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 Overview of
the Immune System
Jose I. Diaz, M.D., Ph.D.
[email protected]
 Studying the Immune System
Lots of Details
Many rules with exceptions
Knowledge is evolving; many issues are not
completely understood
Host Defense is a Team Effort; main team
components are:
1. Epithelial barriers
2. Innate Immune System; more than
500 millions of years ago
3. Adaptive or Acquired Immune System;
appears on vertebrates to protect against
viruses more than 200 millions of years
ago
How Old is the Immune System?
(Food for thought wont be tested)
Life on earth emerged about 3.5
billion years ago
Single-cell organisms such as
eubacteria, archeabacteria and
eukaryotes flourished
600 million years ago multicellular
metazoans began after dramatic
increase of atmospheric O2
The rich diversification of metazoan
was an evolutionary big band
Each metazoan that exist today,
including vertebrates to which we
belong, appeared more than 500
million years ago and have an innate
immune system
Vertebrates with jaws have adaptive
immune systems that recognize
bacteria, viruses, fungi and parasites
Definitions

Immunity: resistance to infectious

disease
Immune System: cells, tissues and
molecules mediating immunity
Immune Response: immune system
response to microbes leading to
immunity; also response to damaged
cells and tissues
Immunology: study of immune system
and immune responses
The physiologic function of the immune
system is host defense = preventing
and eradicating infection
Nave: never exposed before to Ag
 Immune System Cells
Immune cells circulate in blood and are
produced in bone marrow (BM); they are
derived from precursor stem cells
Also known as White Blood Cells or WBC or
Leukocytes are divided in two families:
Phagocytes, such as macrophages, dendritic
cells, neutrophils, eosinophils, basophils and
mast cells and Lymphocytes, such as B cells,
T cells and natural killer or NK cells
Review next two slides explaining how these
cells are produced in the BM or
hematopoiesis (further explained during
our first SG discussion), leukocyte
nomenclature and morphology
 Hematopoiesis
Leukocytes or WBC are seen
as a buffy coat after
Adaptive
spinning whole blood; This is a
Immune
thin layer of white cells
System Lymphoid
Cells

Innate
Immune
System
Myeloid
Cells

Thrombocytes or Coagulate blood

Platelets
Erythrocytes or
Red Blood Cells (RBC) Carry O2
 Leukocyte Morphology
Eosinophil
Platelet

Band =
young Red Blood Cell
neutrophil
mast cell in
Lymphocyte tissues =
macrophage or Basophil
Neutrophil
histiocyte
in tissues =
Monocyte Granulocytes =
Neutrohils + Eos+ Basos =
Polymorphonuclear Leukocytes
Granulocytes + Monos = Phagocytes
Phagocytes + Lymphocytes =
WBC = Leukocytes
 Innate Immune System

Macrophage: most famous immune

defender; its name means large eater
(macro = large; phage = eater)
They have antennae (receptors) that
recognize microbes find me, eat
me signal called phagocytosis
They are garbage collectors that clean
tissue debris, protect from microbial
invasion and present their antigens to
the adaptive immune system
 Phagocytosis

phagolysosome
 Innate Immune System

Most importantly, they are sentinels that

alarm the immune system when we are
under attack, releasing cytokines that
recruit other immune cells
Other members of the innate immune
system include other phagocytes with
distinct morphological features, such as
dendritic cells, neutrophils, eosinophils,
basophils and mast cells
and two killer systems: NK cells or natural
killer cells and the Complement system
 Question
Based on what you have learned on previous slides about
leukocytes, which of the following statements is CORRECT?

Select the best answer

Neutrophils are phagocytes of the innate immune system but

are not granulocytes
NK cells are lymphocytes and considered part of the innate
immune system

Granulocytes are phagocytes of the innate immune system

Lymphocytes are leukocytes of the innate immune system

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 Correct Answer!
Phagocytes is a family of innate cells that
include: macrophages (called monocytes in
blood), dendritic cells and granulocytes
subdivided in neutrophils, eosinophils and
basophils Neutrophil or PMN
Called granulocytes because contain
numerous cytoplasmic granules (lysosomes)
that stain red in eosinophils, dark blue in
basophils and purple or neutral in
neutrophils
Granulocytes are also called
Polymorphonuclear Leukocytes because Eosinophil
they have segmented (polymorphous) nuclei
in contrast to lymphocytes and monocytes,
which are called Mononuclear Leukocytes
because they have a round single nucleus
Most abundant granulocyte in blood is the
Neutrophil also called PMN
(Polymorphonuclear Neutrophil) Basophil
Adaptive Immune System

