Download Chap 43 Immune Syst

Chapter 43
Immune System
Preliminary
Protective
Measures
Organism defense is summarized by . . .
Nonspecific defenses
• Skin and mucous membranes: 1st line of
defense
– Oil, sweat glands create acidic pH (3.5)
• Prevents microbial growth
• Normal flora of bacteria release acids
– Antimicrobial proteins in saliva, tears, mucous
secretions
• Lysozyme in sweat, tears, saliva attack bacterial cell
walls
– Nostril hairs and mucus in lungs traps bacteria
– Stomach acids kill many bacteria
• Phagocytic cells
– Neutrophils (60-70%of WBCs): phagocytosis
of bacterial cells (cell lysis)
– Monocytes (5% of WBCs); migrate to tissues,
enlarge to become macrophages
• Have ameboid locomotion; sometimes reside in lymph
notes
– Eosinophils: contain granules of cytotoxic
chemicals against bacterial capsules; good
against parasitic worms
– Natural killer (NK) cells: kill body cells which
are infected with a virus; not phagocytic, but
attack plasma membrane and cause cell lysis
Inflammatory response
• At site of physical injury or bacterial entry . . .
– Vasodilation: increases blood supply to area
– Vessels become more permeable; allow localized edema
• Chemical signals
– Histamine: release from circulating basophils and mast
cells in connective tissue
– Prostaglandins promote blood flow to the area, reduce
pain
– Phagocytes attracted to the area by chemokines
• Neutrophils kill bacteria, then monocytes transform into
macrophages and clean up the area
Simplified view of inflammation
RTDC: Rubor, Tumor, Dolor, Calor
(reddening, swelling, pain, localized heat -- fever)
Systemic inflammation
• Caused by severe infections
(e.g. meningitis, appendicitis)
• Bone marrow releases more neutrophils
• Fever in response to bacteria toxins or
pyrogens released by leukocytes
– Moderate fever inhibits some microorganisms
• Also facilitates phagocytosis and tissue repair
Antimicrobial proteins
• Complement proteins
– Interact in a cascade which results in cell lysis
• Interferons
– Secreted from virally-infected cells: cause
neighboring cells to make antiviral proteins
which prevent infection
– Most effective against short-term infections
(e.g. colds, flu)
Real
Immune
System
Specific immunity
• Distinguished from nonspecific immunity by
demonstrating:
–
–
–
–
Specificity
Diversity
Self/nonself recognition
Memory cells
Development and
maturation of
lymphocytes
Perform
different roles
in immunity
Specificity
• Lymphocytes: two types and two different
responses
– B cells produce humoral immunity (antibodies float
freely in blood plasma); cells mature in bone marrow
and then circulate freely
– T cells produce cell-mediated immunity (antibodies
remain attached to lymphocytes); cells are produced in
bone marrow then migrate to thymus gland for further
development
• Specificity = immune system’s ability recognize
and eliminate specific “invaders”
Diversity
• Antigen (Ag) = foreign substance which elicits a
response from the immune system
• Antibody (Ab) = antigen-binding immunoglobulin
(protein) which forms in response to the
presence of an antigen
Typical Antibody Molecule
Variable (sticky) ends
Light protein
chain
Heavy protein
chain
Disulfide bridges
hold protein chains
together
• Antigens are large molecules displayed on
surfaces of cells/organisms; have unique
molecular shapes; are proteins or polysaccharides
• Antigen receptor = lymphocyte membrane protein
which binds an Ag to the cell
– In B cells the antibodies migrate in a transmembrane
fashion and are secreted from the lymphocytes
– In T cells the antibodies are similar to B-cell Abs, but
remain attached to leukocyte by their “stems”
• Diversity = ability to recognize millions of Ags by
their antigenic markers
An antigen and its several epitopes (antigenic determinants)
Source of specific responses
• Each lymphocyte responds to only one kind of Ag
• Response is determined during embryonic
development -- before encountering any Ags
• Encounter between Ag and lymphocyte activates
a lymphocyte; it divides and differentiates -produces large groups (clones) of response
lymphocytes (effector cells)
• Therefore, each original Ag activates only a very
small number of the millions of potential response
cells.
