The Immune System: Nature’s ‘Self’ Defence · The Immune System: Nature’s ‘Self’ Defence ©2007 Daniel Price all text & Illustrations An Illustrated Introduction

The Immune System: Nature’s ‘Self’ Defence

©2007 Daniel Price all text & Illustrations

An Illustrated Introduction

At the BSI, we are not immune to questioning!As a complement to our ‘beginner’s guide’ to the immune system presented on the following pages, we invited secondary students to submit their questions about Immunology via our website. These were answered by a panel of professional immunologists.

We present a selection below :-

“Are there any poisonous things in the immune system?” CH, Haberdashers Askes Boys School, Elstree, Age 13

Under normal circumstances the immune system does a good job in protecting us from infection with bacteria and viruses but during certain serious infections it can overreact, causing damage to the body. Lots of tiny molecules are involved in immune responses and are released during infection. These molecules, called cytokines, can wake cells up to help fight the infection or send cells to sleep when they are not needed, and this process is very tightly controlled. These molecules are very important in fighting infection but if you were to buy some of these molecules from a ‘science supermarket’ they would be labelled with a skull & crossbones and ‘toxic’ (poisonous). This is because if you have too many of these molecules, and their presence isn’t under the control of the immune system, they can make you very ill. In very serious infections the immune system is sometimes unable to control the release of cytokines from cells. This causes the immune system to overreact and creates a ‘cytokine storm’. This causes damage to many organs and tissues causing the infected person to become very sick. These molecules, therefore, are not normally toxic unless the immune system is targeted by a particularly nasty (virulent) bacteria or virus.Dr Caroline Rowland, DSTL Biomedical Services

I guess you mean, ‘poisonous for people’ here. Many of the molecules produced by white blood cells are ‘poisonous’ for bacteria. However the immune system also has cells (cytotoxic T cells) that can kill other cells of the body that have become infected. They use a variety of toxic molecules to kill the infected cells, and it is only because the molecules are directed against the right target, that they do not do a lot of damage in the body.Professor David Male, Immunology & Cell Biology Group, The Open University

Yes. Lots. Cytotoxic T cells produce perforin which punches holes in cell walls; macrophages produce highly toxic oxygen radicals; anti-viral interferons are what make you feel sick when you have the ‘flu. When the immune system is working well, all of these poisons are more dangerous to the infectious organisms than they are to you.Dr Simon Milling, Sir William Dunn School of Pathology, Oxford University

“How does immunology affect the way we live today?” CH, Haberdashers Askes Boys School, Elstree, Age 13

In my view, the major effects on people’s lives are:

1. The development and widespread use of vaccines, with reduced infectious disease and increased life-expectancy.2. Immunologists have been at the forefront of developments in cell biology, molecular biology, and genetics. Our understanding of these areas, and many of the techniques used to investigate cells, were developed by immunologists. 3. The methods have been adapted for the diagnosis of many diseases, forensic science, environmental monitoring, geneology and population studies.

4. Understanding immune reactions has been critical in the development of transplantation techniques, and devising treatments for autoimmune diseases, and immunodeficiencies.Professor David Male, Immunology & Cell Biology Group, The Open University

The biggest contributions to date include: the understanding of how vaccines work to prevent infectious disease and stem cell treatment [bone marrow transplantation] for leukaemia/lymphoma sufferers.Professor Sarah Howie, MRC Centre for Inflammation Research, University of Edinburgh

“If the cells in your body remember which bacteria are good for you and which are bad. If someone were to develop amnesia, would their cells forget which bacteria are good for you and which are bad too?” KG, Haberdashers Askes Boys School, Elstree, Age 13

This is all about memory. Amnesia is about what the brain does – it remembers patterns and events, and the memory is stored in the connections between nerve cells. The immune system remembers the molecules on the surface of bacteria, but this memory resides in lymphocytes, and is quite different to the memories stored in the brain.Professor David Male, Immunology & Cell Biology Group, The Open University

No – immune ‘memory’ is a different biological process from brain memory so the immune system would still remember even if the brain forgot.Professor Sarah Howie, MRC Centre for Inflammation Research, University of Edinburgh

No. Immunological memory is not thought to depend on your brain. Perhaps we could use this immunological memory to find out about the history of a person with amnesia - though there might be many easier ways!Dr Simon Milling, Sir William Dunn School of Pathology, Oxford University

“If we do make vaccines, and everyone survives diseases then wouldn’t the world get overpopulated?” KM, Haberdashers Askes Boys School, Elstree, Age 13

The World is indeed getting overpopulated. This is partly due to the fall in incidence of infectious diseases, and the corresponding rise in life-expectancy. The reduction in infectious disease is itself only partly due to vaccines - sanitation and clean water are at least as important as vaccines. For many thousands of years, infectious diseases were a major limitation on lifespan, and this is still true in some countries, but in most developed countries the diseases of age (such as heart disease) now limit how old we can reach. In the future, the availability of food/water and other resources may limit population growth even more than disease. The other major factor is how many children are born, which is affected by education and the availability of contraception. So, even if we had vaccines to all the main infectious diseases, this would cause an increase in average lifespan, across the World, but the most important factors affecting the World population would be the birth-rate and the incidence of all diseases, not just infectious diseases.Professor David Male, Immunology & Cell Biology Group, The Open University

If you just did the sums then yes – but life is about more than sums and healthy people can make informed choices about how many offspring they will have. Healthy people also tend to contribute more to the world’s resources than sick ones.Professor Sarah Howie, MRC Centre for Inflammation Research, University of Edinburgh

In countries where people usually survive through childhood to become adults, the birth-rate is often lower because parents expect their children to grow up to be healthy. Successful vaccinations, and many other wealth-associated factors, help this to happen and might actually help prevent overpopulation.Dr Simon Milling, Sir William Dunn School of Pathology, Oxford University

“Bird flu sounds like such a timid flu, so why is it so deadly?” DD, Haberdashers Askes Boys School, Elstree, Age 13

The simple answer is because humans are not used to dealing with it. The more complicated answer is that the immune system has never had the opportunity previously to recognise and react against the bird flu virus, and that the virus itself may be able to divide particularly rapidly in some humans.Professor David Male, Immunology & Cell Biology Group, The Open University

