The Immune

System
Immunology
 Immunity: All the mechanisms used by the
body as protection against foreign bodies.
 immune system: The collection of cells,
tissues, and molecules that mediate
resistance to infections is called the
 Immune response : The coordinated
reaction of these cells and molecules to
infectious microbes .
The Immune System
 physiologic function of the immune
system

 prevent infection

 eradicate infections
 Importance of the immune
system in health and disease
Role of the immune system Implications
Defense against infections Deficient immunity results in increased
susceptibility to infections; exemplified
by AIDS .
Vaccination boosts immune defenses
and protects against infections
Defense against tumors Potential for immunotherapy of cancer

The immune system can injure cells Immune responses are the cause of
and induce pathologic inflammation allergic, autoimmune, and other
inflammatory diseases
The immune system recognizes and Immune responses are barriers to
responds to tissue grafts and newly transplantation and gene therapy
introduced proteins
 What types of immune responses protect
individuals from infections?
 What are the important characteristics of
immunity, and what mechanisms are
responsible for these characteristics?
 How are the cells and tissues of the immune
system organized to find and respond to
microbes in ways that lead to their elimination?
Overview of the Immune System
Immune System

Adaptive
Innate
(Specific)
(Nonspecific)
2 line of defense
o
1o line of defense Protects/re-exposure

Cellular Components Humoral Components Cellular Components Humoral Components

Interactions between the two systems

 A summary of innate and acquired immunity

INNATE IMMUNITY ACQUIRED IMMUNITY

Rapid responses to a Slower responses to
broad range of microbes specific microbes

External defenses Internal defenses

Skin Phagocytic cells Humoral response

Mucous membranes Antimicrobial proteins (antibodies)
Secretions Inflammatory response
Invading
microbes Natural killer cells Cell-mediated response
(pathogens) (cytotoxic
lymphocytes)
 Comparison of Innate and Adaptive
Immunity

Innate Immunity Adaptive Immunity

• No time lag • A lag period

• Not antigen specific • Antigen specific

 No memory • Development
of memory
Innate Host Defenses Against Infection
 Anatomical barriers
 Mechanical factors
 Chemical factors
 Biological factors
 Humoral components
 Complement
 Coagulation system
 Cytokines
 Cellular components
 Neutrophils
 Monocytes and macrophages
 NK cells
 Eosinophils
Innate, Surface Defenses
 Skin
 physical barrier to microbes
 Keratin resistant to most bacterial enzymes & toxins
 secretions are acidic pH 3-5
 Mucosa
 physical barrier & produces a variety of protective chemicals
 Gastric mucosa
 very acidic & produces proteolytic enzymes
 Saliva & lacrimal fluid contain lysozyme
 Mucous
 traps bacteria & moves them away from epithelial surface
Anatomical Barriers - Mechanical Factors

System or Organ Cell type Mechanism

Skin Squamous epithelium Physical barrier

Desquamation
Mucous Membranes Non-ciliated epithelium Peristalsis
(e.g. GI tract)
Ciliated epithelium (e.g. Mucociliary elevator
respiratory tract)
Epithelium (e.g. Flushing action of
nasopharynx) tears, saliva,
mucus, urine
Anatomical Barriers - Chemical Factors

System or Organ Component Mechanism

Skin Sweat Anti-microbial fatty

acids
Mucous Membranes HCl (parietal cells) Low pH
Tears and saliva Lysozyme and
phospholipase A
Defensins (respiratory & GI Antimicrobial
tract)
Surfactants (lung) Opsonin
Anatomical Barriers - Biological Factors

System or Organ Component Mechanism

Skin and mucous Normal flora Antimicrobial

membranes substances
Competition for
nutrients and
colonization
Humoral Components
Component Mechanism

Complement Lysis of bacteria and some viruses

Opsonin
Increase in vascular permeability
Recruitment and activation of phagocytic cells
Coagulation system Increase vascular permeability
Recruitment of phagocytic cells
Β-lysin from platelets – a cationic detergent
Lactoferrin and Compete with bacteria for iron
transferrin
Lysozyme Breaks down bacterial cell walls

Cytokines Various effects

Cellular Components

Cell Functions

Neutrophils Phagocytosis and intracellular killing

Inflammation and tissue damage
Macrophages Phagocytosis and intracellular killing
Extracellular killing of infected or altered self
targets
Tissue repair
Antigen presentation for specific immune
response
NK and LAK cells Killing of virus-infected and altered self targets

Eosinophils Killing of certain parasites

Innate, Internal Defenses
 Based on recognition of surface
carbohydrates (glycocalyx)
 Glycocalyx is recognized as “self” or “non-self”

