Transcript Document

MCMP 422
• Tony Hazbun
• RHPH 406D
• [email protected]
– Include MCMP 422 in the subject line
MCMP422
Immunology
• Immunology is important personally and
professionally!
• Learn the language - use the glossary and index
• RNR - Reading, Note taking, Reviewing
• All materials in Chapters 1-5 are examinable
(with exceptions) plus extra material from class
What and why?
•
Immunology: Science of how the body responds to
foreign agents
•
Immune system: the organs, cells and molecules that
defend and respond to pathogens/allergens
• Organ transplantation, cancer, immunodeficiency diseases,
infectious diseases
Immunology
• How do we recognize foreign structures?
• How do we recognize self vs non-self?
• How do we stop and remove invading agents?
Pharmacy and Therapy Perspective
• How can we use the immune system as a
therapeutic agent?
• How do drugs affect the immune system?
Chapter 1 Concepts
What components make up the immune system?
Cells, organs, cytokines and other molecules involved in the
immune system
What is the goal of the immune system?
To clear pathogens in our body
How do we classify immune responses?
Innate and adaptive immune responses
What are the side effects of the immune system?
Autoimmune diseases, Allergies, Transplantation Rejection
Machinery of the Immune system
1. Tissues/organs
bone marrow, thymus, spleen, lymph nodes
2. Cells
lymphocytes, dendritic cells, macrophages, natural killer
cells, granulocytes (neutrophils, basophils, eosinophils),
mast cells
3. Blood-borne proteins
complement and mannose-binding proteins
Origin of Immunology - individuals who survived a disease seemed
to be untouched upon re-exposure
Vaccination/Immunization - procedure where disease is prevented
by deliberate exposure to infectious agent that cannot cause
disease.
Vaccinia - mild
disease caused by
cowpox
Edward Jenner - first
demonstration of
vaccination
Pathogen - any organism that can cause disease
Figure 1-2
Diversity of Pathogens
• Four Classes
-Bacteria
-Fungi
-Viruses
-Parasites
• Opportunistic pathogens
e.g. Pneumocystis
carinii
• Pathogen-Host relationship
How Clean are You?
Part of body
Head (scalp)
Surface of skin
Saliva
Nose mucus
Faeces
Bacteria
1,000,000 /cm2
1000 /cm2
100,000,000 /g
10,000,000 /g
over 100,000,000 /g
Defenses against Pathogens
Physical Defenses
1. Skin
- Tough water-proof Barrier
- Pathogen Penetration is difficult
- Breached by wounds/mosquito
2. Mucosal surfaces
- line body cavities
- epithelial cells covered with mucus
- mucus thick fluid layer containing
glycoproteins, proteoglycans and enzymes
- e.g. mucus in lungs traps pathogens
Immune Defenses
1. Innate - physical defenses are part of innate immunity
2. Adaptive
Physical Barriers
•
Lungs: Mucus, cilia trap and
move pathogens
•
Nose: Mucus traps pathogens
which are then swallowed or
blown out
•
Mouth: Friendly bacteria, Saliva
•
Eyes: lysozyme
•
Stomach: acid neutralization
•
Intestine: Friendly bacteria
•
Urogenital tract: Slightly acid
conditions
Immunity: Three Basic Parts
Recognition
(Binding event)
Pathogen
(Foreign)
Immune
disorders
(Self)
Signal
Effector mechanisms
Effector Cells
Complement
Two types of Immunity - Innate or Adaptive
Innate Immunity
• Ancient system - present in invertebrates
• naïve, immediate, everyday immunity
• Molecules recognize common features of
pathogens
– Lectin
– Phagocytes, large lymphocytes (NK cells)
– Complement
Adaptive Immunity
• Newer system - present in fish, birds, human
• specialized, late, immunity
• Molecules recognize specific features of
pathogens
– Antibodies
– B and T cells - small lymphocytes
– Immunological memory
Example of Innate Immunity
Figure 1-5 part 1 of 2
Complement - blood borne (serum) proteins that tag pathogens or
attack them directly
Effector cell - engulf bacteria, kill virus infected cells, attack
pathogens
Endocytosis - process by which extracellular material is taken up
One type of
effector cell is the
phagocyte
Innate Immunity
Figure 1-6
Cytokines = signaling molecules --> inflammation/adaptive immunity
Phagocytosis = “phagos” means to eat
Inflammation is sometimes an unwanted by-product!
