Modeling the Immune System

Transcription

1 An Introduction to Modeling the Immune System School of Computer and Communication Sciences EPFL, SS

2 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.

3 Master Modelling the immune system Staff The lecturers Immunologists: Nathalie Debard Jean-Pierre Kraehenbuhl HSeT HSeT Modelers: Alcherio Martinoli (Jean-Yves Le Boudec EPFL EPFL; sabbatical) Teaching assistant Irina Baltcheva EPFL

4 Master Course outline munology Part I: the Immune System ( weeks 1 to 7) (ND,JPK) Date Teacher Cours Online activity 20 Feb JPK Basic concepts in Immunology none 27 Feb JPK Innate Immunity Exercises: introduction 05 March JPK/ND Students presentations 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 ool box Part II: modeling toolbox (weeks 8 to 11) (AM, IB) You already know most of them The necessary background will be reviewed Non-spatial, macroscopic deterministic models Non-spatial, macroscopic stochastic models Microscopic and spatial models Simulation issues Article-based learning

5 Master Course outline ase studies Part III: Case Studies (weeks 12 to 14) Short introduction Student seminar: You chose one paper, study it, re-implement the results in a critical fashion, submit a report, and final defense You will review the work of another team (report and defense) Teams of 1 or 2 students (recommended) valuation Evaluation Course project (40%) + oral exam (60%) Course project: 40% report, 40% defense, 20% review Assisted exercises during the semester not graded (dry-run exercises for course project and oral exam)

6 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

7 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 Master mathematical and computational methods Understand the system you are modeling

8 A note on Web Sites Main Public visibility and material (course presentation, lectures, assignments) Entry point for student area (moodle) Archive of past editions (not ready yet) Support Moodle Modeling and biology assignments; upload, download files Forums: exercises/projects; general announcements Initial access: course key Further access: usual gaspar login Support Immunology Online E-learning of immunology Protected, full access via login request (different from gaspar) Unprotected, partial access via assignment hyperlinks in moodle

9 Defence against infection hree lines f defence pithelial arrier First line of defense nnate munity daptive munity 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. Second line of defense Defence mechanisms protect the host: the first and second lines of defence (epithelial barriers and innate immunity are common to invertebrates and vertebrates the third line (adaptive immunity) is specific to vertebrates Third line of defense

10 First line of defence: the epithelial barriers pithelial 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 physical factors chemical factors immunological factors

11 First line of defence: the epithelial barriers Physical barrier Stratified epithelia: multiple cell layers rapid cell turn over Simple epithelia: membrane specialization mucus secretion rapid cell turn over

12 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

13 Second line of defence: innate immunity ole of the pithelial cells leukocytes nate immune responses ccur in two sequential teps: 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 circulating in the blood & scattered in organs the recognition of the disease-causing agent. Macrophages Mast cells Neutrophils the immediate activation of defensive effector mechanisms to eradicate it. forming tissues that separate the outside from the inside world oth events take place t the disease site. molecules produced by innate immune cells or the liver. acute phase proteins complement cytokines & chemokines

14 The complement Killing Disruption of microbes by osmotic cell lysis Opsonization: coating microbes with complement and clearance by phagocytosis ecruitment f killers vascular changes (dilatation & increased permeability) chemotaxis (leukocyte attraction)

15 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 allows to mount rapid and efficient defences when and if the agent reappears. increases the likelihood that individuals will survive to reproductive age. The adaptive immune system consists of: cells called lymphocytes. molecules that lymphocytes produce, including antibodies "cytokines". organs called lymphoid organs where lymphocytes divide and reproduce, mature, and perform some of their functions. Lymphocytes migrate in and out of lymphoid organs.

16 Third line of defence: adaptive immunity ells & olecules ediating daptive esponses T and B lymphocytes Lymphocytes are the primary cells of the adaptive immune system. They are formed in primary lymphoid organs in a process called lymphopoiesis. 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.

17 Third line of defence: adaptive immunity ells & olecules ediating daptive esponses T and B lymphocytes Unique features: Generation of the immune repertoire associated to the naïve lymphocytes Distribution of the naïve lymphocytes in the secondary lymphoid organs where they encounter antigens Distribution of the effectors cells where they have to control invading microbes Lymph nodes Spleen MALT

18 Third line of defence: adaptive immunity ells & olecules ediating daptive esponses molecules cytokines produced by B and T lymphocytes antibodies produced by B lymphocytes 2 forms: membrane bound: receptor secreted: antibody Structure Function

19 Third line of defence: adaptive immunity ells & olecules ediating daptive esponses molecules antibodies cytokines promote T cell growth. promote antibody production. activate lymphocytes & macrophages They include: Interleukins interferons chemokines

20 Third line of defence: adaptive immunity he adaptive sponse Mounting an adaptive immune response requires: 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.

21 Third line of defence: adaptive immunity he adaptive sponse 1. A recognition phase: recognition of the pathogen or other foreign material by lymphocytes Antigen MHC classi MHC classii HC olecules

22 he adaptive sponse Third line of defence: adaptive immunity Mounting an adaptive immune response requires: 1. A recognition phase: recognition of the pathogen or other foreign material by lymphocytes ntigen resentation

23 Third line of defence: adaptive immunity he adaptive sponse ctivation roliferation Mounting an adaptive immune response requires: 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.

24 Third line of defence: adaptive immunity he adaptive sponse Mounting an adaptive immune response requires: 4. The effector phase, during which effector lymphocytes are dispatched to the sites of antigen entry..

25 Disease-causing agents Bacteria Viruses Protozoa Worms Fungi PAMPs vs antigen ifestyles

26 Viral infection Defense against microbes

27 Defense against microbes Viral infection Bacterial infection

28 Master Modelling the immune system earning bjectives 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.

29 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.