You are on page 1of 70

The Immune System:

Immunocytology, Immunophysiology
and Intro to Immunopathology
Marc Imhotep Cray, M.D.
BMS and CK Teacher

Companion learning tools: Additional learning tools:

IVMS Immunology Notes Reading:

Microbiology and Immunology
4 Pathophysiologic High Yield Cases On-Line Textbook
with Discussion Univ. of South Carolina SOM

e-Medicine Article
Acute Respiratory Distress

A scanning electron microscope image of a

single neutrophil (yellow), engulfing anthrax
bacteria (orange)
Defense Mechanisms

• All structures and processes that provide a

defense against pathogens.
• Defenses:
– Innate (nonspecific):
• Inherited as part of the structure of each organism.
– Adaptive (specific):
• Prior exposure (B lymphocytes).

N.B.-As much of immunology is also a hematology discussion, for

horizontal integration also see — IVMS Hematology-Comprehensive
Blood Physiology and Pathology Review

IVMS USMLE Step 1 Prep. 2

Nonspecific Immunity

• External:
– Skin:
• Protective barrier to resist infection.
– GI tract:
• Gastric juice acidity.
– Respiratory tract:
• Mucus and cilia.
– Urinary tract:
• Urine acidity.
– Reproductive tract:
• Vaginal acidity.

IVMS USMLE Step 1 Prep. 3


• Distinguish between the kinds of carbohydrates that

are produced by mammalian cells and those produced
by bacteria.
– Bacterial carbohydrates “flag” the cell for phagocytic attack.
• 3 major groups of phagocytic cells:
– Neutrophils:
• 1st to arrive at infection.
– Mononuclear phagocyte system:
• Macrophages and monocytes.
– Organ-specific phagocytes:
• Microglia and Kupffer cells.
IVMS USMLE Step 1 Prep. 4
Phagocytosis (continued)

• Diapedesis:
– Neutrophils and
monocytes are
able to squeeze
through tiny
gaps between
endothelial cells.

IVMS USMLE Step 1 Prep. 5

Phagocytosis (continued)

• Connective tissue has a resident population of all

leukocyte types.
– Neutrophils and monocytes are highly mobile.
• Recruited to site of infections by chemotaxis:
– Movement toward chemical (chemokines) attractants.
– If infection has spread, new phagocytes from the blood are
attracted to infection.
• Phagocytes engulf particles similar to amoeba.

IVMS USMLE Step 1 Prep. 6

Phagocytosis (continued)

– Particle becomes
surrounded by
– Forms vacuole.
• Vacuole fuses with
lysosomes which digest
the particle.
– If lysosomes are released
into the infected area
before vacuole is
completely fused:
• Contribute to the

IVMS USMLE Step 1 Prep. 7


• May be a component of nonspecific defense

• Cell wall of gram – bacteria contains
– Endotoxin stimulate release of cytokines:
• Interleukin-1, interleukin-6, and tumor necrosis factor:
– Produce fever, increase sleepiness, and decrease plasma iron.

IVMS USMLE Step 1 Prep. 8

Nonspecific Immunity

• Body temperature is regulated by

hypothalamus (thermoregulatory center).
– Thermostat reset by endogenous pyrogens.
• Endogenous pyrogens:
– Cell wall of gram – bacteria contains endotoxin.
– Endotoxin stimulates monocytes and
macrophages to release cytokines:
• Interleukin-1, interleukin-2, TNF.
– Increased activity of neutrophils.
– Increased production of interferon.

IVMS USMLE Step 1 Prep. 9

Interferons (Cytokines)

• Act as short-acting messengers that protect other

cells in the vicinity from viral infection.
• a interferon:
– Inhibits viral replication, increases NK cells, and induces
MHC-I antigens.
• b interferon:
– Inhibits viral replication, increases NK cells, and induces
MHC-I antigens.
• g interferon:
– Activates macrophages and induces MHC-II antigens.
• Immunological defense against infection and cancer.

