1) THE IMMUNE SYSTEM
a) How do immune cells recognize foreign cells?
b) Macrophage engulfing yeast cell
c) Macrophage: a phagocytic cell present in many tissues that functions
in innate immunity by destroying microbes and in adaptive (acquired)
immunity as an antigen-presenting cell.
d) Microbe: Any of the microorganisms, especially those causing diseases
or infections.
2) WHO ARE OUR ENEMIES?
a) Macrophage Engulfing Bacteria
b) Immune cells such as this macrophage can be found in the body fluids
and tissues of most animals.
c) Macrophage: a phagocytic cell present in many tissues that functions
in innate immunity by destroying microbes and in adaptive (acquired)
immunity as an antigen-presenting cell.
3) Lymphocytes Respond to SPECIFIC Pathogens
a) The immune system enables an animal to avoid or limit many
infections.
b) Bacteria
c) Lymphocyte
d) Lymphocyte: a type of white blood cell that mediates immune
responses. The two main classes are B cells and T cells.
4) Pathogens: Infectious agents that cause disease; mostly viruses,
bacteria, protists, and fungi. A foreign molecule or cell does not have to
be pathogenic to elicit an immune response.
a) “Athlete’s Foot” – Tinea pedis - Caused by: Trichophyton rubrum or
Trichophyton mentagrophytes : Fungus
b) Borrelia burgdorferi – Bacteria - Agent of “Lyme Disease”: transmitted
primarily by ticks.
5) ANIMAL DEFENSES Must detect and discriminate:
a) Immune System: an animal body’s system of defenses against agents
that cause disease.
b) Innate Immunity: a form of defense common to all animals that is
active immediately upon exposure to pathogens and that is the same
whether or not the pathogen has been encountered previously.
c) Adaptive (previously called Acquired) Immunity: a vertebrate-specific
defense that is mediated by B lymphocytes (B cells) and T
lymphocytes (T cells). It exhibits specificity, memory, and self nonself recognition.
d) “Chicken Pox” – Virus: Varicella zoster
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6) BARRIERS AND MOLECULAR RECOGNITION PROTECT
a) Why aren’t organisms sealed off from pathogens?
b) GAS EXCHANGE
c) NUTRITION
d) REPRODUCTION
e) Organisms must be open systems to avoid equilibrium.
7) TWO TYPES OF MOLECULAR RECOGNITION Innate Immunity (found in all
animals and plants) and Adaptive (Acquired) Immunity (found only in
vertebrates).
a) Innate immunity:
i) Present at birth.
ii) Rapid
iii) Broad recognition by a small set of receptor proteins of molecules
or structures absent from animals but common to microbes.
iv) Molecular recognition activates internal defenses.
v) Includes barrier defenses.
b) Adaptive (acquired) immunity: Immunity that results either from
exposure to an antigen or from the passive injection of
immunoglobulin’s.
i) Molecular recognition with a immense arsenal of receptors
ii) TREMENDOUSLY SPECIFIC recognition of a feature typically found
on a particular part of a particular molecule in a particular
pathogen.
iii) Activated after the innate immune response.
iv) Slower response.
8) Innate Immunity of Invertebrates
a) What attacks? - Microbe: a unicellular or small multicellular organism
including bacteria, protozoa, some algae and fungi, viruses and some
worms.
b) What Defends?
c) Exoskeleton – barrier defense – external and internal.
d) Lysozyme – enzyme to digest microbial cell walls.
e) Hemocytes (circulating in hemolymph) and phagocytosis.
f) Antimicrobial peptides secreted by cells in the hemolymph disrupt
plasma membranes.
9) GFP and ANTIMICROBIAL PEPTIDES
a) GFP (green fluorescent protein) .
b) Fruit flies genetically engineered to express GFP when antimicrobial
peptide genes are activated.
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c) TOP FLY: injected with bacteria
d) BOTTOM FLY: No bacterial injection.
e) Recognition protein receptors might bind to:
10)
TOLL RECEPTOR
11) Innate Immunity of Vertebrates Barrier Defenses
a) Mosquito breaks first line of defense (skin), infects human with
plasmodium, human contracts malaria. Plasmodium (purple) - Protist
b) Epithelial tissues block pathogens.
c) Skin secretions from oil and sweat glands: pH 3 5
d) Saliva, tears, mucus and lysozyme.
e) Stomach – acidic environment.
f) Ciliated epithelial cells sweep airways to prevent infection of lungs.
