CHAPTER 1

OVERVIEW OF THE IMMUNE SYSTEM

 THE IMMUNE SYSTEM

able to recognize subtle chemical

differences that distinguish one foreign
pathogen from another.
able to discriminate between foreign
molecules and the body’s own cells and
proteins.
 Two related activities
of immune response

EFFECTOR RESPONSE MEMORY RESPONSE

 immune system recruits a variety of cells  more rapid and heightened immune
and molecules to mount an appropriate reaction that serves to eliminate the
response.
pathogen and prevent disease .
 ELEMENTS OF THE PRIMITIVE
IMMUNE SYSTEM

 innate immunity - persist in vertebrates.

adaptive immunity - highly evolved system of

specific responses.
Historical Perspective

Innate Immunity

Adaptive Immunity

Comparative Immunity

Immune Dysfunction and Its Consequences

 HISTORICAL PERSPECTIVE

• The Latin term immunis - “exempt,” is the source of the

English word immunity, meaning the state of protection from
infectious disease.

• Thucydides - earliest written reference to the phenomenon of

immunity can be traced back by the great historian of the
Peloponnesian War.
• 430 BC - describing a plague
in Athens.
- had recovered from
the plague could nurse the sick
because they would not
contract the disease a second
time.
• 15th Century - Chinese and Turks – performed “first recorded
attempts to induce immunity deliberately.

• Variolation - suggest that the dried crusts derived from smallpox

pustules were either inhaled into the nostrils or inserted into small
cuts in the skin.

• 1718 - Lady Mary Wortley Montagu, the wife of the British

ambassador to Constantinople, observed the positive effects of
variolation on the native population and had the technique
performed on her own children.
• 1798 - The method was significantly improved by the English physician
“Edward Jenner”.
• - His technique of inoculating with cowpox to protect against smallpox
spread quickly throughout Europe.
• Cholera- in science serendipity in combination with astute observation
led to the next major advance in immunology, the induction of
immunity.
• Louis Pasteur - succeeded in growing the bacterium thought to cause
fowl cholera in culture and then had shown that chickens injected with
the cultured bacterium developed cholera.
Pasteur - grew a fresh culture of the bacterium with the intention of
injecting it into some fresh chickens.
“Pasteur hypothesized and proved that aging had weakened the virulence of
the pathogen and that such an attenuated strain might be administered to
protect against the disease.”

Vaccine - (from the Latin vacca, meaning “cow” attenuated strain.

- in honor of Jenner’s work with cowpox inoculation.
“Pasteur extended these findings to other diseases, demonstrating that it
was possible to attenuate, or weaken, a pathogen and administer the
attenuated strain as a vaccine.”
• Bacillus anthracis – Pasteur first vaccinated one
group of sheep with heat-attenuated anthrax
bacillus.
- classic experiment at Pouilly-le-Fort in 1881.

“These experiments marked the beginnings of the

discipline of immunology.”

• 1885 - Pasteur administered his first vaccine to a

human, a young boy who had been bitten
repeatedly by a rabid dog.
 EARLY STUDIES REVEALED HUMORAL AND
CELLULAR
COMPONENTS OF THE IMMUNE SYSTEM

 Emil von Behring and Shibasaburo Kitasato “in 1890” gave

the first insights into the mechanism of immunity.
earning Nobel prize in medicine in 1901.
 demonstrated that serum (the liquid, noncellular component of
coagulated blood) from animals previously immunized to
diphtheria could transfer the immune state to unimmunized
animals.
Elvin Kabat in 1930 - a fraction of serum first called gamma-globulin
(now immunoglobulin) was shown to be responsible for all these
activities.

 Antibodies- active molecules in the immunoglobulin fraction

Humoral immunity- mediated by antibodies contained in
body fluids (known at the time as humors).
• 1883 - discovery that a serum component
could transfer immunity.
• Elie Metchnikoff - demonstrated that cells
also contribute to the immune state of an
animal.
• Phagocytes - able to ingest (phagocytose)
microorganisms and other foreign material.
 EARLY THEORIES ATTEMPTED TO EXPLAIN
THE SPECIFICITY OF THE ANTIBODY–
ANTIGEN INTERACTION
Antigen - the greatest enigmas facing early immunologists was the
specificity of the antibody molecule for foreign material, (the general
term for a substance that binds with a specific antibody).

