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Workshop on Infectious Disease Ontology. http://www.bioontology.org/wiki/index.php/Infectious_Disease_Ontology. Introduction to the Human Immune System. The immune system serves as an interface between host and microorganisms. >90% of the cells in/on our body are bacterial - PowerPoint PPT Presentation
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Workshop on Infectious Disease Ontology
http://www.bioontology.org/wiki/index.php/Infectious_Disease_Ontology
Introduction to the Human Immune System
• >90% of the cells in/on our body are bacterial – 1013 human cells in our body– 1012 bacteria on the skin– 1010 bacteria in the mouth– 1014 bacteria in the gastrointestinal tract
• much of the DNA in the human genome is of viral origin
• 10% of your body weight is microbial
The immune system serves as an interface between host and microorganisms.
• commensals (normal microflora)– We provide warmth, moisture, glucose,
amino acids.– They aid in the digestion of cellulose.– They stimulate capillary growth and
development of mucosal immunity.– Protect us from pathogenic
microorganisms.
• Parasites (pathogens)
The immune system serves as an interface between host and microorganisms.
Organism: vast number of coupled biochemical networks organized as modules.
Commensals and parasites: mobile modules.
Different types attach to a different piece of our network:•Bacteria have plugged into our metabolic network•Viruses use our replicative network
Commensalism and parasitism
•Generation times:•Human: ~ 25 years•Microbe: ~ hours to days
•The constraint of multi-cellularity•Our cells have evolved special functions and must cooperate with each other.•Prokaryotes and viruses are not constrained this way. They have evolutionary flexibility.
Human versus microbial evolvability
The immune system is an interface between multi-cellular organization and unicellular autonomy, a
reversion back to a prokaryotic system of organization.
Unicellular lifestyle
Extreme somatic diversification
Rapid adaptation
Immune Specificity
Somatic diversification
Immune Memory
Innate Immunity
Adaptive Immunity
Conferred by proteins whose genes are inherited
Conferred by proteins whose genes are somatically diversified
Innate Immunity
Adaptive Immunity
Somatically diversified receptor genes
Proteins recognize pathogen-specific epitopes
Inherited receptor genes
Proteins recognize evolutionarily conserved patterns
•Can adapt – requires exposure•Provide specificity and memory
•Always ready – respond immediately•Provide constant surveillance
Pattern Recognition Receptors Antigen Receptors
Pathogen-associated Molecular Patterns
Antigen
•Epithelial barriers•Phagocytic cells (neutrophils, macrophages, dendritic cells)•Pattern recognition receptors•NK cells•Complement system
•B lymphocytes•T lymphocytes•Antigen receptors•Antibodies
Dendritic Cells
Antigen Receptors
TH cell activation of macrophagesBCR marking of pathogen for phagocytosis and complement
Innate Immune
System
Detect pathogen
Adaptive Immune
System
Confer immune specificity and memory
Dendritic cell activation of T lymphocytes
Components of the Immune System and their Role in Immune Responses
Figure 1-3
Cells of innate immunity
!
Figure 1-3
Primary lymphoid tissue
Secondary lymphoid tissue
Importance of unicellular lifestyle
Innate Immune Response
Components of the Immune System and their Role in Immune Responses
Figure 2-4
Epithelial Barriers:what happens after a breach?
the immune response
Macrophages and immature dendritic cells are resident in tissues.
Phagocytosis by macrophages and dendritic cellsMacropinocytosis by immature dendritic cells.
Communication: cytokines and chemokines
Inflammation and Recruitment
The adaptive immune response is initiated by the recognition of non-self by the innate system.
Adjuvant: material added to innoculum to stimulate the innate immune system.
Expressed on:•Macrophages•Neutrophils•immature dendritic cellsand are secreted.
Receptors of the innate immune system recognize features common to many pathogens (repeated patterns).
Stimulate:•Ingestion of pathogen•Expression of co-stimulatory molecules, cytokines, chemokines
C-type lectins (carbohydrate-binding):•Mannose receptor: recognizes particular orientation and spacing of certain sugar residues•Dectin: binds glucans present in fungal cell walls
Scavenger receptors: 6 forms; recognize anionic polymers and acetylated low-density lipoproteins.
Chemotactic receptors: for example, the Met-Leu-Phe receptor on neutrophils that binds N-formylated peptides produced by many bacteria and guides neutrophils to the site of infection.