The players are the lymphocytes:

B cells, which produce antibodies (Ab)
and mediate Humoral Immunity
T cells, which produce cytokines and
mediate Cellular Immunity
NK cells are lymphocytes but belong to
the innate immune system
In contrast to phagocytes, lymphocytes
cannot be distinguished morphologically;
We rely on the type of leukocyte cluster
designation (CD) molecule they express on
their cell surface
 Cluster Ag Designation System
T-Cell Associated Cell Distribution
CD3 Thymocytes, peripheral T cells
CD4 peripheral helper Th cells
CD8 peripheral cytotoxic T cells or CTL
B-Cell Associated Cell Distribution
CD19 Marrow pre-B cells and mature B cells but not
plasma cells
CD20 Marrow pre-B cells after CD19 and mature B
cells but not plasma cells
Monocyte/Macrophage Cell Distribution
Associated
CD11c Granulocytes, monocytes, and macrophages
CD13 Immature and mature monocytes and granulocytes
CD14 Monocytes
CD15 Granulocytes
CD33 Myeloid progenitors and monocytes
CD64 Mature myeloid cells
NK-Cell Associated Cell Distribution
CD16 NK cells and granulocytes
CD56 NK cells and a subset of T cells
Stem and Progenitor Cell Cell Distribution

Associated
 Adaptive System: Humoral

B cells produce antibodies (Ab) aka

immunoglobulins (Ig); discovered studying
smallpox during the 1790s
Immunity to smallpox was conferred by
proteins in the blood of immunized
individuals; Thus was a humoral immunity
Ab or Ig are Y shaped molecules that have
2 identical Fragments Binding Atigen
(Fab) regions (can grab 2 Ag molecules)
Antigen (Ag) are microbial molecules
recognized by lymphocytes
 Adaptive System: Humoral
The tail of the Y or Fragment Crystalline (Fc) binds
to receptors on immune cells like macrophages and
activates them
Fab is made of two peptide chains, one light and one
heavy that
prolongs
to make the
Fc region
 Adaptive System: Humoral

Ab may have 5 different kinds of Fc

called isotypes, which facilitate
different biological functions
75% of Ig in blood is IgG and another
25% is IgM and IgA with very little IgE
in serum
IgD is non-secreted and remains on B
cells membrane acting as the B cell Ag
receptor
 Adaptive System: Humoral

After becoming activated, B cells mature

to plasma cells producing larger quantities
of Ab
Thus, B cells can make several classes of
Ab against the same Ag, each mediating
different functions
They first Ab made by B cells is IgM, then
they switch to IgG, then to others such as
IgA or IgE which helps customizing the
immune response depending on location and
type of microbe
 Adaptive System: Humoral

Different classes of Fc are Ab recognizes Ag on its

recognized by different innate Fab site
cell types depending on their Fc Ab may switch to
receptors different classes of Fc
Thus, different Ig classes to but Fab always retain
same Ag induce different same
biological responses mediated Thus, Ag specificity
by different innate cells always remains the same
Adaptive System: Humoral

Abs dont kill but label microbes for

destruction planting on them the kiss
of death
This tagging for destruction is called
opsonization
Some Abs bind to the viral surface
molecules mediating the entrance of
the virus into the host cell
These neutralizing Abs can prevent
viral infection
 Adaptive System: Humoral
Fab grabs the invading microbes
Fc is available to bind to receptors
(Fcr) on immune cells and proteins
destroying the microbes (macrophages,
complement)
When Ab is not bound to Ag, Fc
region is not able to bind to Fcr and
has no biological activity
When Fab grabs Ag, Fc becomes an
active opsonizer that enhances
macrophages appetite or activate other
immune cells
 Question
Based on what you have learned on previous slides about B cells
and Ab, which of the following statements is the LEAST correct?

Select the most INCORRECT statement

B cells differentiate into plasma cells which produce larger

quantity of Ab
Ab are Y shaped molecules with 2 Fab regions that bind Ag
and 1 Fc region that bind to immune cells Fcr
IgD is a non-secreted Ig which is not found in the serum in
any significant quantity and resides on B cell surface
B and T cells are easily distinguished because they have
striking morphological differences
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 Correct Answer!

