Download 40. Lymphatics System

Lymphatics and the Immune
System
Lymphatic System
 One way system: to
the heart
 Return of collected
excess tissue fluid
 Return of leaked
protein
 “Lymph” is this fluid
 Edema results if
system blocked or
surgically removed
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 Lymph capillaries
 Have one way minivalves allowing
excess fluid to enter but not leave
 Picks up bacteria and viruses as well
as proteins, electrolytes and fluid
(lymph nodes destroy most
pathogens)
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 Lymph capillaries
 Absent from bone, bone marrow, teeth, CNS
 Enter lymphatic collecting vessels
 Lymphatic collecting vessels
 Similar to blood vessels (3 layers), but thin & delicate
 Superficial ones in skin travel with superficial veins
 Deep ones of trunk and digestive viscera travel with
deep arteries
 Very low pressure
 Distinctive appearance on lymphangiography
 Drain into lymph nodes
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 Lymph nodes: bean shaped organs along
lymphatic collecting vessels
 Up to 1 inch in size
 Clusters of both deep and superficial LNs
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Lymph Nodes
Superficial groups
-Cervical
-Axillary
-Inguinal
Deep groups
-Tracheobronchial
-Aortic
-Iliac
Drainage
-Superior R 1/4 of body: R
lymphatic duct (green) *
-The rest: thoracic duct *
*
*
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Fibrous capsule sends in dividing trabeculae
Afferent & efferent lymphatic vessels
Lymph percolates through lymph sinuses
Follicles: masses of lymphoid tissue divided into
outer cortex & inner medulla (details in later slides)
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Macrophages
on reticular
fibers consume
pathogens and
foreign particles
Usually
pathogen free
lymph enters
lymph trunks
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Lymphatic Trunks
(all are paired except
the intestinal trunk)
 Lumbar
 Intestinal
 Receives fatty
lymph (chyle)
absorbed
through lacteals
in fingerlike villi
of intestines
 Bronchomediastinal
 Subclavian
 Jugular
10
20%
Lymph ducts
(variable)
 Thoracic duct:
everyone has
*  20% also have
a right
lymphatic duct
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The Immune System
 Recognizes specific foreign molecules
 Each exposure (to the same pathogen) increases the
effectivity of the response
 Lymphoid organs
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Lymph nodes
Spleen
Thymus
Tonsils
Small intestine & appendix aggregated lymphoid
nodules
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Basic Immunology
 Depends on the ability of the immune system to
distinguish between self and non-self molecules
 Self molecules are those components of an
organism's body that can be distinguished from
foreign substances by the immune system
 Autoimmunity is an immune reaction against self
molecules (causes various diseases)
 Non-self molecules are those recognized as
foreign molecules
 One class of non-self molecules are called antigens
(short for antibody generators) and are defined as
substances that bind to specific immune receptors
and elicit an immune response
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Lymphocytes
the primary cells of the lymphoid system
 Respond to:
 Invading organisms
 Abnormal body cells, such as virus-infected
cells or cancer cells
 Foreign proteins such as the toxins released
by some bacteria
 Types of lymphocytes
 T cells (thymus-dependent)
 B cells (bone marrow-derived)
 NK cells (natural killer)
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T Cells
 80% of circulating lymphocytes
 Some of the types:
 Cytotoxic T cells: attack foreign cells or body
cells infected by viruses (“cell-mediated
immunity”)
 Regulatory T cells: Helper T cells and
suppressor T cells (control activation and
activity of B cells)
 Memory T cells: produced by the division of
activated T cells following exposure to a
particular antigen (remain on reserve, to be
reactivated following later exposure to the
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same antigen)
B Cells
 10-15% of circulating lymphocytes
 Can differentiate into plasmocytes (plasma cells)
when stimulated by exposure to an antigen
 Plasma cells produce antibodies: soluble
proteins which react with antigens, also known
as immunoglobulins (Ig’s)
 “Humoral immunity”, or antibody-mediated
immunity
 Memory B cells: produced by the division of
activated B cells following exposure to a
particular antigen (remain on reserve, to be
reactivated following later exposure to the same
antigen)
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NK Cells
 5-10% of circulating lymphocytes
 Attack foreign cells, normal cels infected
with viruses, cancer cells that appear in
normal tissues
 Known as “immunologic surveillance”
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“Humoral” vs “Cell mediated”
 Cell-mediated immunity - direct attack by activated
T cells (react with foreign antigens on the surface of
other host cells)
 Antibody-mediated (humoral) immunity – attack
by circulating antibodies, also called immunoglobins
(Ig’s), released by the plasma cells derived from
activated B cells
“humor” – from old-fashioned word for stuff in the blood,
like ‘good humors’ and ‘bad humors’
These two systems interact with each other
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Ab
B Lymphocytes