“Man flu” sounds much more dangerous, but only causes symptoms in half the population!! You can’t always trust a name!Dr Simon Milling, Sir William Dunn School of Pathology, Oxford University

“Will the cancer vaccine be given to all people with cancer, or will most people still have to use chemotherapy?” AP, Haberdashers Askes Boys School, Elstree, Age 12

Each cancer is different, and this means that only some of them will respond to vaccines. For many cancers, chemotherapy will still be the main option, or even using vaccination, chemotherapy and radiotherapy in combination.Professor David Male, Immunology & Cell Biology Group, The Open University

In theory, if a vaccine worked perfectly in all cases, chemotherapy might become unnecessary. In practice, we are many many years from having fully effective cancer vaccines, so chemo- and radiotherapy are here to stay for a while.Dr Simon Milling, Sir William Dunn School of Pathology, Oxford University

“How many white blood cells are there in your body?” V, Haberdashers Askes Boys School, Elstree, Age 13

We usually quote a figure of 2 x 1012 lymphocytes in an adult. These cells will have an average lifespan of about one month. If we add to this the daily production of short-lived neutrophils and the numbers of long-lived mononuclear phagocytes distributed in tissues, I would estimate 3 – 4 x 1012 cells in total, at any one time, or 3 - 4% of body mass.Professor David Male, Immunology & Cell Biology Group, The Open University

By my calculation…there are about 4,300 - 10,800 cells per cubic millimetre of blood in a healthy adult. And 5 - 6 litres of blood. I guess (really a guess) half of white blood cells will actually be in the

blood, the others will be visiting other parts of the body. So that’s about 4.3 x 1010 to 1.3 x 1011 cells. If laid end-to-end they would reach from London to Stavanger in Norway (about 890 km)!! (Assuming a diameter of 10 micrometres per cell, and assuming my maths is correct!)Dr Simon Milling, Sir William Dunn School of Pathology, Oxford University

“If immunology vaccines infect a slight amount of a disease into you to train your white blood cells to tackle it, why not use slight amounts of cancerous cells in vaccines to prevent cancer?” AKK, Haberdashers Askes Boys School, Elstree, Age 12

Yes, it can work, but only in some cases, because the immune system needs to recognise something to attack, and the cancers are often so similar that the immune system cannot recognise them. Another problem with vaccination is getting the dose right – just giving a small dose does not necessarily mean that it will produce a useful immune response - sometimes it can do exactly the opposite.Professor David Male, Immunology & Cell Biology Group, The Open University

Good idea and this has been tried in various forms at various times – the problem is that the cancerous cells are only a bit different from all your normal cells [unlike bacteria and viruses which are very different] so it is hard to get the immune system to actually recognise them. A similar approach does however work where the cancer is caused by a virus and is the basis for the new vaccine against cervical cancer which is due to a papillomavirus infection.Professor Sarah Howie, MRC Centre for Inflammation Research, University of Edinburgh

Good idea. So good, that it is already being done!Dr Simon Milling, Sir William Dunn School of Pathology, Oxford University

And finally…

“What part of the body takes up the function of the thymus gland when it reduces in size and activity towards adulthood?” AG (a teacher!), Carmel RC College, Age 38

Memory T cells are very long-lived so the need to provide large numbers of new T cells declines with age. T cells may develop not just in the thymus but in secondary lymphoid tissues in adults.Professor David Male, Immunology & Cell Biology Group, The Open University

Introduction

Some form of organised immune system is found in a majority of the multicellular animals present on Earth – from the most simple to the most complex. Mirroring other evolutionary developments, the complexity of the immune system has in many ways developed in tandem with the complexity of animal life itself. Put another way, systems of increasing structural complexity require ever more complex systems to safeguard them.

Some of the most successful organisms on Earth are microbes (bacteria, viruses and protozoans) – single-celled organisms that occupy a huge variety of environments. They are extremely versatile, able to replicate incredibly quickly, and very adept at exploiting their surroundings. To the microbe, multicellular animals (humans included) represent ideal environments in which to live, feed, reproduce and from which to spread to other hosts – especially since the board and lodging come free! It is perhaps no surprise then to find that the average microbial colonist does not always have its host’s best interests at heart! In this light, we can more clearly understand how the immune system has, in many ways, developed expressly to deal with such microscopic foes since, despite their size, their ability to rapidly replicate means that they could rapidly overwhelm a hapless host if left unchecked.

The following text is an attempt to portray the enormous complexity of the most highly developed form of the immune system in an accessible form. For familiarity’s sake, we are asking you to imagine this in the context of the human body – but in truth the same general principles apply to a wide range of mammals, the taxonomic grouping to which humans belong.

The Body Metropolis

The human body may be likened to a hugely complex colony or city – albeit one with a unique level of cooperation between its inhabitants (its cells) for the purposes of shared survival – with numerous different areas specialising in particular activities, all of which contribute towards achieving this shared goal (whether it be acquiring and absorbing food, absorbing oxygen, or disposing of waste products). In this context, the immune system may be viewed as the body’s ‘police force’ – patrolling its precincts, identifying wrongdoers or trespassers (generally pathogens), and clearing up vandalism (dying cells) – also ensuring that these processes are carried-out quickly and efficiently, with the minimum of damage to the fabric (and legitimate inhabitants) of the city itself. This is

the delicate balancing act that the immune system has to maintain since, in combating intruders, it can’t itself then be responsible for inflicting further damage to the ‘city’, and thereby jeopardising its survival!

Like any city, the body has its streets and highways – its blood and lymphoid systems (about which more of later) – and just as streets might aid a police force patrolling a city, in the body these systems allow the constituents of the immune system to patrol the body effectively.

Imagining the human body in this way, as a ‘Body Metropolis’ within which the immune police force attempts to maintain law and order, should aid us in unravelling the often complex processes that underlie immune function, and hopefully provide for some entertainment along the way!