IVMS USMLE Step 1 Prep. 10


• Molecules that stimulate the production of specific

– Combine specifically with antibodies produced.
• Foreign to blood and other body fluids.
• Immune system can distinguish “self” molecules
from nonself antigens.
• Large, complex molecules can have different
antigenic determinant sites.
– Areas of the molecules that stimulate production of, and
combine with different antibodies.

IVMS USMLE Step 1 Prep. 11


• Small organic molecules can become antigens

if they bind to proteins.
• Become antigenic determinant sites on the
– By binding haptens to proteins in the laboratory,
new antigens are created for research or
diagnostic purposes.

IVMS USMLE Step 1 Prep. 12


• Tests that use the

complex reaction to
produce clumping
• Agglutinated particles
can be used to assay a
variety of antigens.
• Generally use antibodies
that exhibit specificity
for just 1 antigenic
determinant site.

IVMS USMLE Step 1 Prep. 13

Lymphocytes and Lymphoid Organs

• Derived from stem cells in the bone marrow.

– Stem cells produce the specialized blood cells.
• Replace themselves by cell division so the stem cell
population is not depleted.
– Lymphocytes produced by this process seed the
thymus, spleen, and lymph nodes.
• Produce self-replacing lymphoid colonies in these organs.
• Primary lymphoid organs:
– Since bone marrow and the thymus produce the T and
B lymphocytes.
• Both T and B cells function in specific immunity.

IVMS USMLE Step 1 Prep. 14

Lymphocytes (T cells)

• Cell mediated immunity:

• Lymphocytes that seed the thymus become T cells.
– Have surface characteristics and immunological function
that differ from other lymphocytes.
• Do not secrete antibodies.
• Must come in close or direct contact to destroy them.
– 65 – 85% of the lymphocytes in blood and most of the
lymphocytes in the germinal centers of lymph nodes and
• Attack host cells that have become infected with
viruses, fungi, transplanted human cells, and
cancerous cells.
IVMS USMLE Step 1 Prep. 15

• Grows during childhood, gradually regresses

after puberty.
• Lymphocytes from the fetal liver and spleen;
and bone marrow postnatally, seed the
– Become transformed into T cells.
• In adulthood, repopulation is accomplished
by production in secondary lymphoid organs.
IVMS USMLE Step 1 Prep. 16
Secondary Lymphoid Organs

• Lymph nodes, spleen, tonsils, and Peyer’s

– Located in areas where antigens could gain entry
to the blood or lymph.
• Lymphocytes migrate from the primary
lymphoid organs to the secondary lymphoid
– Spleen filters blood.
– Secondary lymph nodes in tonsils and Peyer’s
patches filter lymph.
IVMS USMLE Step 1 Prep. 17
B Lymphocytes (B cells)

• Humoral immunity:
– Most of the lymphocytes that are not T cells are B
lymphocytes (B cells).
• Processed in the bone marrow.
– Function in specific immunity.
– B cells combat bacterial and some viral infections.
• Secrete antibodies into the blood and lymph.
– Provide humoral immunity as blood and lymph are body fluids
– Stimulate production of memory cells:
• Important in active immunity.

IVMS USMLE Step 1 Prep. 18

B Lymphocytes (continued)

• Others are transformed

into plasma cells:
– Produce 2000 antibody
proteins/sec. when
exposed to antigen.
• These antigens may be
isolated molecules or may
be molecules at the
surface of an invading
foreign cell.
– Serves to identify the
• Secrete antibodies that
bind to antigens.

IVMS USMLE Step 1 Prep. 19

Local Inflammation

• Bacteria enter body (break in skin):

– Inflammatory reaction initiated by nonspecific mechanisms
of phagocytosis and complement activation.
• Complement activation attracts new phagocytes to the area.
– After some time, B lymphocytes are stimulated to produce antibodies
against specific antigens.
– Attachment of antibodies to antigens amplifies nonspecific
• Activates complement.
– Antibodies promote phagocytic activity of neutrophils, macrophages,
and monocytes (opsinization).

