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Immunocomputing The natural immune system and its computational metaphors by Ian Nunn, [email protected], 2002 Organization of This Lecture • Overview of the Immune System (IS): – – – – – The innate IS The adaptive IS The immune response Antibodies and the Clonal Selection principle Immune network theory • The key computational aspects • The symbol ↓ means significant explanatory text or diagram follows later Views of the Immune System • A collection of lymphoid organs, cells principally leukocytes ( lymphocytes ↓ and phagocytes ↓), and molecules that are interrelated in function • A related collection of bodily defenses: – – – – Physical barriers (skin, mucous membranes) Physiology (temperature, ph, enzymes in secretions) Innate IS ↓(phagocytes) ~ cellular level Adaptive IS ↓(lymphocytes) ~ molecular level • The innate IS and the adaptive IS are interactive • It’s all molecular chemistry: proteins and peptides Anatomy of the Immune • • 1 System Primary lymphoid organs (black/red) Secondary lymphoid organs (blue/yellow) The Antagonists • Infectious foreign agents called pathogens: – Viruses (cold, influenza, smallpox) – Bacteria (anthrax, E. coli) – Multi-cellular parasites (malaria) – Fungi • Foreign proteins and toxins • Pathogens express cell surface and soluble proteins called antigens (Ag) • Agent identification problem: how to detect and remove pathogens or harmful non-self elements without attacking beneficial self elements (autoimmune reaction) Immune 1 Defense Response of various ‘subsystems’ to pathogens The Innate Immune System • System available at birth, non-adaptive in makeup, providing an immediate response to invasion • Principal components are: – Complement ↓ system, a class of ~25 blood proteins – Phagocytes that are scavenger cells including macrophages ↓ ingest foreign material and assist the adaptive immune response – Natural Killer (NK) ↓ Cells, a type of lymphocyte The Complement System • Proteins that bind to the surface of certain types of bacteria • Promotes two mechanisms ↓ of elimination after binding: – lysis: the complement ruptures the cell membrane – opsonization: the bound complement marks the pathogen for destruction by macrophages • Self cells have surface regulatory proteins that prevents complement binding Macrophages • Scavenger role • Have receptors for: – Certain types of bacteria directly – Complement on opsonized bacteria • Activated partly by Th1 cell ↓ lymphokine ↓IL-2 • Known as antigen presenting cells ↓(APC): – ingest and then digest pathogens and antigens – present the Ag peptides at their surface to T cells ↓ via class II major histocompatibility complex (MHC) molecules that are contained only in IS cells Macrophage Bacterial 1 Ingestion Step 1: an opsonized antigen is ingested Step 3: MHC/peptide complex presented on surface Step 2: antigen peptides are bound by class II MHC molecules Macrophages (cont.) • Secrete cytokines (IL-1) ↓ after activation: • Cytokines are a class of signalling molecules that: – Induce inflammatory response, physiological changes that facilitate the activity of IS cells: • Elevated temperature • Increased blood flow and blood vessel permeability – Trigger liver to produce acute phase protein (ATP) a complement molecule which binds to bacteria activating a macrophage response Natural Killer Cells • Bind to carbohydrates on surface of self cells • Can’t recognize specific antigens unlike Tk cells ↓ or killer cells of the adaptive immune system • Healthy self cells express an inhibitory signal • Virus-infected cells may lose inhibitory ability thus activating NK cells • Activated NK cell injects chemicals that trigger apoptosis ( programmed cell death) or lysis The Adaptive Immune System • Characterized by a two-phase, primary and secondary response to pathogens ↓ • Principal components are ~ 1012 short-lived (4 – 7 days) lymphocytes created in bone marrow at the rate of 107 per day: – T-cells ↓ which mature in the thymus gland – B-cells ↓(majority) which mature in bone marrow Lymphocyte Growth • Pleuripotent or common haemopoietic stem cells in bone marrow at birth • Differentiate into progenitor cells including: – Myeloid type → phagocytes – Lymphoid type → B and T lymphocytes • These grow into immature precursor cells in bone marrow • Precursor cells mature in primary lymphoid organs • Mature cells: – Activate and differentiate in bodily tissue – Some (B cells ↓) multiply in secondary lymphoid organs Lymphocyte Maturation Cell Structure • Each antigen exhibits many unique structural regions