Jules Bordet at the Pasteur(1900)

Institute expanded the concept of immunity by demonstrating specific
immune reactivity to nonpathogenic substances, such as red blood cells
from other species.
 Two major theories

Selective theory - dates to Paul Ehrlich in 1900. In an attempt to explain

the origin of serum antibody.
• “side-chain receptors “- Ehrlich proposed that cells in the blood
expressed a variety of receptors

Instructional theories - selective theory was challenged in 1930s and

1940s.
 formally disproved in the 1960s, by which time information was
emerging about the structure of DNA, RNA, and protein.
THE IMMUNE SYSTEM INCLUDES INNATE
AND
ADAPTIVE COMPONENTS
E-COLI ADHERING TO URINARY EPITHELIAL
CELLS
 THE SKIN AND THE MUCOSAL SURFACES
PROVIDE
PROTECTIVE BARRIERS AGAINST INFECTION

• Skin and the surface of mucous membranes

- included in this category because they are effective
barriers to the entry of most microorganisms.
 TWO DISTINCT LAYERS OF
SKIN
• Epidermis( thinner outer layer)- consists of
dead cells Sebum consists of lactic acid
and fatty acids
and is filled with a waterproofing protein
called keratin.

• Dermis(thicker layer) - composed of

connective tissue, contains blood vessels,
hair follicles, sebaceous glands, and sweat
glands
 PHYSIOLOGIC BARRIERS TO INFECTION INCLUDE
GENERAL CONDITIONS AND SPECIFIC MOLECULES
Physiologic barriers - contribute to innate immunity include temperature,
pH, and various soluble and cell associated molecules.
Many species are not susceptible to certain diseases simply because their
normal body temperature inhibits growth of the pathogens.

Gastric acidity - an innate physiologic barrier to infection because very few

ingested microorganisms can survive the low pH of the stomach contents.
 Class of receptors

 Toll-like receptors (TLRs),

TLR2 recognizes the
 Lipopolysaccharide (LPS) found
on Gram-negative bacteria.

 It has long been recognized that

(a) Electronmicrograph of macrophage (pink)
systemic exposure of mammals to attacking Escherichia coli (green). The bacteria are
phagocytized as described in part b and breakdown
relatively small quantities of purified products secreted. The monocyte (purple) has been
LPS leads to an acute inflammatory recruited to the vicinity of the encounter by soluble
factors secreted by the macrophage. The red sphere
response. is an erythrocyte.
(b) Schematic diagram of the steps in phagocytosis of
a bacterium. [Part a, Dennis Kunkel Microscopy,
Inc./Dennis Kunkel.]
 CELLS THAT INGEST AND DESTROY PATHOGENS
MAKE UP A PHAGOCYTIC BARRIER TO INFECTION

Phagocytosis - conducted by specialized cells, such as blood monocytes,

neutrophils, and tissue macrophages

Types of Phagocytosis
Phagocytosis- important innate defense mechanism is the ingestion of
extracellular particulate material.
Endocytosis - the general term for the uptake by a cell of material from
its environment.
 INFLAMMATION REPRESENTS A COMPLEX
SEQUENCE OF EVENTS THAT STIMULATES
IMMUNE RESPONSES
• Inflammatory response - Tissue damage caused by a wound or by an
invading pathogenic microorganism induces a complex sequence of
events
collectively.

• Roman physician Celsus described the “four cardinal signs of

inflammation” as rubor (redness), tumor (swelling), calor (heat), and
dolor (pain).
 ADAPTIVE
IMMUNITY
Adaptive immunity displays four characteristic
attributes:
Antigenic specificity
 Diversity
 Immunologic memory
 Self/non self recognition
Antigenic specificity - immune system permits it to distinguish
subtle differences among antigens

Diversity - immune system is capable of generating tremendous.

- its recognition molecules, allowing it to recognize billions of
unique structures on foreign antigens.

Immunologic memory - immune system has recognized and

responded to an antigen

Self/nonself recognition - immune system normally responds

only to foreign antigens, indicating that it is capable
T LYMPHOCYTES
 migrate to the thymus gland
 arise in the bone marrow
to mature.

