The immune system in health and disease
This essay was written by Victor Tybulewicz and was first published in the 2000 Mill Hill Essays.
Every day of our lives we come into contact with a large variety of microorganisms such as viruses, bacteria and fungi. Many of these, known as pathogens, are capable of causing disease, yet most of the time we do not succumb to infection. Moreover when we do, the course of disease is usually short-lived. The reason we are able to ward off these microbes is because of our natural defenses which are known as the immune system. This system manages to eliminate very efficiently most incoming microorganisms, often without us realizing we have even been infected.
Its importance can best be seen in those patients in whom it is defective. This situation, known as immunodeficiency, results in frequent, overwhelming and sometimes life-threatening infections. Perhaps the best known cause of such a condition is infection with the virus HIV leading to Acquired Immunodeficiency Syndrome or AIDS. This virus infects and destroys particular cells of the immune system, without which the patient becomes very susceptible to a variety of bacterial, viral and fungal infections. It is these secondary infections and not the original HIV infection which are life-threatening. Immunodeficiencies are also caused by certain rare genetic diseases. Perhaps the best known of these is Severe Combined Immunodeficiency which made the headlines in the 1970’s with the famous case of David, “the boy in the bubble”. Infants born with Severe Combined Immunodeficiency usually die of overwhelming infections within the first year or two of life. However David was placed in a large plastic chamber which was kept completely sterile. He survived in this chamber until he was twelve, though eventually he too died of infection.
Another common immunodeficiency occurs following treatment with drugs which damage the immune system. For example, immunodeficiency is a common side effect of chemotherapy for cancer and patients undergoing such treatment become more susceptible to infections. All of these examples illustrate how we are being continuously exposed to potentially dangerous microorganisms and how most of the time our immune system eliminates them without us even being aware of the threat.
So, how does the immune system provide this kind of protection? The study of the immune system is relatively recent and its origins can be traced to Edward Jenner in the late eighteenth century. He discovered that humans could be protected against smallpox by inoculation with cowpox, also known as vaccinia, a relative of the smallpox virus. This procedure became known as vaccination and has become one of the most effective methods of combating infectious diseases. The principle of vaccination is that the vaccinated individual develops a specific immune response against cowpox which, because of the similarity of the viruses, also provides protection against smallpox. So effective is this procedure that a World Health Organization driven vaccination campaign against smallpox finally eliminated the disease completely in 1979, the first, and so far only, human disease to have been completely eradicated.
The next major advance in the study of the immune system came at the end of the nineteenth century with the discovery that the blood serum of animals that had been vaccinated contained substances known as antibodies, which specifically bound to the pathogenic organism. These, if transferred experimentally to another animal, resulted in the recipient becoming protected against the infection. Antibodies turned out to be proteins known as immunoglobulins which circulate in the blood and are a crucial component of the immune system’s defense against pathogens. The substances to which antibodies bind, for example viral proteins, are called antigens and it was shown that animals can make antibodies specific for a vast array of different antigens. How this is accomplished became a major focus of research for many decades. Work at the National Institute for Medical Research and at the Rockefeller Institute in New York unravelled the structure of immunoglobulins and showed that the portions of these molecules capable of binding to antigens were extremely variable. Further work showed that the way this variability was achieved was by an unusual mechanism operating at the level of the genes which contain the information required to make immunoglobulin proteins. It turned out that these genes exist in hundreds of small segments which are joined together in many different combinations to produce immunoglobulin genes with sections that are extremely variable, resulting in the potential production of tens of millions of different immunoglobulins. This vast diversity is the key to the ability of organisms to mount effective immune responses against the huge array of different pathogens they may encounter.
But where do these antibodies come from? A key discovery made in the 1960’s showed that certain white blood cells known as lymphocytes are critical for the immune response; if these cells were eliminated from rats they were incapable of mounting such a response. Lymphocytes circulate in the blood and the lymphatic system, patrolling the body for signs of infection, and come in two major types, B and T lymphocytes. B lymphocytes produce antibodies and are thus able to combat pathogens that are found in the blood or other body fluids. However some pathogens, in particular viruses, infect cells and are hidden inside them where they cannot be detected and eliminated by antibodies. These kinds of infections are dealt with by T lymphocytes which use a specialized protein on their surface known as a T cell receptor to probe the surface of potentially infected cells. Virally infected cells show characteristic changes in another set of cell surface proteins and it is these that are detected by the T cells through their T cell receptors. Once a T cell recognizes such an infected cell it then latches on to it and kills it, thereby preventing the virus replicating.
Like the antibodies produced by B lymphocytes, the T cell receptors on T lymphocytes need to be able to recognize a very large number of different pathogens. Work in the 1980’s showed that just like the immunoglobulins, the genes for the T cell receptor also undergo a process of joining together of many different gene segments producing a potential repertoire of millions of T cell receptors, with the ability to recognize a vast number of different pathogens.
The gene rearrangements that give rise to antibodies and T cell receptors are random in nature: sometimes they result in useful proteins which can recognize pathogens, but they can also generate proteins which react with the body’s own tissues. Clearly this would be disastrous since it would lead to the immune system attacking and destroying healthy cells. In healthy individuals the immune system does not do this, and is thus said to be tolerant of “self” tissues. The mechanism whereby the immune system achieves such tolerance has been a focus of research for many decades. It is now known that during their development, lymphocytes potentially capable of reacting against self-antigens are specifically eliminated by a process known as “education”. In other words, the developing immune system has to learn to distinguish between the body’s own antigens and foreign antigens, such as those of pathogens. Research has shown that the immune system of newborn animals undergoes such education, actively acquiring self-tolerance in the first few weeks of life. If newborn mice are injected with tissues from a different strain of mice, their immune system treats these as self-tissues and becomes tolerant to them. In contrast, a similar treatment of adult mice fails to generate tolerance, but rather induces the mice to mount a vigorous immune response and hence reject the foreign tissue.