called epitopes (~1016 possible varieties) • Lymphocytes have (~105) identical secretable surface protein receptors called antibodies (Ab) ↓ • At any time the immune system has a set of ~108 different Ab types called its repertoire • An antibody exhibits a unique structural region or binding site called a paratope expressing a range of affinities ↓ for binding a specific set of epitopes Ag Epitopes and Ab 1 Paratopes Antigen (Ag) showing epitopes and B cell lymphocytes showing antibody (Ab) paratopes (receptors) Protein Structure (Folding) Courtesy www.stanford.edu/group/pandegroup/Cosm/ Shape-Space Representation • Factors affecting Ab/Ag binding include: – Molecular shape of paratopes and epitopes – Charge distribution – Relationship of corresponding chemical groups – Not covalent (chemical) bonding • A binding site parameterizes an L-dimensional shapespace ↓ • A paratope is at the center of a volume Ve of complementary epitopes with which it can bind called its recognition region • e is called the affinity threshold ↓ 1 Shape-Space • Paratopes (•), epitope complements (x) and affinity thresholds (ε) in shape-space (V) Spatial Distance • Measures degree of interaction (affinity) • For Ag(ag1, ag2 ,…,agL) and Ab(ab1, ab2 ,…,abL) expressed as vectors in shape-space: Euclidean: Manhattan: D L (ab ag ) i i 2 i 1 L D | abi agi | i 1 Hamming: 1 if abi agi D i where i i 1 0 otherwise L Affinity Threshold (ε) • Distance or match score is inversely proportional to complementarity or affinity for binding • A binding function measures affinity or strength of binding: – – Its domain is the set of possible distances Its range is the set of binding values • The affinity threshold ε is that value of distance above which which binding actually occurs Affinity Binding 1 Functions a) Threshold (step) binding function b) Sigmoid binding function Activation Threshold • A lymphocyte may bind multiple antigens (epitopes) of the same type • A lymphocyte may also bind multiple antigens of related type • A lymphocyte can’t become activated before the number of receptors bound exceeds an activation threshold • Different cell types have different activation thresholds • Different cell types behave differently on activation Lymphocyte Binding Different, Structurally Related Antigens3 The Adaptive Immune Response • Immune response (IR) in the adaptive immune system has two phases ↓ : – Primary response to antigen A (some Ab present): • Initial lag phase • Ab concentration then increases , levels off and falls – Secondary response to antigen A: • Short lag phase • faster buildup to greater maximum level with slower drop off – Response to a new unknown but related antigen B after primary response to A: • Similar to secondary response to A but less pronounced. Called immunological cross-reaction Primary and Secondary 1 IR The Adaptive Immune Response (cont.) • Demonstrates adaptation, reinforcement learning and associative memory needed for immunization - called a generalization capability • Characteristics of an associative memory ↓ are: – Robust both to noise (binding occurs over a range of antigen types) and component failure (destruction of individual lymphocytes) – Stored data recovered by reading same or similar data (IR) • Restricted by Th cell dependency ↓ The T Cell • A lymphocyte that along with B cells ↓ are the major elements of the adaptive immune system • Three major subclasses: – Helper (CD4, T4 or Th ) T cells ↓ assist a range of leukocytes in antigen identification – Cytotoxic (killer or Tk) T cells ↓ destroy pathogens by lysis – Suppressor (CD8) T cells express a negative effect on immune cell generation preventing autoimmune reaction • Population diversity created in thymus by combinatorial rearrangement of genes but no somatic mutation ↓ Th Cell Functioning • Binds (recognizes) only linear conformations of epitopes on unfolded (digested) antigen peptide/MHC complex on a macrophage • Secrete IL-2 lymphokines on activation and express IL-2 receptors • IL-2 promotes cellular growth, activation and regulation particularly of self, B cells and macrophages • Th cells differentiate into: – Th1 cells that activate Tk cells and macrophages inducing an inflammatory response – Th2 cells that activate B cells Th Cells and Self-Tolerance • Most self epitopes occur in the thymus and bone marrow • An immature Th cell activated by binding a self epitope suffers apoptosis (clonal deletion or negative selection) • Process called central tolerance • Some may still be auto(self)reactive. A second mechanism, costimulation is required: – Signal I