The Strong Arms of the Law

In its most complex form, as exemplified in humans, the immune system may be divided into two branches, or arms, that can function independently, or more often, together. These are the ‘Innate’ and ‘Adaptive’ arms of the immune system. The Innate system is akin to the lower ranks of the police force, being trained to deal with a given number of set situations. Further, it does not require ‘additional training’ in order to maintain law and order. The Acquired/Adaptive Immune System, however, represents the detectives and forensic pathologists of the cellular world that adapt their expertise and methods to each situation. They retain information about criminals they have previously encountered in order to identify the villains more quickly should they offend again.

The ‘Innate’ Sense of the Immune System

As is suggested by the name, the Innate system ‘knows’ how to combat a range of potential pathogens without being specifically notified or trained in advance. In broad terms, aspects of it function like police foot- or panda car patrols, patrolling the streets and highways of a city looking for typical signs of trouble. Additional important, yet often overlooked front-line aspects of the innate system are the skin and mucosal layers lining the outer surface of the body and digestive and respiratory passages, respectively. In addition to forming fixed barriers to infection – like border controls and gates encountered when entering a country – they are lined with fixed cells, called ‘mast cells’, that are able to react to a range of infectants and induce a localised immune reaction.

These Cells are Big Eaters

A dedicated group of cells known as phagocytes may be likened to ‘bobbies on the beat’, as they can independently respond to, and home in on, chemical and molecular clues emanating from trouble spots – these may either originate from damaged tissues, other constituents of the immune system, or from the pathogens themselves. This is much like a police patrol observing signs of physical damage to property, hearing the sirens of police cars, or receiving calls for assistance over the walkie-talkie. Once in the area, these cells also have the ability to identify, upon contact, certain characteristic elements of the surfaces of pathogens (actually known as pathogen-associated molecular patterns, or PAMPs for short) – thus allowing them to ‘feel the collar’ of the target intruder! It is rather as if in the realm of the cellular city, certain thieves and robbers do indeed wear the regulation eye mask, flat cap and stripy sweater (not to mention carrying their booty in a bag marked ‘swag’!)

Once they apprehend a target, these cells literally engulf it, and break it down internally – hence the name ‘phagocyte’, literally meaning ‘cell eater’. If you’ve ever seen an amoeba moving under the microscope and engulfing prey, phagocytes are strikingly similar in their behaviour – perhaps representing a vestige of our evolutionary past when we were all single cells! Examples of phagocytes are macrophages and neutrophils.

A Most Unwelcome ‘Complement’ for Bugs

Pursuing our ‘stripy-sweatered’ criminal analogy, it should be noted that not all of our microbial adversaries go about their business in quite so obvious a fashion – either by appearance or behaviour. Through the power of evolution some have learnt to alter their characteristics, such that they don’t arose suspicion and attract the attentions of the ‘long arm’ of the Innate Immune System – and without such clues our phagocytes are unable to track and locate their targets. To combat this, evolution on the part of the host has thrown up a further development – known as the ‘Complement’ system. This consists of a family of proteins that ordinarily circulate unnoticed in the blood, until certain stimuli cause them to spring into action, assemble, and interact in such a way that they are able to target the more surreptitious intruder. As such, they are perhaps similar to undercover policemen – able to circulate swiftly around the Body Metropolis unnoticed, and hence able to interact closely, and with a larger number, of potential targets.

There are a variety of activation pathways in the Complement system. In one scenario, it is primed to be activated by certain elements on the surface of pathogens (as with phagocytes) – but these are instead more subtle features that ‘up-close’ the pathogen isn’t able to disguise as easily as merely dispensing with its stripy sweater (this is termed the so-called ‘Alternate Pathway’). In another scenario, the Complement proteins are activated indirectly by another cue, providing by further circulating proteins (mannose-binding lectins [MBLs]), that first ‘point the finger’ at the felon by binding to it (this is the ‘Mannose-binding Lectin Pathway’). Once activated the Complement system finally reveals itself, assembling via a ‘chain reaction’ which punctures holes in the target cell and neutralises it.

Like any good policeman, once done, the Complement system also raises the alarm by producing chemotactic chemicals that attract (both directly and indirectly) other elements of the innate system, such as the phagocytes, who are then able to recognise their targets more easily, thanks to the identifying markers provided by the Complement proteins themselves, and generally assist in mopping up the ‘crime scene’. Complement proteins also help to clear the path to the trouble spot by functioning as vasodilators, both directly and indirectly, and stimulating the release of histamine from mast cells and other cells called basophils. The effects of histamine will be familiar to those who suffer from hay fever – swelling and redness of the tissues. However, in the appropriate context this response is actually helpful to the elements of the innate immune system – widening blood vessels and making tissues more permeable to the immune cells.

A further facet of the Complement system is initiated via interactions with elements of the Adaptive Immune System (about which more later) and this is known as the ‘Classical Pathway’.

Cellular Specialists

As with any good drama, there are a whole range of other players engaged in the everyday struggle for law and order played out on the streets of the Body Metropolis. The Natural Killer (NK) cell is like an undercover assassin that specialises in neutralising cells who have been ‘turned’ via infection with viruses (akin to a person harbouring a criminal). The NK cell recognises that a criminal is being hidden because the cell helping them is behaving oddly (in most cases it has lost a molecule that is usually displayed on its surface, known as MHC class I). As viruses are fond of hijacking cellular machinery, and even genes, for their own replication, the NK cell causes the cell to self-destruct (via a process called ‘apoptosis’) thus ensuring the destruction of the cell replication machinery. Eosinophils are a further group of cells that appear to have developed to specialise in attacking the cell membranes of large (multicellular) parasitic organisms. These cells are much like specialised law-enforcement units.

Justice Gone Mad…?

In presenting our analogy of innate ‘law and order’ in the Body Metropolis, we must remind ourselves, however, that in the comparably more complex realm of a real city, delivery of such on-the-spot justice would be unlikely to produce desirable results in the long term! And indeed, although our cellular ‘bobbies on the beat’ are certainly effective in a great variety of contexts in the cellular city, we shall now see how, even at a cellular level, the immune system has taken account of some of the limitations of such an approach and developed other methods.

