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The Immune System
• Immune system provides resistance to disease
– Infectious agents
• Free in the 'humors' that circulate
• Within our 'infected' cells
– Our own abnormal and cancerous cells
• Made up of two systems
– Innate (nonspecific) defense system
– Adaptive (specific) defense system
video
The Immune System
• Immune system is a functional system rather than organ system
– Cells utilize blood, lymph and lymphoid tissue, loose fibrous tissues of skin and mucosa
– Cells circulate performing surveillance and carrying instructions to proliferation/activation centers
• Innate and adaptive defenses are intertwined
– Both release and recognize many of the same defensive molecules
– Innate responses release proteins that alert cells of adaptive system to foreign molecules
– Adaptive system enhances innate actions
Representative Groups of Infectious Agents
• Numerous Species and Forms within each Group• Evolutionary battle between our defenses and theirs• Virus is non-living• Infectious agents depicted not to scale
Figure 21.1 Simplified overview of innate and adaptive defenses.
Surface barriers• Skin• Mucous membranes
Internal defenses• Phagocytes• Natural killer cells• Inflammation• Antimicrobial proteins• Fever
Innatedefenses
Adaptivedefenses
Humoral immunity• B cells
Cellular immunity• T cells
First Line of Defense: Surface Barriers
• Surface barriers are skin and mucous membranes, along with their secretions
Second Line of Defense: Cells and Chemicals
• Innate system necessary if microorganisms invade
deeper tissues
– Phagocytes
– Natural killer (NK) cells
– Inflammatory response (macrophages, mast cells,
WBCs, and inflammatory chemicals)
– Antimicrobial proteins (interferons and complement
proteins)
– Fever
• Many second-line cells have pattern recognition
receptors
Phagocytes
• Neutrophils
– abundant but killed during response
– no ‘memory’ of the agent maintained by these cells
• Macrophages (monocytes)
– Free
– Fixed
• Act using
– phagocytosis (obviously) either by acidification or
respiratory burst (strong oxidizers) in the phagolysosome
• Helper T cells stimulate respiratory burst
– Defensin antimicrobial peptides – create holes
– Toxic release into the extracellular fluid
Phagocytosis.
Innate defenses Internal defenses
A macrophage (purple) uses its cytoplasmicextensions to pull rod-shaped bacteria (green)toward it. Scanning electron micrograph (4800×).
Phagocytosis.
Lysosome
Acid
hydrolase
enzymes
Phagosome
(phagocytic
vesicle)
Events of phagocytosis.
Phagocyte forms
pseudopods that
eventually engulf the
particles, forming a
phagosome.
1
2
3
4
5
Phagocyte adheres
to pathogens or debris.
Lysosome fuses
with the phagocytic
vesicle, forming a
phagolysosome.
Toxic compounds
and lysosomal
enzymes destroy
pathogens.
Sometimes
exocytosis of the
vesicle removes
indigestible and
residual material.
Agents identified by • carbohydrate 'signature’, if
present• If not, agent may be coated with
opsonins• antibodies or complement
proteins• Opsonization
Opsonins act as “handles” for phagocytes to grab on to, enhancing phagocytosis
Example of cooperation between innate and adaptive immune systems
Natural Killer (NK) Cells
• Large granular lymphocytes circulating in blood and lymph
• Generalists:
– Attack cells that lack “self” cell-surface receptors called major histocompatibility complex (MHC) proteins
– kill before adaptive immune system is activated
• Kill by inducing apoptosis in cancer cells and virus-infected cells, not phagocytosis
• Stimulate inflammation (chemical release)
Inflammation: Tissue Response to Injury
• Inflammation is triggered whenever body
tissues are injured
– Injuries can be due to trauma, heat, irritating
chemicals, or infections by microorganisms
• Benefits of inflammation:
– Prevents spread of damaging agents
– Disposes of cell debris and pathogens
– Alerts adaptive immune system
– Sets the stage for repair
Inflammation: Tissue Response to Injury
• Inflammatory chemical release
– Chemicals are released into ECF by injured tissues,
immune cells, or blood proteins
– Macrophages and epithelial cells bear pattern recognition
receptors called “Toll-like receptors” (TLRs)
• 11 types of TLRs recognize specific classes of infecting microbes
• Activated TLRs trigger release of cytokines
Innate defenses Internal defenses
Inflammatorychemicalsdiffusing fromthe inflamedsite act aschemotacticagents.
Capillary wall
Basementmembrane
Endothelium
4
321
Chemotaxis.
