The immune system is all that stands between us and the hordes of microbes, such as the HIV virus pictured below, that threaten us constantly. But how does the system work? In the first of two supplements, the origins of the human immune system come under the microscope
THE longest that anyone has lived without an effective immune system is 12 years. Doctors at a hospital in Houston, Texas, managed to keep a boy born with “severe combined immunodeficiency” (SCID) alive for this long. But to do so they had to enclose him in the microbe-free world of a plastic bubble soon after birth. The boy had no direct contact with anyone. Nurses passed sterilised food in through an airlock, and he breathed filtered air to ensure that no bacteria, fungi or viruses reached his lungs.
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Doctors hoped to cure the boy eventually by transplanting bone marrow from a relative – bone marrow is the source of all the cells that make up the immune system. But the operation was unsuccessful, and soon afterwards the boy died.
The plight of “the boy in the bubble” illustrates how much we need an immune system. To most microorganisms, our bodies are a huge potential source of food,warmth and living space. Bacteria, viruses, fungi and other microbes are constantly trying to invade us, and to remain healthy we must fight off millions of them daily.
The familiar disease-causing organisms or pathogens – for example, the viruses that cause influenza or measles, for example – are just the tip of the iceberg. These are the “professional” invaders, the ones we are less successful against. It takes time to combat them, so they cause a disease in the process.
There are many more microorganisms, in water, soil, air and food – even in our own digestive tract – that do not cause any disease in normal, healthy people. But when the immune system is defective – as in SCID, or in AIDS – these organisms can invade the body, producing what are called”opportunistic infections”. Most children with SCID die of such infections before they are a year old.
Barriers to infection
The front line
FACED with this onslaught of microbes, how does the normal human body defend itself and stay healthy? To begin with, it keeps out as many potential pathogens as possible with barriers such as the skin, and other nonspecific defences.
The skin, which is waterproof, is impenetrable to most invaders, and it produces fatty acids that many microorganisms find toxic. Areas not covered by skin, such as the eyes, mouth, lungs and digestive tract are more vulnerable, but they have alternative defences. Tears, saliva, urine and other body secretions contain lysozyme, an enzyme that can kill certain types of bacteria by splitting the molecules found in their cell walls. Mucus in the nose and airways engulfs bacteria and stops them penetrating the membranes. Cilia – tiny beating “hairs” – then push the mucus out of the airways into the throat, where it is swallowed. In the stomach, acid kills most of the microorganisms in food, as well as starting the process of digestion.
Helping us to keep pathogens out are a vast population of harmless commensal bacteria. The bulk of these live in our intestines, where they benefit from free food. These bacteria – the “gut flora” – unwittingly help to exclude more harmful microbes by filling all the available ecological niches in the gut. Other commensals live in the vagina and on the skin. The vagina secretes a carbohydrate which the bacteria feed on, producing lactic acid in the process. This makes vaginal secretions acidic and thus hostile to many fungi, bacteria and viruses.
Microorganisms that breach these outer defences are much more difficult to deal with, because the body must somehow distinguish them from its own cells. It also has to kill them without doing too much damage to its own tissues – a task that is far from easy.
Evolution
Layers of complexity
HUMAN BEINGS are not alone in facing these problems: all animals, even the very simplest sponges and worms, have to defend themselves against attack. By looking at the immune systems of such animals, we can see that some parts of our immune defences resemble theirs. This tells us that our immune system has evolved very gradually, over hundreds of millions of years, from simple beginnings to its present complexity. At the same time, certain microorganisms have been continually evolving new ways to overcome our defences. The “biological arms race” with these pathogens has done much to shape our immune system.
During the evolution of the immune system, new types of immune cells have emerged to add to the original, comparatively simple system of lower animals. New control systems have developed to keep these cells in check, and the new and old systems have become integrated so that they work together. This has produced an immune system of quite extraordinary complexity in vertebrates, particularly mammals. Because the system has built up bit-by-bit, it often seems unnecessarily complex and rather illogical. But the important thing is that it works – most of the time.
Among the more recent evolutionary additions are the molecules called antibodies – the one part of the immune system that most people have heard of. Special cells known as B cells, or B lymphocytes, produce the antibodies. The family of cells to which they belong, the lymphocytes, are relative newcomers to the immune system. They have been around for a mere 400 million years, since the early vertebrates appeared on Earth.
