The central problem dealt with by the immune system is invasion by microbial pathogens

Introduction to the Immune Response

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 immunityNatural immunity, very old in evolution

Anatomic barriers:skin- epidermis has keratin, low pH, prevents bacterial growthmucous 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 (all cells) delivers macromolecules to endosomesPhagocytosis (monocytes, macrophages, neutrophils) engulfs particles/organisms via receptors, degrades them in lysosomes the receptor for this binds lipopolysaccharides on bacteria.

Endocytosis/Phagocytosis

Inflammatory Response

Vasodilation- increase in blood vessel diameter increase in capillary permeability, exudate released

influx of phagocytic cellsMargination- adherence to capillary wallExtravasation- exit from capillaryChemotaxis-migration towards area of inflammation

Soluble mediators involved in inflammationAcute phase proteins- released by liver,bind polysaccharides, initiate complement cascade

Histamine- released following injury, stimulate vasodilationKinins- released following injury, stimulate vasodilation, stimulate pain receptors in skin

Receptors involved in innate immunityDiscriminate between pathogens and selfUse 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

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 surfaceBinds Ag on the surface of other cells

These receptors/cells help remove Ag from the body

Robert Koch- discovered antibody responsesInjected 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 receptorResults in release of receptorInduces 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 TheoryBurnett (1950s)

Only certain cells make Ab

Every one of these cells makes a different AbEach cell produces Abs of a single specificityAb is displayed on cell surfaceSpecificity 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 tissuesSpleen, 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 surfaceAg presented in context of major histocompatability molecules (MHC)Also can express soluble proteins (cytokines) to activate cellsPart of the innate immune system, but activate acquired immunity

Effector CellsB cells- Make and secrete Ab

Bind and remove (neutralize) AgHelp 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 cellsCD8 T cells- kill cells expressing Ag on their surface (with MHC)

Stops spread of virusesCan 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

InflammationAltered vascular permeabilityEdema

FeverErythema

Cells of the Immune System

Granulocytes

50-60% of circulating white cellsPhagocyticFcRShort lived

Neutrophils (PMNs)

Mast Cells/Basophils/Eosinophils

Highly granular

Highly granularGranules contain mediatorsFcR-usually hold IgEIf IgE cross-linked, release mediators

Monocytes/MacrophagesPhagocytic FcR allows binding to Ag:Ab complexesAg presentation Initiates responses of T cells

Dendritic Cells (DC)

Found all over bodyLong processes, intercalate between cellsCan trap Ag on surface, traffic to Lymph nodesAlso found in tissuespresent Ag and aid differentiation

Inflammatory cells are not Ag-specificInteract with Ag via secondary receptors(FcR)Involved in inflammationActivation of acquired responses

Cells of the Immune System

LymphocytesAg-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 AbT 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 fluidPicked up in capillary sinuses

These coalesce into lymphatic vesselsForm into larger ducts

Fluid returned to subclavian veinPumped by action of adjacent muscles

Drains every part of bodyLymph nodes screen for pathogens Nodes packed with leukocytes

(lymphocytes, APCs, no granulocytes)

Organs of the Immune System

Lymph NodeCortexMostly virgin B cellsLocal concentrations called folliclesProliferation leads to germinal centers

ParacortexMostly T cellsCan move up to help B cellsExit to blood

MedullaB 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, differentiateInto B cells, myeloid/erythroid lineages

Cytokines cause stem cell differentiation and proliferation

Memory cells and plasma cells reside here

ThymusT cell differentiation occurs here

Cells learn self from non-self

Progenitors from marrow enter

Move to subcapsular space

Percolate through

Pick up T cell markers

Commit to CD4 or CD8 lineage

SpleenWhite Pulp

Functions like lymph nodeWBC arrive via blood, no afferent lymphaticsLeave via efferent lymphatics

Red PulpRemoves old RBCRecovers iron

Gut Associated Lymphoid Tissue (GALT)

Largest lymphoid tissue

Contains IgA+ B cells

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