12)
YOU
13) EXAMPLE: External Innate Defense by Mucous Membranes
a) Ciliated epithelial cells sweep mucus or entrapped microbes upward to
prevent invasion of the lungs.
14) Innate Immunity of Vertebrates - Cellular Innate Defenses
a) Remember: Innate – Broad and fast recognition.
b) Pathogens that enter the body do so at the risk of detection by
leukocytes – white blood cells (WBC).
c) WBC use receptors to recognize microbes: TLR (Toll-like receptor
signaling).
d) WBC’s: neutrophils, macrophages, eosinophils, dendritic cells, natural
killer cells.
e) Lymphatic system involved.
f) Protist: Trypanosoma (purple string-like with flagella).
g) Red circles: blood cells - Infection through a Tse Tse Fly Causes
African Sleeping Sickness – fatal without treatment.
15) Cellular Innate Defenses: Toll-like Receptor (TLR)
a) Look first at the Toll-like receptor: TLR: A membrane receptor on a
phagocytic white blood cell that recognizes fragments of molecules
common to a set of pathogens but absent from the vertebrate body.
b) Named after the Toll receptor discovered in insects.
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16) DETECTION OF INVADING PATHOGENS IN MAMMALS TRIGGERS
PHAGOCYTOSIS AND DESTRUCTION- Phagocytic Cells
a) Two main types of phagocytic cells in the mammalian body are
neutrophils and macrophages.
b) Neutrophils – circulate in the blood. Tends to self-destruct as they
destroy foreign invaders, limiting their life span to a few days.
Signaled from infected tissues.
c) Macrophage: migrates through body or reside in organs or tissues.
Functions in innate immunity by destroying microbes and in adaptive
immunity as an antigen-presenting cell. Macrophages are mature
monocytes.
17) More Phagocytes
a) Eosinophil: A type of white blood cell with low phagocytic activity that
is thought to play a role in defense against parasitic worms by
releasing enzymes toxic to invaders. Found beneath mucosal surfaces.
b) Dendritic cells: An antigen presenting cell, located mainly in lymphatic
tissues and skin, particularly efficient in presenting antigens to helper
T-cells, thus initiating a primary immune response. Derived from
monocytes.
18) CELLULAR INNATE DEFENSES IN VERTEBRATES INCLUDE: Natural
Killer Cells
a) Natural Killer Cell: (from lymphoid stem cells) a type of white blood
cell that can kill tumor cells and virus-infected cells as part of innate
immunity. Circulate through body to detect ABNORMAL ARRAY OF
SURFACE PROTEINS.
b) NOT MACROPHAGES! They release chemicals leading to cell death.
19) DIFFERENTIATION OF BLOOD CELLS
a) Multipotent stem cells in bone marrow give rise to two specialized sets
of stem cells.
b) Basophil: WBC <1% of all leukocytes but are essential to the
nonspecific immune response to inflammation because of their role in
releasing histamine to dilate blood vessels.
20) VERTEBRATE CELLULAR INNATE DEFENSES INVOLVE THE LYMPHATIC
SYSTEM
a) Human lymphatic system a network that distributes the fluid called
lymph throughout the body.
b) Lymph: the name given to tissue fluid that has entered the lymph
capillaries and is found in larger lymph vessel
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c) Lymphatic system: The tissues and organs, including the bone
marrow, spleen, thymus, and lymph nodes, that produce and store
cells that fight infection and disease.
d) Interstitial fluid: the fluid filling the spaces between cells in most
animals.
21) MORE INNATE IMMUNITY OF VERTEBRATES Antimicrobial Peptides and
Proteins
a) Pathogen recognition triggers production and release of peptides and
proteins that attack pathogens or interrupt their reproduction.
b) Some act like insect antimicrobials that disrupt membrane integrity.
i) UNIQUE TO VERTEBRATES:
ii) Interferons are proteins that provide innate defense by interfering
with viral infections.
c) Complement System: a group of ~30 inactive blood proteins that are
activated by substances on surface of many microbes. Activation can
lead to lysis of invading cells.
