basic concepts in immunology...basic concepts in immunology rafael sirera universitat politècnica...

Basic Concepts in Immunology

Rafael Sirera

Universitat Politècnica de València

– Protect • Against invaders Tolerate

commensals (or mutualistic)

• From ourselves: neoplasms

– Tissue repair and remodeling • Scavenger

• Fibrosis

Physiological Role of the Immune System

Who’s Got Immune System?

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

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

• 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

• 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

• 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

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

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

Pattern Recognition Receptors

The Complement System

Biological Effects of the Complement System

• 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

T cell recognition of a peptide-MHC complex

Recognition of Antigens by Adaptive Immune System

B cell recognition of free antigens

Pathways of antigen processing and presentation

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

APC oncogenesis implications

Role of Thymic Epithelial Cells in Self Recognition and Tolerance

Central and peripheral tolerance

Subsets of T lymphocytes & MHC interaction

Immunological Synapse, Negative vs Positive Costimulation

magnitude of the

immune response

The balance

between positive

and negative

regulatory signals

Antibody structure & Classes

Effector Functions of Antibodies

The Fc Receptors

Differences among IgG subclasses for human Fcγ receptors

IgG2

IgG4

IgG1

IgG3

complementclassic

pathway

placentalcrossing

ADCC phagocitosis

Functions of antibodies, Biotech approach

Cellular Cooperation

The Cytokine Network

Classes of Lymphocytes

Cytokines and Checkpoints Play a Master Role in

Immune System Homeostasis or Tolerance

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.