Neutrophils follow chemical trail.
Diapedesis.
Neutrophils flatten and squeeze out of capillaries.
Margination.
Neutrophils clingto capillary wall.
Leukocytosis.
Neutrophils enter blood from bone marrow.
Four cardinal signs of acute inflammation:
Redness
Heat
Swelling
Pain
Impairment of function (maybe a fifth)
Stages of inflammation:
1. Inflammatory chemical release
2. Vasodilation and increased vascular permeability
3. Phagocyte mobilization
Figure 21.3 Events of acute inflammation.
Innate defenses Internal defenses
Tissue injury
Initial stimulus
Physiological response
Signs of inflammation
Result
Release of inflammatory chemicals
(histamine, complement,
kinins, prostaglandins, etc.)
Release of leukocytosis-
inducing factors
Leukocytosis
(increased numbers of white
blood cells in bloodstream)
Leukocytes migrate to
injured area
Margination
(leukocytes cling to
capillary walls)
Diapedesis
(leukocytes pass through
capillary walls)
Phagocytosis of pathogens
and dead tissue cells
(by neutrophils, short-term;
by macrophages, long-term)
Area cleared of debris
Pus may form
Healing
Locally increased
temperature increases
metabolic rate of cells
Possible temporary
impairment of
function
Temporary fibrin
patch forms
scaffolding
for repair
Leaked clotting
proteins form
interstitial clots
that wall off area
to prevent injury to
surrounding tissueHeat
Arterioles
dilate
Local hyperemia
(increased blood
flow to area)
Increased capillary
permeability
Attract neutrophils,
monocytes, and
lymphocytes to
area (chemotaxis)
Capillaries
leak fluid
(exudate formation)
Leaked protein-rich
fluid in tissue spaces
Redness Pain Swelling
Antimicrobial Proteins
• Antimicrobial proteins enhance innate defense
by:
– Attacking microorganisms directly, or
– Hindering microorganisms’ ability to reproduce
• Most important antimicrobial proteins
– Interferons• Virus infected cells may secrete IFNs that “warn” healthy
neighboring cells
– IFNs enter neighboring cells
» Block synthesis of virus, degrade viral RNA – nonspecific
– May also activate NK cells, macrophages
– Complement proteins
Figure 21.5 The interferon mechanism against viruses.
Innate defenses Internal defenses
Virus
Viral nucleic acid
New
viruses
Antiviral
mRNADNA
Nucleus
mRNA for
interferon
Interferon
receptorInterferon
Virus
enters cell.
1
2
3
4
5
Interferon
genes
switch on.
Host cell 1 Host cell 2
Binds interferon
from cell 1; interferon
induces synthesis of
protective proteins
Infected by virus;
makes interferon;
is killed by virus
Antiviral
proteins block
viral reproduction.
Interferon
binding stimulates
cell to turn on genes
for antiviral proteins.
Cell
produces
interferon
molecules.
Antimicrobial Proteins (cont.)
• Complement
– Complement system consists of ~20 blood
proteins that circulate in blood in inactive form
– Provides major mechanism for destroying foreign
substances
– Activation enhances inflammation and also
directly destroys bacteria
• Enhances both innate and adaptive defenses
• Acts in an orderly fashion (similar to clotting)
Figure 21.6 Complement activation.
Activated by antibodies
coating target cell
Classical pathway Lectin pathway Alternative pathway
Activated by lectins
binding to specific sugars
on microorganism’s surface
Activated spontaneously. Lack of
inhibitors on microorganism’s
surface allows process to proceed
Together with other complement
proteins and factors
Pore
Complement
proteins
(C5b–C9)
Membrane
of target cell
MACs form from activated
complement components (C5b
and C6–C9) that insert into the
target cell membrane, creating
pores that can lyse the target cell.
Stimulates histamine
release, increases blood
vessel permeability,
attracts phagocytes by
chemotaxis, etc.
Coats pathogen
surfaces, which
enhances phagocytosis
Opsonization:
C3
C3bC3a
C3b
C5b
C6
C7
C8
C9
C5aEnhances inflammation:
MA
C
Antimicrobial Proteins (cont.)