Inflammatory cells = WBC’s contributing to inflammation
Inflammation
•
•
1.
Inflammation - local accumulation of fluid and cells involved in
the immune response
What happens when inflammation is induced
Blood capillary dilation => heat (calor) & redness (rubor)
- Local dilation of blood capillaries = increase of blood to the area
(DOES NOT increase blood flow)
1. Vascular dilation (vasodilation) => swelling (tumor) & pain
(dolor)
2. Extravasation - movement of cells/fluid into connective tissue.
A) change in adhesiveness of the endothelial tissue allowing
immune cells to attach and migrate into the connective tissue
B) vascular dilation - gaps in endothelial cells
Example of inflammation gone bad: Sepsis
Systemic inflammatory response syndrome (SIRS)
Results from the body's systemic over-response to infection
Treatment: broad-spectrum antibiotics and supportive therapy
Disturbance of innate immunity during sepsis and multiorgan
dysfunction syndrome (MODS) probably linked to uncontrolled
activation of the complement system
Future Drug therapies could be used that modulate proinflammatory and anti-inflammatory factors
Innate and Adaptive responses
Innate
Adaptive
 Pathogen independent
 Immediate (hours)
 Pathogen-dependent
 Slower (days)
Neutrophils
Macrophages
Mast cells
Eosinophils
Basophils
NK cells
“Large Lymphocytes” = NK
cells
Dendritic cells
B cells
T cells (CD4 or CD8)
“Small Lymphocytes” = B &
T cells
Both systems “talk” to each other to modulate response
Both systems use leukocytes = white blood cells
What if Innate Immunity is not Enough?
• Innate immunity keeps us healthy most
of the time
• Some pathogens escape the innate
immune process
• Need a specific system to adapt to a
specific pathogen
- Hence vertebrates evolved the
Adaptive immune response
Principles of Adaptive Immunity
1. Lymphocytes each with different
specificity generated by gene
rearrangements
2. Small fraction of total pool of
lymphocytes can recognize the
pathogen
3. Pathogen recognizing lymphocyte
is amplified - Clonal
amplification
4. Pathogen recognizing lymphocyte
can persist providing long-term
immunological memory
5. Primary vs Secondary immune
response
eg. Influenza/Measles/Vaccination
Characteristics of Innate vs Adaptive Immunity
INNATE
Figure 1-7
= genes are constant
ADAPTIVE
= genes are rearranged
Leukocytes - white blood cells that increase the
immune response to ongoing infection
Innate vs Adaptive Molecular Recognition
• Most important difference: Receptors used to recognize
pathogens
• Innate immunity: Receptors recognize conserved structures
present in many pathogens (usually a repetitive pattern)
Pathogen-associated Molecular Patterns (PAMPs):
LPS, peptidoglycan, lipids, mannose, bacterial DNA and viral
RNA
e.g. Mannose-binding Lectin (MBL)
• Adaptive immunity: Receptors recognize a specific structure
unique to that pathogen
e.g. Antibodies
Flowchart of Hematopoiesis
Pluripotent
stem2
cell
Figure 1-11 part
1 of
Self-renewal
Flowchart of Hematopoiesis
Figure 1-11
Leukocytes
Myeloid Lineage
Granulocytes (Myeloid progenitor)
Polymorphonuclear leukocytes (PMLs)
Figure 1-9 Neutrophils:
partMost
3 abundant
of 6
Phagocyte
Effector cells of Innate Immunity
Short-lived - Pus
Eosinophils:
Worms/intestinal parasites
Amplify inflammation
Bind IgE
Very Toxic - Pathogen and host
Chronic asthma
Basophils:
Rare
Unknown function
Bind to IgE
• Circulate in blood
• Bigger than PMLs
• Look similar
• Immature form of
macrophage
Figure 1-9 part 5 of 6
• Scavengers
• Phagocytose
pathogens, cells,
debris
• Secrete cytokines
Figure 1-13
Macrophages respond by two mechanisms - use 2 different receptors.
