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Chapter 1

Elements of the Immune system


and their Roles in Defense

Introduction
Immunology is the study of physiological mechanisms that
are used to defend the body from invasion by foreign or
infectious agents
In response to diseases caused by infectious agents, the
body develops cells dedicated to defense these form the
immune system
Protective/adaptive immunity takes time to develop, while
microorganisms can rapidly multiply and cause disease
Immunity involves two responses:
1. Flexible but specific defenses of the adaptive immune response
2. Fixed defenses of the innate immune response

Defenses Facing Invading Pathogens

The Ubiquitous Enemy- Microbes


Microbes
Survive on animal & plant products
Release digestive enzymes
Grow on living tissues (extracellular) where they are bathed in
nutrients
Other (intracellular) microbes infect animal/human cells, utilizing hostcell sources

Some microbes are harmless and some even helpful


e.g. E. Coli in our intestines (colicins)

Many others cause disease


human pathogens

There is a constant battle between invading microbes and the


immune system
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Immunity-The Immune Response


People who survive a specific infection become immune to it
protective immunity
To provide protective immunity, the immune system must first
engage the microorganism
There is lag time between infection and protection (~7days)
The first infection is the most dangerous one

This understanding led to the concept of immunization or


vaccination
Disease is prevented by prior exposure to an attenuated/killed
infectious agent

Historical Perspective
430 BC- Thucydides recognized that only those who had
recovered from the plague could nurse the sick without
becoming sick again.
Fifteenth century- Chinese and Turks used dried crusts from
smallpox pustules (inhaled or inserted into small cuts in the
skin variolation) to induce immunity.
1796- Jenner realized milkmaids who had contracted cowpox
(mild disease symptoms compared to smallpox) were not
susceptible to smallpox.
He theorized that using fluid from a cowpox pustule would induce
immunity to smallpox
Tested theory on 8 yr old boy- inoculated boy with fluid from cowpox
pustule then later injected the boy with smallpox. The boy didnt
contract smallpox.
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Historical Perspective
Origins of immunology attributed
to Edward Jenner
Discovered in 1796 that cowpox
vaccinia protected from human
smallpox
Procedure called vaccination
Prevents severe disease by
exposing the immune system to
the infectious agent in a
weakened or killed state.
Provides long term protection
against the real pathogen with
very little risk of becoming sick.

The Nature of Pathogens

Any organism with potential to cause disease is a pathogen


Influenza and typhoid bacillus are examples of what we call a
pathogen.

Opportunistic pathogens cause disease if the bodys


defenses are weakened or it gets into a part of the body it
isnt normally found.
Constant evolutionary struggle between the host and the
pathogen
REPLICATION TIMES favor the PATHOGEN!!!

The Four Kinds of Pathogen that Cause


Human Disease

Examples
of the types
of
pathogen
are listed,
along with
the
diseases
they cause

The Diversity of Human Pathogens,


Refer
to
Figure
1.3
Blastophores
(yeast-like cells)

Cocci-grape like clusters

Pseudohyphae

Candida albicansnormal inhabitant of the


human body, thrush &
systemic infections

Staphylococcus aureusgram positive bacterium


that colonizes human
skin, pimples & boils
(other strains = food
poisoning)

Mycobacterium
tuberculosiscauses
tuberculosis
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Commensal Bacteria
-Over 1000 microbial
species in the human gut
(normal flora).
-These bacteria typically
cause no harm to the host.
-Commensal = eat at the
same table. Not harmful
-When a round of antibiotics
is taken, there is no
specificity for the pathogen
so a large percentage the
bacteria (good and bad) are
killed.
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Skin and Mucosal Surfaces Physical Barriers Against Infection


Skin is first line of external defense against infection
Tough impenetrable barrier
Skin continuous with epithelia lining
Respiratory
Gastrointestinal
Urogenital tracts

The impermeable skin gives way


to specialized tissues that are
more vulnerable to microbe attack;
Known as mucosal surfaces or mucosae
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Skin and Mucosal Surfaces Physical Barriers Against Infection


Mucosal surfaces are bathed in mucus; thick fluid containing
glycoproteins, proteoglycans, and enzymes - protective
Lysozyme in tears (~ 40% of protein) and saliva
antibacterial
Respiratory tract mucus is continuously removed to clear
unwanted material
Stomach, vagina, skin acidic protective
Defensins poke holes in the pathogen

