MCB 150: Molecular Immunology
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Transcript of MCB 150: Molecular Immunology
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MCB 150: Molecular Immunology
Spring 2007Prof. Ellen Robey
Prof. Robert BeattyProf. Laurent Coscoy
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Overview of the Immune system
Microbes: why they are formidable foes.
Gross anatomy of the immune system
Cells of the immune system
Effector mechanisms: how the immune system protects
Immune recognition of pathogens: innate vs adaptive immunity
Cytokines and the inflammatory response
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Microbes are ubiquitous in nature, extraordinarily diverse, rapidly evolve to exploit opportunities to infect hosts and to
evade their immune systems.
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Exponential Growth
1
10
100
1000
10000
100000
1000000
10000000
100000000
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25Time (minutes/10)
# of bacteria
8 hours = 280 trillion bacteria!!!!
Exponential growth
Num
ber o
f bac
teria
Time (hrs)
Many pathogens can expand rapidly in the nutrient-rich environment of the host.
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Some microbes hijack cellular machinery to replicate and spread. Intracellular pathogens
include viruses (influenza, HIV) and intracellular bacteria (listeria) and intracellular parasites
(malaria, toxoplasma).
Listeria bacteria using the actin cytoskeleton of the host cell to spread from cell to cell. (Portnoy lab)
Toxoplasma parasites (red) and dendritic cells (green) within a mouse lymph node. (Robey lab)
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Pathogens rapidly evolve to avoid the host immune response
Virally encoded decoy receptors
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Overview of the Immune system
Microbes: why they are formidable foes.
Gross anatomy of the immune system
Cells of the immune system
Effector mechanisms: how the immune system protects
Immune recognition of pathogens: innate vs adaptive immunity
Cytokines and the inflammatory response
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First some key definitions:
Pathogen: microbe that causes disease
Antigen: material (from a pathogen) that induces an immune response
Innate (natural) immunity: rapid, non specific immune response
Adaptive (acquired) immunity: slower, specific immune response
Leukocytes: blood cells
Lymphocytes: specialized blood cells that mediate adaptive immunity (e.g. T and B cells)
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The cells of the immune system circulate through the body via
lymph and blood. Pathogens and their antigens are transported from
tissues via lymphatic vessels to the lymph nodes where they
encounter immune cells.
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The cells of the immune system spend much of their time in
lymphoid organs. They develop (arise) in primary lymphoid
organs, and they interact with antigens in secondary lymphoid
organs.
Thymus: primary lymphoid organ for T cell development
Bone marrow: primary lymphoid organ for B cell development
Lymph nodes: collect antigens from tissues
Spleen: collects antigens from blood stream
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Overview of the Immune system
Microbes: why they are formidable foes.
Gross anatomy of the immune system
Cells of the immune system
Effector mechanisms: how the immune system protects
Immune recognition of pathogens: innate vs adaptive immunity
Cytokines and the inflammatory response
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Many different types of blood cells participate in the immune response to microbes:
Innate immune cells: “phagocytes” macrophage, neutrophils, dendritic cells
Adaptive immune cells: “lymphocytes” T cells, B cells
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QuickTime™ and aTIFF (LZW) decompressorare needed to see this picture.Most blood cells act to fight infection.
Adaptive immunityInnate
immunity
Blood cells lineages.
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QuickTime™ and aTIFF (LZW) decompressorare needed to see this picture.Lymphocytes of the adaptive immune system
T helper cells: regulate other immune cellsT cytotoxic (killer) cells: kill infected cellsB cells: produce antibodies (immunoglobulin)
Dendritic cells and macrophage: directly kill microbes by phagocytosis and other mechanisms. They also help to activate T cells (connection between innate and adaptive immunity)NK cells are lymphocytes that have characteristics of innate and adaptive immunity.
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Overview of the Immune system
Microbes: why they are formidable foes.
Gross anatomy of the immune system
Cells of the immune system
Effector mechanisms: how the immune system protects
Immune recognition: innate and adaptive
Cytokines and inflammation
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Immune Effector Mechanisms:
Cell-mediated immunity:Phagocytosis (cellular eating)cytotoxcity (cellular killing)
Humoral immunity:complement: group of serum proteins that can directly kill
pathogens.antibodies: (also called immunoglobulin) proteins secreted
by B cells that bind directly and specifically to pathogens. Antibodies target pathogens by marking them for destruction by other components of the immune system.
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Macrophage fight microbes by engulfing and digesting them (phagocytosis or cellullar eating).
A macrophage engulfing yeast
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Bacteria fight back against phagocytosis
A macrophage attempting to engulf a bacterium
Streptococcus pneumoniae, that is covered with a slimy coat.