Lymphocytes cannot be distinguished

morphologically as they have very similar
appearance regardless of subset type: T
cells, B cells or NK cells look alike
Lymphocytes can only be distinguished
using specific markers called CD molecules;
These molecules have specific functions
and are selectively expressed in various
lymphocyte subsets
T cells are CD3 positive, B cells are CD19
and CD20 positive and NK cells are CD16
and CD56 positive
 Adaptive System: Cellular
There are three kind of T cells
Killer T Cells = cytotoxic
lymphocytes = CTLs
Helper T cells = Th Cells
Regulatory T cells = Treg
CTLs destroy cells infected with virus
by inducing cell suicide (assisted suicide)
Th Cells are cytokine factories (IL-2,
-IFN) secreting these on demand to
help other immune cells (B cells,
macrophages)
Treg cells prevent immune overreaction
 Adaptive System: Cellular

Ab are secreted by B cells and recognize

diverse molecules such as proteins, lipids,
carbohydrates or nucleic acids but cant
kill viruses once inside of infected cells
T cells have receptors (TCR) which function
like Ig on B cells but stay on cell surface
(are not secreted), recognize only proteins
and require presentation by other cells
called antigen presenting cells (APC); T
cells can kill virus infected cells
Adaptive System: Cellular
Antigen Presentation to T Cells

Proteins called MHC present Ag (for

major histocompatibility complex involved
in transplant rejection)
Class 1 MHC alerts CTLs of whats going
on inside of cells, like viral infection
Class 2 MHC alerts Th Cells of whats
going on outside of cells, like bacterial
infection
Class 1 is found on all nucleated cells
Class 2 is found only on APC
(macrophages, dendritic cells, B cells and
endothelial cells)
 Antigen Presentation to T Cells

TCR must recognize MHC and

Ag peptide simultaneously

Class 1 Class 2
smaller peptide larger peptide

MHC without Peptide MHC with Peptide

 Adaptive System Activation
B and T cells are very powerful; To prevent
misuse of power, B and T cell activation is a
restrictive process (tightly controlled)
There are two check points called signals 1
and 2, a two key system that insures
activation occurs only at the right time and
place
Signal 1 = MHC-Ag peptide on APC or
infected cell presented T cell with a
specific TCR for both MHC and A peptide
(Ag specific)
Signal 2 = B7 on APC surface binds CD28
on T cell surface (is not Ag specific) but APC
only produce B7 when there is real infection
Adaptive System Activation
 Question
Based on what you have learned on previous slides about T cells
and APC, which of the following statements is most correct?

Select the best answer

T cells only become activated when recognizing foreign
protein peptide bound to MHC on surface of APC (signal 1)
and B7 on surface of APC (signal 2)
Class 1 MHC present extracellular protein Ag peptides to
CTL
Helper Th cells and Ab are the best weapons of the immune
system against viruses and directly kill virally infected cells
Helper Th cells can recognize foreign proteins, lipids and
carbohydrates while CTL only recognize foreign proteins
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 Correct Answer!
B and T cells are very powerful and tightly regulated;
their activation requires two signals: 1 = Ag specific =
requires MHC-bound Ag peptide on APC surface
recognized by Ag-peptide specific TCR on T cell surface,
2 = non-Ag specific = requires B7 production by APC
recognized by CD28 on T cell triggered by APC
recognition of microbe (resting APC not producing B7
DO NOT activate T cells)
Ab can block viruses from entering (infecting) cells;
However, once cells are infected with virus Ab are
useless
CTL and NK cells are the only lymphocytes capable of
killing virally infected cells
CTL and Th cells only recognize protein previously
processed by APC into Ag peptides; the only lymphocyte
that recognize lipids, carbohydrates or nucleic acids
are some of the B cells
 Secondary Lymphoid Organs

Lymphatics are a non-pressurized system

draining fluid from tissues into blood, which
is a pressurized system
Microbial Ag is transported from tissues to
the nodes by APC and lymphatic fluid
B and T cells travel from one node to another
in search of Ag, often never found
Nodes are like dating bars facilitating
the encounter between lymphocytes, APC
and Ag
 Secondary Lymphoid Organs
A = Afferent lymphatic
C = Cortex D = Sinuses B = Sub capsular sinus
Follicle

