mcmp 422 tony hazbun rhph 406d [email protected] –include mcmp 422 in the subject line
TRANSCRIPT
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?
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
Chapter 1 Concepts
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
Figure 1-2
Pathogen - any organism that can cause disease
• Four Classes-Bacteria-Fungi-Viruses-Parasites
• Opportunistic pathogense.g. Pneumocystis carinii
• Pathogen-Host relationship
Diversity of Pathogens
Part of body BacteriaHead (scalp) 1,000,000 /cm2Surface of skin 1000 /cm2Saliva 100,000,000 /gNose mucus 10,000,000 /gFaeces over 100,000,000 /g
How Clean are You?
Defenses against Pathogens
Physical Defenses1. 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 Defenses1. Innate - physical defenses are part of innate immunity2. 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
Pathogen
Signal
Effector mechanisms
Effector Cells Complement
Immunity: Three Basic Parts
Recognition(Binding event)
(Foreign)
(Self)
Immunedisorders
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
Figure 1-5 part 1 of 2
Complement - blood borne (serum) proteins that tag pathogens or attack them directlyEffector cell - engulf bacteria, kill virus infected cells, attack pathogensEndocytosis - process by which extracellular material is taken up
Example of Innate Immunity
One type of effector cell is the phagocyte
Figure 1-6
Cytokines = signaling molecules --> inflammation/adaptive immunityPhagocytosis = “phagos” means to eatInflammation is sometimes an unwanted by-product!Inflammatory cells = WBC’s contributing to inflammation
Innate Immunity
Inflammation
• Inflammation - local accumulation of fluid and cells involved in the immune response
• What happens when inflammation is induced
1. 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 pro-inflammatory and anti-inflammatory factors
Innate and Adaptive responses
Innate
Pathogen independent Immediate (hours)
NeutrophilsMacrophagesMast cellsEosinophilsBasophilsNK cells“Large Lymphocytes” = NK
cells
Adaptive
Pathogen-dependent Slower (days)
Dendritic cellsB cellsT cells (CD4 or CD8)“Small Lymphocytes” = B & T cells
Both systems “talk” to each other to modulate responseBoth 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 responseeg. Influenza/Measles/Vaccination
Figure 1-7
Characteristics of Innate vs Adaptive Immunity
Leukocytes - white blood cells that increase the immune response to ongoing infection
INNATE ADAPTIVE
= genes are constant = genes are rearranged
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
Figure 1-11 part 1 of 2Flowchart of Hematopoiesis
Pluripotent stem cellSelf-renewal
Figure 1-11Flowchart of Hematopoiesis
Leukocytes
Myeloid Lineage
Figure 1-9 part 3 of 6Neutrophils:Most abundantPhagocyteEffector cells of Innate ImmunityShort-lived - Pus
Eosinophils:Worms/intestinal parasitesAmplify inflammationBind IgEVery Toxic - Pathogen and hostChronic asthma
Basophils:RareUnknown functionBind to IgE
Granulocytes (Myeloid progenitor)Polymorphonuclear leukocytes (PMLs)
Figure 1-9 part 5 of 6• Circulate in blood• Bigger than PMLs• Look similar• Immature form of macrophage
• 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 lymphocytesNK cells
Innate immunity
Small lymphocytesB cellsT cells
Adaptive immunity
Figure 1-9 part 2 of 6
Lymp
• Large lymphocyte with granular cytoplasm• Effector cell of innate immunity
1) kill viral infected cells2) secrete cytokines that interfere with virus infections
• B cells have B cell receptors and secrete Ab
• T cells have T cell receptors
• Adaptive IR• Small and immature• Activated by pathogen• Two types
- B cell- T cell
Erythroid Lineage
Figure 1-9 part 6 of 6• Giant nucleus• Resident of bone marrow• Fusion of precursor cells• Fragments to make platelets
• 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 Colony-Stimulating Factor (GM-CSF), Recovery from Neutropenia and protection against Bacterial/fungal/parasitic disease
Plasma
Red blood cells
White blood cells
Centrifuged blood sample
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
Figure 1-15
The lymph system and sites of lymphoid tissue
Primary (Red) and Secondary (yellow)GALT, BALT, MALTThoracic DuctLymphpatic vessels - fluid collectionLymph nodes - junctions of vessels
RecirculationDraining Lymph nodeEdema - is worse when patient is inactiveAfferent (entry)Efferent (exit)
Figure 1-17 part 1 of 2
Communications CenterAfferent vessels bring in the lymph from infected tissueEfferent vessels place of exit for non-activated lymphocytes
B-cell area(follicle)
Lymphocytes
T-cell area
artery
Activated by dendritic cell
T helper cell (lymph node) T helper cell
(Infection site)
Activate B cells
Make Antibodies
Activate Macrophages
Cytotoxic T cell (Infection site)
Kills infected host cells
Lymphocyte not activated
Efferent lymph
PathogenDendritic cells
Afferentlymph
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 T-helper cells - secrete cytokines (soluble proteins) and have receptors that contact B-cells. This helps the B-cells 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.
Figure 1-19
Anatomy of immune function in the Spleen
• 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
Activated lymphocytes
M cells
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
B-cellsBCR is Immunoglobulin (Ig)Plasma cells - effector cells that secrete Ab
T-cellsTc = cytotoxic (CD8+)
TH = helper T-cells (CD4+)Th1 (inflammation)Th2 (help B-cells make AB)
Small lymphocyte sub-types
Recognition modules of Adaptive immunity
B cells T cells
B-cell receptor (BCR)
Antibody is a secreted form of BCR TCR is membrane bound
T cell receptor (TCR)
B-cells T-cell
Native vs Denatured
Antigen processing
Major Histocomp-atibility (MHC)
APC - Antigen Presenting Cells
Professional APC- macrophages- B cells-Dendritic cells
MHC I - all nucleated cells - intracelluar pathogens e.g. virus
MHC II - immune cells - APC - extracellular
MHC
Interact with cytotoxic T cells
Interact with helper T cells
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
Parasite +
Mast cell
Inflammation
Mast cell activated
Expel and/or destroy
pathogen
• Neutralization• Opsonization• Inflammation
Parasitic infection
Antibodies
Principles of Adaptive Immunity
DiversitySpecificityMemorySelf-tolerance
Gene Rearrangement is the source of Diversity
Germline configuration - the exact form of genes you inheritSomatic cells - all the cells of the body except germ cells
Diversity1. Alternative combinations2. Imprecise joints3. Different types of chains4. B-cells - somatic hypermutation
All this can happen in the absence of antigen
Clonal Selection
1. Each cell = one receptor2. Millions of lymphocytes
are generated3. Small subset will
recognize a pathogen4. Proliferation and
differentiation5. Acquired immunity - the
adaptive immunity provided by immunological memory
Figure 1-22Antibodies are usually very specific
Few specific lympho
cytes
Many lymphocytes
Some memory lymphocytes
Concept Behind Vaccination
•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
Mechanism of Self-tolerance
Selection of T cells
1. Thymocytes - immature T-cells
2. Positive selection-Self MHC-cortex (epithelial cells)
3. Negative selection
Immunodeficiencies
Inherited deficienciese.g. Bubble boy disease
Stress induced nutrition, emotional
Pathogen caused deficienciesHIV - attacks CD4 T lymphocyte
Figure 1-32
• IgE
• IgG
• CD4 TH1
• CD8 CTL
Cells and molecules involved in Hypersensitivity Diseases
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
Hygiene Hypothesis or Global Warming Hypothesis
Inflammatory Adaptive Immune Response