IVMS USMLE Step 1 Prep. 20

Local Inflammation (continued)

• Leukocytes interact with

adhesion molecules in
endothelial cell.
• Chemotaxis occurs, attracting
– Diapedesis occurs.
– First to arrive are
neutrophils, then
monocytes, and T
• Adherence of monocytes
to extracellular matrix
proteins promotes
conversion into

IVMS USMLE Step 1 Prep. 21

Local Inflammation (continued)

• Mast cells secrete

histamine, cytokines,
and TNF-a.
– Increases
– Vasodilation of
blood vessels.
– Recruit neutrophils.

IVMS USMLE Step 1 Prep. 22

Local Inflammation (continued)

• Characteristic effects of inflammation:

– Redness and warmth.
• Histamine stimulated vasodilation.
– Swelling (edema).
– Pus.
• Accumulation of dead leukocytes.
– Pain.
– If infection continues, endogenous pyrogens

IVMS USMLE Step 1 Prep. 23


• Antibody proteins are also known as

– Found in the gamma globulin class of plasma
• Different antibodies have different structure,
as the antibodies have specific actions.

IVMS USMLE Step 1 Prep. 24

Antibodies (continued)

IVMS USMLE Step 1 Prep. 25

Antibody Structure

• 100 million trillion

antibody molecules that
contain 4 polypeptide
• 2 long H chains are joined
to 2 shorter L chains.
– Fab regions are variable.
• Provide specificity for a
bonding to an antigen.
– Fc region of different
antibodies are constant.
• B cells have antibodies
that serve as receptors
for antigens.
IVMS USMLE Step 1 Prep. 26
The Complement System

• Nonspecific defense system.

– The combination of antibodies with antigens does not
cause destruction of the antigens or pathogen.
• Antibodies serve to identify the targets for
immunological attack.
– Stimulate opsinization.
• Antibody-induced activation of the complement.

IVMS USMLE Step 1 Prep. 27

The Complement System

• The complement proteins are designated C-1 to C-9.

– These proteins are in an inactive state.
• Become activated by the attachment of antibodies to antigens.
• Complement proteins can be subdivided into 3
– C1: recognization.
– C4, C2, C3: activation.
– C5-C9: attack (complement fixation).

IVMS USMLE Step 1 Prep. 28

The Complement System (continued)

• Classic pathway:
• Antibodies of IgG and IgM attach to antigens on invading
cell membranes.
– Binding to C1 activates the process.
• Activated C1 hydrolyzes C4 into C4a and C4b.
• C4b binds to the cell membrane and becomes an active
• C4b splits C2 into C2a and C2b.
• C2a attaches to C4b and cleaves C3 into C3a and C3b.
– Alternate pathway converges with classic pathway.
• Fragment C3b becomes attached to the complex in the cell
• C3b converts C5 to C5a and C5b.
IVMS USMLE Step 1 Prep. 29
Fixation of Complement Proteins

IVMS USMLE Step 1 Prep. 30

Complement Fixation
• C5b and C6 through C9 are inserted into bacterial cell
membrane, to form a membrane attach complex (MAC).
– Create large pores in membrane, causing osmotic influx of H20.
• Complement proteins kill the cell.

IVMS USMLE Step 1 Prep. 31

Complement Fragments

• Chemotaxis:
– C5a acts as a cytokine to attract neutrophils and
monocytes to the site.
• Attract phagocytes.
• Opsinization:
– Phagocytes have receptors for C3b.
• Form bridges between phagocyte and victim cell.
• C3a and C5a stimulate mast cells to secrete
– Increase blood flow and capillary permeability.
• Bring in more phagocytes.

IVMS USMLE Step 1 Prep. 32

Killer (Cytotoxic) T Cells

• Cell mediated destruction.

– Can be identified by the CD8 coreceptor.
• Destroy specific cells with antigens on their surface.
– Must be in actual contact with their victim cells.
• Secrete perforins:
– Perforins polymerize in the cell membrane and form
cylindrical channels through the membrane.
• Osmotic destruction of the cell.

IVMS USMLE Step 1 Prep. 33

Killer (Cytotoxic) T Cells (continued)

• Secrete granzymes:
– Enter the victim cell
activating caspases:
• Enzymes involved in
• Destruction of
victims cell’s DNA.