E = Paracortex
Medullary cords = F
G = Efferent
lymphatic

4. Nave lymphocytes
2. Lymphocytes enter nodes from exits nodes efferent
blood crossing venules wall and lymphatics and travel
locate then in cortex (B cells) or to next node;
paracortex (T cells) activated lymphocytes
eventually cross back
3. Nave lymphocytes may
to blood and move to
1. Ag travel in lymphatic fluid or inside encounter protein Ag delivered
tissues
macrophages and dendritic cells from by APC and become activated
tissues, entering nodes afferent lymphatics
 Secondary Lymphoid Organs
Other secondary lymphoid
organs include
Spleen, a blood filter that
contains microbial invasion
of blood and which
macrophages are very
effective against
encapsulated bacteria
MALT or mucosa
associated lymphoid
tissue, the largest
lymphoid organ in the body
and functions very similar
to lymph nodes
 Adaptive Immune System
Tolerance to Self

B and T cell receptors are so diverse

that many could recognize self Ag,
leading to autoimmune disease
B and T cells are educated to
discriminate between self and non-self
Ag from dangerous microbial outsiders
B cells are educated in Bone Marrow
and T cells in Thymus; These primary
lymphoid organs generate all mature
lymphocytes
The mechanisms are not well understood
 Primary (Nave) and
Secondary (Memory)
Adaptive Immune Responses
Secondary
response to
Ag X is
faster and
more vigorous
than primary
response
Antibody
levels decline
after each
immunization
 Powerful Properties of the
Adaptive Immune System
Diversity and Specificity: lymphocytes
recognize millions of Ag (each one express a
customized specific or clonal receptor); Those
recognizing self Ag are eliminated or
neutralized (tolerance to self)
Clonal Expansion and Contraction: Ag specific
lymphocytes with exposure and
thereafter, adapting to circumstances
Specialization: responses are optimally
customized depending on body location and
type of microbes
Memory: responses to repeated exposures are
faster and more vigorous
 Innate versus
Adaptive Immunity

Adaptive immunity is like custom made

shoes; it requires time to fabricate them
Innate immunity is like fast common fit
shoes immediately available
The innate immune system produces non-
customized weapons ready at all times and
effective against most common microbes
The adaptive immune system is on call to
fight against less common microbes with
more powerful customized weapons
 Innate versus
Adaptive Immunity
The adaptive immune system is mobilized
by the innate immune system when this
is incapable to defeat the enemy with
conventional weapons
It takes time preparing customized
weapons, about 1 week because it
requires cell growth and clonal expansion
However, the adaptive immune system
remembers previous dangerous infections
and responds quicker and more
vigorously to new attacks (Immunological
Memory)
 Innate System Rules

The innate system is our first line of

defense before the adaptive system
gets ready
Is effective in killing common microbes
of daily life to which responds always
the same (no memory)
The adaptive system recognizes a huge
number of microbes but is not ready
for immediate fight and doesnt
distinguish which microbes are
dangerous
 Innate System Rules

The innate system recognizes uncommon

dangerous pathogens but cant kill them
effectively without killing too may human
cells (too much collateral damage)
However, the innate system is good in
sensing danger, alarming the adaptive
system and giving permission to respond
with powerful customized weapons
Also acts like a coach designing a game
plan for the adaptive system
 Question
Based on what you have learned on previous slides about
lymphoid organs and the contrasting features of the innate and
acquired immune systems, which of the following statements is
the most correct?

Select the best answer

The acquired immune system is more powerful than the
innate immune system and acts independently from this one

Ag enters lymph nodes from afferent lymphatics travelling

free in the lymphatic fluid or transported inside APC
B and T lymphocytes are generated in the BM but both must
complete self-Ag immunotolerance education in the thymus
The innate immune system is not as specific as the adaptive
immune system but has a superior immunological memory
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 Correct Answer!
Concentration of Ag in strategic parts of the body (lymph
nodes) allows lymphocytes encountering cognate Ag in less
than 24 hours
Ag escorted by APC or free in lymphatic fluid flows from
tissues to local nodes via afferent lymphatics and meet B
cells in cortical follicles and T cells in paracortex
Nave B and T cells enter the nodes from blood after
crossing nodes high endothelial veins; continue circulating
from one node to another searching for their rarely found
cognate Ag and when so, they become activated, return to
the blood and move to the tissues under attack
There is continuous cross-talk between innate and
acquired immune systems; without the alarm from the
innate immune system, the powerful acquired system wont
become activated and we wont enjoy its immunological
memory
T cell tolerance education to self Ag occurs in thymus; B
cell tolerance education occurs in BM