For instance, you will be aware that despite its undoubted elegance and flexibility in responding spontaneously to a range of intruders without the requirement for prior ‘intelligence’ – not to mention its ability to mount a rapid response (a role that is absolutely vital for a huge range of nasties) – the Innate system is ultimately reliant upon predetermined cues in order to act. Furthermore, certain by-products of this de-centralised, self-governing, approach are on occasion less desirable – especially if the initial infraction has been able to spread to other parts of the city.

For example, one of the consequences is something that is (somewhat evasively) termed in the real world ‘collateral damage’ (e.g. damaged property and the injury of innocent bystanders). In the cellular context we mean the tissue damage that is an almost inevitable consequence of inflammation and the actions of the various participants involved – the results of a system acting, as it were, without central coordination or higher command. A ‘city-wide’ response of this nature could be just as damaging as the actions of the ‘bad guys’ themselves! That is why, on other

occasions, a different approach is called for, and has indeed been provided, by that other (long) arm of the immune system’s brand of justice.

The Immune System ‘Acquires’ Intelligence

What is really called for here is a system that is able to sift the available evidence (like DNA and fingerprints), keep clear records of individuals previous felonies, and conduct thorough investigations before apprehending the wrongdoer cleanly and efficiently, with little or no harm to the ‘neighbours’ – and definitely without breaking anything in the process! What we want, in effect, is a detective department – and not any old detective department – we want possibly the best detective department (backed up by forensics) that has ever existed, and luckily our Body Metropolis is equipped with such a service – and it is known as the Adaptive Immune System.

The Lymphoid System

We earlier referred to something called the lymphatic system when we were comparing the vessels of the body to the streets of a city. Having already discussed the important role of the blood system in carrying and transporting important elements of the Innate Immune System, we can now discuss what is in some ways its ‘Adaptive’ equivalent. Like the streets of a busy city, the blood system is crowded with numerous amounts of traffic (not the least of which are the important oxygen transporting red cells), making it difficult to identify offenders amongst the mass. What we want therefore are specialised areas where the criminals may be washed towards our detectives, as if with a giant hose. How reassuring to learn, therefore, that such a system exists – and it is known as the lymphoid system. Lymph consistently washes the streets and houses of the cellular city (blood and tissues) and transports any detritus (containing pathogens) towards specialised areas called lymph nodes. The lymph nodes are home to the ace investigators of the adaptive immune detective department – the helper T lymphocytes (Th cells).

The “Brains” of the Operation

Before we discuss these key guardians of the Adaptive Immune System, we should point out that they are merely one of a plethora of types of lymphocyte that all play extremely important roles (these include cytotoxic T cells [Tcs] and B cells). However, as is suggested by their name, these ‘helper’ cells play an extremely important coordinating role in the Adaptive Immune System and may be likened to the “brains” of the operation – they don’t really get directly involved in first-line activities, and rely upon a whole series of other cells to gather their intelligence for them (more Mycroft Holmes than Sherlock).

‘T’ stands for thymus, and ‘B’ for bone marrow – representing the areas of the body where these cells undergo maturation. The lymph nodes are ultimately home to the lymphocyte family – forming their headquarters!

Gathering Intelligence

Intelligence gathering is indeed key to the function of the immune system as a whole, and the Adaptive Immune System has a whole team of supporting intelligence officers constantly roving the Body Metropolis picking up bits-and-pieces of information (antigen) – literally as it transpires. Although many immune cells are able to function as so-called ‘antigen-presenting cells’ or APCs (including certain members of the Innate ‘team’), the truly dedicated professionals are known as dendritic cells. These cells spend their lives gathering fragments from the blood and lymphoid systems and ferrying it back to present to the lymphocytes (Th, but also Tc and B cells) at the lymph nodes. It should be noted that they do not themselves assess the information that they carry (aside from processing it into a form understandable to the other cells) – they merely pick-up anything that happens to come their way and present it to others for evaluation, and this can include material that is harmless and actually originates from the host. Equally, such information could relate to foreign pathogens.

How then is such a system to be properly regulated such that danger signs are recognised and harmless material ignored? This is key to our earlier discussion regarding distinguishing between ‘self’ (innocent bystanders) and ‘non-self’ (criminals), and before we can go any further we must take a little detour to explain.

Everything is on File

A further remarkable aspect of the Adaptive Immune System is that, without prior interaction, it has the ability to recognise and identify the essentially limitless range of characteristics (broadly ‘shapes’) represented by antigens derived from things such as cell membranes and other cellular matter. Recognition ultimately occurs via cell receptors carried on lymphocytes. During the early life of an individual, multitudes of lymphocyte cells are generated by a specialised process, each with a unique receptor able to recognise a particular, specific, shape. Only a few of each specific cell are generated, otherwise the number of cells would be impossible to manage – however we are still talking about an awful lot of cells! The same process occurs for all lymphocytes, including: Th cells, Tc cells, and B cells.

During this early period, the immune system undergoes an important period of maturation where it ‘learns’ about ‘self’ tissues. Hoovered up, processed self-antigens, representing the sum total of possible molecular fragments derived from self tissues, are presented to the B- and T cells. As it is too early in the life of the individual for them to be encountering foreign material, it is assumed that all such antigen is ‘self’, and thus safe. Thus T- and B cells that react to such material are either destroyed, or their function is suppressed – as they would otherwise cause nothing but trouble within the body. This is known as the generation of ‘immunological tolerance’, and its discovery was a milestone in the

history of Immunology. At the end of this process we have a whole range of T- and B cells, able to act and cooperate based on their individual recognition of highly specific markers, excluding those originating from ‘self’ (noting that separate T cell [inc. Th and Tc] and B cell repertoires will have been produced, yet all sharing recognition of the same specific target markers).

In the context of our Body Metropolis analogy, it is as if every unique distinguishing characteristic of every single member of the city population were identified ‘at birth’ and then removed from the vast banks of identifying ‘police files’ already generated (as represented by each unique T- and B cell). In a sense, the system assumes that every citizen, by virtue of their native birth, will be naturally law abiding and therefore the Adaptive Immune System is essentially made blind to their activities (at least under ordinary circumstances). As we shall see later in the context of cancer, this is sometimes a dangerous assumption…

What we are left with, however, is what amounts to a huge record of every single remaining possible distinguishing characteristic (imagine the world’s most comprehensive ‘photo-fit’ archive), and since harmless ‘self’ characters have already been removed – what’s left is, by definition, ‘non-self’ and assumed to be harmful to some degree. Thus any stranger wandering into our Body Metropolis would soon be alarmed to discover that the police were already ready and waiting for them – equipped with ‘wanted’ posters and specialised recruits at the ready!