IVMS USMLE Step 1 Prep. 34

Helper T Cells

• Identified by CD4
• Indirectly
participate by
regulating the
response of both
T killer and B cells.
• B cells must be
activated by
helper T cells
before they
IVMS USMLE Step 1 Prep. 35
Interaction of Macrophages,
Helper T and Killer T cells

Insert fig. 15.18

IVMS USMLE Step 1 Prep. 36

Suppressor T Cells

• Indirectly participate in the specific immune

• Inhibit T cell and B cell activities.
• Affect the amount of antibodies secreted.
• Moderate immune response.

IVMS USMLE Step 1 Prep. 37


• Interleukin-1:
– Secreted by macrophages and other cells.
• Activates T cells.
• Interleukin-2:
– Released by helper T cells.
• Activates killer T cells.
• Interleukin-3:
– Serves as a growth factor.
• Activates killer T cells.
• Interleukin-4:
– Secreted by T cells.
• Required for proliferation and clone development of B cells.
• G-CSF and GM-CSF:
– Promote leukocyte development.
IVMS USMLE Step 1 Prep. 38
Subtypes of Helper T Cells

• TH1:
– Produces interleukin-2 and gamma interferon.
• Promotes cell mediated immunity and activates killer T cells.
• Stimulates NO production.
– Interleukin-12:
• Changes “uncommitted” helper T cells into TH1 cells.
• TH2:
– Secretes interleukin-4, interleukin-5, and interleukin-10.
• Promotes humoral immunity and stimulates B lymphocytes.
– Activates mast cells.

IVMS USMLE Step 1 Prep. 39

T Cell Receptor Proteins

• Only protein antigens are recognized by most T

– T cell receptors cannot bind to free antigens.
– In order for T cells to respond to foreign antigens:
• Antigen must be presented to T cells on the membrane of
antigen presenting cells.
– Chief antigen presenting cells are macrophages and dendritic
– To interact with correct T cells, dendritic cells migrate
to secondary lymphoid organs.
• Secrete chemokines.

IVMS USMLE Step 1 Prep. 40

Major Histocompatability Complexes

• All cells except mature RBCs are genetically marked

with histocompatability antigens on the membrane
– Also called human leukocyte antigens (HLAs).
• The histocompatability antigens are coded for a
group of genes called MHC located on chromosome
• MHC genes produce 2 classes of MHC molecules:
– Class-1.
– Class-2.

IVMS USMLE Step 1 Prep. 41

Major Histocompatability Complexes

• MHC class-1:
– Produced by all cells but RBCs.
– Picks up cytoplasmic peptides and transports
to membrane.
• Killer T cells (cytotoxic) interact with
– Coreceptor CD8 permits each type of T cell to
interact only with a class-1 MHC molecules.

IVMS USMLE Step 1 Prep. 42

Major Histocompatability Complexes(continued)

• MHC class-2:
– Produced only by antigen-presenting cells and B cells.
• Present class-2 MHC together with antigens to helper T
• Activates T cells.
– Helper T cells react with antigens.
• Promotes B cell response.
– Appear only on cell membrane when cell is
processing antigens.
– Coreceptor CD4 interacts with only a specific class of
MHC molecule.

IVMS USMLE Step 1 Prep. 43

Coreceptors on Helper and Killer T cells

IVMS USMLE Step 1 Prep. 44

T Cell Response to a Virus

• Foreign particle infects body.

– Macrophages engulf by phagocytosis.
– Partially digested virus particles (foreign
antigens) are moved to surface of cell
– Foreign antigens forms a complex with class-2
MHC molecules.
– Presented to helper T cells.

IVMS USMLE Step 1 Prep. 45

T Cell Response to a Virus (continued)

• Macrophages secrete interleukin-1 and TNF.

– Interleukin-1 stimulates cell division and proliferation
of T cells.
• Activated T cells secrete M-CSF and g- interferon.
– Promote the activity of the macrophages.
• Killer T cells destroy infected cell if class-1 MHC
– Helper T cells activate B cells.

