-usually holdHighly
IgE granular
If IgE cross-linked, release mediators
Monocytes/Macrophages
Phagocytic
FcR allows binding to Ag:Ab complexes
Ag presentation
Initiates responses of T cells
Dendritic Cells (DC)
Found all over body
Long processes, intercalate between cells
Can trap Ag on surface, traffic to Lymph nodes
Also found in tissues
present Ag and aid differentiation
Inflammatory cells are not Ag-specific
Interact with Ag via secondary receptors
(FcR)
Involved in inflammation
Activation of acquired responses
Cells of the Immune System
Lymphocytes
Ag-specific
B cells
Formed in bone marrow in mammals
Produce Ab
On cell surface
Secreted
Virgin B cells are IgM+ IgD+
Memory B cells are IgG+, IgA+, IgE+
Do not express IgD
T cells
Formed in thymus
Express T cell markers
CD3, CD4, CD8
Ag-specific via TCR
CD4 cells = helper
CD8 cells = cytotoxic
B cells make Ab
T cells regulate immune response
do not secrete their receptor
Lymphatic System
Fluid in blood leaks out of capillaries
must be returned to circulation
pressure in vessles too great to diffuse back
Lymphoid system recovers fluid
Picked up in capillary sinuses
These coalesce into lymphatic vessels
Form into larger ducts
Fluid returned to subclavian vein
Pumped by action of adjacent muscles
Drains every part of body
Lymph nodes screen for pathogens
Nodes packed with leukocytes
(lymphocytes, APCs, no granulocytes)
Organs of the Immune System
Lymph Node
Cortex
Paracortex
Mostly virgin B cells
Local concentrations called follicles
Proliferation leads to germinal centers
Mostly T cells
Can move up to help B cells
Exit to blood
Medulla
B cells differentiate into
plasma cells
Cells egress from here
Ag enters via afferent vessel
Enters cortical sinus
Percolates through
Trapped by DC/Macrophages
B and T cells activated
Bone Marrow
Stem cells reside here, differentiate
Into B cells, myeloid/erythroid lineages
Memory cells and plasma cells reside here
Cytokines cause stem cell differentiation and proliferation
Thymus
T cell differentiation occurs here
Progenitors from marrow enter
Move to subcapsular space
Percolate through
Pick up T cell markers
Commit to CD4 or CD8 lineage
Cells learn self from non-self
Spleen
White Pulp
Functions like lymph node
WBC arrive via blood, no afferent lymphatics
Leave via efferent lymphatics
Red Pulp
Removes old RBC
Recovers iron
Gut Associated Lymphoid Tissue (GALT)
Largest lymphoid tissue
Contains IgA+ B cells
gd T cells present
M cells endocytose Ag in lumen
Transport it to pocket
Seen by immune cells in pocket
Ag transported by M cells activates B cells in follicle
B cells differentiate into IgA-producing plasma cells
Plasma cells migrate to submucosa an secrete IgA