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# dwcorne Teaching bic ais School of Mathematical and Computer

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```									       Natural and “Artificial”
Immune Systems

This is lecture 19 of Biologically Inspired Computing; about
Natural and Artificial Immune Systems.
It borrows much from a tutorial presentation by Jon Timmis, now
at York.
Overview
• What are Artificial Immune Systems?
• Background immunology
– Why use the immune system as a metaphor for
computation
• Immune System Inspired algorithms
Artificial Immune Systems
• Relatively new branch of computer science
• Using natural immune system as a metaphor for solving
computational problems
– Not modelling the immune system – too hard
– What the IS does is detect invading/unusual things;
• What AISs (usually) do is detect rare/suspicious events, by
borrowing computational ideas from the IS
• Variety of applications so far …
–   Fault detection (Taylor, Corne)
–   Computer security (Forrest, Kim)
–   Novelty detection (Dasgupta)
–   Robot behaviour (Lee)
–   Machine learning (Hunt, Timmis, de Castro)
Basic Immunology I
The Role of the Immune System
• It protects our bodies from infection, operating via:
- A first line nonspecific line of defence: barriers
- A second nonspecific line of defence: general attack.
Then comes specific (i.e. targeted) defence, comprising:
– Primary immune response
• Launches a response to invading pathogens
– Secondary immune response
• Remembers past encounters, leading to:
• Faster response the second time around
Basics and Terms
A Pathogen is any agent (bacterium, virus, etc) that can cause us trouble
THE IMMUNE SYSTEM IS OUR PRIMARY DEFENSE AGAINST
PATHOGENS
IT CONSISTS OF NONSPECIFIC AND SPECIFIC DEFENSES.
NONSPECIFIC DEFENSES ARE THE BODY'S FIRST LINE
AGAINST DISEASE. THEY ARE NOT DIRECTED AGAINST A
PARTICULAR PATHOGEN. THEY GUARD AGAINST ALL
INFECTIONS, REGARDLESS OF THEIR CAUSE.
SPECIFIC DEFENSES ARE ATTEMPTS BY THE BODY TO
DEFEND ITSELF AGAINST PARTICULAR PATHOGENS.
Since Pathogens must enter the body in order to cause disease, the body's
first line of defense is to keep pathogens out. So, what organ is used
for this?
Basics II
The Body's MOST IMPORTANT Nonspecific Defense is the
SKIN. UNBROKEN Skin provides a continuous layer that protects
almost the whole body. Very Few Pathogens can penetrate the layers
of dead cells at the skin's surface.
Oil and sweat glands at the surface of the skin produce a salty an acidic
environment that kills many bacteria and other microorganisms.
The importance of the Skin as a Barrier against Infections becomes
obvious when a small portion of skin is broken or scraped off:
Infection almost always follows.
Infections are a result of the penetration of the broken skin by
microorganisms normally present on the unbroken skin.
Pathogens also enter the body through the Mouth and Nose, but the body
has Nonspecific Defenses that protect those openings.
MUCOUS MEMBRANES are Tissues
that protect the interior surfaces of the
body that may be exposed to pathogens.
They serve as a barrier and secret MUCUS,
a sticky fluid that traps pathogens.
MUCUS, CILIA, and HAIRS in the Nose
and Throat trap Viruses and
Bacteria. Pathogens that make it to the
Stomach are destroyed by Stomach Acid
and Digestive Enzymes.
Many Secretions of the Body, including
MUCUS, SALIVA, SWEAT, and
TEARS, CONTAIN LYSOZYME, AN
ENZYME THAT BREAKS DOWN
THE CELL WALL OF MANY
BACTERIA.
But what happens if something gets past all that ?
The Inflammatory Response
This is the SECOND LINE OF DEFENCE
When Pathogens get past skin and mucous
membranes, and enter the Body, this
Second Line of Defence comes into play,
triggered by injury to tissues in the body.
The injured cells release a protein called
HISTAMINE, which starts the a series of
changes called the Inflammatory Response.
THE INFLAMMATORY RESPONSE IS A NONSPECIFIC
DEFENSE REACTION OF THE BODY TO TISSUE
DAMAGE.
Histamine increases blood flow to the injured area and
increases the permeability of the surrounding capillaries, as
a result, Fluid and White Blood Cells (WBC) leak from
blood vessels into nearby tissue.
Pathogens are attacked by PHAGOCYTES, WHICH ARE
White Blood Cells THAT ENGULF AND DESTROY
PATHOGENS
The most common
Phagocyte, 50 to 70 percent
of the White Blood Cells in
the body, is the
NEUTROPHIL.
Neutrophils circulate freely
through blood vessels, and
they can squeeze between
cells in the walls of a
capillary to reach the site of
infection. They then engulf
and destroy any pathogens
they encounter
Another type of Phagocyte
(also a White Blood Cell)
is the MACROPHAGE;
they consume and destroy
any pathogens they
encounter, they also rid the
body of worn out cells and
cellular debris.
Some Macrophages are
stationed in the tissues of
the body, awaiting
pathogens, while others
move through the tissues
and seek out pathogens.
NATURAL KILLER CELLS are large white blood cells that, unlike
phagocytes, attack cells that have been infected by pathogens, Not the
Pathogen Themselves. They are particularly effective in killing
Cancer Cells and Cells Infected with Viruses.
A Natural Killer Cell punctures the cell membrane of its target cell,
allowing water to rush into the cell, causing the cell to burst
But if all that is not enough …
IF A PATHOGEN IS ABLE TO GET PAST THE BODY'S
NONSPECIFIC DEFENSES, THE IMMUNE SYSTEM
REACTS WITH A SERIES OF SPECIFIC DEFENSES
THAT ATTACK THE DISEASE CAUSING AGENT.