occurs when activation threshold exceeded – Signal II IL-1cytokines provided by innate IS • Signal I without II triggers apoptosis, a negative selection or down-regulatory signal T Cell 3 Tolerization Tk 3 Cell Activation T 2 Cell Activation The B Cell • Two major subclasses: – Plasma cells ↓ that produce and secrete antibodies (no lymphokines), a defense reaction – Memory cells ↓ that express the associative memory characteristic • Antigen processing: Plasma cells digest bound antigens and present Ag peptides at their surface via class II MHC molecules B Cells and Self Tolerance • Initial tolerization occurs in bone marrow • Affinity maturation ↓ may produce autoreactive clones through somatic hypermutation ↓ • Distributed tolerance (occurs in lymph nodes throughout body) by costimulation: – Signal I occurs when activation threshold exceeded – Signal II provided by Th2 cell IL-2 lymphokines during antigen processing • Signal I without II triggers apoptosis B Cell Antigen Processing • B cells digest bound antigens and present Ag peptides at their surface via class II MHC molecules • A Th2 cell binds to the peptide/MHC complex and returns a signal II IL-2 lymphokine contributing to the B cell’s activation • Activated B cells travel to the secondary lymphoid organs as part of the affinity maturation process B Cell Affinity Maturation • Affinity maturation is a cyclical process involving plasma B cells: – Selection: activation by Th2 cell lymphokines and threshold regulated antigen binding – Proliferation: clonal division in lymph nodes expressing somatic hypermutation ↓and receptor editing ↓ – Differentiation: after leaving lymph node, into plasma and memory cells The Affinity Maturation 1 Principle B Cell Adapted Population Diversity3 The Memory Problem • B cells live only a few days (10 max) • How is memory effected? Theories: – A long-lived variety of B cell – Restimulation by long lived (years) traces of antigens in the body - a kind of low level chronic infection – Both Intracellular Pathogenesis • Intracellular pathogens (viruses, some bacteria) are invisible to B cells • Viral antigen is captured by a macrophage, presented to a Th cell which releases IL-2 lymphokines • Non-IS cells contain class I MHC molecules that transport internal viral peptides to the cell surface • Class I MHC/peptide complexes are bound by killer T cells which are activated in part by costimulation by IL-2 • Tk cells kill infected cells by exercising an effector function (lysis, apoptosis induction, toxic chemical injection) The Adaptive Immune System’s Response to Infection1 I. Macrophage ingests Ag, presents MHC/peptide at surface, releases IL-1 II. T cell binds MHC/peptide and IL-1, activates Activated T cell develops, releases IL-2 B cell binds antigen and IL-2, activates Activated B cell clones, differentiates into plasma and memory cells Plasma cell releases antibodies which bind antigens III. IV. V. VI. The Antibody Molecule • A soluble form of leukocyte receptor also called an immunoglobulin (Ig) • Two identical light (L) and heavy (H) chains ↓ • A constant region ↓ responsible for IS cell binding and available in a few varieties called isotypes that determine effector selection – there are 5 Ig classes • A variable region ↓ responsible for Ag binding • Variable region is a concatenation of three genes, V (Variability), D (Diversity) and J (Joining) each from a separate gene library ↓ • Binding is Ab paratope to Ag epitope The Antibody a) b) 1 Molecule Heavy (H) and light (L) chains; variable (V) and constant (C) regions of the antibody molecule The V, D and J gene libraries from which the antibody DNA is assembled Combinatorial And Junctional Diversity • Occurs in the bone marrow when lymphocytes are first created • Expressed by random combinatorial joining of a D and J gene followed by a V gene in the VH chain • Junction misalignment if amino acids don’t line up causing some to be dropped (Frame shift). Many are nontranslatable or unproductive and are dropped • Productive recombinations result in cells which repeat with V and J genes of VL chain • Estimated combinatorial diversity from both chains ~5x107 Somatic Hypermutation • Expressed in B cell (somatic) clonal reproduction • Mutation rate 109 times normal (hyper) • Types of mutation in Ab V region (receptor): – Point mutations – Short deletions – Insertion of random gene sequence (receptor editing ~25%) • Results: – Most non-functional or low affinity receptors eliminated by apoptosis (mechanism not understood) and negative selection – Some are autoreactive and eliminated by