Figure 3.3
Innate, Internal Defenses
 Phagocytes
 Macrophages: derived from monocytes
 Free Macrophages: roam through tissues
 Fixed Macrophages: Kupffer cells (liver) & microglia (brain)
 Ingest cellular debris, foreign material, bacteria, fungi
 Neutrophils: ingest pathogens
 Eosinophils: weakly phagocytic. Attack parasites
(degranulation)
 Mast Cells: phagocytic of various bacteria
  Major events in the local inflammatory response

Pathogen Pin Blood clot

Macrophage
Blood
Chemical signals clotting
Phagocytic cells elements
Phagocytosis
Capillary

Red blood cell

1 Chemical signals released 2 Fluid, antimicrobial proteins, 3 Chemokines released by various 4 Neutrophils and macrophages
by activated macrophages and clotting elements move kinds of cells attract more phagocytose pathogens and
and mast cells at the injury from the blood to the site. phagocytic cells from the blood cell debris at the site, and the
site cause nearby capillaries Clotting begins. to the injury site. tissue heals.
to widen and become more
permeable.

Figure 43.6
Innate, Internal Defenses:
Inflammation
 tissue response to injury
 Triggered by injury – trauma, heat, chemical
irritation, infection, etc.
 Beneficial effects
 Preventsspread of injury
 Disposes of cellular debris & pathogens
 Promotes repair
Innate, Internal Defenses:
Inflammation
 cardinal (major) signs of inflammation
 Redness
 Heat
 Swelling
 Pain
Innate, Internal Defenses:
Inflammation
 Inflammatory response: signs are
associated with vasodilation & increased
vascular permeability
 Dilation:redness, heat
 Permeability: edema, (increased pressure)
pain
 Pain also associated with bacterial toxins &
some mediators (kinins, PGs)
Innate, Internal Defenses:
Inflammatory Response
 Mechanisms causing vasodilation & vascular
permeability
 Injured cells release inflammatory mediators
 Histamines
 Kinins
 Prostaglandins
 Complement
 Cytokines (also activated by receptors on macrophages in
response to microbial glycocalyx)
Innate, Internal Defenses:
Inflammatory Response
 Edema
 Dilutes harmful substances
 Provides nutrients (& O2) for repair
 Enhances entry of clotting protein
Events in
Inflammation

Figure 21.3
Innate, Internal Defenses:
Inflammatory Response
 Phagocyte mobilization: infiltration of damaged
area by neutrophils & macrophages
Innate, Internal Defenses:
Inflammatory Response
 Leukocytosis: leukocytosis inducing factors
released by injured cells promote rapid release
of WBCs from marrow
 Margination: increased vascular permeability
causes decreased fluid in vessels; blood flow
slows & neutrophils are able to move to vessel
margins. Here endothelial markers (CAMs) allow
neutrophils to cling to vessel walls
(pavementing).
Innate, Internal Defenses:
Inflammatory Response
 Diapedesis: neutrophils migrate through
capillary walls
 Chemotaxis – inflammatory chemicals attract
neutrophils to move up the chemical
concentration gradient (neutrophils respond first)
 As the process continues, monocytes diapedes
into the area & become macrophages. With
chronic inflammation, macrophages predominate
Inflammatory Response:
Phagocytic Mobilization

Figure 21.4
Innate, Internal Defenses:
Inflammatory Response
 Macrophages clean up cellular debris &
pathogens
 If pathogens were associated with the injury,
activation of the complement cascade occurs &
elements of adaptive immunity join the process
Innate, Internal Defenses
 Phagocytic mechanisms:
 Adherence: cell binds to invader
 Aided by opsonization (a chemical process that enhances
binding via complement & antibodies)

 Ingestion: formation of phagolysosomes

 Respiratory Bursts: merge phagosome with lysosome & flood
phagolysosome with free radicals (macrophage)
 Defensins: proteins that crystallize out of solution & pierce
pathogen membranes (neutrophils)
Mechanism of Phagocytosis

Figure 21.2
Innate, Internal Defenses
 Natural Killer Cells:
 Small population of large granular lymphocytes
 Non specific for “non-self”
 Not phagocytic: attack is by release of perforins that
perforate the target cell plasma membrane.
 Shortly after perforation the target nucleus disintegrates.
 Release chemicals that enhance the inflammatory
response
Innate, Internal Defenses
 Viral replication – (viruses lack metabolic
processes) Viruses release nucleic acid (RNA or
DNA) into cytoplasm. The information on the
nucleic acid is incorporated into the cell’s DNA.
Normal cellular mechanisms then produce viral
structural components. Multiple new viral
particles are produced & released from the cell
(sometimes killing the cell)
Innate, Internal Defenses
 Antiviral proteins: interferon & complement
 Interferon: some cells produce & release
interferons (IFNs) when invaded by virus
 Released interferons stimulate nearby cells to
produce proteins (PKR)(Protein kinase R) that
interfere with viral replication by disrupting
protein synthesis & the ribosome
 Not virus specific.
Interferon (IFN)

