Immune System: Immunocytology, Immunophysiology and Intro to Immunopathology
1. The Immune System:
Immunocytology, Immunophysiology
and Intro to Immunopathology
Companion tools:
Prepared and Presented by
Marc Imhotep Cray, M.D.
BMS and CK Teacher
Recommended Reading:
Microbiology and
Immunology On-Line
Textbook - University of
South Carolina SOM
http://www.imhotepvirtualmedsch.com/
A scanning electron microscope image of a
single neutrophil (yellow), engulfing anthrax
bacteria (orange)
From:
http://upload.wikimedia.org/wikipedia/comm
ons/f/f2/Neutrophil_with_anthrax_copy.jpg
Clinical:
e-Medicine Article
Acute Respiratory Distress
Syndrome
2. 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.
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4. Phagocytosis
• 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.
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6. 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.
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7. Phagocytosis
(continued)
– Particle becomes
surrounded by
pseudopods.
– 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
inflammation.
IVMS USMLE Step 1 Prep.
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8. Fever
• May be a component of nonspecific defense
system.
• Cell wall of gram – bacteria contains
endotoxin.
– 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.
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9. 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.
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10. 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.
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11. Antigens
• Molecules that stimulate the production of specific
antibodies.
– 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.
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12. Haptens
• Small organic molecules can become antigens
if they bind to proteins.
• Become antigenic determinant sites on the
proteins.
– By binding haptens to proteins in the laboratory,
new antigens are created for research or
diagnostic purposes.
IVMS USMLE Step 1 Prep.
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13. Immunoassays
• Tests that use the
antigen-antibody
complex reaction to
produce clumping
(agglutination).
• 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.
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14. 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.
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15. 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
spleen.
• Attack host cells that have become infected with
viruses, fungi, transplanted human cells, and
cancerous cells.
IVMS USMLE Step 1 Prep.
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16. Thymus
• Grows during childhood, gradually regresses
after puberty.
• Lymphocytes from the fetal liver and spleen;
and bone marrow postnatally, seed the
thymus:
– Become transformed into T cells.
• In adulthood, repopulation is accomplished
by production in secondary lymphoid organs.
IVMS USMLE Step 1 Prep.
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17. Secondary Lymphoid Organs
• Lymph nodes, spleen, tonsils, and Peyer’s
patches.
– Located in areas where antigens could gain entry
to the blood or lymph.
• Lymphocytes migrate from the primary
lymphoid organs to the secondary lymphoid
organs.
– Spleen filters blood.
– Secondary lymph nodes in tonsils and Peyer’s
patches filter lymph.
IVMS USMLE Step 1 Prep.
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18. 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
(humors).
– Stimulate production of memory cells:
• Important in active immunity.
IVMS USMLE Step 1 Prep.
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19. 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
enemy.
• Secrete antibodies that
bind to antigens.
IVMS USMLE Step 1 Prep.
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20. 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
responses.
• Activates complement.
– Antibodies promote phagocytic activity of neutrophils, macrophages,
and monocytes (opsinization).
IVMS USMLE Step 1 Prep.
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21. Local Inflammation
(continued)
• Leukocytes interact with
adhesion molecules in
endothelial cell.
• Chemotaxis occurs, attracting
leukocytes.
– Diapedesis occurs.
– First to arrive are
neutrophils, then
monocytes, and T
lymphocytes.
• Adherence of monocytes
to extracellular matrix
proteins promotes
conversion into
macrophages.
IVMS USMLE Step 1 Prep.
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23. 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
released.
IVMS USMLE Step 1 Prep.
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24. Antibodies
• Antibody proteins are also known as
immunoglobulins.
– Found in the gamma globulin class of plasma
proteins.
• Different antibodies have different structure,
as the antibodies have specific actions.
IVMS USMLE Step 1 Prep.
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26. Antibody Structure
• 100 million trillion
antibody molecules that
contain 4 polypeptide
chains.
• 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.
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27. 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.
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28. 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
components:
– C1: recognization.
– C4, C2, C3: activation.
– C5-C9: attack (complement fixation).
IVMS USMLE Step 1 Prep.
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29. 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
enzyme.
• 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
membrane.
• C3b converts C5 to C5a and C5b.
IVMS USMLE Step 1 Prep.
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31. 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.
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32. 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
histamine:
– Increase blood flow and capillary permeability.
• Bring in more phagocytes.
IVMS USMLE Step 1 Prep.
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33. 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.