When skin and mucosal barriers are


breached - immune system responds
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Physical Barriers that Separate the Body


from its External Environment

Strong barriers to
infection provided by the
skin, hair, and nails are
colored blue
More vulnerable mucosal
membranes are colored
red
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Innate Immune Response Leads to


Inflammation
The physical barriers have been breached. Now what?
The Innate Immune response starts to work to clear the new
invader
This is the next line of defense after physical barriers are
breached
Innate = determined by the genes you inherited from your
parents
Adaptive cells (T and B change the genes for their receptors)

Innate response consists of two parts


Recognition
Recruitment of effect mechanisms (cells)
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Complement (Innate)
- Series of proteins that act to tag an invader for uptake
(phagocytosis) by other immune cells or by poking holes in the
microbe by completing the complement cascade.

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Inflammation

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Immune Defense-Innate Vs. Adaptive Immunity


1. Innate immune system

Is the first line of defense against infections

It works rapidly

Gives rise to the acute inflammatory response

Has some specificity for microbes

Uses different receptors to recognize pathogens

2. Adaptive immune system

Takes longer to develop (~7 days)

Is highly specific for antigens, including those associated with microbes

Uses one type od receptor to recognize many different pathogens

Primary immune response = first time the adaptive immune response is


activated against a pathogen.

Secondary immune response = any time the adaptive immune response is


activated against a pathogen that it has been exposed to before

Remembers that it has encountered a microbe previously


(i.e. shows memory)

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Innate and Adaptive Immunity Work Together


The innate and adaptive immune systems work together
through.
Direct cell contact
Interactions involving chemical mediators
Cytokines and Chemokines

Many of the cells of the innate immune system are the same
cells used by the adaptive immune system
Vaccinations require that the innate immune system is
engaged in order to provide memory.
Innate immune system activates and aids in the adaptive immune
response.

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Adaptive lymphocyte selection and


proliferation
-A single lymphocyte will have a receptor
with a single specificity. One cell may
have many receptors (~120,000) but all
will recognize the same epitope.
-When a foreign epitope is recognized by
the lymphocyte receptor (selected), the
cell will proliferate (expansion).
-Want a lot of that specific receptor to
recognize the invader.
- 1 receptor specificity = 1 T or B cell
-Generally takes about a week before the
benefits of a primary immune response
are realized.
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Innate and Adaptive


-People lacking innate immunity
cant control the infection at all.
Innate immunity cells are needed
to activate the adaptive cells.
-- People lacking adaptive
immunity can control the infection
initially but cant clear it.

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Principle Characteristics of
Innate and Adaptive Immunity, Figure 1.8

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Cells of the Immune System


1. Lymphoid cells

20-50% of white blood cells

T cells, B cells, and NK cells

2. Mononuclear phagocytes

Monocytes that circulate in the blood and

Macrophages found in tissues

3. Granulocytic cells These are called granulocytes

Neutrophils

Eosinophils

Basophils
based on morphology and cytoplasmic staining characteristics

4. Dendritic cells

Main function is the presentation of antigen to T cells


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Hematopoiesis
The generation of the cellular elements of blood, including:
Red blood cells (RBC)
White blood cells (WBC) or leukocytes
Megakaryocyte - Platelets

These cells originate from pluripotent hematopoietic stem


cells (HSC) whose progeny differentiate and divide under the
influence of various hematopoietic growth factors
HSC give rise to other cells in a process called self-renewal,
becoming more mature stem cells that commit to different
lineages

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Types of Hematopoietic Cells

The
pluripotent
stem cell
divides and
differentiates
into more
specialized
progenitor cells
that give rise to
the
lymphoid
lineage
myeloid
lineage
erythroid

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Abundance of Leukocytes in Blood

Most
abundant
leukocytes
are the
neutrophils
Followed by
lymphocytes

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Leukocyte Versus Lymphocyte


Leukocytes

A general term for a white blood cell


Lymphocytes, granulocytes, monocytes are all leukocytes

Lymphocytes

A class of white blood cells that consist of small and large


lymphocytes

Two classes of lymphocytes


1. Small lymphocyte (adaptive immunity cells)
B lymphocytes (B cells)
T lymphocytes (T cells)
2. Large granular lymphocytes
Natural killer (NK) cells, lymphocytes of innate immunity
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Lymphoid Cells
Lymphocytes are divided into three classes
1. B cells (Igs receptor)
2. T cells (TCR)
3. NK cells (Natural killer cells)

