Download Modeling the Immune System

An Introduction to
Modeling the Immune System
School of Computer and Communication Sciences
EPFL, SS 2007-08
http://swis.epfl.ch/teaching/modeling_immune_system/
Master “Modelling the immune system”
Aims
The aims of this Master course are:
‰ Understand the immune system in order to model it
‰ Acquire knowledge about the tools required to model the immune system
‰ Review how the models can be used, what types of questions can be
addressed, and what technical problems are encountered.
‰ Forster collaboration between the modelers and the biologists.
Master “Modelling the immune system”
Staff
‰ The lecturers
¾ Immunologists:
Nathalie Debard
Jean-Pierre Kraehenbuhl
HSeT
HSeT
¾ Modelers:
Alcherio Martinoli
(Jean-Yves Le Boudec
EPFL
EPFL; sabbatical)
‰ Teaching assistant
Irina Baltcheva
EPFL
Master Course outline
mmunology ‰ Part I: the Immune System ( weeks 1 to 7) (ND,JPK)
Tool box
Date
Teacher
Cours
Online activity
20 Feb
JPK
Basic concepts in Immunology
none
27 Feb
JPK
Innate Immunity
Exercises: introduction
05 March
JPK/ND
12 March
JPK
Antigen presentation
none
19 March
JPK
T cell immunity
none
02 April
JPK
B cell immunity
Article-Based Learning: introduction
09 April
JPK/ND
Students’ presentations
Students’ presentations
‰ Part II: modeling toolbox (weeks 8 to 11) (AM, IB)
¾ You already know most of them
¾ The necessary background will be reviewed
ƒ Non-spatial, macroscopic deterministic models
ƒ Non-spatial, macroscopic stochastic models
ƒ Microscopic and spatial models
¾ Simulation issues
¾ Article-based learning
Master Course outline
Case studies ‰ Part III: Case Studies (weeks 12 to 14)
Evaluation
¾ Short introduction
¾ Student seminar:
¾ You chose one paper, study it, re-implement the results in a critical
fashion, submit a report, and final defense
¾ You will review the work of another team (report and defense)
¾ Teams of 1 or 2 students (recommended)
‰ Evaluation
¾ Course project (40%) + oral exam (60%)
¾ Course project: 40% report, 40% defense, 20% review
¾ Assisted exercises during the semester not graded (dry-run exercises
for course project and oral exam)
Why Modeling the Immune System ?
Aims
‰ The Immune System provides protection against microbes and cancer cells &
allows individual to survive in a hostile microbe-rich environment
‰ The immune system is a complex, networked, multi-component system
What is Modeling ?
‰ Apply mathematical and computational methods to understand the behavior
of a complex interaction
‰ To do a good modeling study you need to both
¾ Master mathematical and computational methods
¾ Understand the system you are modeling
A note on Web Sites
Main
Support
Support
‰ http://swis.epfl.ch/teaching/modeling_immune_system/
¾ Public visibility and material (course presentation, lectures, assignments)
¾ Entry point for student area (moodle)
¾ Archive of past editions (not ready yet)
‰ http://moodle.epfl.ch/course/view.php?id=229
¾ Moodle
¾ Modeling and biology assignments; upload, download files
¾ Forums: exercises/projects; general announcements
¾ Initial access: course key
¾ Further access: usual gaspar login
‰ http://epfl.bio-med.ch/
¾ Immunology Online
¾ E-learning of immunology
¾ Protected, full access via login request (different from gaspar)
¾ Unprotected, partial access via assignment hyperlinks in moodle
Defence against infection
Three lines
of defence
Epithelial
barrier
First line of defense
Second line of defense
nnate
mmunity
Adaptive
mmunity
‰ Invertebrates & vertebrates are
continuously exposed to microbes
‰ Some microbes are beneficial for
their host, other use strategies
to establish their niches that are
deleterious to the host.
‰ Defence mechanisms protect the host:
¾ the first and second lines of defence (epithelial barriers
and innate immunity are common to invertebrates and
vertebrates
¾ the third line (adaptive immunity) is specific to vertebrates
Third line of defense
First line of defence: the epithelial barriers
Epithelial barriers ‰ All body surfaces in
contact with the
environment are covered
by epithelial tissues
‰ Epithelial tissues are
made of cells that
separate 2 compartments
‰ Epithelial tissues
constitute a first line of
defense through
¾ physical factors
¾ chemical factors
¾ immunological
factors
First line of defence: the epithelial barriers
Physical
barrier
‰ Stratified epithelia:
¾ multiple cell layers
¾ rapid cell turn over
‰ Simple epithelia:
¾ membrane specialization
¾ mucus secretion
¾ rapid cell turn over
First line of defence: the epithelial barriers
Chemical
barrier
lumen
Epithelium
‰ Microbicidal peptides that disrupt bacterial cell walls:
α defensins (Paneth cells) and β defensins (epithelial cells)
Lamina propria
‰ Proteins that sequester iron and zinc: lactoferrin (goblet cells)
‰ Enzymes produced by mucus cells that hydrolyze components of bacteria cell walls:
lysozyme,
phospholipase A2
Second line of defence: innate immunity
Role of the
epithelial cells
& leukocytes
nnate immune responses
occur in two sequential
steps:
¾ the recognition of the
disease-causing agent.
¾ the immediate activation
of defensive effector
mechanisms to
eradicate it.
Both events take place
at the disease site.
The innate immune system is an evolutionary ancient form of host defense
that exists throughout the animal kingdom.
It consists of :
‰ a wide variety of cells
¾ circulating in the blood
& scattered in organs
Macrophages
Mast cells Neutrophils
¾ forming tissues
that separate the outside
from the inside world
‰ molecules produced by
innate immune cells or the liver.
