Workshop on Infectious Disease Ontology

Introduction to the Human Immune System

>90% of the cells in/on our body are bacterial –10 13 human cells in our body –10 12 bacteria on the skin –10 10 bacteria in the mouth –10 14 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 T H cell activation of macrophages BCR 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

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Cells of innate immunity !

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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 cells Macropinocytosis 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 cells and 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 Macrophages Neutrophils Dendritic cells Phagocytosis Cell-associated pattern recognition receptors 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 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

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Figure 9-9 part 1 of 2

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Figure 9-12 Germinal Center Reaction (Affinity Maturation)

Motility: two-photon microscopy Experiments to study motility. Mike Cahalan UC 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?

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B cell ReceptorT cell Receptor

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Antibody Neutralization Complement activation Induction of phagocytosis

Figure 8-27 T helper cells Activate macrophages and B cells

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Dendritic cells Adaptive Immune Response T lymphocyte B lymphocyte T helper cellCytotoxic T cell Plasma cell Antibody Neutralization Complement activation Induction of phagocytosis Macrophage activation killing

Dendritic Cells Antigen Receptors T H cell activation of macrophages BCR 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.

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Ag processing and presentation

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Figure 1-28 MHC I loading

Figure 1-29 MHC II loading

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Maintenance of Self Tolerance Clonal Deletion Anergy Requirment for co-stimulatory molecules

V(D)J Recombination generation 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 receptor B cell receptor (immunoglobulin, antibody), T cell receptor

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B cell ReceptorT cell Receptor

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Figure /23 Rule