Nave lymphocytes or small lymphocytes are resting cells


that have not interacted with antigen
Lymphoblasts are lymphocytes that have interacted with
antigen and proliferate

Lymphoblasts eventually differentiate into effector cells or into


memory cells

Effector cells eliminate antigen

Plasma B cells that secrete antibody

Cytokine-producing T helper cells (TH) - CD4 cell

T cytotoxic cells (TC) CD8 Cell

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Natural Killer Cells


NK cells (large granular lymphocytes) are found throughout
the tissues of the body but mainly in the circulation
Constitute 5-10% of lymphocytes in human blood
Contain cytotoxic substances which are important for protection
against viruses and some tumors
Secrete cytokines which
Prevent viral replication and
Helps to activate T cell-mediated immunity

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Neutrophils
Effectors of innate immunity specialized in the capture,
engulfment and killing of microbes
Work in the anaerobic conditions found in damaged tissue
Are short-lived and die at site of the infection one the major reasons
for pus formation at the site of injury
Pus former = pyogenic
Are phagocytic cells that contain toxic substances in intracellular
granules (primary and secondary granules)
Employ oxygen-dependent and oxygen-independent pathways to
destroy pathogens

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Mononuclear Phagocytes
Monocyte progenitors in the bone marrow differentiate into
pro-monocytes, which enter the blood, where these
differentiate into monocytes
Monocytes circulate in the blood for about 8 hours, then
mature and migrate into tissues, they are then referred to as
macrophages.
Both monocytes and macrophages are phagocytic
Monocytes in the peripheral blood
Macrophages in the tissues

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Mononuclear Phagocytes
Differentiation of monocyte into macrophage requires
changes
Monocyte cells enlarge 5-10 times
Increased intracellular organelles
Increased phagocytic ability
Production of hydrolytic enzymes
Secretion of soluble factors

There are tissue specific fixed macrophages and free


macrophages we will focus on the fixed

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Dendritic Cells
Dendritic cells are so called because of their many surface
membrane folds, similar in appearance to dendrites of the
nervous system
These folds allow maximum interaction with other cells of
the immune system
What is the dendritic cells main job?

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Dendritic Cells (cont.)


Most dendritic cells
Possess high levels of surface MHC class II molecules
Can also present with MHC I
Process and present peptide antigens to T cells
Their role is to recognize microbial antigens through innate receptors
and process and present them to T cells of the adaptive immune
system

Follicular dendritic cells (FDC) hold intact antigens in


specialized areas of lymphoid tissues
Not related to the dendritic cell above
Found in germinal centers of secondary lymphoid tissues

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Mast Cells
Mast cells are found in the skin, connective tissue and
mucosal epithelial tissue of the respiratory and digestive
tracts
The origin of mast cells is uncertain but precursors
differentiate in the bone marrow and mature in tissues
When activated mast cells degranulate, they release
pharmacological mediators (e.g. histamine) which cause
Vasodilation
Increase vascular permeability
Attract leukocytes to the site of degranulation

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Eosinophils
Eosinophils are granular leukocytes which stain with eosin
(red)
They are present at low levels in the circulation (1-6% of blood
leukocytes
Eosinophils have some phagocytic activity but are primarily
responsible for extracellular killing of large parasites such as worms
They usually bind to an antibody-coated parasite and release the
contents of their granules (degranulate) onto the parasite surface
One of the three granulocytes

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Basophils
Basophils are granulocytes which stain with basic dyes (blue)
and are present in very low numbers in the circulation (<0.2%
of the granular leukocytes)
Basophils and mast cells are very similar in morphology
Both contain and release large characteristic electron-dense granules
in their cytoplasm during allergic reactions (e.g. histamine)
Like all the granulocytes, basophils are produced from stem cells in
the bone marrow

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Megakaryocyte
Megakaryocyte is a bone marrow cells responsible for the
production of blood platelets when its cytoplasm becomes
fragmented
These fragments are blood platelets
Megakaryocytes account for less than 1% of bone marrow cells but
can be 10 to 15 times larger than a typical red blood cell
The nucleus of the megakaryocyte is very large and lobulated, which,
under a light microscope, can give the false impression that there are
several nuclei

