basic concepts in immunology...basic concepts in immunology rafael sirera universitat politècnica...
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Basic Concepts in Immunology
Rafael Sirera
Universitat Politècnica de València
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– Protect • Against invaders Tolerate
commensals (or mutualistic)
• From ourselves: neoplasms
– Tissue repair and remodeling • Scavenger
• Fibrosis
Physiological Role of the Immune System
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Who’s Got Immune System?
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The Immune System is a Supersystem
• Non parenchymatous cells and tissues • Work coordinately • Relationship molecules
• Membrane • Soluble
• Local and systemic effects • Activation, Proliferation (clonal expansion),
Differentiation • Genomic diversity & somatic mutation • Chekpoints & Feedbacks
• Crucial Point: Has to be prepared to fight
the unknown. • Millions of worthless clones
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Reasons for Complexity
• Eradicate the pathogen not damaging the host
• Recognize very specifically the pathogen
• Risk diversity
• Adapt the best strategy to combat each pathogen
• Immunological memory
• The need for innumerable control mechanisms for – Abrogating non necessary
responses
– Homeostasis
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• Recognition of “damaged self”: broken tissues of cells lead to the
liberation of intracellular components to the milieu
• Recognition of “microbial non-self”: molecular structures that are unique
to microorganisms and that are not produced by the host
• Recognition of “missing self”: Presence of MHC on membrane
• Recognition of “stressed self”: molecular structures expressed only on
infected or altered cells of the host
Strategies of immune recognition by innate system
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• Recognition of “self”
– Thymic polyclonal positive selection of cells that recognize self MHC
• Tolerance of “self”
– Thymic monoclonal deletion of autereactive cells (recognize self-
peptides) to prevent autoimmunity
• Recognition of “altered self”
• new molecular species expressed in transformed cells
Strategies of immune recognition by adaptive system
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• The innate immune system recognizes endogenous molecules that are produced by or released from damaged and dying cells.
– Damage-associated molecular patterns (DAMPs)
• The innate immune system recognizes molecular structures that are characteristic of microbial pathogens but not vertebrate cells.
– Pathogen-associated molecular patterns (PAMPs)
• The innate immune system uses several types of cellular receptors, present in different locations in cells, and soluble molecules in the blood and mucosal secretions to recognize PAMPs and DAMPs
– Pattern recognition receptors (PRRs)
– The innate immune system does not react against normal, healthy cells and tissues
The Specificities of Innate Immune Recognition
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Examples of DAMPs & PAPMs
Damage-Associated Molecular Patterns
Stress-induced proteins HSPs (cellular)
Nuclear proteins HMGB1
Crystals Monosodium urate, ATP
Polymers (CHO) Hyaluronan & Heparan
Pathogen-Associated Molecular Patterns Microbe Type
Nucleic acids ssRNA Virus
dsRNA Virus
CpG Virus, bacteria
Proteins Pilin Bacteria
Flagellin Bacteria
Cell wall lipids LPS Gram-negative bacteria
Lipoteichoic acid Gram-positive bacteria
Carbohydrates Mannan Fungi, bacteria
Glucans Fungi
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Apoptosis vs Necrosis
Apoptosis
Orchestrated caspase signaling
cascade leading to phagocyte
clearance of apoptotic bodies
Immunogenic endogenous molecules
are not released
Necrosis
Cellular and organelle swelling
and, most importantly, rupture of
the plasma membrane
Release of DAMPs that can elicit
an inflammatory response
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Pattern Recognition Receptors
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The Complement System
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Biological Effects of the Complement System
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• Point mutations in normal genes
• Overexpressed normal genes
• Molecular mishaps (reverse strand,
intron sequences, alternative splicing)
• Embryonic genes
• Tissue-restricted differentiation
antigens
• Translocation fusion proteins
• Viral genes
• Alternative glycosylation
Acquire Immune System in Action: Tumor Antigens
TAA TSA
Tolerance
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T cell recognition of a peptide-MHC complex
Recognition of Antigens by Adaptive Immune System
B cell recognition of free antigens
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Pathways of antigen processing and presentation
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The Antigen Presenting Cell (APC) Concept
cell populations specialized to capture
microbial and other antigens, display
them to lymphocytes, and provide
signals that stimulate the proliferation
and differentiation of the lymphocytes
• Dendritic cells
• Macrophages
• B lymphocytes
• Follicular dendritic cells (FDC)
• Thymic epithelial cells
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APC oncogenesis implications
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Role of Thymic Epithelial Cells in Self Recognition and Tolerance
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Central and peripheral tolerance
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Subsets of T lymphocytes & MHC interaction
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Immunological Synapse, Negative vs Positive Costimulation
magnitude of the
immune response
The balance
between positive
and negative
regulatory signals
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Antibody structure & Classes
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Effector Functions of Antibodies
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The Fc Receptors
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Differences among IgG subclasses for human Fcγ receptors
IgG2
IgG4
IgG1
IgG3
complementclassic
pathway
placentalcrossing
ADCC phagocitosis
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Functions of antibodies, Biotech approach
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Cellular Cooperation
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The Cytokine Network
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Classes of Lymphocytes
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Cytokines and Checkpoints Play a Master Role in
Immune System Homeostasis or Tolerance
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Conclusions
• Every single cells by presenting their own proteins is surveyed by the immune system
• Adaptive immune system receptors recognize specifically tumoral antigens
• But it is necessary a tissular alteration to trigger an immune response
• Pattern recognition receptor are scattered through the body
• The complement system is a major responsible of the cytolytic activities of antibodies
• The effector functions of antibodies relay in the constant region and not the antigen binding
site part
• The recognition of antigen is necessary but not enough to initiate an immune response.
• The immunologic synapse components and cytokines are the limiting factor for the generation
of an immune response and its quality
• Therapeutic strategies can harness the immune system to specifically target tumour cells and
this is particularly appealing owing to the possibility of inducing tumour-specific immunological
memory, which might cause long-lasting regression and prevent relapse in cancer patients.