The most “primitive” type of immune cell is one that engulfs and digests invaders in the same way that an Amoeba obtains its food – by phagocytosis. All invertebrates, from sponges upwards, have immune cells of this type, called phagocytes. Once they have engulfed invading microorganisms, phagocytes usually kill them, although some cunning types of bacteria block the killing mechanism and thrive inside the phagocytes. There are two methods of killing the invaders, either by digestive enzymes, or by chemical reactions, controlled by enzymes, that release toxic products. Small packages within the cell, known as lysosomes, contain the death-dealing enzymes. These lysosomes give the phagocytes a granular appearance.
There are two main types of phagocytes. The first are large cells with a single, horseshoe-shaped nucleus – the monocytes and macrophages. The second group are smaller cells with an irregular, many-lobed nucleus, known as polymorphonuclear neutrophils, or PMNs. The two groups have slightly different roles within the body.
Macrophages are the principal “rubbish collectors” in the body’s tissues. They develop from monocytes, which occur in the blood but make up only 6 per cent of the white blood cells or leukocytes (the cells in the blood responsible for immunity). The main function of these monocytes is to replenish the macrophage population. After leaving the bone marrow, a monocyte circulates for one or two days in the blood, before squeezing between the cells of the blood-vessel wall and migrating into the tissues. There it develops into a macrophage.
Macrophages may continue to wander through the tissues, eating up microorganisms and other foreign bodies that they find. (Those in the lungs, for instance, engulf dust and fibres, as well as microorganisms.) Other macrophages settle down and attach themselves to certain tissues – principally in the liver, kidney and spleen. These cells lie in wait: they are ready to engulf any invaders or debris, that is travelling in the body fluids that flow past them. Known as the reticuloendothelial system, these sedentary macrophages play a vital role in keeping the body clean internally.
Polymorphonuclear neutrophils, or PMNs, the second type of phagocyte, are much more common in the blood than monocytes, making up 60 per cent of all white blood cells. Every minute of the day, the bone marrow produces 80 million of these cells. They, too, migrate through the walls of the blood vessels into the tissues, and are an essential part of our immune system, wiping out many infections before they have a chance to get going. Unfortunately, researchers use several different names for these important cells, including neutrophils, polys, neutrophil polymorphs, and granulocytes.
PMNs, unlike macrophages, are very short-lived, surviving for no more than a few days. They move towards sites of infection attracted by various chemicals, including some bacterial products and substances that escape from our own cells when the cells are damaged. The PMNs arrive first, but at a major site of infection the long-lived macrophages take over from the PMNs later.
Complement proteins
Helping the phagocytes
PHAGOCYTES are an excellent form of defence, particularly against bacteria. But to be useful to the body, they must “recognise” their target. If they engulfed cells at random, they would cause enormous damage to the body’s own cells. So how do phagocytes identify the enemy?
The cell walls of bacteria are very varied, but there are some chemical features common to all, and others that are characteristic of particular groups of bacteria. Several of these chemical markers stimulate phagocytes into action. Exactly how they do this is unknown, but the inherent “stickiness” of bacteria is probably involved. Bacteria have a habit of sticking to the outer membranes of other cells – a necessary prelude to invading the body. By sticking to a phagocyte, bacteria may unwittingly stimulate it to engulf and digest them.
Phagocytes that can respond to the chemical markers of bacterial cell walls probably represent the simplest type of immune system – some distant invertebrate ancestor of ours could well have developed such cells for its defence. Although the rest of our immune system is the product of hundreds of millions of years of evolution, large parts of it are just a refinement of this system. One of the main roles of antibodies, for example, is to expand the range of invaders that phagocytes can recognise, and improve their ability to engulf those invaders.
One of the earliest refinements to this phagocytic defence force may well have been a group of proteins called complement. These proteins occur in the blood and participate in immune reactions. Macrophages and monocytes synthesise complement proteins, but most come from cells elsewhere in the body, particularly the liver.
The complement proteins are normally inactive, but in the right circumstances they interact to produce various defensive proteins. Some of these complement products stick to invading microorganisms, particularly bacteria and yeasts, making them recognisable to phagocytes as aliens. Others are powerful enzymes, that form a “membrane attack complex” and destroy the membranes of invading microorganisms. A third group of protein fragments attract phagocytes and stimulate them to become more active.
Microorganisms activate the complement system in two distinct ways, known as the classical pathway and the alternative pathway. To trigger the classical pathway, they must first bind to antibodies. The alternative pathway probably evolved much earlier and allows certain microorganisms to activate complement directly, without the involvement of antibodies. The names of the complement pathways are misleading – they merely reflect the order in which immunologists discovered them. From an evolutionary perspective, the alternative pathway is much older. The classical pathway is a new set of reactions, grafted on to the original set to allow complement and antibodies to interact.