Megakaryocyte function is determined by a large number of


cytokines, including thrombopoietin
Thrombopoietin is a glycoprotein hormone produced mainly by the
liver and kidney that regulates the production of platelets by the bone
marrow
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Erythrocytes
Erythrocytes bind to immune complexes composed of antigen
and antibody and carry these complexes to the liver where
these are cleared by Kupffer cells
Erythrocytes have an important immunological role in clearing
immune complexes from the circulation in persistent
infections and in some autoimmune diseases
Kupffer cells = phagocytic cells of the liver that line the
hepatic sinusoids

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Site of Hematopoiesis in Humans


Changes During Development
The site for hematopoiesis
changes with age
In early embryo, blood cells
are first produced in the yolk
sac and later in the fetal liver
From months 3-7 of fetal life
the spleen is the major site of
hematopoiesis
As bones develop (4-5
months) hematopoiesis shifts
to the bone marrow
In adults hematopoiesis occurs
mainly in the bone marrow

Hematopoiesis is active
throughout life because blood
cells are both vital and short-lived
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Neutrophils are Mobilized from the Bone


Marrow, and Target (home) to Infection Sites

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Mononuclear Phagocyte System


Mononuclear phagocyte system
System of phagocytes located mainly in the organs and tissues
Monocytes are present in the blood stream and settle in the tissues as
macrophages

Macrophage-like cells in the liver Kupffer cells


Macrophage-like cells in the brain Microglia

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Process of Phagocytosis
Macrophage (pink)

E. Coli (green)

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Phagocytic process
Several stages
1. Phagocyte attraction to the site of infection
2. Phagocyte contact with the microbe
3. Ingestion (endocytosis)
4. Killing of the ingested microbe by means of oxygen and oxygenindependent mechanisms

Opsonization

Way of making microbes more palatable to the phagocyte

Molecules coating a microbe, such as complement or antibody


facilitate contact and ingestion of the microbe

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Macrophages are Key Players in the Innate


and Adaptive Immune Response

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Macrophages Respond to Pathogens by


Using Different Receptors to Stimulate
Phagocytosis & Cytokine Secretion
Bacterium (red) binds to cellphagocytic receptors of the
macrophage (blue)
Bacterium is engulfed into an
endocytic vesicle called a
phagosome

Fusion of the phagosome with


lysosomes forms an acidic
vesicle called a phagolysome
Contains toxic molecules and
hydrolytic enzymes that kill the
bacterium
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Macrophages Respond to Pathogens by


Using Different Receptors to Stimulate
Phagocytosis & Cytokine Secretion
Bacterial component binding
to a signaling receptor
sends a signal to the
macrophages nucleus
This initiates the transcription
of genes for inflammatory
cytokines

The cytokines are


synthesized and secreted
into the extracellular space
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Mechanisms of Protection
Antigens- Any molecule or molecular fragment that can be bound to by an
antibody or be bound by an MHC molecule and presented to a T-cell.
Can be proteins, lipids, or sugars
Can be found on the surface or secreted by microorganisms
Antibodies (immunoglobulins)- Proteins molecules synthesized by cells of
immune system part of the humoral immunity
Humors = bodily fluids
That recognize antigens

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Adaptive Immunity
Occasionally the infection outruns the innate immune
response
Innate immunity has a restricted number of receptors to recognize
pathogens

This activates the adaptive immune system


The adaptive immune system is mediated by lymphocytes
Which expand into effector cells and also persist as memory cells

The adaptive immune system generates a huge diversity of


immunoglobulins (Ig) and T cell receptors
Upon infection, only the B cells with specific Ig, or T cells with
specific receptors, are stimulated to proliferate and
differentiate into effector cells
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Adaptive Immune System: What Abs Do

- Neutralization bind to toxin


or pathogen and stop it from
being able to cause harm to
host
- Opsonization target the
pathogen or molecule for
destruction similar to
complement components

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Organs of the Immune System


Distinguished by function
Primary and secondary lymphoid organs
Thymus and bone marrow are primary organs
Where maturation of lymphocytes takes place
Lymph nodes, spleen and mucosal-associated tissues are
secondary organs
Which trap antigen and promote lymphocyte activation

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Lymphocytes and Lymphoid Tissues


Lymphocytes are
Found in lymphoid tissues,
blood and lymph
Activated in the secondary
lymphoid tissues
Arise from stem cells in bone
marrow

B cells - mature bone


marrow
T cells - mature thymus
Primary lymphoid tissues
Bone marrow and thymus

Secondary lymphoid tissue


and lymphatics
Spleen, lymph nodes, peyers
patches

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Lymphatic System

Small lymphocytes travel in


blood and lymph.
Antigens are carried to lymph
nodes, as are lymphocytes,
enabling interactions
When an antigen is encounter
the lymphocyte will no longer
recirculate.