T-cell receptor
 its maturation within the
thymus, the T cell comes to express a
unique antigen-binding
molecule,
 CELLS OF IMMUNE SYSTEM

Lymphocytes
B cells, mature in Bone Marrow (CD19, CD20) in
periphery they express a unique surface antibody
Plasma cells differentiated B cell, short lifespan, antibody
factory
Memory B cell (CD45RO), long life span
T cells, mature in Thymus (CD3, CD4, CD8)
• Two Major subsets, TH (CD4) and TC (CD8)
• Third type TS not as clear
• Mature T cell expresses TCR
• TCR cannot recognize antigen on its own
• MHC I (all nucleated cells) or MHC II (APCs) is required
• TH cells secrete cytokines
• TC less cytokines, more cytotoxic (virus and tumor
survailance)
• Antigen Presenting Cells

Number of Cells capable of Antigen Presentation

Dendritic Cell (DC) professional APC
Macrophages, B cells
Besides Antigen They Provide Co-stimulation
APCs are a safeguard against autoimmunity
APC INTERACTING WITH T CELL
 MAJOR HISTOCOMPATIBILITY
COMPLEX (MHC)
Genetic Complex With Multiple Loci
MHC I – CTLs
MHC II - TH
MHC I+2-microglobulin
• 3 classes A, B, C (human)
• 2 classes K and D (mouse)
MHC II
• 3 classes DP, DQ, DR (human)
• 2 classes IA, IE (mouse)
• Highly Polymorphic in Humans
 PROCESSING AND
PRESENTATION OF ANTIGENS
First Protein Antigens Must Be Broken Down
Form Complexes With MHC I or II
Exogenous Antigens
• Antigens Processed Thru Endocytic Pathway
• Binding of Ags To MHC II
• Expression of MHC II+Ags On Surface
• CD4 T Cells Recognize Ag Thru Class II MHC
Endogenous Antigens
• Antigens Processed Thru Cytosolic Pathway
• Produced Within Cell, Ex. Virus Ag, Cancer Ag
• MHC I Molecules Bind Ag in ER
•
 PROCESSING AND
PRESENTATION OF ANTIGENS
 CLONAL SELECTION OF
LYMPHOCYTES AND MEMORY
Ag Reactivity Determines Clonal Expansion
Immunologic Memory is By-product of Clonal Expansion
Humoral Primary Response
• 7 Days Before Antibody Levels Rise
• Antibody Titer is Low Compared to Secondary
Humoral Secondary Response
• 1-2 Days Antibodies Are Detected
• Antibody Titer Higher (100-1000 fold higher)
• Lasts Longer
 CLONAL SELECTION OF
LYMPHOCYTES AND MEMORY
Cell Mediated Response
(TH or CTL) is Similar
• Primary Response 10-14
Days For Skin Rejection
• Secondary Response
Starts Immediately
ABERRANT RESPONES – ALLERGY,
ASTHMA, ANAPHYLAXIS

Asthma/Allergies Attacks Are Very

Common
Mediated Thru IgE
IgE Binds Mast Cells, Basophils
Re-exposure Cross Links IgE
Causes Degranulation, Histamine,
prostanoids
 COMPARATIVE IMMUNITY

a determined search for antibodies, T cells, and B cells

in organisms of the non vertebrate phyla has failed to
find them.

Insects and plants provide particularly clear and

dramatic examples of innate immunity that is not based
on lymphocytes.
Drosophila
melanogaster
- invasion of the interior
body cavity of the fruit fly.
by bacteria or molds
triggers the synthesis of
small peptides that have
Severe fungal infection in a fruit fly (Drosophila
strong antibacterial or melanogaster) with a disabling mutation in a signal-
antifungal activity. transduction pathway required for the synthesis of the
antifungal peptide drosomycin.
 IMMUNE DYSFUNCTION AND
ITS CONSEQUENCES
Innate and adaptive immunity depicts a multicomponent interactive system
that protects the host from infectious diseases and from cancer.

There are several common manifestations of immune dysfunction:

Allergy and asthma
 Graft rejection and graft-versus-host disease
Autoimmune disease
 Immunodeficiency
 • Allergy and asthma
a results
of inappropriate immune responses, often to common antigens
such as plant pollen, food, or animal dander
 GRAFT REJECTION AND GRAFT-VERSUS
-HOST DISEASE

• GvHD, the donated bone marrow or

peripheral blood stem cells view the
recipient’s body as foreign, and the
donated cells/bone marrow attack the
body.
• There are two forms of GvHD:
1. Acute graft versus host disease
(aGvHD).
2. Chronic graft versus host disease
(cGvHD).
• Autoimmunity Disease
- cancause a number of chronic
debilitating diseases.
The symptoms of
autoimmunity differ depending
on which tissues and organs are
under attack.
• Immunodeficiency
- immune system is not able to fight
off infections or viruses effectively.
- SECONDARY DISORDERS
- AIDS. cancers of the immune
system, like leukemia. immune-
complex diseases, like viral
hepatitis. multiple myeloma
(cancer of the plasma cells, which
produce antibodies