22) INNATE: Local Inflammatory Response
a) Inflammatory response: An innate immune defense triggered by
physical injury or infection of tissue involving the release of substances
(e.g. histamine) that promote swelling, enhance the infiltration of
white blood cells and aid in tissue repair and destruction of invading
pathogens.
b) Histamine: A substance released by mast cells that causes blood
vessels to dilate and become more permeable in inflammatory and
allergic responses.
c) Mast cells: A vertebrate body cell that produces histamine and other
molecules that trigger inflammation in response to infection and in
allergic reactions.
d) Cytokines – proteins that helps recruit and activate lymphocytes.
23) Local vs. Systemic Response
a) Local Inflammatory Response – don’t ignore! Infection can lead to a
response that is systemic!
b) Systemic: throughout the body. Systemic responses: fever, septic
shock.
c) Chronic (ongoing) inflammation (e.g. Crohn’s disease).
24) Evasion by Pathogens AVOIDING MOLECULAR RECOGNITION OR
DESTRUCTION
a) Adaptations have evolved in some pathogens that enable them to
avoid detection or destruction by phagocytic cells.
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b) AVOID MOLECULAR RECOGNITION: Streptococcus pneumoniae: outer
surrounding capsule interferes with molecular recognition.
c) AVOID DESTRUCTION: Mycobacterium tuberculosis
d) Mycobacterium tuberculosis pictured being engulfed by macrophage.
e) Can grow and reproduce inside of macrophages HIDDEN FROM INNATE
IMMUNE SYSTEM.
25) VERTEBRATES ARE UNIQUE! THEY HAVE INNATE AND ADAPTIVE
IMMUNE SYSTEMS! Adaptive response recruited by the actions that occur
in the innate response.
a) Adaptive/Acquired Immunity: a vertebrate-specific defense that is
mediated by B lymphocytes (B cells) and T lymphocytes (T cells). It
exhibits specificity, memory, and self-nonself recognition.
b) B cells & T cells have their origin in the bone marrow as lymphoid stem
cells.
c) Both are a type of white blood cell called lymphocytes.
i) Some stem cells mature in the Bone marrow and become B cells.
ii) Some stem cells will migrate to the Thymus to mature and become
T cells.
26) ANY substance that elicits a B or T cell RESPONSE is called an
ANTIGEN.
a) Epitope: a small, accessible region of an antigen to which an antigen
receptor or antibody binds.
b) An antigen can have several different epitopes.
27) Adaptive Immunity – Receptors Provide Pathogen Specific Recognition
a) Each antigen receptor binds to just one part of one molecule (the
epitope) of one specific pathogen.
b) Cells of the immune system produce MILLIONS of DIFFERENT antigen
receptors. Even so….
c) The approximately 100,000 antigen receptors found on any B or T cell
are all absolutely IDENTICAL.
d) If specific antigen receptor binds a particular epitope (specificity for a
particular epitope) – B or T cell activation is triggered.
e) Any pathogen having a molecule with that epitope can be bound by
that B or T cell antigen receptor.
f) These cells are pictured with 5 or 6 antigen receptors each – in reality
there are about 100,000 on each cell.
28)
a)
b)
c)
Adaptive Immunity: B-cell Antigen Receptors
B-Cell Receptor:
Y shaped
2 heavy chains, 2 light chains.
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d) Constant region: little variation in amino acid sequences between
receptors.
e) Variable region’s amino acid sequence varies extensively.
f) Antibodies have a similar structure without the transmembrane region.
29) B-cells Antigen Receptors and ANTIBODIES
a) Antibodies have a similar structure to the B cell antigen receptor,
without the transmembrane region.
b) The antigen receptor of a B cell binds to an epitope. Following binding,
the B cell gives rise to a plasma cell that secrete a soluble form of
the antigen receptor called an ANTIBODY; a.k.a: immunoglobulin (Ig)
a) B cell antigen receptors and antibodies bind to antigens in the blood
and lymph. This is considered a humoral immune response.
30) Adaptive Immunity: T-cell Antigen Receptors
a) T-cell receptor: Two different polypeptide chains; α chain and β chain
(linked by disulfide bridge).
b) Two different variable regions found on the top of the α & β chains
forms a single antigen binding site. Variable region’s amino acid
sequence varies extensively.
c) Constant region: little variation in amino acid sequences between
receptors. α & β chains anchor in the plasma membrane.
d) T cell receptors bind ONLY to fragments of antigens presented on the
surface of the host cell.