negative selection – A very few may have increased affinity due to conformational change and positive selection – Total coverage of antigen repertoire thought to be complete The Clonal Selection Principle • Governs generation of new lymphocytes by plasma cells: – Clonal copies of parents under somatic hypermutation – Elimination of autoreactive & unproductive clones – Proliferation and differentiation resulting from antigen activation of B cells – Autoimmune disease the result of autoreactive clones resistant to early elimination by self-antigens • The total number of lymphocytes kept relatively constant over time by regulation • Responsible for maintaining Ab repertoire diversity – recall: repertoire is ~108, ~107 replaced daily so complete replacement in 10 days Combinatorial Diversity and Shape Space Coverage • Generational diversity Other Mutational Effects • Clones may express different isotypes by recombination in the constant region of the antibody called isotype switching Immune Network Theory • A theory to explain the self-regulation and memory properties of the IS • An Ab may display epitopes called idiotopes to distinguish them from Ag epitopes • An Ab’s set of idiotopes called its idiotype • An idiotope may be recognized by a set of antibody paratopes • Direction of recognition results in activation or suppression in the network The Immune a) b) 1 Network Cascading recognition: antibody view Cascading recognition: sets of idiotopes and paratopes A Complex Adaptive System • The IS is a complex adaptive system: – Large populations of several classes and sub-classes of agents with specific unique behaviors – No central control – Able to regenerate its (self) elements – Overall population is self-regulating – Able to adapt to any external influence through an ability to generate diversity • A rich example of a multi-agent or swarm system Features Of Computational Interest • Pattern recognition: through affinity binding – Self-recognition by tolerization – Intrusion detection by lymphocyte / antigen receptor binding • Feature extraction: through Macrophage and B cell antigen digestion and MHC/peptide (feature) presentation • Reinforcement learning: – exhibited by the adaptive immune response (AIR) in response to repeated infection – Clonal selection selects for cells with higher affinity • Memory: – AIR exhibits associative memory in the cross-reactive response. – A result of the affinity maturation principle by which high affinity long-lived memory cells are produced Features Of Computational Interest (cont.) • Self-Regulation: through AIR and lymphocyte population regulation • Generation of diversity: – Part of affinity maturation process (clonal production) – One mechanism: Combinatorial gene recombination and junction editing in primary lymphoid organs – Another mechanism: Somatic hypermutation in secondary lymphoid organs • Point mutations (explore local optima) • Short deletions • Random insertions or receptor editing (escape from local optima) • Adaptation: IS can respond to novel conditions through AIR and ability to generate diversity Features Of Computational Interest (cont.) • Optimization: the immune response and clonal selection result in increasingly better response to stimulus over time through higher affinity clones • Distributed and Collaborative processing: the various agents in the IS interact cooperatively with each performing a unique set of functions to achieve – Distributed detection – Distributed defense • Robust and scalable: – Noise tolerant: due to affinity binding (recognition region) – Component failure tolerant : affinity maturation ensures a large population of agents that carry desirable characteristics • Garbage collection: activity of phagocytes Other Concepts • Formalism: allow mathematical treatment – Shape space and identification parameters • Binding functions and affinity threshold • Stochastic nature of affinity binding – Can model with differential equations • Neat concepts: – – – – – Negative selection Costimulation and chemical signaling Helper and suppressor functions Threshold mechanisms (affinity and activation) Cross-reactivity References 1. 2. 3. de Castro, L.N. and Von Zuben, F.J. Artificial immune Systems: Part I – Basic Theory and Applications. Technical Report TR DCA 01/99, December, 1999. Eales, L.J. Immunology For Life Scientists A Basic Introduction. John Wiley & Sons, Chichester, 1997. Hofmeyr, S.A.Introduction to the Immune System. In Design Principles for the Immune System and Other Distributed Autonomous Systems. Oxford University Press, New York, 2001.