The receptor for antigens is an antibody on B cell
surface
B lymphocytes can respond to millions of foreign antigens
 This capability exists before exposure to any antigens
 Each lineage of B cell expresses a different antibody, so the complete set
of B cell antigen receptors represent all the antibodies that the body can
manufacture
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A B cell identifies pathogens when antibodies on its surface bind to a
specific foreign antigen
This antigen/antibody complex is taken up by the B cell and processed
by proteolysis into peptides (small pieces)
As the activated B cell then begins to divide (“clonal expansion”), its
offspring secrete millions of copies of the antibody that recognizes
this antigen
These antibodies circulate in blood plasma and lymph, bind to
pathogens expressing the antigen and mark them for destruction by
complement activation or for uptake and destruction by phagocytes
Antibodies can also neutralize challenges directly, by binding to
bacterial toxins or by interfering with the receptors that viruses and
bacteria use to infect cells
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The needs…
 To be able to attack cells
which have been infected
 T cells target “alien” cells – they
reject transplanted organs,
destroy our own cells that have
been infected, and kill some
cancer cells: these are all treated
as foreign because they have
altered (antigenic) proteins on
their surfaces
 To be able to take care of
small extracellular antigens
such as bacteria which multiply
outside cells, the toxins they
make, etc.
 Antibodies made by plasma cells
(differentiated B lymphocytes)
bind to antigens on bacteria,
marking them for destruction by
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macrophages
Development of lymphocytes
Originate in bone marrow from lymphoid stem cells
B cells stay in bone marrow, hence “B” cells
T cells mature in thymus, hence “T” cells
These divide rapidly into families
Each has surface receptors
able to recognize one
unique type of antigen=
immunocompetence
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Lymphocytes
 Naive immunocompetent lymphocytes “seed”
secondary lymphoid organs (esp. lymph nodes)
 “Antigenic challenge” – full activation upon
meeting and binding with specific antigen
 The B cell’s antigen receptor is an antibody (see slide
20)
 Full activation
 Gains ability to attack its antigen
 Proliferates rapidly producing mature lymphocytes
 Mature lymphocytes re-circulate seeking same
pathogens
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Components of the immune system
Innate immune system
Adaptive immune system
 Response is non-specific
 Pathogen and antigen
specific response
 Lag time between
exposure and maximal
response
 Cell-mediated and
humoral components
 Exposure leads to
immunologic memory
 Found only in jawed
vertebrates
 Exposure leads to
immediate maximal
response
 Cell-mediated and
humoral components
 No immunological
memory
 Found in nearly all forms
of life (plants & animals)
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Innate immunity
 The dominant system of host defense in most
organisms
 Inflammation is one of the first responses
 Redness, swelling, heat and pain
 Chemical and cellular response
 During the acute phase of inflammation, particularly
as a result of bacterial infection, neutrophils migrate
toward the site of inflammation in a process called
chemotaxis, and are usually the first cells to arrive at
the scene of infection
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Lymphoid Organs
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Lymph nodes
Spleen
Thymus
Tonsils
Small intestine &
appendix aggregated
lymphoid nodules
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Lymphoid Tissue
Specialized connective
tissue with vast quantities
of lymphocytes
 Lymphocytes become
activated
 Memory
 Macrophages & dentritic
cells also
 Clusters of lymphoid
nodules or follicles
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Thymus
 Prominent in newborns, almost disappears
by old age
 Function: T lymphocyte maturation
(immunocompetence)
 Has no follicles because no B cells
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Lymph Nodes
 Lymphatic and immune systems intersect
 Masses of lymphoid tissue between lymph
sinuses (see next slide)
 Some of antigens leak out of lymph into
lymphoid tissue
 Antigens destroyed and B and T
lymphocytes are activated: memory
(aiding long-term immunity)
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 Follicles: masses of lymphoid tissue divided into
outer cortex & inner medulla
 All follicles and most B cells: outer cortex
 Deeper cortex: T cells, especially helper T cells
 Medullary cords: T & B lymphocytes and plasma
cells
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lymphangiogram
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Spleen
 Largest lymphoid tissue; is in LUQ posterior to stomach
 Functions
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Removal of blood-borne antigens: “white pulp”
Removal & destruction of aged or defective blood cells: “red pulp”
Stores platelets
In fetus: site of hematopoiesis
 Susceptible to injury; splenectomy increases risk of
bacterial infection
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Spleen
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Tonsils
Simplest
lymphoid
tissue:
swellings of
mucosa, form
a circle
*
*
Crypts get
infected in
childhood
Palatine (usual
tonsillitis)
Lingual
(tongue)
*
Pharyngeal
(“adenoids”)
Tubal
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Parts of the intestine are so densely packed with
MALT (mucosa-associated lymphoid tissue) that
they are considered lymphoid organs
 Aggregated lymphoid
nodules (“Peyer’s
Patches”)
 About 40 follicles, 1 cm
wide
 Distal small intestine
(ileum)
 Appendix
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The Lymphatic System and Our immune response:
Did you know?
 Laughing lowers levels of stress hormones and
strengthens the immune system. Six-year-olds
laugh an average of 300 times a day. Adults
only laugh 15 to 100 times a day.
 3000 BC The ancient Egyptians recognize the
relationship between exposure to disease and
immunity.
 1500 BC The Turks introduce a form of
vaccination called variolation, inducing a mild
illness that protects against more serious
disease.
 1720 Lady Mary Wortley Montagu promotes the
variolation principle, launching a campaign to
inoculate the English against smallpox.
 A macrophage can consume as many as 100
bacteria before undergoing apoptosis.
What does the lymphatic system
do?
 Return interstitial fluid
 Capillaries only reabsorb 15%
 Funneled into subclavian veins
 Absorb and transport lipids
from intestines
 Generate and monitor
immune responses
 lymphatic system movie
What is in the lymphatic system?
 Lacteals and
lymphatic
capillaries
 Overlapping
epithelial cells
 Lymph vessels
and ducts
 What happens
if blockage
occurs?
 See next slide!
What is in the lymphatic system?
 Lymphatic trunks
 Lumbar, brachiomediastinal, intestinal, jugular,
subclavian, intercostal
 R lymphatic duct: R arm, R thorax, R head
 Thoracic duct: everything else
What is in the lymphatic system?
 Red bone marrow
 Hemopoiesis: what
types of leukocytes are
manufactured here?
 Mucosa-associated
lymphatic tissue
 Sprinkling of
lymphocytes in mucosa
membranes
 Peyer’s patch: small
intestine nodules of
lymphatic tissue
What is in the lymphatic
system?
 Thymus
 Secretes thymopoietin for Tcell development
 T-cells mature here
 Thymus atrophies with age
 Tonsils
 Palatine (2), lingual (2),
pharyngeal (1; adenoid)
 Tonsillectomy: remove palatines
 Gather, remove and “learn”
pathogens from food/air
 Calculate risk in childhood:
inviting invasion
– Payoff: greater
immunocompentency later in
life
What is in the lymphatic system?
 Lymph nodes
 Filters lymph fluid for antigens,
bacteria, etc.
 B-lymphocytes made here
 Some T-lymphocytes and
macrophages congregate
 Afferent (more) and efferent
(less) vessels
– lymph fluid exits through hilum
 Common site for cancer—Why?
 Hodgkin’s lymphoma: lymph
node malignancy
– Etiology unknown
 Non-Hodgkin’s lymphoma: all
other cancers of lymphoid
tissue
– Multiplication/metastasis of
lymphocytes
– 5th most common cancer