Figure 21.5
Innate, Internal Defenses
 Complement – a group of plasma proteins (20)
that are activated in the presence of foreign
substances
 Complement activation enhances & amplifies
inflammation
 Bacteria & some other cell types are lysed by
complement activation
 Complement activation enhances both innate &
adaptive defenses
 Complement is an important set of proteins which are found in the
blood or serum.
 Complement activation occurs as a cascade. The products of one
reaction will cause another reaction to occur, resulting in the
activation of a cascade of several complement components.
 There are nine complement proteins, named c1-c9, some of which
can be cleaved into smaller active fragments.
 Once complement components are activated they have many
effects. These affects include:
 an increase of blood vessel permeability
 chemotactic attraction of phagocytes to the site.
 opsonization - one complement protein can coat microbes
making them more likely to be phagocytized by a WBC.
 cytolysis - once activated some complement proteins will bind to
pathogens and form holes in its membrane, killing the pathogen.
Gram- cells w/ their exposed outer membrane and parasites w/o
a cell wall are particularly vulnerable.
Innate, Internal Defenses
 Complement activation pathways
 Classical pathway: requires antibodies
 Antibodies bind to target (antigen)

 Complement protein C1 binds to the antibody-

antigen complex (complement fixation)

 Alternative pathway: complement factors interact with
microorganism glycocalyx
 Both pathways lead to a cascade of protein activation,
leading to activation of C3
Innate, Internal Defenses
 C3 is the start of the; Final Common Pathway
 C3 cleaves to form C3a & C3b
 C3a (& C5a) enhance inflammation by increasing
histamine release, increasing vascular permeability &
stimulating chemotaxis
 C3b coats bacterial membrane supplying adhesion
points (opsonization)
 C3b initiates the cascade forming the membrane
attack complex (MAC)
 The MAC forms a hole in the cell membrane &
enhances Ca2+ influx  cell lysis
The complement system serves
three main functions
 Opsonization and phagocytosis. C3b coats microbes and promotes the binding
of these microbes to phagocytes, by virtue of receptors for C3b that are
expressed on the phagocytes. Thus, microbes that are coated with complement
proteins are rapidly ingested and destroyed by phagocytes. This process of
coating a microbe with molecules that are recognized by receptors on phagocytes
is called opsonization.

 Inflammation. Some proteolytic fragments of complement proteins, especially

C5a and C3a, are chemoattractants for leukocytes so they promote leukocyte
recruitment (inflammation) at the site of complement activation.

 Cell lysis. Complement activation culminates in the formation of a polymeric

protein complex that inserts into the microbial cell membrane, disturbing the
permeability barrier and causing either osmotic lysis or apoptosis of the microbe.
Innate, Internal Defenses
 C-reactive proteins (CRP) produced by the liver
in response to inflammatory molecules can
activate the classical pathway by binding to
membrane & activating C1. Also participates in
opsonization.

 Fever – a systemic response to infection.

Leukocytes & macrophages release pyrogens
that raise the hypothalamic “set point” for
temperature
Cell Death
 Orderly Self Destruction and Disorderly
 Neutrophils (5.0 x 1010) Last For a Few Days
 Aberrant Apoptosis Can Give Rise To Leukemia
 Apoptosis (orderly)
 Reduction In Cell Volume
 Chromatin Condensation
 DNA Degradation
 M Ingest Membrane Bound Bodies
 No Inflammation
 Necrosis
 Burstingof Cell Due To Injury
 Contents Released To Environment
 Inflammation
Cytokine: A small protein released by cells that has a specific effect
on the interactions between cells, on communications between cells or on
the behavior of cells. The cytokines includes the interleukins, lymphokines
and cell signal molecules.

Unlike classic hormones, cytokines act either in an autocrine manner (on

producer cells) or in a paracrine manner (on neighbor cells).