• Fever
– Abnormally high body temperature that is systemic response to invading microorganisms
– Leukocytes and macrophages exposed to foreign substances secrete pyrogens
– Pyrogens act on body’s thermostat in hypothalamus, raising body temperature
– Benefits of moderate fever
• Causes liver and spleen to sequester iron and zinc (needed by microorganisms)
• Increases metabolic rate, which increases rate of repair
Part 2 – Adaptive Defenses
Adaptive immune system is a specific defensive system• eliminates almost any pathogen or abnormal cell in
body• Shortcoming: must be primed by initial exposure to
specific foreign substance• Priming takes time
Characteristics of adaptive immunity• It is specific: recognizes and targets specific antigens• It is systemic: not restricted to initial site• It has memory: mounts an even stronger attack to
“known” antigens (second and subsequent exposures)
Two Main Branches Of Adaptive System
Humoral (antibody-mediated) immunity
• Lymphocytic antibodies circulate freely in body fluids
– Bind temporarily to target cell
– Temporarily inactivate
– Mark for destruction by phagocytes or complement
• extracellular targets - B cells are activated by circulating antigens directly
Cellular (cell-mediated) immunity
• Lymphocytes act against target cell
– Directly—by killing infected cells
– Indirectly—by releasing chemicals that enhance inflammatory response; or
activating other lymphocytes or macrophages
• Cellular targets – T cells are activated by antigens presented by antigen
presenting cells via Major Histocompatibility Complex (MHC)
Antigens• Targets of all adaptive immune responses
• Most are large, complex molecules not normally found in body (nonself)
– foreign proteins
– Polysaccharides
– Lipids
– nucleic acids
– seen on many foreign invaders or a product of their activity
• Characteristics of antigens
– Can be a complete antigen or hapten (small molecule that may initiate
immune response if it attaches to one or our proteins; allergens)
– Contain antigenic determinants – portion of the molecule that fits into
antigenic receptors on immune cells or that is presented by antigenic
presenting cells
– Can be a self-antigen – presented by membrane proteins called MHC• MHCs and self antigens are genetically controlled
Figure 21.7 Most antigens have several different antigenic determinants.
Antigenic determinantsAntigen-bindingsites
Antibody A
Antibody B
Antibody C
Antigen
Lymphocytes
Lymphocyte development, maturation, and activation
• T and B lymphocytes share common development and steps in their life
cycles
• Five general steps:
1. Origin
2. Maturation
• Immunocompetence
• Self-tolerance
• Those that don’t pass the ‘tests’ are destroyed by apoptosis
3. Seeding secondary lymphoid organs and
circulation
4. Antigen encounter and activation
5. Proliferation and differentiation
Figure 21.8 Lymphocyte development, maturation, and activation.
1
2
3
4
5
Adaptive defensesHumoral immunity
Cellular immunity
Red bone
marrow
Lymphocyte
precursors
Thymus
Red bone marrow
Lymph node
Antigen
Primary lymphoid organs
(red bone marrow and thymus)
Secondary lymphoid organs
(lymph nodes, spleen, etc.)
Origin
Maturation
Seeding secondary lymphoid organs and
circulation
Antigen encounter and activation
Proliferation and differentiation
• Both B and T lymphocyte precursors originate in
red bone marrow.
• Lymphocyte precursors destined to become T cells
migrate (in blood) to the thymus and mature there.
• B cells mature in the bone marrow.
• During maturation lymphocytes develop
immunocompetence and self-tolerance.
• Immunocompetent but still naive lymphocytes leave
the thymus and bone marrow.
• They “seed” the secondary lymphoid organs and
circulate through blood and lymph.
• When a lymphocyte’s antigen receptors bind its
antigen, that lymphocyte can be activated.
• Activated lymphocytes proliferate (multiply) and then
differentiate into effector cells and memory cells.
• Memory cells and effector T cells circulate continuously
in the blood and lymph and throughout the secondary
lymphoid organs.
Slide 6
Lymphocytes (cont.)
• Antigen receptor diversity
– Genes, not antigens, determine which foreign substances the immune system will recognize
• Variety of immune cell receptors are result of acquired genetic knowledge of microbes
– ∼25,000 different genes codes for up to a billion different types of lymphocyte antigen receptors
• Huge variety of receptors: gene segments are shuffled around, resulting in many combinations
Antigen-Presenting Cells (APCs)
• Engulf antigens and present fragments of antigens to
T cells for recognition
• Major types
– Dendritic cells – cells of connective tissue and epidermis
that phagocytize infectious agents and present antigens to
T cells in the lymphatic system
– Macrophages - widely distributed in connective tissues
and lymphoid organs, they phagocytize infectious agents,
present antigens to T cell, causing T cell activation, and
receiving a dose of stimulating ‘super-macrophage’
inducing substances: cytokines
– B cells – present antigens to helper T cells but not to
activate them – stimulate cytokine release that stimulates
B cell division
Figure 21.10 Dendritic cell.
