Transcript Introduction_to_the_Human_Immune_System

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
–
–
–
–
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)
Commensalism and parasitism
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
Human versus microbial evolvability
•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.
The immune system is an interface between multicellular 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
Conferred by proteins
whose genes are inherited
Innate
Immunity
Conferred by proteins whose
genes are somatically diversified
Adaptive
Immunity
Innate
Immunity
Adaptive
Immunity
Inherited receptor genes
Somatically diversified receptor genes
Proteins recognize evolutionarily
conserved patterns
Proteins recognize pathogen-specific
epitopes
•Always ready – respond immediately
•Provide constant surveillance
Pattern Recognition
Receptors
Pathogen-associated
Molecular Patterns
•Can adapt – requires exposure
•Provide specificity and memory
Antigen Receptors
Antigen
•Epithelial barriers
•Phagocytic cells (neutrophils,
macrophages, dendritic cells)
•Pattern recognition receptors
•NK cells
•Complement system
•B lymphocytes
•T lymphocytes
•Antigen receptors
•Antibodies
Dendritic cell activation of T lymphocytes
Dendritic Cells
Detect pathogen
Innate Immune
Adaptive Immune
System
System
Confer immune
specificity and memory
Antigen Receptors
TH cell activation of macrophages
BCR marking of pathogen for phagocytosis and complement
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
Components of the Immune System
and their Role in Immune Responses
Innate Immune Response
Figure 2-4
Epithelial Barriers:
what happens after a breach?
the immune response
Macrophages and
immature dendritic cells
are resident in tissues.
Communication: cytokines
and chemokines
Phagocytosis by macrophages
and dendritic cells
Macropinocytosis by immature
dendritic cells.
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.
Receptors of the innate immune system recognize
features common to many pathogens (repeated patterns).
Expressed on:
•Macrophages
•Neutrophils
•immature dendritic cells
and are secreted.
Stimulate:
•Ingestion of pathogen
•Expression of co-stimulatory molecules, cytokines,
chemokines
Four main types of cell-associated receptors:
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.
toll-like receptors of innate immunity
Innate Immune System
Epithelial barriers
Soluble pattern recognition receptors
Phagocytosis
Cell-associated
pattern recognition
receptors
Macrophages
Neutrophils
Dendritic cells
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
Components of the Immune System
and their Role in Immune Responses
Adaptive Immune Response
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.
Adaptive Immune Response
•
•
•
•
•
•
•
•
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.
Figure 8-4
Figure 9-9 part 1 of 2
Figure 9-11
Germinal Center Reaction
(Affinity Maturation)
Figure 9-12
Experiments to study motility.
Motility: two-photon
microscopy
Mike Cahalan
UC Irvine
http://crt.biomol.uci.edu/index.html
Mike cahalan videos. I plan on 3 but maybe 4. they run fast.
Adaptive Immune Response
Dendritic cells
T lymphocyte
Cytotoxic T cell
T helper cell
B lymphocyte
What effector functions?
Plasma cell
Antibody
Figure 1-16
Figure 1-17
B cell Receptor
T cell Receptor
Figure 3-8
Antibody
Neutralization
Complement activation
Induction of phagocytosis
Figure 8-27
T helper cells
Activate macrophages
and B cells
Figure 8-31
Adaptive Immune Response
Dendritic cells
T lymphocyte
Cytotoxic T cell
killing
T helper cell
Macrophage activation
B lymphocyte
Plasma cell
Neutralization
Complement activation
Induction of phagocytosis
Antibody
Dendritic cell activation of T lymphocytes
Dendritic Cells
Detect pathogen
Innate Immune
Adaptive Immune
System
System
Confer immune
specificity and memory
Antigen Receptors
TH cell activation of macrophages
BCR marking of pathogen for phagocytosis and complement
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
Somatic Diversification
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
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
MHC I loading
Figure 1-28
MHC II loading
Figure 1-29
Figure 5-2
Maintenance of Self Tolerance
• Clonal Deletion
• Anergy
• Requirment for co-stimulatory molecules
V(D)J Recombination
generation of antigen receptor genes
Antigen, antigen receptor
B cell receptor (immunoglobulin, antibody), T cell receptor
Highly Diverse Repertoire of Antigens
•Large number of pathogens
•Evolve more rapidly than humans
•Somatic variation of immunogenic proteins

Highly Diverse Repertoire of Antigen Receptors
•V(D)J recombination
•Somatic hypermutation
•Gene conversion
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