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 8-27T 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 1-29

MHC 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