Four main types of cell-associated receptors:
toll-like receptors of innate immunity
Innate Immune System
Epithelial barriers
Soluble pattern recognition receptors
MacrophagesNeutrophilsDendritic cells
PhagocytosisCell-associated
pattern recognitionreceptors
Chemokine secretion
Cytokine secretion
Initiation of Adaptive Immune Response
Innate Immune System
•Initial response to microbes (surveillance and detection of non-self)•Recognizes structures characteristic of microbial pathogens
•Not on mammalian cells•Necessary for survival of microbe
•Receptors are encoded in germline DNA•will also recognize stressed or injured tisssue
Stimulates adaptive response and can influence its nature
Adaptive Immune Response
Components of the Immune System and their Role in Immune Responses
The specificity of the adaptive immune system is mediated by antigen receptors:•B cell receptor (BCR), immunoglobulin (Ig), antibody (Ab)•T cell receptor (TCR)
Each developing lymphocyte expresses a unique antigen receptor whose gene was somatically generated.
In any individual, the naïve lymphocyte population has a highly diverse antigen receptor repertoire.
How do we get them activated?
The adaptive immune response is initiated by the recognition of non-self by the innate system.
Adjuvant: material added to innoculum to stimulate the innated immune system.
• Naïve lymphocyte encounters mature dendritic cell.• Lymphocyte stops re-circulating, becomes a lymphoblast.• 1 lymphoblast can give rise to ca. 1000 daughter cells.• B cells undergo somatic diversification of the
immunoglobulin genes (somatic hypermuation)• Lymphocytes differentiate to become effector cells:
• B cells plasma cells• T cells cytotoxic T cells or helper T cells
• Activation induces changes in cell-adhesion molecules• Cells execute their effector functions.• Contraction of the response: a small number of effector
cells remain as memory cells.
Adaptive Immune Response
Figure 8-4
Figure 9-9 part 1 of 2
Figure 9-11
Figure 9-12Germinal Center Reaction
(Affinity Maturation)
Motility: two-photonmicroscopy
Experiments to study motility.
http://crt.biomol.uci.edu/index.html
Mike CahalanUC Irvine
Mike cahalan videos. I plan on 3 but maybe 4. they run fast.
Dendritic cells
Adaptive Immune Response
T lymphocyte
B lymphocyte
T helper cellCytotoxic T cell
Plasma cell
Antibody
What effector functions?
Figure 1-16
Figure 1-17
B cell Receptor T cell Receptor
Figure 3-8
Antibody
NeutralizationComplement activationInduction of phagocytosis
Figure 8-27 T helper cells
Activate macrophagesand B cells
Figure 8-31
Dendritic cells
Adaptive Immune Response
T lymphocyte
B lymphocyte
T helper cellCytotoxic T cell
Plasma cell
Antibody
NeutralizationComplement activationInduction of phagocytosis
Macrophage activationkilling
Dendritic Cells
Antigen Receptors
TH cell activation of macrophagesBCR marking of pathogen for phagocytosis and complement
Innate Immune
System
Detect pathogen
Adaptive Immune
System
Confer immune specificity and memory
Dendritic cell activation of T lymphocytes
Adaptive Immune System
•Initiated by innate system•Diverse set of receptors (somatic diversification)•Recognizes pathogen-specific epitopes (immune specificity)•Clonal expansion followed by contraction of the immune response•Immune memory•Specialization for extracellular and intracellular pathogens
Maintenance of Self Tolerance
Generation of BCR and TCR genes: V(D)J recombination
BCR genes undergo additional diversification: somatic hypermutation
Maintenance of self tolerance
TCR: Antigen processing and presentation
Clonal Selection Hypothesis
Somatic Diversification
Clonal Selection Hypothesis
proposed to explain the observation that antibodies are only produced in an individual against antigens to which the person has been exposed.
Figure 1-15
Ag processing and presentation
Figure 1-27
Figure 5-17
Figure 3-20
Figure 3-21
Figure 1-28MHC I loading
Figure 1-29MHC II loading
Figure 5-2
Maintenance of Self Tolerance
• Clonal Deletion• Anergy• Requirment for co-stimulatory molecules
V(D)J Recombinationgeneration of antigen receptor genes
•Large number of pathogens•Evolve more rapidly than humans•Somatic variation of immunogenic proteins
•V(D)J recombination•Somatic hypermutation•Gene conversion
Highly Diverse Repertoire of Antigens
Highly Diverse Repertoire of Antigen Receptors
Antigen, antigen receptorB cell receptor (immunoglobulin, antibody), T cell receptor
Figure 3-11
B cell Receptor T cell Receptor
Figure 3-5
Figure 3-7
Figure 4-2
Figure 3-7
Figure 4-4
Figure 4-7
Figure 4-8
Figure 4-5
12/23 Rule