Download Immunocomputing - Carleton University

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.