31) Antigen Recognition by T-Cells Depends on the presenting MHC
molecule
a) Top of the MHC (major histocompatibility complex) molecule cradles
an antigen fragment.
b) MHC molecule can display MANY DIFFERENT antigen fragments.
c) T-cell antigen receptor is specific for a SINGLE antigen.
32) Antigen Recognition by T-Cells
a) Pathogen (whole or part) infects or is taken into host cell. Enzymes
cleave antigen into “antigen fragments”.
b) Antigen fragment binds to an MHC molecule inside the cell.
c) MHC molecule takes fragment to cell surface for ANTIGEN
PRESENTATION…
d) Permits MOLECULAR RECOGNITION by the T cell antigen receptor.
e) This action is required for a T cell to participate in the adaptive
immune response.
33)
B-cell and T-cell comparison
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34) Four Important Characteristics of Adaptive Immunity
And Their Mechanisms
a) 1. DIVERSITY of B and T cell receptors – how does this occur?
b) 2. Adaptive immunity has SELF-TOLERANCE (does not react to its own
molecules and cells).
c) 3. CELL PROLIFERATION triggered by activation increases the number
of B and T cells SPECIFIC for an antigen by CLONAL SELECTION
d) 4. MEMORY allows for a strong and more rapid response to antigens
PREVIOUSLY encountered.
35)
a)
b)
c)
DIVERSITY of B cell and T cell receptors
1. Each person
2. Each person
3. 20,000 protein-coding genes in human genome. Amino acid
sequence variation
d) 4. Each lymphocyte
e) 5. Each lymphocyte
36) Diversity Mechanism: The B-cell light chain
a) B Cell and T Cell Development: Lymphocyte Diversity by Gene
Arrangement
b) In this example, the gene for the light chain of the membrane bound
B-cell receptor/antibody is used as an example of gene arrangement
and receptor diversity.
c) Single Ig light chain gene.
d) Three gene segments: V (40 different segments), J (5 different
segments), C (single segment)
e) Functional gene built from one copy of each segment.
f) Early B cell development – recombinase randomly links one V segment
to one J segment +INTRON + C segment.
g) Transcription  Translation  polypeptide assembly.
37) SELF-TOLERANCE TESTING
a) Immature lymphocyte receptors are tested for self tolerance.
b) If self-reactive - the receptors on the lymphocytes would be specific
for epitopes on the organisms own molecules.
c) If found to be specific for “self” – rendered nonfunctional or destroyed
by apoptosis.
d) MATURING LYMPHOCYTES ARE TESTED IN THE THYMUS OR THE BONE
MARROW TO MAKE SURE THEY ARE NOT SELF-REACTIVE –
SOMETHING THAT CAN CAUSE AUTO-IMMUNE DISEASES.
38) B cell and T cell Development: Proliferation by Clonal Selection and
Immunological Memory
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a) Effector Cells: (example is a plasma cell) a lymphocyte that has
undergone clonal selection and is capable of mediating an adaptive
immune response.
b) Memory Cells: one of a clone of long-lived lymphocytes that give rise
to effector cells if the same antigen is encountered again in an animals
life.
c) B-cell effectors are PLASMA CELLS, which secrete ANTIBODIES.
d) T-cell effectors are HELPER T-CELLS and CYTOTOXIC T-CELLS.
(1)
Cytotoxic T-cells: A type of lymphocyte that, when
activated, kills infected cells as well as certain cancer cells and
transplanted cells.
(2)
Helper T-cells: a type of T cell that, when activated,
secretes cytokines that promote the response of B cells (humoral
response) and cytotoxic T cells (cell-mediated response) to
antigens.
39) Immunological Memory
a) PRIMARY IMMUNE RESPONSE (not innate immune response): The
production of effector cells during the first exposure to an antigen.
b) Primary immune response peaks ~10-17 days after initial exposure.
c) SECONDARY IMMUNE RESPONSE:
d) When individual is exposed again to same antigen.
e) Faster – peaking 2-7 days after exposure.
f) Greater magnitude
g) Lasts longer
h) Relies on the reservoir of B and T memory cells (can last decades).