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Target cell killing by a cytotoxic (killer) lymphocyte
A cytotoxic T lymphocyte (CTL) killing a cell that has been infected by a virus. NK cells use a
similar mechanism to eliminate tumor cells.
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Overview of the Immune system
Microbes: why they are formidable foes.
Gross anatomy of the immune system
Cells of the immune system
Effector mechanisms: how the immune system protects
innate and adaptive immunity
Cytokines and inflammation
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Found in:
Substances that trigger:
Receptors:
all multicellullar organisms
A limited number of pathogen-associated molecular patterns (PAMPs)
A limited number of Pattern Recognition Receptors (PRRs) expressed on many cells types
Vertebrates only
Virtually any component of pathogens
Highly variable receptors of 2 types: antibody made by B cells and TCR made by T cells
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Comparison of innate and adaptive immune recognition
Receptors that mediateinnate immune recognition: Toll-like receptors (TLR)
Receptors that mediate adaptive immune recognition: Antibody and the T cell receptor (TCR)
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The genes encoding the T cell antigen receptor (TCR) are assembledby DNA rearrangement as T cells develop in the thymus
TCR locus:structure in germline
TCR locus:structure in T cells
DNA rearrangement(rag1, rag2)
transcriptionRNA splicingtranslation
T cell
V segments D J C
The genes encoding the antigen receptors of T and B cells are assembled by DNA rearrangement as these cells develop. As a result of V(D)J recombination, every B and T cells expresses a unique version of the antigen receptor.
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Overview of the Immune system
Microbes: why they are formidable foes.
Gross anatomy of the immune system
Cells of the immune system
Effector mechanisms: how the immune system protects
Immune recognition: innate and adaptive
Cytokines and inflammation
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Cytokines: (also called interleukins)
Small secreted peptides that used for intracellular communication between cells of the immune system
Can turn on or off immune responses
Mediate inflammation
Chemokines: subset of cytokines that specialize in regulating cell motility
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Inflammation: a complex series of events induced by tissue damage(described in medical literature in 1500s)
• Redness (rubor)
• Pain (dolor)
• Swelling (tumor)
• Heat (calor)
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Infection can induce inflammation, but even sterile injuries can be sufficient to induce inflammation.
Inflammation occurs when injured tissues release mediators that promote vasodialation (increased blood flow) and chemotaxis (directed
migration) of leukocytes.
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Inflammation causes blood cells to move
from blood stream to site of injury
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Blood cells (leukocytes) travel from the blood stream into tissues by a process known as extravasation
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Blood cells can also be attracted to sites of infection by products produced by pathogens, as well as by
chemoattractants made by host (chemokines, inflammatory meditators).
Neutrophils (a type of white blood cell) are attracted to bacterial products. Here they are moving toward a gradient of the
bacterial peptide fMLP.
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Why study the immune system?
Importance of the immune system in human health
Provides model systems for studies of:gene regulationmolecular recognitionsignal transductionetc, etc
Provides powerful techniques for use in medicine and science
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Diseases associated with immune system dysfunction
• Autoimmunity (SLE, Arthritis, Myasthenia gravis, Graves disease)
• Immunodeficiency (inherited, acquired)• Allergy (environment, drugs)• Cancer (Leukemia, Lymphoma)
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Myasthenia gravis
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Asthma & Allergy
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Therapeutics
• Vaccination• Adoptive immunotherapy• Transplantation
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Vaccination: THE major successCases per
100,000population
Cases per100,000
population
Cases per100,000
population
Diphtheria
Polio
Measles
year
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Treating cancer
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Tissue Transplantation
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Powerful methods for detecting and quantitating proteins and cells based on the highly specific binding of antibodies
(immunoglobulins)
• ELISA: enzyme-linked immunosorbant assay (measures small amounts of hormones, drugs, microbes in body fluids)
• Western blot (detects disease associated proteins)• Flow cytometry (quantifies various cell types in
mixed population-- HIV patients)
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Western Blot
•Separate proteins by size using PAGE gel
•Transfer gel to blotting membrane•Probe membrane with antibody
specific for protein of interest•Detect bound antibody by
chemiluminesence
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ImmunofluoresenceImmunofluoresence
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Flow Cytometry: Quantitative Single-cell Immunofluoresence
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Innate (natural) immunity
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Found in:
Substances that trigger:
Receptors:
all multicellular organisms
A limited number of pathogen-associated molecular patterns (PAMPs)
A limited number of Pattern Recognition Receptors (PRRs) expressed on many cells types
Vertebrates only
Virtually any component of pathogens
Highly variable receptors of 2 types: antibody made by B cells and TCR made by T cells
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Innate Immunity
Innate immune effector mechanismsPhysical and biochemical barriers (defensins)Phagocytosis and reactive oxygenCell autonomous defenses
ApoptosisInterferons and PKR
Innate immune recognitiondiscovery of the Toll-like receptorsmammalian TLRs and their ligandsnon-TLR recognition of PAMPs
Connections between adaptive and innate immunity
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Physical & Biochemical barriers
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Defensins
• Originally isolated from frog skin based on their ability to kill bacteria
• Small polypeptides (<10kDa) secreted at mucosal surfaces• Direct bacteriocidal properties• Insertion into biological membranes leading to target cell
lysis• Inhibited by cholesterol (specificity)
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QuickTime™ and aTIFF (Uncompressed) decompressor
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Hanging out with Tolstoy 1909
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In 1882, the Russian scientist Ilya Mechnikov was working in Messina, Italy, studying the larvae of the sea star. When he inserted a thorn into a larva, something weird happened. Mechnikov noticed strange cells gathering at the point of insertion. The cells surrounded the thorn, eating any foreign substances that entered through the ruptured skin. Mechnikov was thrilled. He decided to name these new cells phagocytes from the Greek words meaning "devouring cells."