Clonal Selection Theory
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Immune response sequences
Long-lived memory cells
Lag period
Short-lived plasma cells
Immunological memory
• Based on memory cells
• Memory cells are not active during primary
response
• Previously-encountered Ag activates clone
of memory cells for secondary immune
response
• Acquired immunity (long term) is based on
memory cells
– Immunity to chicken pox, measles, mumps, etc.
– Immunity to any vaccinations (contain antigens)
Self and Nonself
• Ability to distinguish between a body’s own
molecules vs. foreign molecules
• Ag receptors on lymphocytes detect
foreign molecules; no lymphocytes exist to
react against a body’s own molecules under
normal circumstances
– Self-tolerance = lack of destructive immune
response to a body’s own cells
• Failure of this mechanism results in autoimmune
disorders
Cell Surface Markers
• Major Histocompatibility Complex (MHC)
– Glycproteins on lymphocyte plasma membranes and
other plasma membranes of other nucleated cells.
– “Self markers” come from a family of genes
– At least 20 MHC genes and 100 alleles exist for each
gene.
• Possible combinations are astronomical, not probable that any
two individuals would inherit the same combinations of alleles
– Two main classes
• Class I MHC: found on nucleated cells
• Class II MHC: found on specialized cells, i.e. macrophages, B
cells and activated T cells
– MCHs function to present Ag on the cell surface by
binding to it, thus facilitating Ag binding to a T cell
Antigen Presentation
Any nucleated cell
Identifies “self”
in immune syst.
Any specialized cell
Role of Helper T Cells
and their descendents
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Immune Responses
• Humoral immunity
– Response to toxins, free bacteria, and viruses
– Antibodies are secreted and circulated in
blood
• Cell-mediated immunity
– Response to intracellular bacteria and viruses,
fungi, protozoans, worms, transplanted tissues,
and cancer cells
– Depends on direct action of certain
lymphocytes, not antibodies
Cytotoxic T cells
• When Ag-activated TC cells are inhabited
by pathogens
– Infected cell displays MHCI molecules
– TC cells recognize MHCI and bind to cell
• Surface molecule CD8 has an affinity for MHCI
• TC releases perforin (protein) which forms a lesion
(hole) in target cell membrane; cell lyses and
released Ags (viruses) are now exposed to
circulating Abs
• TC cells continue to live after destroying the target
cells; also can kill cancer cells which develop
continuously in the body
TC and Cancer
• Cancer cells display distinctive markers
called tumor antigens
• TC cells recognize markers as nonself,
attach, and lyse cells
• Some types of cancer cells have reduced
MHCI proteins so that TC cells have less
ability to recognize and destroy them
Humoral Response
• B cells produce Abs against extracellular
pathogens
– Response occurs when Ag epitope binds to B
cell receptors
• B cells differentiate into clones of plasma cells (Absecreting cells) and memory cells
Humoral Response
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Helper T lymphocytes
• They function in both humoral and cellmediated immunity
• Antigen-presenting cells (APC)
– . . . are cells which ingest Ags – B cells and
macrophages
• They alert Imm. Sys. (via TH cells) that foreign
molecules are present
• They can phagocytose foreign material
• TH cells bind to MHC II (on specialized cells)
and become induced to differentiate into:
– Activated TH cells: secrete cytokines, i.e.