Roots of allergy
Killing larger parasites
BACTERIA, viruses and yeasts are much smaller than mammalian cells, so our phagocytes can easily engulf them. But not all invaders are this small. There are many multicellular parasites, such as flukes (parasitic flatworms) and nematode worms, whose size defeats the phagocytes. To deal with these parasites, special types of cell have evolved, known as eosinophils, basophils and mast cells. These cells, like the phagocytes, have granules which contain defensive enzymes. But unlike phagocytes, they can readily release the contents of their granules outside the cell (degranulate). This allows them to attack invaders that phagocytes cannot engulf.
With eosinophils, the main defensive agent in the granules is an enzyme, called major basic protein or MBP. This powerful enzyme breaks down the body wall of parasites such as blood flukes.
The eosinophil has protein receptors that bind specifically to one of the complement proteins. The complement protein concerned binds to these parasites, so the receptors allow the eosinophil to bind to its target via the complement protein. Eosinophils also have receptors for antibodies, which act in the same way as the complement proteins – as “middle men” binding to the parasite. Once the eosinophil has bound to its “middle men”, the cell discharges its granules into the restricted space between itself and the parasite. Because most of the MBP remains within this space it causes minimal damage to the body’s own cells.
The role of mast cells and basophils in fighting parasites is more indirect: they do not appear to release substances that attack the parasite itself. Instead, they produce a variety of mediators, or chemical messengers, that stimulate a concerted attack by the immune system at the site of infection. Some of these mediators attract other cells, such as eosinophils. Other chemical mediators, including histamine and prostaglandins, make the blood vessels dilate and increase the permeability of the capillaries in the vicinity. These changes – which we observe as reddening and swelling, or “inflammation” – allow other white blood cells to reach the site of infection more rapidly.
Mast cells can degranulate in response to various signals. Some of the complement products trigger them directly, adding to the inflammation produced by the complement proteins themselves. Indirect triggering occurs by way of a special type of antibody, known as IgE (immoglobulin E), which will be described in the second supplement.
Although useful against parasites, mast cells can also cause allergies. This happens if the normal control mechanisms break down and the body begins making IgE antibodies in response to harmless substances, such as pollen or cat fur. The mediators released from the mast cells produce the allergic symptoms. In the case of hayfever, for example, there is intense inflammation of membranes in the nose and eyes during the pollen season.
Common origins
Ancient and modern
DESPITE their great diversity, the many cells of the immune system have a common origin in the body. They all develop from a single type of cell, the pluripotent stem cell. During their development, however, stem cells can follow one of two pathways. The first pathway gives a cell called a common myeloid progenitor, that can then develop into a monocyte, PMN, eosinophil, basophil or mast cell – the more “primitive” cells of the immune system. The second pathway gives a cell called a common lymphoid progenitor, that develops into a lymphocyte. Lymphocytes and the lymphatic system are the most recent evolutionary additions to our defences, but they work closely with the more ancient parts of the immune system.
The cells that develop from the lymphoid lineage are even more diverse than those of the myeloid lineage in the ways they attack invaders. The three main groups are B lymphocytes (or B cells), T lymphocytes (or T cells), and null cells, of which the best known type are the natural killer cells (NKs). B cells are responsible for producing antibodies, and are very specific for their target (their “antigens”). By contrast, NKs kill invaders directly, but are not specific. T cells cannot be summed up as easily as the other two groups, because they include at least four different types of cell with contrasting roles. However, they are all specific for their targets, just as B cells are.
This specificity, shown by B cells and T cells, is what marks lymphocytes out from the rest of the immune cells. The phagocytes and other “primitive” cells can respond to widespread chemical markers, such as cell-wall components common to certain bacteria. But this system has distinct limitations. It fails to act against some types of bacteria, and it is not much use against viruses, which are very diverse chemically. The triumph of the lymphocytes, as we shall see in the next supplement, is that they can produce a highly specific receptor for any chemical marker.
How the complement proteins work
THE CENTRAL complement reactionis the splitting of a protein, known as C3. Various enzymes can split this molecule, and the reaction occurs spontaneously all the time. Splitting exposes a reactive surface on C3b which can stick to a bacterial membrane or yeast cell wall. Another protein, called B, can bind to C3b, and when split by one of the proteases forms the new protein C3b,Bb. This acts as an enzyme, and splits C3 very efficiently so it amplifies the original response. But C3b,Bb is quickly inactivated by another protein unless it is bound to the right sort of membrane – so complement is unleashed only when needed.
As the reaction proceeds, the microbe acquires a coat of C3b, and C3b,Bb. Phagocytes have receptors for C3b, so they bind to it and engulf the invader.