Phagocytosis was discovered by Ilya Mechnikov in 1882
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Phagocytosis “cellular eating”
3. Phagosome fuses with lysosome.
1. Bacterium attaches to membrane
2. Bacterium is ingested, forming phagosome,
4. Lysosomal enzymes digest the bacteria.
5. Digested material is released from cell.
Phagocytes: macrophage, neutrophils, dendritic cells
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Phagocytes use a variety of methods to destroy ingested microbes.
(household bleach)
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Macrophage fight microbes by phagocytosis and production of toxic molecules
A macrophage produces reactive oxygen species to aid in destruction of the microbe
Reactive oxygen is revealed by the blue dye, NBT
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Innate Immunity
Innate immune effector mechanismsPhysical and biochemical barriers (defensins)Phagocytosis and reactive oxygen speciesCell autonomous defenses
ApoptosisInterferons and PKR
Innate immune recognitiondiscovery of the Toll-like receptorsmammalian TLRs and their ligandsnon-TLR recognition of PAMPs
Connections between adaptive and innate immunity
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Some microbes hijack cellular machinery to replicate and spread. Intracellular pathogens include viruses (influenza, HIV) and intracellular bacteria (listeria) and intracellular parasites (malaria, toxoplasma).
cell-autonomous defense: cell produces an immune response that acts on itself
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Apoptosis: Cellular Suicide
•Nuclear fragmentation•Proteolysis•Blebbing•Death
Remnantsundergophagocytosis
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Apoptosis versus Necrosis•Tidy: contents of cells degraded from within, producing small cellular “blebs”
•Programmed from inside the cell
•Messy: contents of cell released.
•Induced by external insult
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Cell death by necrosis is more likely to produce inflammation.
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Interferons are cytokines that are produced in response to viral infection.
Produce an “anti-viral state” in target cells.
Acts on cell that produces it, as well as neighboring cells.
Together with dsRNA, act to triggering the Protein Kinase R(PKR) pathway.
Shuts down protein synthesis machinery of cells, thus preventing viral replication.
Cells can avoid being hijacked by viruses by activating the Protein Kinase R (PKR) pathway. PKR is triggered by dsRNA and interferon.
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Protein Kinase R:Interfering with Infection
RNA-bindingdomain
Kinasedomain
dsRNAor
interferon
PKR
eIF2a
PhosphorylatedPKR
(active)
PhosphorylatedeIF2a
(inactive)
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Innate Immunity
Innate immune effector mechanismsPhysical and biochemical barriers (defensins)Phagocytosis and reactive oxygenCell autonomous defenses
ApoptosisInterferons and PKR
Innate immune recognitiondiscovery of the Toll-like receptorsTLRs and their ligandsnon-TLR recognition of PAMPs
Connections between adaptive and innate immunity
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Comparison of the adaptive and innate immune responses
innate adaptive
Response time hours days
Response to identical to primary stronger response uponrepeat infection second exposure
Receptors that pattern recognition receptors antibodies and T cell antigen receptors (TCR)Mediate pathogen Toll-like receptors (TLR)Recognition limited diversity, unlimited diversity
fixed in germline generated by V(D)J recombination
Ligands Pathogen associated molecular virtually any component of pathogenpatterns (PAMPs)