Figure 21.11-1 Clonal selection of a B cell.
Adaptive defenses Humoral immunity
Primary response
(initial encounter
with antigen)
Antigen
Antigen binding
to a receptor on a
specific B lymphocyte
(B lymphocytes with
noncomplementary
receptors remain
inactive)
Proliferation
to form a
clone
Activated B cells
Plasma cells
(effector B cells)
Secreted
antibody
molecules
Memory B cell—
primed to respond
to same antigen
Naïve cells
Figure 21.11-2 Clonal selection of a B cell.
Memory B cell—
primed to respond
to same antigen
Secondary response
(can be years later)Clone of cells
identical to
ancestral cells
Subsequent
challenge by same
antigen results in
more rapid response
Plasma
cells
Secreted
antibody
molecules
Memory
B cells
No longer naïve
Figure 21.12 Primary and secondary humoral responses.
Primary immuneresponse to antigenA occurs after a delay.
Secondary immune response toantigen A is faster and larger; primaryimmune response to antigen B issimilar to that for antigen A.
First exposure
to antigen A
Second exposure to antigen A;
first exposure to antigen B
Time (days)
An
tib
od
y t
ite
r (a
nti
bod
y c
on
ce
ntr
ati
on)
in p
lasm
a (
arb
itra
ry u
nit
s) 104
103
102
101
100
0 7 14 21 28 35 42 49 56
Anti-
bodies
to A
Anti-
bodies
to B
Figure 21.13 Active and passive humoral immunity.
Humoral
immunity
Active Passive
Naturally
acquiredArtificially
acquired
Naturally
acquiredArtificially
acquired
Infection;
contact with
pathogen
Vaccine;dead orattenuatedpathogens
Antibodies passed frommother tofetus viaplacenta; orto infant inher milk
Injection ofexogenousantibodies(gammaglobulin)
Antibodies
• Antibodies—also called
Immunoglobulins (Igs)—are proteins
secreted by plasma cells
– Make up gamma globulin portion of blood
• Capable of binding specifically with antigen
detected by B cells
• Grouped into one of five Ig classes
Figure 21.14a Antibody structure.
Adaptive defenses Humoral immunity
Antigen-binding site
Hinge region
Stem region
Heavy chain
variable region
Heavy chain
constant region
Light chain
variable region
Light chain
constant region
Disulfide bond
3-D Antibody structure.
Antibodies (cont.)
• Antibody targets and functions
– Antibodies do not destroy antigens; they inactivate and tag
them
• Form antigen-antibody (immune) complexes
– Defensive mechanisms used by antibodies
• Neutralization – antibodies attach to antigenic determinants
preventing antigens from binding to receptors on cells and marking
them for phagocytosis
• Agglutination – antibody attaches to two or more determinants
forming clumps
• Precipitation – soluble antigens are bound creating precipitates that
can be engulfed by phagocytes
• Complement fixation – opsonization – antibodies attach to antigens
on cell surface aligning complement proteins leading to open holes
which destroy cell
Figure 21.15 Mechanisms of antibody action.
Adaptive defenses Humoral immunity
AntigenAntigen-antibody
complexAntibody
Inactivates by Fixes and activates
Neutralization(masks dangerousparts of bacterial
exotoxins; viruses)
Agglutination(cell-bound antigens)
Precipitation(soluble antigens)
Complement
Enhances Enhances Leads to
Phagocytosis Inflammation Cell lysis
Chemotaxis
Histamine
release
Cellular Immune Response
• T cells are more complex than B cells both in
classification and function
• Two populations of T cells are based on which
cell differentiation glycoprotein receptors are
displayed on their surface
– CD4 cells usually become helper T cells (TH)
that can activate B cells, other T cells, and
macrophages; direct adaptive immune response
• Some become regulatory T cells, which moderate
immune response
– Can also become memory T cells
Cellular Immune Response
– CD8 cells become cytotoxic T cells (TC) that are
capable of destroying cells harboring foreign
antigens
• Also become memory T cells
• Helper, cytotoxic, and regulatory T cells are
activated T cells
• Naive T cells are simply termed CD4 or CD8
cells
Figure 21.16 Major types of T cells.