What is in the lymphatic
system?
Spleen: dense sieve of reticular
CT
 Functions
 Erythropoiesis in fetus
 Stores platelets
 Salvages and stores RBCs parts for
recycling (RBC graveyard)
 Red pulp
 Dispose of damaged/dead RBCs
and pathogens
 Old RBCs aren’t flexible enough to
get through sieve
 White pulp
 Lymphocytes and macrophages
 B-cells proliferate here
 If splenectomy: liver and marrow
take over duties
What’s behind non-specific
immunity?
 Phagocytes
 Macrophages: tissue-living
monocytes
 Neutrophils: digestion and
killing zone (H2O2; superoxide
ion and hypochlorite (bleach))
 Eosinophils: less avid
digesters
 Basophils and mast cells: it
mobilize other WBCs (via
histamine and heparin)
 some phagocytosis
 Natural Killer cells (NK cells):
type of T-cell
 Only attack infected or
cancerous host cells

What’s behind non-specific
immunity?
Inflammation
 Redness, swelling, heat, pain
 Bradykinin: pain stimuli from mast cells
 Histamine: what two things does it do?
 Leukocyte migration
 Margination
– http://www.med.ucalgary.ca/webs/kubeslab/home/
 Diapedesis: http://www.constantinestudios.com/animation4.html
 Chemotaxis
 Phagocytosis