interleukin-2 (IL-2);
- stimulate B cells --->plasma cells;
- induce TC cells ---> active “killers”
– Memory TH cells: IL-1 from APCs activates TH
and IL-2 secretes from activated TH cells
– Suppressor T Cells: may suppress immune
system when Ag is no longer present
Summary:
Cascade of interactions in response to Ag
Ag from bacterial cell
Differentiation into either:
CD4 protein enhances binding
Cytotoxic T cells
• Ag-activated TC cells kill cells that are
infected by pathogens (TC cells can recognize any
type nucleated cell which is infected)
– Infected cells displays MHCI molecules
• TC recognizes MHCI and binds to cell
– Surface molecule CD8 has affinity for MHCI
– TC releases perforin (protein) which forms a lesion (hole)in plasma
membrane of target cell; cell lyses
» Released Ags are now exposed to circulating Abs
» TC cells continue to live after destroying target cells; also
can kill cancer cells which constantly develop in the body
Cytotoxic T Cell Reaction
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TC and Cancer
• Cancer cells display distinctive markers
called tumor antigen
• TC cells recognize markers as nonself,
attach, and lyse the cancer cells
• Some types of cancer cells have reduced
MHCI proteins so that TC cells have less
ability to recognize and destroy them
Humoral Response
• B cells produce Abs against extracellular
pathogens (bacteria, viruses)
– Response occurs when Ag epitope binds to B
cell receptors
• B cells differentiate into clones of plasma cells
(Ab-secreting cells) and B memory cells
Mechanisms of B cell activation
• T-dependent antigens: Ags from infected
cells evoke cooperation between
macrophages, TH cells, and B cells
– Produce Abs only WITH involvement of TH
cells via cytokines such as IL-2
– Most Ags are T-dependent
– Memory cells are produced in T-dependent
responses
• T-independent antigens: Ags trigger humoral
responses without macrophages OR T cell
involvement
– Usually long chains of repeating units such as those
found in bacterial capsules and flagellae
– B cell is stimulated directly by Ag (long chains)
– Ab response is usually much weaker response caused by
T-dependent Ags
– No memory cells produced in this response
• All B cells (no matter the stimulation) produce
plasma clones
– 2,000 Abs/sec for 4-5 day life span of plasma cell
Antibody reaction with epitope
Variable
region
Constant
region
Antibody only
recognizes this part
Antibody Groups: based on heavy-chain constant regions
Circulating; respond to initial exposure; activates
the complement pathway.
MOST ABUNDANT; circulating; against bacteria,
viruses, toxins; triggers the complement reaction
Most from cells with mucous membranes; prevents
attachment by bacteria and viruses; in tears, saliva,
sweat, and colostrum (1st 3 days of milk from breasts)
Most are on exterior of B cells; probably is the Ag-receptor that
initiates B cell differentiation
“stem” attaches to mast cells/ basophils; triggers the
release of histamine and other allergy-causing chemicals
Role of antibodies in ridding
the body of antigens
-- cellular or soluble
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Result = phagocytosis or cytolysis
Monoclonal Antibodies (Mabs)
• Ordinary Abs in an organism tend to be
polyclonal Abs (produced in response to
too many epitopes)
– Unsuited for research work -- too many
undesirable, interfering cross reactions
• Monoclonal technique developed in 1975
produced a pure and eternal supply of Abs
all from one clone of cells
Monoclonal Antibody Method
Treat variety
of B-cells with
aminopterin
(only hybridomas
will survive)
Pure monoclonal antibodies will react with only
one Ag such as HCG -- the basis of pregnancy
tests.
Some autoimmune disorders
• 1. Lupus erythematosis: against components of
body’s own cells -- especially DNA
• 2. Rheumatoid arthritis: inflammation of cartilage
and bones in joints
• 3. Insulin-dependent diabetes (Type 1): against
insulin-producing beta cells of the pancreas
• 4. Multiple sclerosis (MS): T cells infiltrate CNS
(central nervous system) and destroy myelin of
neurons
• 5. Heart valve/tissue damage: reaction to
repeated streptococcal infections
Immunity and blood types
• Immune reactions dictate which blood
types may or may not be transfused
• ABO blood groups are good example of
nonself recognition
• Transfusion reaction occurs when RBCs
agglutinate when wrong type is transfused
Blood types and serum antibodies
RBC Antigen
Serum antibody (ies)
A
Anti-B
B
Anti-A
AB
none
O
Anti-A and anti-B
Rh Factor
• Another blood group Ag; found originally in
Rhesus monkeys (research animals)
• Rh incompatibility occurs when father is Rh+,
mother is Rh-, and the fetus is Rh+
– Small amounts of blood from the fetus leak across the
placenta; mother’s lymphocytes react with IgG anti-Rh
Abs; subsequent pregnancies anti-Rh Abs pass across
placenta into fetus and destroy fetal RBCs; baby is
born either dead or as a “blue baby” -erythroblastosis fetalis
– Can be prevented in subsequent children by injecting
mother with anti-anti-Rh Abs which destroy Rh+ RBCs
before mother develops imunological memory.