40) How do B cells and T cells help to fight off pathogens?
a) Humoral (antibody-mediated) immune response: The branch of
adaptive immunity that involves the activation of B cells and that
leads to the production of antibodies, which defend against
bacteria and viruses in body fluids.
b) Cell-mediated immune response: the branch of adaptive immunity that
involves the activation of cytotoxic T cells, which defend against
infected cells. Specialized T-cells destroy infected host cells.
c) Remember – acquired immune responses are activated after innate
defenses take effect and develop more slowly.
41) Helper T cells TRIGGER both humoral and cell mediated immune
responses.
a) Antigen presenting cell engulfs pathogen, presents antigen fragments
complexed with class II MHC molecules.
b) Helper T cell binds to complex with its antigen receptor and CD4
accessory protein.
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c) Binding of helper T cell promotes secretion of cytokines by antigen
presenting cell and helper T cell – stimulates proliferation of helper T
cells that in turn secrete other cytokines to activate B cells and
cytotoxic T cells.
42)
No Immune Response Pathogens Reproduce In and Kill Infected Cells
43) How Do Cytotoxic T-Cells Destroy Infected Host Cells?
a) Perforin (forms pores in infected cell) compromises infected cell
membrane integrity.
b) Granzymes enter by endocytosis (break down proteins) and initiate
apoptosis.
c) Antigens now exposed to antibodies.
44) ACTIVATION OF A B CELL BY A HELPER T CELL
a) Helper T cell activated (Seen before)
b) 2. When B cell identifies same antigen – engulfs and presents with
class II MHC molecule and Helper T cell activates B cell.
c) 3. Activated B cell Proliferates by Clonal selection
45) How Do Antibodies Dispose of Antigens?
a) Interfere with pathogen activity or mark pathogen for inactivation or
destruction.
46)
Overview of Adaptive Immune Response: Humoral vs. Cell-mediated
47) Immunoglobulin: a diverse group of plasma proteins, made up of
polypeptide chains that are one of the primary mechanisms for protection
against organisms. Two different forms exist. The first group of
immunoglobulin’s lie on the surface of mature B cells, enabling them to
bind to thousands of antigens. Once bound, the B plasma cells secrete
the second type of immunoglobulin’s, antigen specific antibodies which
circulate in the blood and accumulate in lymphoid tissue, especially the
spleen and lymph nodes.
a) For any given B cell: Antibodies differ from B-cell receptors only in the
constant region of the heavy chain. In place of the transmembrane
region, the heavy chain contains sequences that determine where the
antibody will distributed. Five major classes.
b) Ig: Immunoglobulin (antibody)
c) IgM: First responder in almost every immune response during initial
exposure. Blood.
d) IgG: principal Ig in blood. Only class that crosses placenta to confer
passive immunity on fetus.
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e) IgA: Principal Ig in exocrine secretions such as tears, saliva, mucus,
breast milk.
f) IgE: Plays a major role in allergic reactions.
g) IgD: Present on surface of B cells that have not yet been exposed to
antigen.
48) Active and Passive Immunity
a) Active immunity can develop from the introduction of antigens through
immunization
b) Passive immunity is a short term immunity conferred by the transfer of
antibodies to a fetus or nursing infant.
49) Immune Rejection
a) Skin transplants, Blood transfusions, Tissue or Organ Transplants
b) These example cells, like pathogens can be recognized and attacked
by immune defenses.
50) ALLERGIC RESPONSE
a) Allergies are exaggerated or hypersensitive responses to certain
antigens called allergens.
51) Autoimmune diseases
a) Type 1 diabetes – cytotoxic T cells attack insulin producing beta cells
of the pancreas.
b) Multiple sclerosis – T-cells infiltrate CNS. Destruction of myelin sheaths
of neurons.
c) Systemic lupus – generates antibodies against histones and DNA
tissues and organs (joints, skin, kidneys, heart, lungs) resulting in
chronic inflammation.
d) Rheumatoid arthritis – antibody mediated response leads to damage
and inflammation of the cartilage and bones of joints.
52) Immunodeficiency: A disorder in which the ability of an immune
system to protect against pathogens is defective or absent.
a) SCID: Severe combined immunodeficiency disorder – functioning
lymphocytes are rare or absent.
b) Acquired Immunodeficiency syndrome (AIDS) caused by a virus, both
escapes and attacks the acquired immune response. HIV infects helper
T-cells. HIV escapes with antigenic variation – the virus mutates at a
very high rate during replication preventing recognition and
elimination by the immune system. ~39.5 million infected worldwide.
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