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Transcript of Introduction to the immune system Vivekanandan Perumal [email protected] 011-26597532...
![Page 1: Introduction to the immune system Vivekanandan Perumal vperumal@bioschool.iitd.ac.in 011-26597532 Office hours Wednesday and Friday 5-6pm.](https://reader033.fdocuments.in/reader033/viewer/2022061605/5697bfd61a28abf838cadad6/html5/thumbnails/1.jpg)
Introduction to the immune system
Vivekanandan [email protected]
011-26597532Office hours Wednesday and Friday 5-6pm
![Page 2: Introduction to the immune system Vivekanandan Perumal vperumal@bioschool.iitd.ac.in 011-26597532 Office hours Wednesday and Friday 5-6pm.](https://reader033.fdocuments.in/reader033/viewer/2022061605/5697bfd61a28abf838cadad6/html5/thumbnails/2.jpg)
Immunity
• Immunity is body's ability to resist or eliminate potentially harmful foreign materials or abnormal cells
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History: what imparts Immunity?
• Emil von Behring and Kitasato (1890)– Serum from vaccinated animals was protective
(diptheria)
• Metchinkoff (1880)– Cell based Immunity
• Merrill Chase (1940)- Transfer of WBC (immunity to tuberculosis)
Both serum and cells contribute to immunity
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Immunology- nobel prizes
• Since 1901 there have been 19 Nobel Prizes for immunology-related research.
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The immune system
A functional system – NOT an organ system:
Complex system – includes• Skin – physical barrier• Lining of mucus membranes – physical barrier• Secretions – tears, mucus etc - antimicrobial• Blood cells and vasculature – WBCs• Bone marrow• Liver – makes complement proteins• Lymphatic system and lymphoid organs• Most tissues – have resident immune cells
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Immunity • Immunity (immunis- Latin-exempt, state of protection from
infectious diseases)• Immunity is body's ability to resist or eliminate potentially
harmful foreign materials or abnormal cells • consists of following activities:
– Defense against invading pathogens (viruses & bacteria) – Removal of 'worn-out' cells (e.g., old RBCs) & tissue debris (e.g.,
from injury or disease) – Identification & destruction of abnormal or mutant cells (primary
defense against cancer) – Rejection of 'foreign' cells (e.g., organ transplant) – Inappropriate responses:
• Allergies - response to normally harmless substances • Autoimmune diseases
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The Immune System
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Overview of the Immune System
Immune SystemInnate(Nonspecific)
1o line of defense
Adaptive(Specific)2o line of defense
Interactions between the two systems
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A typical immune response
INNATE IMMUNITY Rapid responses to a
broad range of microbes
ACQUIRED IMMUNITYSlower responses to
specific microbes
External defenses Internal defenses
Skin
Mucous membranes
Secretions
Phagocytic cells
Antimicrobial proteins
Inflammatory response
Natural killer cells
Humoral response(antibodies)
Cell-mediated response(cytotoxic lymphocytes)
Invadingmicrobes
(pathogens)Complement
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Innate immunity vs Adaptive Immunity
No memory
• No time lag
• Not antigen specific
• A lag period
• Antigen specific
• Developmentof memory
Innate Immunity(first line of defense)
Adaptive Immunity(second line of defense)
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The innate immune System
Innate Immune SystemExternal defenses
Internal defenses
Interactions between the two systems
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Innate immune system External defenses
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Anatomical Barriers - Mechanical Factors
• Skin
• Flushing action of saliva, tears, urine
• Mucociliary escalator
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Anatomical Barriers – Chemical factors
Antimicrobial Peptides in sweat
Lysozyme in tears /salivaHCl in stomach
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Anatomical Barriers – Biological factors
Normal flora – microbes in many parts of the body
Normal flora – competes with pathogensfor nutrients and space
Normal flora – > 1000 species of bacteria
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Innate immune system internal defenses
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Innate immune system: components of Blood
Complement proteins
Coagulation proteins
Cytokines
WBCs
Extracellular
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White blood cells (WBCs)Macrophages
B-lymphocytes
T-lymphocytes
Natural killer(NK) cells
Mast cells
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Neutrophils in innate immune response
• Most abundant WBCs (~50-60%)
• Efficient phagocytes
• Most important cells of the innate immune system
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Phagocytosis
• Phago = to eat• Cyte = cell
• WBCs (eg. Neutrophils) – find, eat and digest microbes !
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How do neutrophils find microbes ?
• https://youtu.be/I_xh-bkiv_c
• https://www.youtube.com/watch?v=ZUUfdP87Ssg
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How do neutrophils eat and digest microbes ?
Granules
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What’s in the granules ?
Lysozyme – digests bacterial cell wall; other antimicrobial proteins
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Additional role of neutrophils
Triggers inflammatory response
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Monocytes
• Monocytes (~5% of WBCs)
• Migrate into the tissues and become Macrophages
Lung Bone
Liver Brain intestine
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Macrophages
• “Big eaters”
• Phagocytosis of microbes in tissue (neutrophils are present only in blood)
• Antigen presentation
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Natural killer cells
• Not B-lymphocytes / T-lymphocytes
• Important part of the innate immune system
• Kill virus /bacteria infected cells (Intracellular pathogens)
• Kills cancer cells
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NK cells differentiate choose cells to kill ?