Taking the Cellular and Humoral Approach

The Adaptive immune response is divided into two categories: cellular and humoral. The former is enacted by the cytotoxic T cells (Tc) with assistance from helper T cells (Th) and the cells of the Innate system, whilst the latter is facilitated by our friends the B cells via circulating entities called ‘antibodies’. The two approaches reflect the need to be able to tackle a range of adversaries. The former approach is effective at dealing with criminals ‘hiding within houses’ (intracellular pathogens inside cells) as the Tcs interact directly with body cells; whilst the humoral approach (as is suggested by the name – ‘humoral’ meaning ‘fluid’) is based on elements carried in the bloodstream and is effective at tackling criminals at large on the streets (pathogens outside the cell).

As with any team, a coordinated effort often leads to the best result. Though our Tc and B cells can act independently they are much more efficient when helped by the helper T cell (Th). In a sense, the Th is important in ‘confirming’ the suspicions of the Tc or B cells, that the evidence they have encountered is in fact ‘criminal’. Therefore, in the case of the Tc cells, both a Tc and a Th may simultaneously encounter a dendritic cell carrying antigen that is specific to them both (possible criminal evidence). If the evidence is identified as ‘foreign’ by the Th, successful activation is permitted and the Th co-stimulates the Tc into action (alternatively, the Th may license the dendritic cell to activate the appropriate Tc cell when later encountered). A similar process can occur for B cells, and ‘costimulation’ is a useful insurance policy for ensuring that an immune response is appropriate – since even at this level of specificity, mistakes are still possible.

So far, so good, but we lack one thing – numbers…

A Drawback…

Having been somewhat condescending about the approach of the ‘bobbies on the beat’, as exemplified by the cells of the Innate Immune System, what cannot be denied is their ability to respond quickly and effectively to threats. Highly trained though they are, the members of our elite Adaptive immune response teams are (at least initially) extremely few in number. The Innate response is therefore vital for controlling the early stages of infection, since

there is a significant lapse in time before our Adaptive response ‘teams’ are able to mobilise. Happily, our friends the Th cells, once stimulated, are also able to upregulate the activity of the Innate immune response so that they can get to work quickly and effectively. Unfortunately, the Innate system isn’t able to deal with all forms of threat, which is why certain infections (especially viruses) are sometimes able to kill the host before an effective response is mounted, or else the collateral damage resulting from an escalating Innate response unable to contain a spreading infection produces the same outcome.

What the Adaptive Immune System really requires is time. In terms of our imagined Body Metropolis this would be considered ‘recruitment and training time’ – supplementing the ranks of the team under the ‘team leader’ (as represented by the activated Th, Tc or B cells). In cellular reality this actually amounts to a form of cloning (think Sci-Fi thriller territory).

Once the Adaptive immune response is up-and-running, however, there really is no stopping it and its startlingly specificity comes to the fore.

It is interesting to note that the principle of vaccination, first perfected by its founding father Dr Edward Jenner, hinges on the principle of mimicking an initial exposure to a pathogen, yet with a harmless version of a particular pathogen, so that if the real thing is subsequently encountered, the Adaptive Immune System has already prepared its recruits in advance.

Conducting House-to-House Enquiries

In facilitating the Cellular Adaptive immune response the cytotoxic T cell has a very specific role and, in our imagined metropolis, would be an officer who spent their time conducting ‘house-to-house’ enquiries, checking that all was well with the inhabitants. In terms of the body this reassuringly translates into comprehensive cellular surveillance of body cells – checking that they aren’t harbouring intracellular pathogens (criminals) or that they haven’t become cancerous.

Body cells are continuously presenting self peptides derived from their own structure via receptors on their surface (almost akin to an alibi). If the cell has become infected with a virus or bacteria, through natural cell activities, some of this material is likely to be incorporated into the general antigen-presentation procedure. This is kind of akin to a silent alarm operated by a threatened shop keeper that discretely lets the authorities know that trouble is afoot. Tcs, especially if they have been activated and cloned, will be actively looking for evidence of their specific target organism and will respond if they find such evidence.

Alas, in our somewhat ruthless city, the result is not a happy one for either the pathogen or the host cell, as the Tc destroys both in one fell swoop. However, the approach is at least clinical…

Knowing their A–Z

In our quest to seek out villains (pathogens) it would make sense to direct the forces of the law to places where they are likely to be found within the Metropolis. Not much point looking in irrel-evant places, especially when we are so short of time! The same is true for our immune cells – they need to peruse the tissues the pathogens are likely to be present. As they move through our blood vessels, how do they know where to exit into the tissues? They use a system much like a postcode directing letters to the correct address. Lymphocytes have a postcode (otherwise known as a ‘homing receptor’) that recognises the houses in a particular street (otherwise known as a ‘vascular addressin’). Lymphocytes expressing a homing receptor that binds to a particular vascular addressin can therefore exit the blood at the appropriate point and enter that tissue. Furthermore, lymphocytes may be attracted by chemical signals carried through the body, like following a trail of breadcrumbs or sweets or an enticing aroma (these are otherwise known as chemokines).

Anti-body? – au contraire!

Moving on to the Humoral Adaptive immune response, as we have already hinted, B cells have two functions: (1) they produce criminal detection entities we have already termed antibodies, and (2) as well as responding to APCs they can also function as an APC themselves by hovering up antigen and showing it to Th cells. When the Th cells recognise the antigen-carrying B cell they can help it to make better antibodies.

You will note that what we haven’t dealt with in any detail hith-erto, and this is most certainly not due to their lack of importance, is perhaps the immune system’s ‘trump card’ – the antibody. They are the primary products of the B lymphocyte and one of nature’s marvels in both their flexiblility and deceptive simplicity.