Cytokines involved in Innate immune response

Systemic and Pathologic Consequences of the Acute Inflammatory Responses

TNF, IL-1, and IL-6all act on the hypothalamus to induce an increase in body
temperature (fever), and these cytokines are therefore called endogenous
pyrogens(LPS=exogeneouspyrogen)

IL-1, TNF, and IL-6 induce hepatocytes to express acute-phasereactants,

including CRP and fibrinogen, which are secreted into the blood In severe
infections,

TNF may be produced in large amounts and causes systemic clinical and
pathologic abnormalities

•TNF inhibits myocardial contractility and vascular smooth muscle tone, resulting in a
marked fall in blood pressure, or shock
•TNF causes intravascular thrombosis, mainly as a result of loss of the normal
anticoagulant properties of the endothelium
•Prolonged production of TNF causes wasting of muscle and fat cells.
The blood and lymph systems
Overall view of the lymph system,
showing the locations of major organs

The circulatory system is the means by which

cells of the immune system directly or
indirectly interact with all of the cells of the
body

Lymph nodes: contain high concentrations of

leukocytes that filter out microbes and toxins

Spleen of the blood circulatory system has the

same function as the lymph nodes

lymph nodes and spleen can sometimes become

infected by the organisms that have collected
during filtration
Lymphatic System
 Plasma From Blood Seeps Into Tissue
 Interstitial Fluid Either Goes Back or
Becomes Lymph
 Lymph Enters Lymphatic Vessels
 Thoracic Duct Is Largest Lymphatic Vessel
Empties Into Left Subclavian Vein
 Lymphatic Vessel Depends On Muscle
Contractions For Movement
 One Way Valves Ensure One Direction
 Lymph Nodes Act As Filters For Antigens
Lymphatic System
 Organs Of Immune System

 Primary Lymphoid Organs

 Bone Marrow and Thymus
 Maturation Site
 Secondary Lymphoid Organs
 Spleen, lymph nodes,
 MALT (mucosal associated lymph tissue)
 GALT (gut associated lymph tissue)
 Trap antigen, APC, Lymphocyte Proliferation
 Thymus

 Bilobed Organ on Top of Heart

 Reaches Max. Size During Puberty
 70g infants, 3 g in adults
 95-99% Of T Cells Die in Thymus
 self reactivity or no reactivity to Ag
 Consists of Cortex and Medulla
 Thymus

 Function
 Takes in immature T cells and puts out
mature (immunocompetent) T cells
 Increased diversity of T cells
 T cell selection
Thymus
 Thymus
 T cell selection
 Based on MHC/Ag complex recognition
 Recognize MHC/Non self AG complexes
 Recognize MHC/Self Ag complexes
 Bone marrow

 Function
Hematopoiesis
B cell maturation
B cell selection
Puts out mature, naive B cells
 Lymph Node
 Multiple Afferent Lymphatics
 Cortex
 B-cells, Follicular DCs, M, GCs, Primary Follicles
 Paracortex
T , M, DCs
H
 Medulla
 Plasma Cells
 Post Capillary Venule
 Allow Lymphocyte Migration From Circuilation Into Lymph Node
 One Efferent Lymphatic
 Rich In Abs and Lymphocytes
 Lymph Nodes
 Major cell types
 Lymphocytes
 Macrophages

 Dendritic cells

Structure
 Cortex/paracortex/medulla
 Follicles
 Primary
 Secondary
 Lymph Nodes
 Function
 1st line of response to antigens
 Secondary follicle (Germinal center) is site of B cell
proliferation, mutation, differentiation
 >90% of B cells die through apoptosis
 After Ag stimulation lymphocyte numbers up by 50X in
efferent lymphatic vessel
 Lymphadenopathy: Disease or Enlargement of
Lymph Nodes
 Lymphadenopathy
can occur for a number of reasons,
including the following:
 Infections—the most common reason
 Lymphomas and leukemias—cancers of white blood
cells
 Cancers at other sites that spread to lymph nodes
 Diseases of the immune system,
such as lupus and sarcoidosis
 A long list of many other uncommon diseases.
 Spleen
 Structure

 Ovoid organ in upper left quadrant of abdomen

Microscopic
 Compartmentalized
 Red pulp
 White pulp
 Periarticualr lymphoid sheath
 Site of Ag presentation
 Major cell types
 Lymphocytes
 Macrophages
 Dendritic cells
 RBCs
 Spleen

 Function
 Filters
out older RBCs
 Responds to Ag in circulatory system
 Produces activated B cells
 Tonsils
 Follicular structure
 Contains lymphocytes, macrophages,
mast cells
 Germinal centers appear in response to
Ag
 Protective role in URI (Upper respiratory
tract infections)
 Appendix

 Associated with intestines

 Responds to Ag
 Role in GI (gastrointestinal) immune
response
 MALT
 Lymphoid tissues below epithelium
 Presence of B cells
 Ag presented through unique cell (M cell)
 Preferentially responds with IgA antibody