Lymphoid
tissues and
organs
Thymus
Adaptive defenses Cellular immunity
Immature
lymphocyte
Class II MHC
protein displaying
antigen
CD4
cell
T cell
receptorMaturation
T cell
receptor
CD8
cell
Class I MHC
protein displaying
antigen
APC
(dendritic cell) Memory
cells
Activation Activation
APC
(dendritic cell)
CD8 cells
becomecytotoxic
T cells
CD4 cells
become eitherhelper
T cells or
regulatory
T cells Effector
cells
Blood plasma
CD8CD4
Red bone marrow
Naïve cells
Table 21.6 Role of MHC Proteins in Cellular Immunity
Figure 21.17 Clonal selection of T cells involves simultaneous recognition of self and nonself.
Bacterial antigen
Dendritic
cell
Co-stimulatory
molecule receptor
CD4 T cell
T cell
receptor
(TCR)
CD4 protein
Co-stimulatory
molecule
Class lI MHC
protein
displaying
processed
bacterial antigen
Helper
T cells
Memory
CD4 T cell
Clone
formation
Adaptive defenses Cellular immunity
Dendritic cell engulfs
an exogenous
antigen, processes it,
and displays its
fragments on class II
MHC protein.
CD4 T cell
recognizes antigen-
MHC complex. Both
TCR and CD4 proteins
bind to antigen-MHC
complex.
1
2
2a
2b
3
Co-stimulatory
molecules bind their
receptors.
Clone formation
Activated CD4 T cells
proliferate (clone), and
become memory and
effector cells.
Double recognition
Antigen
presentation
Slide 4
Figure 21.18 The central role of helper T cells in mobilizing both humoral and cellular immunity.
Adaptive defensesHumoral immunity
Cellular immunity
Helper T cells help in humoral immunity Helper T cells help in cellular immunity
Helper T cell
T cell receptor (TCR)
Helper T cell
CD4 protein
MHC II protein
of B cell displaying
processed antigen
IL-4 and other
cytokines
B cell (being activated)CD8 T cell
(becomes TC cell
after activation)
Class I
MHC protein
CD8
protein
APC (dendritic
cell)
Class II MHC
protein
CD4 protein Helper T cell
IL-2
1
2
1
2
3
TH cell binds with the self-nonselfcomplexes of a B cell that has encountered
its antigen and is
displaying it on
MHC II on its surface.
TH cell releases
interleukins as co-
stimulatory signals to
complete B cell
activation.
TH cell binds
dendritic cell.
TH cell
stimulates dendritic
cell to express
co-stimulatory
molecules.
Dendritic cell
can now activate
CD8 cell with the
help of interleukin 2
secreted by TH cell.
Figure 21.19a Cytotoxic T cells attack infected and cancerous cells.
Adaptive defenses Cellular immunity
Cytotoxic
T cell (TC)
PerforinGranule
TC cell
membrane
Target
cell
membrane
Perforin
pore
Target
cell
Granzymes
A mechanism of target cell killing by TC cells.
1 2 3
5
4
TC identifies foreign antigens on MHC I proteins and binds tightly to target cell.
TC releases perforin and granzymemolecules from its granules by exocytosis.
Perforin molecules insert intothe target cell membrane,polymerize, and formtransmembrane pores (cylindricalholes) similar to those producedby complement activation.
The TC detaches
and searches for
another prey.
Granzymes enter the
target cell via the pores.
Once inside, granzymes
activate enzymes that
trigger apoptosis.
Figure 21.20 Simplified summary of the primary immune response.
Cellular
immunity
Humoral
immunityAntigen (Ag) intruder
InhibitsTriggers
Inhibits
Adaptive defenses Innate defenses
Surface
barriers
Internal
defenses
Free Ags
may directly
activate B cell
Antigen-
activated
B cells
Clone and
give rise to
Memory
B cells
Plasma cells
(effector B cells)
Nonspecific killers
(macrophages and
NK cells of innate
immunity)
Antibodies (Igs)
Helper
T cells
Memory
CD4 T cells
Cytotoxic
T cells
Memory
CD8 T cells
Naive
CD4
T cells
Naive
CD8
T cells
Ag-presenting cell
(APC) presents
self-Ag complex
Ag-infected
body cell engulfed
by dendritic cell
Secrete
Cytokines stimulate
Together the nonspecific killers
and cytotoxic T cells mount a
physical attack on the Ag
Circulating lgs along with complement
mount a chemical attack on the Ag
Induce
co-stimulation
Activated to clone
and give rise to
Activates
Activated to clone
and give rise to
Co-s
tim
ula
te a
nd r
ele
ase c
yto
kin
es
Pre
sent
Ag t
o h
elp
er
T c
ells
Becomes
Activates