We have already detailed how the Adaptive Immune System is capable of recognising a potentially limitless range of characteris-tics, and that once one of these has been encountered it induces the system to produce ‘reinforcements’ specifically able to iden-tify that particular characteristic. In the case of Tc cells, the cells thus produced actually carry-out the work directly. In the case of B cells, however, the job of the cloned cells is instead to produce antibodies which then, in turn, prosecute the work. The antibod-ies produced by a particular B cell all match the specificity of the parent cell, and allow it to extend its influence well beyond its own borders.

Antibodies are most certainly not ‘anti-body’, on the contrary, they are most certainly on its side! They are small, highly structured molecules, at one end of which is a criminal detection part, the

‘antigen recognition domain’. Rather than being tied to the B cell, however, the antibody is an independent molecule that is secreted into the blood – and in huge numbers. Antibodies are fed into nu-merous areas of the body including the bloodstream, the airways and the gut lumen during an adaptive immune response, and due to their size and numbers are able to reach ‘hot spots’ quickly. With the intracellular aspect of the response already being covered by the cellular response, the antibodies instead generally target objects outside cells, attaching to their particular target ‘shape’ (or antigen) when they encounter it (this could be a feature on the surface of a bacterium or virus or even a toxin molecule produced by a pathogen, for instance). The fact that such shapes are often presented in repeating patterns on the target surface means that often large numbers of antibodies may bind a single target.

Although they do not actively combat pathogens like Tcs and phagocytes, if the target is bound by sufficient numbers of anti-body it can effectively be neutralised by being physically prevented from functioning effectively. For instance, a virus needs to bind a host cell in order to infect it (like a burglar having to pass through the door or window of a house) – the intervention of large num-bers of antibodies can actually cover its surface and prevent it form making direct contact with host cells (like preventing a criminal from turning the door knob, or making the criminal so big they can’t get through a window!). However, perhaps the most power-ful function of an antibody is in providing an absolutely precise target (and signal) to other elements of the immune system in or-der to allow them to direct their attentions exactly where required. The free end of an antibody therefore functions as docking point for other effectors.

Here, perhaps, attempts to characterise antibodies in terms of a ‘real world’ equivalent within our putative Body Metropolis fall short in being able to do justice to their simple brilliance – since they seem to combine ‘being in all places at one time’ and an abil-ity to efficiently engage other immune elements (as has already noted with the Complement system) with the supremely focused targeting we have already mentioned, not to mention their sheer weight of numbers! They are perhaps something like secret agents, moving and acting swiftly and with precision – and although they themselves in a sense ‘act and don’t ask questions’ (perhaps more like James Bond than we think!) in that they are not responsible for ‘decision making’ themselves, they are acting upon the intel-ligence gathered by the surveillance team of dendritic cells, that has been interpreted by the helper T cells (and other elements) so that they perform with the benefit of the combined ‘intellect’ of a imposing support team (back at ‘lymph node HQ’!). They certainly appear to have a ‘licence to kill’, although we have pointed-out that this doesn’t actually form part of their remit! They leave that to the other elements of the immune system that are able to lock onto their targets accurately as a result of the sterling work by the antibodies.

Joining Innate Sense with Acquired Intelligence

This is where we, in a sense, come full circle, for as a result of the antibodies’ efforts, elements of the Innate Immune System are also benefited. These include the Complement system – since the other activation pathway that we referred to earlier (called the ‘Classical Pathway’) is initiated via the binding of Complement elements to

the end of an antibody, initiating the ‘attack’ sequence – and also phagocytes, who via antibodies are able to ‘recognise’ pathogens that might otherwise evade them. Added to this, the ‘immune complexes’ formed by antibody and pathogen are also swiftly re-moved from the system via filtration through an organ called the spleen, so that they don’t cause obstruction. Thus the antibody forms an elegant bridge between the worlds of the Innate and Adaptive Immune Systems and allows the former to benefit from the centralised coordination provided by the latter – thereby great-ly enhancing its effectiveness.

However…No System of Justice is Ever Perfect!

Having outlined the profound elegance of the immune system – al-beit somewhat ruthless in its efficiency (though thankfully to our huge benefit) – we now have to admit that there are occasions when the immune system malfunctions; needs a helping hand from us to achieve its goals; or else is deceived or betrayed by its own side. Broadly speaking these areas are defined as, respec-tively: autoimmunity, vaccinology/therapeutics and cancer.

In outlining these instances we are providing a moral to our story, of sorts, in which we may be reminded that no system, however complex, comprehensive or flexible, can ever really be said to be 100% infallible. This provides cause to ponder the fact that, if a system shaped by hundreds of millions of years of evolution (as is the case with the immune system) may on occasion fall short of its goals or be mistaken, we might reflect upon our own much more recent attempts at ensuring that ‘justice is served’, and further that ‘with great power comes great responsibility’.

Autoimmunity

Having outlined earlier the process by which the immune system develops so as not to react with its ‘self’, there are nonetheless occasions when this does happen and causes disease. There are a whole range of autoimmune conditions that range from the tar-geting of specific tissues, producing clearly defined conditions, to more broad ranging autoimmunity in which a variety of tissues may be targeted, producing a range of symptoms throughout the body. Due to the inherent complexity of the immune system and the challenges in unravelling its specific activities within the body, clearly defining the precise causes and progression of such condi-tions is often difficult – and not all have been clearly characterised. When considered together, this often makes the development of effective treatments a far from easy prospect – although a great many inroads have been made.

In simple terms, as stated earlier, it is increasingly understood that not all immune cells reacting to ‘self’ are merely deleted during development – some are retained but placed under close regula-tion. This may be because they only react weakly with ‘self’ tissue and are preserved, albeit under supervision; perhaps so as not to narrow the range of immune recognition too greatly – they may provide an ‘ideal fit’ for a pathogen at some point in the future.

There is increasing evidence for a range of ‘regulatory’ T cells that control the reactivity of effector cells, and these may perform the role of regulating those ‘intermittently’ useful effector cells already mentioned, as well as playing an important role in dynamically shaping the reactivity of the immune system; so that instead of the simple deletion/retention response, a much more flexible range of recognition is made possible – so that on occasion a more ‘risky’ immune cell may be employed, but under controlled conditions. There are occasions, however, on which for some reason a strong-ly reactive ‘self’ cell may escape deletion, producing the highly specific symptoms found in some autoimmune conditions – the reasons for this are not entirely clear. It is possible that the shape recognised by the particular cell was not present at the time the decision making process was happening (for example, hormones

that appear during puberty) or instead was hidden behind a barrier (for example DNA, ribosomes etc., within a cell membrane).