Tissue Grafts
• Recall that the MHC is a “biological fingerprint”
unique to each individual
– Foreign MHCs elicit cell-mediated response from
cytotoxic T cells
– Use of immunosuppressant drugs increases chances of
successful transplant
• Cyclosporin A
• FK 506
– For bone marrow transplants:
recipient’s immune system is total destroyed by
radiation; therefore any rejection comes from the
grafted lymphocytes against the recipient’s MHC -close matchings are required
Allergies
• Allergy = hypersensitivity to an allergen
(environmental antigen)
– IgE Abs are commonly involved;
these recognize pollen as allergens
• IgE attach their tails to noncirculating mast cells in
connective tissue; pollen grain bridges the gap
between two adjacent IgEs and mast cell responds
with degranulation -- release of histamine and other
inflammatory agents
– Histamine causes dilation/increased permeability of
arterioles; results in typical symptoms of allergies
» Antihistamine drugs suppress excess histamine
This event triggers the
mast cell to degranulate that is, to release histamines
and other inflammatory
agents from vesicles
called granules.
Random throughout
connective tissue
Anaphylactic shock
• Life-threatening
– Caused by injected/ingested Ags
– Acute allergic response
• Histamine from degranulation of mast cells causes
sudden dilation in peripheral circulation; blood
pressure drops dangerously low
– Death may occur in 2-3 minutes
• Countermeasure is injection of epinephrine directly
through chest wall into the heart
Immune deficiencies
• SCID = severe combined immunodeficiency
– Congenital; failure of both humoral and cell-mediated
immunity
• Hodgkin’s disease (cancer) causes a type of
immunodeficiency
• Some viral infections depress immune system
• Physical/emotional stress compromises immune
system
– Nerves penetrate deep into thymus and affect its
impact on T cells
– Lymphocytes have receptors for neurotransmitters
HIV/AIDS
• HIV-1 (most common and virulent), HIV-2 also a
major strain
– Viruses infect CD4 cells (TH)
• Also requires a coreceptor such as fusin or CCR5
• HIV RNA is reverse-transcribed to DNA and is integrated into
the host DNA (a provirus now); DNA directs production of new
viruses from this privileged location
– Provirus is “invisible” to the immune system
– Rapid mutation of Ags during replication changes epitopes
– Population of TH declines; can’t participate in cell-mediated
immunity
– Secondary infections occur: Karposi’s sarcoma,
Pneumocystis carinii (protozoan) pneumonia
HIV budding from
a CD4 cell; cell
eventually perishes
• HIV-positive means presence of Abs have been detected
– About six weeks into the infection
• AIDS is late stage of HIV infection (10 years incubation
is average)
HIV treatment
• Multiple-drug (“cocktail”) approach is used
to slow viral replication
– DNA synthesis inhibitors
– Reverse transcriptase inhibitors (AZT, ddI)
– Protease inhibitors
• It’s all expensive and can only prolong life
-- is not a cure
• No vaccine currently exists because
no stable epitope can be found
Invertebrate immune systems
• Sponges: intermingled sponge fragments from two
organisms can re-form separately and exclude fragments
from the other sponge
• Coelomocytes: amoeboid cells which destroy foreign
material have been found in many invertebrates
• Earthworms demonstrate memory when given body wall
grafts from same or different populations
– From same population lasts about 8 weeks
– From a different population is rejected in two weeks
• A second graft from same donor to the same recipient rejected in
less than one week -- is this a memory reaction??
End