Uninfected cell / Normal cell
Microbe infected cell / cancer cell
Some cell surface proteins are missing
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How does the killer kill ?
Kills both host cells and microbes
Release of granules with perforins and proteases
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Toll-like receptors (TLRs)
• Transmembrane proteins
• Present on macrophages / few other cells
• Conserved across vertebrates
• Important part of innate immune system
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TLRs – What do they do ?
They look out for microbes (or their components)
They bind to the microbes (or their components)
They trigger a cascade of events to kill or protect against pathogens
THEY ARE INNATE IMMUNE SENSORS
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TLRs – look out for microbes
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TLRs – bind to microbes / components of microbes
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Which microbial components are recognized by TLRs ?
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What happens when a TLR bind to a microbe ?
TLR binding to microbe
Inflammation
Secretion of Cytokines / Interferon
Phagocytosis of infected
cell
Apoptosis of infected cell
Enhanced immune
response
Killing of infected
cell
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Summary: innate response – internal defenses – Cellular (WBCs)
Come into play when the external defenses are breached
• Neutrophils
• Monocytes /macrophages
• NK cells
• TLRs
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Innate immune system: components of Blood
Complement proteins
Coagulation proteins
Cytokines
WBCs
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Cytokines
• Small proteins – secreted by cells of the immune system
• Affect the behaviour of other cells
• signalling molecules
• Key players in innate and acquired immunity
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Which cells release cytokines ?
Cells of the immune system:
• Neutrophils – when they encounter a pathogen
• Macrophages – when they encounter a pathogen
• TLRs – bind to microbe / components of a microbe
• NK cells – on encountering a microbe infected cell /tumour cell
• Lymphocytes – when they are activated
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Examples of cytokines
• Interferons
• Interleukins
• Tumour necrosis factor (TNF)
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Interferons (IFN)
• Signalling proteins produced by by virus infected monocytes and lymphocytes
• Secreted proteins – Key anti-viral proteins
• “Interfere” with virus replication
• Warn the neighbouring cells that a virus is around...
• If we did not have IFNs – most of us may die of influenza virus infection
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How does IFN warn the neighbouring cells ?
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The infected cells release IFN
antiviral stateantiviral state
antiviral state
antiviral state
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Virus infects the neighbouring cells
antiviral stateantiviral state
antiviral state
antiviral state
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Prewarned cells are able to quickly inhibit the virus
antiviral stateantiviral state
antiviral state
antiviral state
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How do interferons inhibit viruses ?
Host protein
Induction
Cascade of events
Virus ds-RNAActivation
Inactive host protein
Active host protein
Inhibition of host protein
synthesis
Virus cannot replicate
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Interleukins
• Interleukins – 1-37
• Not stored inside cells
• Quickly synthesized and secreted in response to infection
• Key modulators of behaviour of immune cells
• Mostly secreted by T-lymphocytes & macrophages
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What to interleukins do ?
Interleukins
Proliferation of immune cells
Activation of immune cells
Increase antibody production Inflammation
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Tumour necrosis factor (TNF)
TNF
Killing of cancer Fever Inflammation
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Complement (C`)
• a large number of distinct plasma proteins that react with one another (C1 thro’ C9)
• Complement can bind to microbes and coat the microbes
• Essential part of innate immune response
• Enhances adaptive immune resposne (taught later)
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Complement proteins: role in innate immune system
C`proteins
Inflammation Facilitates phagocytosis Direct lysis of pathogens
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How do C` proteins facilitate phagocystosis ?
Bacteria coated with C` Neutrophils have C` receptors
Initiation of phagocytosis
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How do C` proteins lyse pathogens?
Membrane attack complex formed by c` proteins
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Coagulation proteins
• Coagulation: mechanism to stop bleeding after injury to blood vessels
Complex pathway involves• Platelets• Coagulation factors• Vitamin K
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How does blood clot ?
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Coagulation: Delicate balance
Coagulation proteins Anticoagulants
Blood clottingInflammationApoptosis (prog. Cell death)
Prevent blood clottingInhibit inflammationInhibit apoptosis
Too much of clotting – Problem Too little clotting - Problem
Maintenance of a balance
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Coagulation and innate immunity
Coagulation proteins
Anticoagulants
Pathogens and cytokines
Increased inflammation and increased apoptosis of infected cells
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Summary: what happens when external defenses fail ?