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34. Killer (Cytotoxic) T Cells
(continued)
• Secrete granzymes:
– Enter the victim cell
activating caspases:
• Enzymes involved in
apoptosis.
• Destruction of
victims cell’s DNA.
IVMS USMLE Step 1 Prep.
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35. Helper T Cells
• Identified by CD4
coreceptor.
• Indirectly
participate by
regulating the
response of both
T killer and B cells.
• B cells must be
activated by
helper T cells
before they
produce
antibodies.
IVMS USMLE Step 1 Prep.
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37. Suppressor T Cells
• Indirectly participate in the specific immune
response.
• Inhibit T cell and B cell activities.
• Affect the amount of antibodies secreted.
• Moderate immune response.
IVMS USMLE Step 1 Prep.
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38. Lymphokines
• 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.
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39. 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.
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40. T Cell Receptor Proteins
• Only protein antigens are recognized by most T
cells.
– 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
cells.
– To interact with correct T cells, dendritic cells migrate
to secondary lymphoid organs.
• Secrete chemokines.
IVMS USMLE Step 1 Prep.
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41. Major Histocompatability Complexes
(MHC)
• All cells except mature RBCs are genetically marked
with histocompatability antigens on the membrane
surface.
– Also called human leukocyte antigens (HLAs).
• The histocompatability antigens are coded for a
group of genes called MHC located on chromosome
6.
• MHC genes produce 2 classes of MHC molecules:
– Class-1.
– Class-2.
IVMS USMLE Step 1 Prep.
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42. Major Histocompatability Complexes
(continued)
• MHC class-1:
– Produced by all cells but RBCs.
– Picks up cytoplasmic peptides and transports
to membrane.
• Killer T cells (cytotoxic) interact with
antigens.
– Coreceptor CD8 permits each type of T cell to
interact only with a class-1 MHC molecules.
IVMS USMLE Step 1 Prep.
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43. 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
cells.
• 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.
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45. 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
membrane.
– Foreign antigens forms a complex with class-2
MHC molecules.
– Presented to helper T cells.
IVMS USMLE Step 1 Prep.
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46. 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
present.
– Helper T cells activate B cells.
IVMS USMLE Step 1 Prep.
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47. 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
cells.
– Stimulate B cell
production,
conversion to plasma
cells, and antibody
production.
IVMS USMLE Step 1 Prep.
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48. 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
suicide).
• Help maintain immunologically privileged sites.
IVMS USMLE Step 1 Prep.
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49. 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.
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51. 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.
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52. 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
antibodies.
IVMS USMLE Step 1 Prep.
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53. 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.
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54. 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.
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55. 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
immunized.
– 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.
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56. Monoclonal Antibodies
• Commercially prepared.
• Exhibit specificity for one antigenic determinant only.
• Results in more sophisticated clinical laboratory
tests.
– May aid in the diagnosis of cancer.
• May result in production of drugs combined with
monoclonal antibodies against specific tumor
antigens.
IVMS USMLE Step 1 Prep.
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57. 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.
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58. 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.
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59. 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.
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60. Immunotherapy for Cancer
• Interleukin-2 activates both killer T and B
lymphocytes.
– 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
sarcoma.
• Tumor infiltrating lymphocyte is promising.
IVMS USMLE Step 1 Prep.
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61. 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.
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62. 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.
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63. Autoimmunity
• 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.
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64. 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.
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65. 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
autoantibodies:
• Rheumatoid arthritis.
IVMS USMLE Step 1 Prep.
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66. Allergy
• 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
antibodies.
– Do not circulate in the blood.
IVMS USMLE Step 1 Prep.
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67. Immediate Hypersensitivity
• IgE antibodies attach
to mast cells and
basophils.
– When exposed again
to same allergen, the
allergen binds to
antibodies attached to
mast cells and
basophils.
• Stimulate secretion of
histamine,
leukotrienes, and
prostaglandin D.
–IVMS USMLE Step 1 Prep.
Produce symptoms.
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68. 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.
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70. Resources for further study:
Vaccine Research Center Information regarding preventative
vaccine research studies
Immune System - from the University of Hartford
Immunobiology; Fifth Edition – Online version of the textbook by
Immunology - BioMed Central (free content) scientific journal
The Microbial World - Animal defenses against microbes - Chapter
in on-line microbiology textbook
Microbiology and Immunology On-Line Textbook - from the
University of South Carolina School of Medicine
IVMS USMLE Step 1 Prep.
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