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Secondary Lymphoid Organs


Meeting place where
lymphocytes circulating blood
encounter antigens brought
from sites of infection
Antigens derived from infections
originating in connective tissues
(as a result of skin wounds) are
carried by the lymphatics to the
nearest lymph node
Dendritic cells activated by
infection also carry antigens

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Circulating Lymphocytes
Encounter Lymph-borne Pathogens in
Draining Lymph Nodes
Lymphocytes leave blood and
enter lymph nodes where they are
activated by pathogens
Pathogens drain from site of
infection (example: foot) to lymph
nodes via afferent lymphatic
vessels
Activated lymphocytes stay in
lymph nodes and divide and
differentiate into effector cells,
while non-activated cells leave
through efferent lymphatics
Lymphocytes recirculate at a rate
of 5 X 106 cells/min
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Architecture of the Lymph Node


Kidney-shaped; packed
with lymphocytes &
macrophages through
which lymph percolates
Pathogens and dendritic
cells carrying pathogens
arrive in afferent lymph
Pathogens are degraded
and used to stimulate
lymphocytes
Lymphocytes arrive at
lymph nodes in arterial
blood; extravasate from
capillaries

Lymph is the mixture of extracellular


fluid and cells that is carried by the
lymphatic system

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Architecture of the Lymph Node


In lymph nodes, there
are discrete sites where
B cells and T cells
congregate
Effector B cells; plasma
cells -secrete antibodies
Lymph node increases in
size due to dividing
lymphocytes - swollen
glands
Expansion occurs in
lymphoid follicles
As lymphocyte
development proceeds,
follicle shape changes germinal center

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2.

Cytotoxic T cells

3.

Helper T cells

5.

1.

4.

B cells

6.
7.

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The Spleen
Filter for blood that removes old or damaged cells = Red pulp
Site where blood-borne pathogens encounter lymphocytes (a secondary lymphoid
organ) = White pulp.
Blood is the only way in and out for lymphocytes as well as pathogens.
Spleenic macrophages and dendritic cells in the spleen take-up antigen and
stimulate T an B-cells.

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The Spleen
White pulp of
spleen consists of
sheath of
lymphocytes called
the periarteriolar
lymphoid sheath
(PALS)
surrounding a
central arteriole
(CA)
T cells are closest
to the CA, while B
cells are more
peripheral, forming
a B cell corona

Germinal centers form between the


T and B cell zones
The marginal zone contains
differentiated B cells
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Mucosal-Associated Lymphoid Tissue (MALT)


Mucosal surfaces lining digestive, respiratory and urogenital
tracts are the major sites of entry for pathogens and are
defended by MALT
Tissues range from loosely organized clusters of lymphoid
cells to well-organized structures tonsils, appendix
The gut associated lymphoid tissues, GALT include tonsils,
adenoids, appendix and Peyers patches that line the gut
Bronchial-associated lymphoid tissues, BALT
Lymphocytes activated in the MALT tend to stay in MALT and
the memory cells serve the MALT in the future.

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A Region of GALT
Peyers
patch

-Pathogens arrive through direct delivery across mucosa


mediated by specialized cells called M cells
-Lymphocytes enter from the blood, if not activated, leave
in the lymphatics.

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Immunological Memory
Lymphocytes that expand persist, providing long term
memory
First time infection results in a primary response which leads to
memory (T and B cells) of the pathogen.
Subsequent infections with the same pathogen, having the same
antigens, will elicit a secondary response which is much faster and
stronger than the original primary immune response.
This is the basis of vaccination

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Comparison of a Primary
and Secondary Immune Response

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Immunodeficiency: Inherited or Infectious


Mutation in immune function genes leads to
immunodeficiency -- different kinds.
In some, only one aspect of immune response is affected
In others, adaptive immunity is completely absent
Leading to devastating vulnerability to all infections

Extreme example of immunodeficiency due to disease is the


acquired immune deficiency syndrome, AIDS
Caused by infection with the human immunodeficiency virus, HIV

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