INNATE IMMUNITY Rapid responses to a
broad range of microbes
ACQUIRED IMMUNITYSlower responses to
specific microbes
External defenses Internal defenses
Skin
Mucous membranes
Secretions
Phagocytic cells
Antimicrobial proteins
Inflammatory response
Natural killer cells
Humoral response(antibodies)
Cell-mediated response(cytotoxic lymphocytes)
Invadingmicrobes
(pathogens)Complement
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Summary: innate response – internal defenses
Cellular
• Neutrophils
• Monocytes /macrophages
• NK cells
• TLRs
Extracellular
• Cytokines
• Complement
• Coagulation
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Introduction to the immune system
Vivekanandan [email protected]
011-26597532Office hours Wednesday and Friday 5-6pm
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Immunology: lecture 3
InflammationAntigensAntibody
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Inflammation
• Complex biological process by which body responds to pathogens and irritants
• Associated with swelling of tissue
• Key player in innate immune repsone
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All roads lead to inflammation
Inflammation
Neutrophils
Monocytes /macrophages
NK cells
TLRsCytokines /IFN
C` proteins
Coagulation proteins
Cellular Extracellular
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Inflammation and vascular changes
• Vasodilatation • Increased capillary permeability
Normal blood vessel Dilated blood vessel
Normal blood vessel
Leaky blood vessel
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Signs of inflammation
Vascular changes
Vasodilatation Capillary permeability
Heat / redness
Temporary loss of
functionFever
Swelling Pain
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Signs of inflammation
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Inflammation and innate immunity
Mast cells – similar to basophils in blood; mast cells are present in tissues and release histamines in response to wound / infection /irritant
Histamine
Pathogen removal
Adaptive immune response
+ + +
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Summary: role of Inflammation in innate immunity
• Initiation of phagocytosis – killing of pathogen
• Limiting the spread of infection
• Stimulate adaptive immune response
• Initiate tissue repair
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Not everything about Inflammation is good
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The good and bad about inflammation
Acute /short-term -Good chronic /long-term - Bad
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Chronic inflammation = tissue damage
• Chronic inflammation - macrophages in the injured tissue.
• Macrophages release toxins (including reactive oxygen species or ROS) that injure tissues
• chronic inflammation is almost always accompanied by tissue destruction.
Normal tissue
Tissue : chronic inflammation
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Chronic inflammation and tissue damage
Reduced tissue
function
Tissue damage
Chronic inflammation
Activation of immune cells
Killing of host cells
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Chronic inflammation and Cancer
ROSO2
- OH-
DNA Mutation
Cancer
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Immunogens / Antigens
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Immunogens and antigens
• Immunogen / antigen: a substance that elicits an immune response [i.e. a humoral (antibody response) or cell-mediated immune response]
Immune response generator
Though the two terms are used interchangeably – there are differences between the two
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Epitope
• Epitope: the portion of an antigen that is recognized and bound by an antibody (Ab) or a T-cell receptor (TCR)
• epitope = antigenic determinant
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Epitopes
•Epitope: the portion of an antigen that is recognized and bound by an Ab or a T Cell receptor
One protein may have multiple antigenic determinant
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Epitopes
• B-cell Epitopes – recognized by B-cells
• T-cell Epitopes – recognized by T cells
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Immunogenicity
• Immunogencity: is the ability to induce a humoral (antibody) and/or cell-mediated immune response.
• Weak immunogens • Strong immunogens
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What determines immunogenicity ?
• Foreignness: essential for immunogenicity (self-responsive immune cells are eliminated during lymphocyte development)
• Size: Bigger>Smaller
• Chemical composition: Proteins > nucleic acids / polysaccharides / lipids
• Structure: Primary /secondary /tertiary structures play a role
• Physical form: Particulate> Soluble
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Host factors affecting immunogencity
• Difference across species (interspecies)
• Differences within a species (intraspecies) - Responders / non-responders to vaccine - differences in disease severity in epidemics
Genetics
Age
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Isoantigens
• Isoantigens: Antigens present in some but not all members of a species
• Blood group antigens – basis of blood grouping
• MHC (major histocompatibility complex)- cell surface glycoproteins
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Autoantigens
• Autoantigens are substances capable of immunizing the host from which they are obtained.
• Self antigens are ordinarily non-antigenic
• Modifications of self-antigens are capable of eliciting an immune response
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Haptens
• Haptens are small molecules which are non-immunogenic, thus could never induce an immune response by themselves.
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Examples of haptens
DO NOT ELICIT an immune response by themselves
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Immunogens / Antigens
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What is an antibody?
• Produced by Plasma cell (B-lymphocytes producing Ab)
• Essential part of adaptive immunity
• Specifically bind a unique antigenic epitope (also called an antigenic determinant)
• Possesses antigen binding sites
• Members of the class of proteins called immunoglobulins
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What does an antibody look like ?
• 2 identical heavy chains • 2 identical light chains
• Each heavy chain – has a constant and a variable region
• Each light chain has a constant and a variable region
H H
L L
Con
stan
t reg
ion
V
aria
ble
regi
on
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Antibody: structure and function
• Fab – fragment antigen binding
• Fc- Fragment constant
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Antibody: Fab
Fab region• Variable region of the
antibody
• Tip of the antibody
• Binds the antigen
• Specificity of antigen binding determined by
VH and VL
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Antibody: Fc
Fc region• Constant region
• Base of the antibody
• Can bind cell receptors and complement proteins
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• Antibodies occur in 2 forms
– Soluble Ag: secreted in blood and tissue
– Membrane-bound Ag: found on surface of B-cell, also known as a B-cell receptor (BCR)
Antibodies exist in two forms