This is called the IMMUNE RESPONSE
A SUBSTANCE THAT TRIGGERS THE SPECIFIC DEFENSES OF
THE IMMUNE SYSTEM IS KNOWN AS AN ANTIGEN.

AN ANTIGEN IS A SUBSTANCE THAT A MACROPHAGE (WBC)
IDENTIFIES AS NOT BELONGING TO THE BODY.
The Immune Response involves several organs, as well as White
Blood Cells in the Blood and Lymph. These include the BONE
MARROW, THYMUS, LYMPH NODES, TONSILS,
Each organ of the immune system plays a different role in defending
the body against pathogens.
Bone Marrow manufactures the billions of WBC needed by the
body every day. Some newly produced WBC remain in the bone
marrow to Mature and Specialize, while others travel to the
Thymus to Mature.
Lymph Nodes Filter Pathogens from the Lymph and expose them to
White Blood Cells
The Spleen, a fist-sized organ located behind the stomach, Filters
Pathogens from the Blood. It is stocked with WBC that respond
to the trapped pathogens.
Where is it?
Primary lymphoid       Secondary lymphoid
organs                 organs

Tonsils and

Thymus

Spleen

Peyer’s patches

Appendix

Bone marrow                      Lymph nodes

Lymphatic vessels
Self/Nonself distinction
In order to Respond to Pathogens, but to avoid responding to and
destroying cells from its own body, Lymphocytes

MUST BE ABLE TO RECOGNIZE A PATHOGEN AS A FOREIGN
INVADER AND DISTINGUISH IT FROM CELLS OF THE BODY.

This is the key to it all, and where most of the inspiration comes
for computational systems.
The Immune Response:
The last line of defence
The general idea is this:
Something has got through the first lines of defence,
and entered the body in force.
If the body has been invaded by this particular nasty thing
before, then special Lymphocytes called B-Cells and T-
Cells are able to recognise these specific pathogens, and
overwhelm them (thanks to the `immune system memory’
If this is a new invasion, then the B-Cells will learn how to
fight this invader. (and then remember for next time).
Specific Antigen Recognition
Nasty thing
This lymphocyte
B-cell or         recognises the
T-cell            red pathogen

Surface receptor molecule

This one doesn’t
B-cell or
T-cell
Generating variety
The receptor molecule is a protein, encoded by a highly variable
gene. There is essentially a combinatorial library of parts in the genome:
Each B or T cell makes up its receptor by choosing:
one of these       and one of these     and one of these, etc…

dna

The result is that an enormous variety of possible surface receptors
could be chosen. This is effectively a method for generating random
receptors. Since recognition need not be exact, it is possible in
practice for a B or T cell to generate a receptor which matches any
given antigen.
Generating variety II
In addition, B-Cells (but not so much T cells) also undergo somatic
hypermutation. Somatic just means in the body, during one’s lifetime.
Hyper just means `a lot’. In a nutshell:

1.    A B-cell recognises an antigen
2.    A complex chain of events then leads to this B-cell dividing,
creating daughters who produce the same receptor.
3.    But these daughter cells may have mutations in their library.
4.    Some of the daughters may recognise the antigen even better.
5.    Back to 1.
Clonal Selection and Negative Selection
The whole process (antigen recognition, consequent production of
new B-cells with similar receptors, repeated …) is called Clonal
selection. In AIS paralance it is also called positive selection (you’ll
soon see why).

But how come the immune system doesn’t generate receptors which
cause it to recognise (and hence then try to destroy) bits and pieces
which are valid and necessary parts of the body?

It does! But B or T cells with such self receptors get destroyed by a
Process called negative selection.