IVMS USMLE Step 1 Prep. 46

T Cell Response to a Virus (continued)

• Foreign antigens
attach to
immunoglobulins on
B cells.
• B cells can present
the antigen with
class-2 MHC
molecules to helper T
– Stimulate B cell
conversion to plasma
cells, and antibody
IVMS USMLE Step 1 Prep. 47
Destruction of T Lymphocytes

• Activated T cells must be destroyed after the

infection has cleared.
• T cells produce a surface receptor called FAS.
– Production of FAS increases during the infection.
• After a few days, activated T cells begin to
produce FAS ligand.
– FAS binds to FAS ligand and triggers apoptosis (cell
• Help maintain immunologically privileged sites.

IVMS USMLE Step 1 Prep. 48

Active Immunity

• Primary response:
– First exposure to pathogen, immune response insufficient
to combat disease.
– Latent period of 5-10 days before measurable amounts of
specific antibodies appear in blood.
• Secondary response:
– Subsequent exposure to same antigen.
– Antibody production is much more rapid.
• Maximum antibody concentration reached in < 2 hrs.
– Maintained longer period of time.

IVMS USMLE Step 1 Prep. 49

Primary and Secondary Immune Responses

IVMS USMLE Step 1 Prep. 50

Clonal Selection Theory

• Mechanism by which secondary responses are produced.

– B lymphocytes inherit the ability to produce a particular antibody.
– T lymphocytes inherit the ability to respond to particular antigens.
• A given B cell can produce only 1 type of antibody with
specificity for 1 antigen.
– Inherited specificity reflected in antigen receptor proteins.
• Exposure stimulates specific lymphocytes to divide many
times until a large population of genetically identical cells
(clone) is produced.

IVMS USMLE Step 1 Prep. 51

Clonal Selection Theory (continued)

• Some of the cells become

plasma cells that secrete
primary response.
• Others become memory
cells that secrete
antibodies during the
secondary response.
• Antigens select
lymphocytes that are
already able to make

IVMS USMLE Step 1 Prep. 52

Active Immunity

• Development of a secondary response

provides active immunity.
• Immunizations induce primary responses.
– Inoculating people with pathogens whose viruses
have been attenuated or destroyed.

IVMS USMLE Step 1 Prep. 53

Immunological Tolerance

• Immunological competence occurs during the 1st

month postnatally.
– Ability to produce antibodies against non-self antigens
while tolerating self-antigens.
• Requires continuous exposure to those antigens.
• Autoantibodies:
– Exposure to self-antigens results in antibody production.
• Autoreactive T cells:
– Killer T cells attack self-antigens.

IVMS USMLE Step 1 Prep. 54

Passive Immunity

• Immune protection produced by the transfer of

antibodies to a recipient from a donor.
– The donor has been actively immunized.
• Person who receives these ready-made antibodies is passively
– Occurs naturally in mother to fetus during pregnancy and
mother to infant during nursing.
• Immunological competence:
– Ability to mount a specific immune response.
– Does not develop until 1 month after birth.
– Passive immunity disappears when infant is 1 month old.
• Infant did not itself produce lymphocytes.

IVMS USMLE Step 1 Prep. 55

Monoclonal Antibodies

• Commercially prepared.
• Exhibit specificity for one antigenic determinant only.
• Results in more sophisticated clinical laboratory
– May aid in the diagnosis of cancer.
• May result in production of drugs combined with
monoclonal antibodies against specific tumor

IVMS USMLE Step 1 Prep. 56

Tumor Immunology

• Tumors are interrelated with the functions of the

immune system.
– Division of tumor cells is not effectively controlled by
normal inhibitory mechanisms.
• Tumor cells also dedifferentiate (become similar to
less specialized cells of an embryo).
– As tumor cells dedifferentiate, they reveal surface antigens
that can stimulate the immune destruction of the tumor.

IVMS USMLE Step 1 Prep. 57

Tumor Immunology (continued)

• Some of these antigens are proteins produced

in embryonic or fetal life.
– Are absent at the time immunological
competence is established.
– Body treats these antigens as foreign.
• Release of these antigens provides the basis of
laboratory diagnosis of some cancers.