1)
Phagocytosis - Phagosome fuses with lysosome - toxic small molecules
and hydrolytic enzymes kill/degrade the bacteria
2)
Signaling - bacterial component binds receptor - initiates transcription inflammatory cytokines synthesized and secreted
• Star-shape
• In tissue
• Cellular messenger
• Cargo cell
• Connective tissue
• Unknown
progenitor
• Granules
• Degranulation
major contributor to
inflammation and
allergies
Lymphoid Lineage Cells
Large lymphocytes
NK cells
Small lymphocytes
B cells
T cells
Innate immunity
Adaptive immunity
Figure 1-9 part 2 of 6
Lymp
• Large lymphocyte with granular cytoplasm
• Effector cell of innate immunity
1) kill viral infected cells
2) secrete cytokines that interfere with virus infections
• Adaptive IR
• Small and immature
• Activated by pathogen
• Two types
- B cell
- T cell
• B cells have B cell
receptors and secrete Ab
• T cells have T cell
receptors
Erythroid Lineage
• Giant nucleus
• Resident of bone
marrow
• Fusion of precursor
cells
• Fragments to make
platelets
Figure 1-9 part 6 of 6
• Gas transport
• Infected by
Plasmodium
falciparum
Lymphoid
Myeloid
Erythroid
Neulasta (Amgen): Granulocyte Colony-Stimulating Factor (G-CSF)
Recovery from Neutropenia & protect against Bacterial disease
Leukine (Schering-Plough): Granulocyte-Macrophage ColonyStimulating Factor (GM-CSF), Recovery from Neutropenia and
protection against Bacterial/fungal/parasitic disease
Centrifuged blood sample
Plasma
White blood cells
Red blood cells
Figure 1-12
High WBC could be a sign of infection or leukemia
Low WBC bone marrow diseases or HIV
Polys = polymorphonucleocytes - mainly neutrophils
High lymphocyte count indicates the bacterial or viral infection
The lymph system and sites of
lymphoid tissue
Figure 1-15
Primary (Red) and Secondary (yellow)
GALT, BALT, MALT
Thoracic Duct
Lymphpatic vessels - fluid collection
Lymph nodes - junctions of vessels
Recirculation
Draining Lymph node
Edema - is worse when
patient is inactive
Afferent (entry)
Efferent (exit)
Figure 1-17 part 1 of 2
Communications Center
Afferent vessels bring in the lymph from infected tissue
Efferent vessels place of exit for non-activated lymphocytes
B-cell area
(follicle)
Lymphocytes
Afferent
lymph
Pathogen
Dendritic cells
T helper cell
(lymph node)
Activate B cells
Make Antibodies
artery
T-cell area
Efferent
lymph Lymphocyte not
activated
Activated by
dendritic cell
T helper cell
(Infection site)
Cytotoxic T cell
(Infection site)
Activate Macrophages
Kills infected
host cells
Lymphocytes enter node through artery
Tcells migrate to the T-cell area and if they meet a
dendritic cell that is carrying pathogens from an
infection site they get activated - to divide into
functional effector cells.
Some T-cells stay in the lymph node and become Thelper cells - secrete cytokines (soluble proteins) and
have receptors that contact B-cells. This helps the Bcells differentiate into plasma cells.
Plasma cells stay in the lymph or leave and pump out
large amount of antibodies - a soluble form of their
cell surface receptor
A second type of activated T-cell is the T-helper cell
that leaves the node to the infected area and interacts
with macrophages and amplify inflammation
Third type of T-cell is the cytotoxic T-Cell which kill
cells infected with pathogen
Remember 5 million lymphocytes are entering node
every minute and only a few are activated in response
to an infection.
Anatomy of immune function in the Spleen
Figure 1-19
• Blood filtering
organ - remove
old/damaged red
cells (red pulp)
• Blood-borne
pathogens e.g.