The standard picture (from the book by Timmis and de Castro) is on
the next slide.
Clonal and Negative Selection
1                        Clonal deletion
(negative selection)

Self-antigen                      Proliferation
(Cloning)                            M

2
M

Antibody
Memory cells
Selection
Differentiation
3                                                                           Plasma cells

Foreign antigens
4
Self-antigen

Clonal deletion
5                      (negative selection)
Clonal and Negative Selection
In the picture, we see the fate of five different B-cells, each with
A different receptor molecule. Note, these are also called antibodies.
Much simplified:
1 & 5. These ones find themselves recognising a `self-antigen’. This leads to them
getting killed off (`clonal deletion’). This happens as part of the cell’s `schooling’.
Before release into the blood (lymph), B-cells (T-cells) are exposed to a full
range of self-antigens in the bone marrow (Thymus). They are killed if they
recognise anything. Hence, those that graduate and enter the system are only
those that will recognise foreign invaders.
2 & 4. These find themselves going round the body a few times without recognising
anything. Thus, they are never stimulated to divide and multiply, and soon die.

3.     Clonal expansion/positive selection: this B-Cell recognises something – the
recognition process causes it to divide, producing daughters who will have
similar, possibly higher affinity, receptors (and those with better affinity will
have more offspring, etc …). They don’t divide forever. Some become stable as
`memory cells’ (ready to fight if infected with the same pathogen again), others
become plasma cells, which secrete lots of the recognising antobody into the blood.
Interim Summary
A pathogen comes along:
If it gets through the barriers (skin, etc), nonspecific lymphocytes
kill it, as part of the `inflammation’ response in reaction to injury.
If it gets past that (I.e. there’s so much of it, it gets into the
bloodstream anyway), then the Immune Response comes into
play, as follows:
If we’ve seen this one before, there are antibodies in the blood
(secreted by memory cells); these antibodies disable and/or tag
the invader. The tagging attracts killer cells to make sure it is
destroyed.
If we haven’t seen this before, B-cells and T-cells are floating
around with a great variety of surface receptors. One of these will
at least recognise it a bit. Clonal expansion then happens, and
with gene variability and somatic hypermutation we eventually
get some B or T cells which are capable of recognising it. The
associated antobodies then disable and tag the invaders.
Some interesting related points
Some ailments are `beyond’ the immune system, since they either
directly disable it, or work faster than it, or both (or something else).

Cancer: the problem here is uncontrolled growth and multiplication
of normal cells. If caused by any specific pathogen (controversial)
then it could be that just a tiny amount needs to go unattacked for a
short time, and the problem starts.
Leukaemia: a cancer of the bone marrow – it (and its treatment) throw
an enormous spanner into the heart of B-cell production.
Vaccination: this is where we deliberately provoke an immune response
to small levels of a pathogen (or something similar to it), so that our IS is
ready if there is a real infection.
AIDS: some T-cells (called Helper T Cells) are the main players in most
of the things we have looked at. E.g. via special messenger molecules, the
activate the clonal expansion of B cells! The HIV virus directly attacks
Helper T-cells, essentially disabling the immune system.
AIS Algorithms
The IS is the inspiration for a whole new field of computer science which is building
systems, for various purposes, which borrow ideas from the workings of the IS. The
basic ideas and algorithms are less easy to pin down (than with EAs, or NNs, e.g.).
However, the most easily abstracted algorithms (which are also most frequently
`borrowed’, are: negative selection and positive selection.

The scenario is typically this:
We need to detect anomalous patterns (network attacks, bank card
fraud, unusual temperature/vibration/pressure patterns in machinery, etc…)
The space of normal patterns is very large and variable (we can’t just say `anything
which doesn’t look like X is bad’.)
We have little or no idea about what anomalous patterns will look like.
So, we use IS ideas: The overwhelmingly common approach is:
Negative selection: generate random detectors (receptors), but filter them by
testing their affinity to known self patterns. Each new pattern / window of data
is then matched against these detectors.
Anomaly Detection: the most
common application of AIS
• The normal behavior of a system is often
characterized by a series of observations over
time.
• The problem of detecting novelties, or anomalies,
can be viewed as finding deviations of a
characteristic property in the system. (I.e. non-
self)
• For computer scientists, the identification of
computer viruses and network intrusions is
considered one of the most important anomaly
Negative Selection Algorithms
Self
strings (S)

Generate
random strings     Match            Detector
(R0)                      No   Set (R)

Yes

Reject                                    Detector Set
(R)

Developing the
detector set                               Strings (e.g.
Match        No
credit card use
patterns)
Yes

Using the                                   Non-self
Detected
detector set
Basic Notes on Negative
Selection Algorithms
• A robust system should detect any foreign/strange activity
rather than looking for specific known patterns of
intrusion.
• No prior knowledge of anomaly (non-self) is required
• This lack of prior knowledge is useful, because we
normally have very few, or no, example data sets of
intruders (e.g. attacking patterns of telnet packets,
fraudulent credit card use patterns), so standard
classification by (e.g. ) NNs can’t be done.
That’s all

you wish.

Generally it has not yet been a clearly successful research area,
since it is not clear that successes so far could not have been
achieved just as well by conventional methods.

However (my personal opinion), the more complex the system
that we need to protect, and the more complex and varied the
potential threats, perhaps the more like natural immune systems
the protection approach needs to be.

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