IVMS USMLE Step 1 Prep. 58

Natural Killer (NK) Cells

• Lymphocytes that are related to, but distinct from

T cells.
• Provide first line of cell-mediated defense.
– NK cells destroy tumors in a nonspecific fashion.
• NK cells attach to cells that lack class-1 MHC antigens.
– Release perforins and granzymes.

• Do not require prior exposure for sensitization to

the tumor antigens.
• Stimulated by interferon.

IVMS USMLE Step 1 Prep. 59

Immunotherapy for Cancer

• Interleukin-2 activates both killer T and B

– Patients treated with lymphocytes with IL-2 produce
lymphokine-activated killer T cells.
• Gamma interferon is used to treat particular
forms cancer.
– Lymphomas, renal carcinomas, melanoma, Kaposi’s
• Tumor infiltrating lymphocyte is promising.

IVMS USMLE Step 1 Prep. 60

Effects of Aging and Stress

• Cancer risks increase with age.

– Aging lymphocytes accumulate genetic errors
that decrease effectiveness.
– Thymus functions decline.
• Stress:
– Tumors grow faster.
• Increased production of corticosteroids.

IVMS USMLE Step 1 Prep. 61

Diseases Caused by the Immune System

• Immune system can be deranged in its

ability to tolerate self-antigens while it
identifies and attacks foreign antigens.
• Diseases caused by the immune system can
be grouped into 3 categories:
– Autoimmune disease.
– Immune complex diseases.
– Allergy or hypersensitivity.

IVMS USMLE Step 1 Prep. 62


• Diseases produced by failure in the immune

system to recognize and tolerate self-antigens.
– Activates autoreactive T cells and stimulates production
of autoantibodies by B cells.
• Failure due to:
– An antigen that does not normally circulate in the blood
may be exposed to the immune system.
• Thyroglobulin.
– A self-antigen that is otherwise tolerated may be altered
by combining with a foreign hapten.
• Thrombocytopenia.
IVMS USMLE Step 1 Prep. 63
Autoimmunity (continued)

– Antibodies may be produced that are directed against

other antibodies.
• Rheumatoid arthritis.
– Antibodies produced against foreign antigens may
cross-react with self-antigens.
• Rheumatic fever.
– Self-antigens may be presented to the helper T cells
together with class-2 MHC molecules.
• Type I diabetes.

IVMS USMLE Step 1 Prep. 64

Immune Complex Diseases

• Damage produced by inflammatory response.

– Antigen-antibody combinations that are free rather
than attached to bacterial or other cells:
• Activate complement proteins and promotes inflammation.
– When large # of immune complexes are continuously
formed, inflammation may be prolonged.
• Hepatitis B.
– Formation of complexes between self-antigens and
• Rheumatoid arthritis.

IVMS USMLE Step 1 Prep. 65


• Abnormal immune responses to allergens.

• Immediate hypersensitivity:
– Dendritic cells stimulate TH2 cells to secrete
interleukin-4 and interleukin-13:
• Stimulate B cells and plasma cells to secrete IgE
– Do not circulate in the blood.

IVMS USMLE Step 1 Prep. 66

Immediate Hypersensitivity

• IgE antibodies attach

to mast cells and
– When exposed again
to same allergen, the
allergen binds to
antibodies attached to
mast cells and
• Stimulate secretion of
leukotrienes, and
prostaglandin D.
– Produce symptoms.
IVMS USMLE Step 1 Prep. 67
Delayed Hypersensitivity

• Symptoms take longer time to develop (hours

to days).
– Is a cell mediated T cell response.
• Symptoms caused by secretion of
lymphokines, not histamine.
– Antihistamines provide little benefit.

IVMS USMLE Step 1 Prep. 68


IVMS USMLE Step 1 Prep. 69

Vaccine Research Center Information regarding preventative vaccine
research studies
Immunobiology; Fifth Edition – Online version of the textbook by Charles
Janeway (Advanced undergraduate/graduate level)
Immunology - BioMed Central (free content) scientific journal
The Inner Life of a Cell - Rendering of the inner functions of the human
Microbiology and Immunology On-Line Textbook - from the University of
South Carolina School of Medicine

IVMS USMLE Step 1 Prep. 70