¾ acute phase proteins
¾ complement
¾ cytokines & chemokines
The complement
¾ Disruption of microbes by
osmotic cell lysis
Killing
¾ Opsonization: coating microbes
with complement and clearance
by phagocytosis
¾ vascular changes
(dilatation & increased
Recruitment
permeability)
of killers
¾ chemotaxis
(leukocyte attraction)
Third line of defence: adaptive immunity
Adaptive
immunity
Features of the adaptive immune system
‰ A host defence unique to vertebrates,
‰ Important for the survival of individuals over the long term.
‰ Mobilizes defences that are adapted to each specific disease-causing agent
‰ Retains a “memory” of previous encounters
¾ allows to mount rapid and efficient defences when and if the agent reappears.
¾ increases the likelihood that individuals will survive to reproductive age.
The adaptive immune system consists of:
¾ cells called lymphocytes.
¾ molecules that lymphocytes produce, including antibodies "cytokines".
¾ organs called lymphoid organs where lymphocytes divide and
reproduce, mature, and perform some of their functions.
Lymphocytes migrate in and out of lymphoid organs.
Cells &
molecules
mediating
adaptive
responses
Third line of defence: adaptive immunity
T and B lymphocytes
¾ Lymphocytes are the primary cells of the
adaptive immune system.
¾ They are formed in primary lymphoid organs
in a process called lymphopoiesis.
¾ They express unique surface receptors to
detect antigen, in a way that endows each
lymphocyte with a structurally unique
receptor that recognizes only a particular
chemical structure called antigen.
Cells &
molecules
mediating
adaptive
responses
Third line of defence: adaptive immunity
T and B lymphocytes
Unique features:
¾ Generation of the immune repertoire associated
to the naïve lymphocytes
¾ Distribution of the naïve lymphocytes in the
secondary lymphoid organs where they
encounter antigens
¾ Distribution of the effectors cells where they
have to control invading microbes
Lymph nodes
Spleen
MALT
Third line of defence: adaptive immunity
Cells &
molecules
mediating
adaptive
responses
molecules
¾ cytokines produced by B and T lymphocytes
¾ antibodies produced by B lymphocytes
2 forms:
• membrane bound: receptor
• secreted: antibody
Structure
Function
Cells &
molecules
mediating
adaptive
responses
Third line of defence: adaptive immunity
molecules
antibodies
cytokines
¾promote T cell growth.
¾promote antibody production.
¾activate lymphocytes & macrophages
They include:
¾ Interleukins
¾ interferons
¾ chemokines
Third line of defence: adaptive immunity
The adaptive
Mounting an adaptive immune response requires:
esponse
1. A recognition phase: recognition
of the pathogen or other foreign material
by lymphocytes
2. An activation phase, whereby
antigen-specific lymphocytes
receive a co-stimulatory signal to
proliferate and differentiate into
effector cells.
3. The clonal expansion of the
antigen-specific lymphocytes.
4. The effector phase, during which
effector lymphocytes are dispatched
to the sites of antigen entry.
5. The contraction phase which
occurs following clearance of the antigen.
6. The memory phase, during which surviving cells
specific for the priming antigen may persist
over long periods of time.
Third line of defence: adaptive immunity
The adaptive
esponse
1. A recognition phase: recognition
of the pathogen or other foreign material
by lymphocytes
Antigen
MHC
molecules
MHC classI
MHC classII
Third line of defence: adaptive immunity
The adaptive
Mounting an adaptive immune response
esponse
requires:
Antigen
presentation
1. A recognition phase: recognition
of the pathogen or other foreign material
by lymphocytes
Third line of defence: adaptive immunity
The adaptive
Mounting an adaptive immune response
esponse
requires:
Activation
Proliferation
2. An activation phase, whereby
antigen-specific lymphocytes
receive a co-stimulatory signal to
proliferate and differentiate into
effector cells.
3. The clonal expansion of the
antigen-specific lymphocytes.
Third line of defence: adaptive immunity
The adaptive
Mounting an adaptive immune response
esponse
requires:
4. The effector phase, during which
effector lymphocytes are dispatched
to the sites of antigen entry. .
Disease-causing agents
Bacteria
Viruses
Protozoa
Worms
Fungi
Lifestyles
PAMPs vs
antigen
Defense against microbes
Viral
infection
Defense against microbes
Viral
infection
Bacterial
infection
Master “Modelling the immune system”
Learning
objectives ‰ Describe three types of systems that integrate microbial signals and state
which innate immune cells instruct the adaptive immune system
‰ Compare the innate and adaptive immune systems in terms of cellular components,
molecular components and tissue organization.
‰ Compare the process of antigen presentation for extra versus intracellular pathogens
‰ Explain the difference between PAMPs and antigens.
‰ Identify the primary, secondary and tertiary lymphoid tissues and describe their role.
‰ Describe the phases associated with the development of both the innate and the
adaptive immune responses.
‰ Compare innate and adaptive immune responses in terms of immune recognition.
‰ Describe which arm of the adaptive immune response is required to protect against
extracellular pathogens, in terms of lymphocytes, antigen recognition strategy and
defense mechanisms.
Home work
1. Study the basic concepts in immunology using the Immunology Online
website.
2. Test your knowledge using the quiz.
3. Questions:
• Describe three main systems, i.e. epithelium, dendritic cells and resident
innate cells, that integrate microbial signals and in which order they operate.
• Which immune cells are able to enter an infection site.
• How do the innate and adaptive immune systems clear a viral or a
bacterial infection.