The downside of the regulated approach is that it relies upon ac-tively damping down aspects of the immune response, and if for some reason this control is affected – perhaps by other physiologi-cal conditions in the body – there is the possibility of the develop-ment of autoimmunity. Added to this, if control isn’t restored the activities of the immune system, as we have already seen, may pro-duce a ‘self-sustaining’ effect whereby the initial reaction causes cell damage and inflammation which then induces further immune responses, producing yet more damage, and so on. If the damage is severe, this may induce permanent changes to tissues such that they provoke an ongoing immune response.

We will here briefly outline a few examples of such condition (also supported by posters available on the BSI website).

Type 1 Diabetes (formerly known as ‘juvenile’ diabetes, due to its early manifestation) is a condition caused by lymphocytes reactive with the beta cells in the pancreas that are responsible for secret-ing insulin. Insulin is a vital hormone controlling entry of glucose into cells and without it cell physiology is affected and also glu-cose begins to build up in the blood, producing a range of serious symptoms. At present, it can only be controlled by administering insulin – and immunological research is focused on switching off or neutralising the self-reactive cells on a long-term basis.

Multiple Sclerosis occurs when the immune system attacks the my-elin sheath that surrounds nerve axons – this can severely hinder nerve impulses. The condition can cause a range of symptoms re-lated to damaged nerves, and loss of muscle use, such as blind-ness and paralysis. It is usually progressive and may be fatal. The condition still isn’t clearly understood, and this hinders attempts to treat it.

Rheumatoid arthritis occurs when the immune system attacks cartilage and bone in the joints. It is an example of a runaway immune reaction, whereby the immune response produces changes in the tissue that provoke further responses. There are a variety of therapies that may alleviate symptoms, but no complete cure has yet been developed. One effective approach uses a monoclonal antibody to block the effect of an inflammatory molecule called TNFα, thereby helping to reduce the degree of immune escalation.

Vaccinology & Therapeutics

There is no doubt that since its first recorded experimental use by Dr Edward Jenner in 1796 to immunise against smallpox, the prin-ciple and practice of vaccination has been a hugely powerful tool for aiding human health. As we stated earlier, vaccines mimic the initial exposure of the body to a given pathogen, without danger of developing the full-blown infection. This prompts the body to recruit effector/memory cells (fully trained ace investigators from ‘lymph node HQ’) specific to that pathogen, so that if and when it is encountered ‘for real’ the body already has the specific resources at its disposal to instantly counter the threat. This addresses the one major weakness in the Adaptive/Acquired immune response – the time required in order for it to develop an effective specific response – which in the case of many infections is time the body doesn’t have.

A range of options for vaccine constitution are available – live at-tenuated (meaning rendered non-pathogenic) vaccines produce potent results since the organism is still able to replicate, ensuring a healthy immune response. However, there is a small chance of reversion to the pathogenic form. Whole killed pathogens are per-haps next in potency, and avoid the danger of the latter.

Beyond this, researchers may instead concentrate on a handful of chosen target molecules. Substances called ‘adjuvants’ are potent stimulators of immune responses in their own right, and can fur-ther increase the effectiveness of a given vaccine. Finally, so-called DNA vaccines have the potential to revolutionise the domain of vaccinology. This involve the introduction of DNA strands (either ‘naked’ or contained with viral vectors) into the host – the DNA is taken up by cells and ‘read’ by them to generate the target mol-ecule. If targeted at the appropriate antigen-presenting cell (e.g. dendritic cells) these molecules can be quickly presented to the immune system. DNA vaccines are presently in development, and although there are current difficulties in generating sufficiently po-tent immune reactions – they have the potential to be ‘packaged’ such that they are relatively heat stable and cheap. Other forms of vaccine may be extremely sensitive to heat, and this introduces difficulties when trying to employ them, for instance, in the Devel-oping World.

Concerted use of the smallpox vaccine throughout the world by the World Health Organization led to its eradication by 1979, and a similar programme is being pursued for poliovirus. Less virulent, but still potentially serious infections such as mumps, rubella, chick-enpox, and measles are routinely controlled by vaccination. Tuber-culosis is effectively controlled in the Developed World through the BCG vaccine, however due to misuse of antibiotics, leading to the development of resistance, and problems with its effectiveness or availability in the Developing World, researchers are required to ac-tively look for novel vaccines and therapeutics to counter it. Other infections, particularly viruses, are proving less easy to treat – and this is usually down to extreme variability in the viral coats that are the natural target for any vaccine. Such problems, amongst others, are encountered with HIV, Hepatitis C and Avian Influenza viruses. In other cases, the sheer complexity of the target pathogen’s life cycle, together with various strategies it has developed to evade detection make the job harder – this applies particularly to the malaria parasite.

As we have hinted elsewhere, there are other means by which the immune system may be manipulated, such as influencing the regu-latory elements such that an immune reaction is either upregulat-ed or downregulated, according to the therapeutic requirements. Further approaches involve blocking or stimulating certain signal-ling molecules or receptors in order to produce a desired outcome – and in this sphere monoclonal antibodies (all of a single spe-cificity) are seen as ideal means to ‘throw’ molecular switches. As always, however, the complexity of the immune system requires that any possible consequences of such therapeutic manipulation must be fully thought through before proceeding.

Cancer

Cancer develops when, in the context of our Body Metropolis, a set of cells becomes ‘selfish’ and no longer regulates their rate of cell division, according to the needs of the body as a whole. Therefore, the numbers of such cells begin to expand relative to other tissue types. The expanding clump of cells is called a tumour. Although the immune system does have a means to recognise cancerous cells, via the system of ‘house-to-house’ enquiries performed by the cytotoxic T cells (Tc) and Natural Killer cells referred to earlier, they are not able to control all of the many forms of cancer that may arise.