malaria
• White pulp
(Immune system)
- similar to lymph
node (except
pathogens enter and
leave by blood)
Figure 1-20
M cells
Activated
lymphocytes
M cells - specialized cells lining mucosal epithelium that deliver
pathogen => activate lymphocytes
Adaptive Immunity
1. Vertebrates only
2. Specificity
- recognition modules - BCR, Ab and TCR
- gene rearrangement is the source of diversity
- clonal selection
3. Small lymphocytes
- types and sub-types
- functions
Recognition concept
Receptor or Antibody molecule
Antigen - structure recognized by an Ab, BCR or TCR
Epitope - particular sub-structure of the Ag that is bound
Affinity - how much a molecule likes to bind to a structure
Small lymphocyte sub-types
B-cells
BCR is Immunoglobulin (Ig)
Plasma cells - effector cells that secrete Ab
T-cells
Tc = cytotoxic (CD8+)
TH = helper T-cells (CD4+)
Th1 (inflammation)
Th2 (help B-cells make AB)
Recognition modules of Adaptive immunity
B-cell receptor (BCR)
B cells
Antibody is a secreted form of BCR
T cell receptor (TCR)
T cells
TCR is membrane bound
Native vs
Denatured
B-cells
T-cell
Antigen
processing
Major
Histocomp
-atibility
(MHC)
MHC
APC - Antigen
Presenting Cells
Professional APC
- macrophages
- B cells
-Dendritic cells
MHC I
- all nucleated cells
- intracelluar
pathogens e.g. virus
Interact with
cytotoxic T cells
Interact with helper
T cells
MHC II
- immune cells APC
- extracellular
MHC class I communicates with cytotoxic T cells (Tc cells)
Cellular ribosomes are subverted into making more virus proteins
Some of those proteins are degraded in the cytoplasm and transported to ER
MHC1 bind to these peptides and help to display them on the cell surface
Cytotoxic T cells = Tc cells, Cytotoxic T-lymphocytes (CTLs)
MHC class II communicates with TH cells (TH1 or TH2)
Also: Dendritic cells interact with naïve T-cells to initiate differentiation
Antibodies
Produced by B-cells
Humoral Immunity - Humor = “body fluids”
Passive immunity - serum transferred to another individual can
confer passive reistance due to transfer antibodies
Antibodies
Parasitic infection
Parasite
+
Mast cell
Inflammation
Mast cell
activated
Expel
and/or
destroy
pathogen
•
•
•
Neutralization
Opsonization
Inflammation
Principles of Adaptive Immunity
Diversity
Specificity
Memory
Self-tolerance
Gene Rearrangement is the source of Diversity
Germline configuration - the
exact form of genes you inherit
Somatic cells - all the cells of
the body except germ cells
Diversity
1. Alternative combinations
2. Imprecise joints
3. Different types of chains
4. B-cells - somatic hypermutation
All this can happen in the absence
of antigen
Clonal Selection
1. Each cell = one receptor
2. Millions of lymphocytes
are generated
3. Small subset will
recognize a pathogen
4. Proliferation and
differentiation
5. Acquired immunity - the
adaptive immunity
provided by
immunological memory
Antibodies are usually very specific
Figure 1-22
Concept Behind Vaccination
Many
Few
specific lymphocytes
lympho
cytes
Some memory
lymphocytes
•Pre-industrialization infants built
immunity naturally
•Post-industrialization polio rate
increased in adults hence a need for
vaccination
Polio Vaccine - Inactive vs Oral “live” version
VDPV - vaccine derived polio virus, cheap and easy to administer
- mutations can lead to polio at extremely low rate
- immunocompromized individuals can be carriers of VDPV
Principle of Self-tolerance
B-cells with BCR that bind to self will undergo Apoptosis
More complicated scheme of selection for T cells
Selection of T cells
1. Thymocytes immature T-cells
2. Positive selection
-Self MHC
-cortex (epithelial
cells)
3. Negative selection
Mechanism of Self-tolerance
Immunodeficiencies
Inherited deficiencies
e.g. Bubble boy disease
Stress induced
nutrition, emotional
Pathogen caused deficiencies
HIV - attacks CD4 T lymphocyte
Cells and molecules
involved in
Hypersensitivity Diseases
Figure 1-32
• IgE
• IgG
• CD4 TH1
• CD8 CTL
Insulin-Dependent Diabetes Mellitus
• Beta cells of the islets of Langerhans in the pancreas are attacked
• Symptoms don’t show up for a long time
• Infection by a specific virus has been correlated with higher rate of IDDM
• Some of the activated CTL and Th1 cells will attack the healthy beta cells
• IDDM also has been correlated with certain polymorphisms (types) of the MHC molecule
Inflammatory Adaptive Immune Response
Hygiene Hypothesis or Global Warming Hypothesis