What’s behind non-specific
immunity?
Interferons
 Virus-infected cells secrete
warning (click here or on movie
to right)
 Can promote cancer cell
destruction
 Complement proteins
 20+ beta-globulins which
perforate bacterial cells
(cytolysis)
 complement movie
 Fever (pyrexia)
 Promotes interferon activity
 Elevates BMR
 Discourages bacteria/viral
reproduction
 fever movie
What is specific immunity?
 Specific response
 Memory for future
reinvasion
 Antibody-based
 B cells primary (but not
only) actors
 Cell-mediated
 T cells only
What are antibodies?
 Antibody: gamma globulin
(protein) which complexes
with a specific antigen
 AKA Immunoglobin (Ig)
 Antigen (Ag): any molecule
which causes an immune
response
 Not necessarily always
dangerous antigen
 Epitopes: different regions
where different antibodies
bind
 Haptens: too small on their
own but can bind with host
molecules and cause
immune response
 Detergent, poison ivy,
penicillin
What do antibodies look like?
 Protein with quaternary structure
 Two light chains, two heavy chains
 Each chain has variable region
 Combine to form antigen-binding site
 Remainder of chains = constant region
What are the five antibody classes?
 IgA: prevents pathogens from sticking
to epithelia
 Can form dimers
 IgD: antigen receptor in B-cell PM
 IgE: stimulates basophils/mast cells
 Secrete histamines, also causes allergic
response
 IgG: most common antibody (75-85%)
 Primary Ig of secondary immune response
 IgM: antigen receptor in B-cell PM
 Can form pentamers
 Predominant Ig of primary immune
response
 Includes anti-A and Anti-B of ABO blood
groups
How many different antibodies are there?
 > 2M
 But we only have ~30,000 genes (not 100,000)
 Central dogma (one gene = one protein) doesn’t appear to apply
 Somatic recombination creates variety
 Shuffling of V and J segments
 http://www.cat.cc.md.us/courses/bio141/lecguide/unit3/humoral/antibodies/abydiv
ersity/vdj.html
What are T cells?
 Migrate from marrow and
develop in thymus
 Have antigen receptors on
PM = immunocompetent
 Mitosis produces clones
 Clonal deletion destroys selfreactive clones
 Good at destroying cells
and stimulating B cells
 They do NOT secrete
antibodies as B cells do
 T cell types movie
What are B cells?
 From marrow: colonize lymph
tissues, organs when mature
 Developing B cells synthesize PM
antibody
 Each cell has a different antibody
covering it
 Mitosis: immunocompetent clones
 One B cell responds to only one
antigen
 Serve as antigen-presenting cells
(APC)
 So do macrophages
 Lets T cells “see” the antigen
 Secrete antibodies into blood, but
do NOT kill cells as T cells do
 B cell types movie
What happens in a cellmediated response?
 The key players:
 Antigen-presenting cell
 Cytotoxic (killer) T cells
(CD8 cells)
 Helper T cells (CD4 cells)
 The ones attacked in HIV
infection
 Suppressor T cells
 Memory T cells
 T cells are “blind” to freefloating antigens
What happens in a cellmediated response?
 The key events:
 Surveillance and recognition
 Attack
 Memory
What happens during
surveillance?
 T cells (helper and
cytotoxic) “feel” cells
 Check for MHC (hotdog bun)
 MHC = major histocompatibility
complex
 MHC-I on all cells
 MHC-II only on APCs
 HLA (human leukocyte antigen)
group = MHC
What happens during surveillance?
 If T cell encounters APC
(recognition):
 Notices a hotdog in the
bun (antigen cradled in
MHC)
 Cytotoxic T cells only
respond to MHC-I complex
 Helper T cells only
respond to MHC-II
 APC then secretes
interleukin-1
 This stimulates T cells to
divide
 This launches immune
response: ATTACK!
What happens during attack?
 Interleukins stimulate T
cells, Helper T cells and
(we’ll get to this later) B
cells
 The “right” T cells and
helper T cells produce
clones
 Cytotoxic clones use
perforin to kill infected or
cancerous cells (“touch
kill”):