Although the development of cancer represents the ultimate ‘be-trayal’ of the body by its cells, it is worth remembering that despite being ‘body cells gone bad’, tumour cells still have access to all of the vast physiological and signalling resources available within the body. Many of them exploit this fact to actively block the immune response, as well as hitching a ride around the body via the blood-stream to colonise other sites. They are ultimately like traitors or double agents who have ‘gone over to the other side’, yet manage

to keep their ultimate intentions secret because they have such an intimate knowledge of how the cellular society operates. As such, they are in many respects the immune system’s worst nightmare – a friend turned enemy who knows all of your secrets and strate-gies! This is why we included a caveat in our earlier description of how the immune system eliminates or controls cells reactive to ‘self’ on the assumption that body cells will generally always behave themselves. In this situation this means that the body is unable to mount an effective response, even if it wants to, due to such flawed assumptions!

Immunology has enormous potential to treat cancer through spe-cialised vaccines. It has been noted that cancer cells do indeed sometimes display distinctive markers that can be used to specifi-cally identify them – and these are potential targets for vaccines. However, as they are essentially ‘self’ tissue, it is absolutely vital that there is absolute certainty that they are specific to the cancer-ous cells. To induce an acquired immune response to markers that are in fact found elsewhere in the body is akin to inducing a form of generalised autoimmunity, and the consequence could be both serious and long term.

A further immunological strategy is to alter the degree of regula-tion that certain effector cells are subject to, via therapies targeted at the very specific regulatory T cells mentioned previously. This would allow certain cells specific to ‘self’ markers present on the surface of cancer cells, that are ordinarily strictly controlled, to be freed from restraint under controlled conditions, allowing the im-mune system to remove its ‘self’ blinkers and see the enemy sitting right under its nose! Again, such an approach would require very careful selection of cellular targets.

In conclusion, there is still much to learn about cancer as a condi-tion, before we can properly employ the immune system to counter it, although the recent development of a vaccine for the sexually transmitted virus human papillomavirus (HPV), a significant causa-tive agent for cervical cancer in women, brings hope that there are additional indirect strategies that may be employable under certain circumstances.

Transplantation Science – The Reward for Years of Hard Graft!

We conclude with one of the great success stories of the last fifty years of Immunology – the development of transplantation sci-ence. Here the elegant and rigorous work of many notable re-searchers has allowed important principles of immune recognition to be uncovered and applied in an important clinical setting – the transplantation of organs and tissues from one indi-vidual to another.

Attempts to transplant skin (and sometimes tissues) for the pur-poses of repairing severe injuries had been attempted for several centuries prior to the 20th Century, however although skin grafts could be successfully transplanted from one part of a given indi-vidual to another part, attempts to graft between individuals in-variably failed – with the graft rapidly degrading.

Before the work of Peter Medawar and others, from the 1940s on-wards, the underlying reasons for this were unknown. It was only through careful experimentation that the essential principles were identified – and that the immune system was ultimately responsi-ble. Having already explored the principle by which a developing individual’s immune system safeguards against attacking ‘self’ tis-sue in preceding sections (whilst retaining recognition of foreign pathogens), we now introduce a further level of complexity to proceedings. For a variety of reasons, the range of certain pro-teins and receptors expressed on human body cells varies between individuals; both in terms of whether a particular protein is present or not, and also in terms of which ‘variety’ of a particular type of

receptor is expressed (in the same way that hair may broadly be defined as just ‘hair’, but more specifically in terms of its colour: black, brown, or blonde). Closely related individuals are more likely to express a similar cocktail of surface features, however (except in the case of identical twins) the degree of variation is striking.

A given individual recognises his or her own cocktail of surface proteins as part of ‘self’ – however, if a graft or organ from anoth-er individual differing markedly in this respect is introduced, these foreign features raise an alarm within the host body, and cause the immune system to swing into action.

By focusing on this aspect of immune recognition, it was gradually realised that certain surface proteins were potent stimulators of graft or organ rejection, and from this sprang the whole principle of ‘tissue typing’ that underlies the matching of organs or grafts to recipients used today in transplantation science. By matching both the varieties of receptors, and ranges of proteins, expressed on donor and recipient tissue, the likelihood of a damaging im-mune response is minimised – although, unless transfer is between twins, the match is never absolutely perfect. Because of this, im-munosuppressive drugs are generally required to dampen down the immune response of the host post-transplantation, and despite their increasing sophistication, the transplant is still vulnerable to the immune system, whilst the host is made more vulnerable to infection.

Despite initial shortcomings, following the first successful heart transplant carried-out by Dr Christiaan Barnard in 1967, transplan-tation of a number of body organs and tissues (heart, lungs, liver and kidneys) has now become an almost routine part of the surgi-cal repertoire – with ever improving outcomes for the patient.

However, a principle that we detailed earlier, which sprang directly from the work of Peter Medawar and contemporaries, and that could still yet revolutionise the arena of transplantation, is ‘immu-nological tolerance’ – the body tolerising itself to ‘self’ antigens. It was recognised both that this was a crucial phase in the early development of the immune system – and that it had potential for use as part of transplantation. It was noted that foreign tis-sue introduced into an organism during the tolerant phase could nonetheless be accepted as ‘self’ tissue, without rejection, due to the special conditions in force at this time. Somehow mimicking this process in a mature recipient of a donated organ or tissues could revolutionise the discipline – and remove the need for the use of immunosuppressive drugs. Our friends the regulatory T cells may be key to this development.

Although the considerable challenges are not to be underestimat-ed, such tantalising goals are what help to drive each new genera-tion of immunological researchers!

Daniel PriceSenior Publications Editor, British Society for Immunology

Acknowledgements

The author is eternally grateful to the BSI’s Education Secretary, Professor Tracy Hussell, for her invaluable comments and input into this work – bringing a professional immunologist’s eye to pro-ceedings! The translation of the text and images into a suitable web format, together with the posters, would not have been pos-sible without the technical wizardry of Leslie Owusu-Appiah.

In addition, Roitt’s Essential Immunology 11th edn and Essentials of Clinical Immunology 5th edn (both Blackwell Publishers) both provided stimulating and essential information about the detailed functioning and interrelationships of the various mechanisms de-scribed.

You can find further information on the BSI website: www.immunology.org