http://www.cellsalive.com/ctl.htm
http://www.cat.cc.md.us/courses/bi
o141/lecguide/unit3/cellular/cmidef
ense/ctls/ctlapop.html
 Helper T cell clones
stimulate more cytotoxic T
cells (and B cells)
What happens during the memory phase?
 During cloning,
some T cells are put
in reserve
 Thousands of these
“hang out” in the
body
 Launch immediate
attack if same
antigen appears
again
 Attack is so quick,
no symptoms
develop
What happens in an antibodymediated response?
 The key events:
 Recognition
 Attack
 Memory
 The key players:
 B cells (plasma and
memory cells)
 Helper T cells
 Free-floating
antigens
What happens during recognition?
 Capping: free-floating antigen
binds to B cell with correct
antibody on its PM
 Endocytosis of antigen-antibody
complex
 Display of hotdog + bun
 Helper T cell binds, secretes
interleukin-2
 Gives B cell the “go” signal
 Clonal selection: only B cells
with correct antibody clone
 Plasma cell differentiation: large
B cells with lots of rough ER
 antigen presentation animation
What happens during attack?


Plasma cells make
millions of antibodies
(IgM) and distribute
in blood plasma
Antibodies
incapacitate
antigens:
1.
2.
3.
4.

Agglutination
Neutralization
Precipitation
Complement fixation
Eosinophils or T cells
then destroy antigens
What happens during memory?
 Primary response (first
exposure)
 takes 3 to 6 days to
produce plasma cells
 Secondary response
 Memory B cells in
reserve form plasma
cells in mere hours
 IgG produced to
combat antigen
Who can’t you do without in
specific immunity?
 _________ cells are the lynch pins for
both antibody- and cell-mediated immunity
 Why?
What is
hypersensitivity?
 Excessive reaction to
an antigen (allergen)
to which most people
do not react
 Includes
 Allergies
 Alloimmunity
(transplants)
 Autoimmunity
 Four types
What are the four types?
 Type I--Acute hypersensitivty
 IgE-mediated, often non-dosage
dependent
 Degranualation of basophils and
mast cells
 Food allergies, asthma, anaphylaxis
(severe type I)
 Type II--antibody-dependent
cytotoxic hypersensitivity
 IgG ir IgM attacks antigens bound
on a cell surface
 Blood transfusion reactions,
penicillin allergy, some drugs, toxic
goiter, myasthenia gravis
What are the four types?
 Type III: immune complex
hypersensitivity
 IgG or IgM bind directly to free-floating
antigens causing precipitation in blood or
tissues
 This activates complement and
inflammation
 Necrosis follows
 Some autoimmmune diseases
(e.g. lupus, glomerularnephritis)
 Type IV: delayed hypersensitivity
 Cell-mediated, after 1/2 to 3 days
 APCS display antigen to CD4 cells,
which activate CD8 cells: specific and
non-specific responses
 Allergies to haptens (poison oak, makeup), graft rejection, TB skin test, type I
diabetes
What is immunization?
 Active immunization
 Vaccine prompts antibody
manufacture
 Also creates B memory cells
 Lasts for years
 Passive immunization
 Injection of antibodies
(gamma globulin serum)
 Also breastfeeding
 Can prevent infection after
exposure
 Antibodies eventually
degrade
 No memory B cells formed
vaccination movie
Why are organ transplants often rejected?
 T-cells attack foreign cell, kill them
 Immunosuppresive drugs
counteract this
 Problem: may have to take these
drugs for rest of life
 Future therapy: add FasL markers
to transplanted cells
 When T-cells w/Fas markers
contact FasL, they commit cell
suicide (apoptosis)

http://www.cat.cc.md.us/courses/bio141/lecguide/unit3/cellular/
cmidefense/ctls/fasan.html
 This is what naturally occurs in the
testes, anterior chamber of eye,
brain (immunologically privileged
areas)
What are autoimmune
diseases?
 Self-attack by immune
system
 Produce autoantibodies
 Lupus erythematosus:
inflammation of CTs
 Fever, fatigue, joint pain,
light sensitivity
 Rheumatic fever:
antibodies attack mitral
and aortic valves
 Others: rheumatoid
arthritis, Type I diabetes,
multiple sclerosis, Grave’s
disease
What are
immunodeficiency
diseases?
 Immune system weakened or
fails to respond
 Severe combines
immunodeficiency disease
(SCID)
 Rare/absent T and B cells
(hereditary)
 Acquired immunodeficiency
syndrome (AIDS)
 Develops from HIV infection
How does HIV cause AIDS?
 HIV: a retrovirus
 What does this mean?
 Extremely high mutation rate
 Infects helper T cells, neutrophils,
macrophages
 Recall: helper Ts needed to stimulate
both T and B cells
 Infects only a small number of
helper Ts though
– Possibly infected cells have FasL
which destroys healthy helper Ts
 Incubation: several months to
years
 Final stages: AIDS
 No immune response capability
 Kaposi’s sarcoma common