This work illustrates another feature of the immune system: animals will mount an immune reaction not only to pathogens, but also to tissues from another animal, as long as these are sufficiently different. The relevant differences perceived by the immune system are primarily differences in the HLA molecules. These are molecules found on the surface of most cells in the body and are recognized by T lymphocytes through their T cell receptors. This reaction to “non-self” tissues is of interest beyond the narrow confines of experimental science, because it is also the underlying cause of rejection of transplanted organs. Organ transplantation has become a routine surgical procedure, but it owes its success to the ability of the physician to control the immune response of the patient to the transplant. Such control is essential for long-term survival of the grafted organ. It is achieved by attempting to choose an organ donor whose HLA molecules are as similar to the HLA molecules of the patient as possible – the more closely matched, the less chance of an immune response which might cause organ rejection. In addition, the patients are given drugs such as Cyclosporin which suppress their immune system and thus stop rejection. However these drugs are sledgehammers in their mode of action, suppressing all immune responses not only to the transplanted organ, but also to any pathogens, so the patients become more susceptible to infections. A holy grail of current transplantation research is to find ways of selectively suppressing the immune response to the transplanted organ, without affecting the general immune response to pathogens.
The immune system has evolved mechanisms to avoid reacting to self. However this state of tolerance occasionally breaks down, with potentially serious consequences leading to “autoimmunity”. One of the most common autoimmune diseases is rheumatoid arthritis. This debilitating disease results from an immune reaction against joint tissues, causing extensive damage to the joints and eventually extreme disability in the patients. The cause of this autoimmune condition is unknown, but one plausible explanation is that the trigger for the disease is infection by a pathogen which contains an antigen that looks similar to an antigen in joint tissues. Thus, while mounting an effective response against the pathogen, the immune system accidentally generates lymphocytes capable of attacking joints. Proof of such a hypothesis awaits isolation of a pathogen which can effectively mimic antigens in joint tissues. Another extremely debilitating autoimmune disease is multiple sclerosis. In this disease the immune system generates lymphocytes which attack and destroy nerves, leading to paralysis of the patient. Once again the cause is unknown, but triggering by mimic antigens on pathogens has been postulated. Certain forms of diabetes are also caused by an autoimmune reaction which destroys cells in the pancreas that produce insulin, a hormone which is required to control levels of sugar in the blood.
Much of the ongoing research in autoimmunity is geared towards understanding the triggers for the diseases, so as to be able to eliminate them and thus prevent the onset of disease. Other research is aimed at developing methods for selectively stopping autoimmune reactions after they have started in order to limit the damage being done by auto-reactive lymphocytes. A recent report from a team at University College London has shown one possible way forward. These researchers treated rheumatoid arthritis sufferers with drugs that eliminated their B lymphocytes, cells which are key in the autoimmune reaction, resulting in an improvement in their condition. Most interestingly, as new B lymphocytes were formed in these patients, they seemed to become “re-educated” to be tolerant of self tissues and no longer mounted attacks on the joints. Currently very few patients have been treated, and they have not been followed for long enough to know if the treatment will give any long-term relief from the disease, but the early results are promising.
While autoimmunity is caused by inappropriate immune responses against self antigens, the immune system can also react inappropriately against foreign antigens, a phenomenon known as hypersensitivity, or allergy. Allergies are caused by a strong immune response to a foreign antigen that is completely innocuous to most people, for example hayfever is an allergic reaction to grass or tree pollen. To develop such an allergic condition the individual needs to be first exposed to the allergen, pollen, and mount an antibody response which includes a type of immunoglobulin called IgE. Following the next exposure to pollen, IgE coats the pollen and in turn binds to white blood cells called mast cells found in mucosal tissues such as those lining the nasal passages and the lungs. Reaction with the pollen-bound IgE causes mast cells to release various chemicals such as histamine that result in the secretion of mucus leading to the familiar symptoms of hayfever. While hay fever is usually a relatively mild condition which can be effectively controlled by anti-histamines, occasionally people can develop very strong allergic reactions leading to a condition known as anaphylactic shock where the sufferer has great difficulty breathing and may die. For example some individuals become extremely hypersensitive to nuts, so that exposure to even the smallest trace quantities can trigger anaphylactic shock.
Asthma is another common disabling allergic disease. This is believed to result from repeated allergic reactions within the lungs leading to a chronic inflammation of the airways. Hence, the patient becomes very sensitive to changes in temperature or airborne pollutants. These can trigger an asthmatic attack, characterised by constriction of the airways of the lungs and increased mucus production, making breathing very difficult. In the extreme, such attacks can be life-threatening. The causes of asthma are unknown, but it has been well documented that its incidence has been increasing dramatically in Western countries over the last fifty years. A commonly held belief is that the increase is due to an increase in airborne pollutants. However this is almost certainly not true, because the level of pollution has actually been decreasing in most developed countries whilst the incidence of asthma was rising. Furthermore New Zealand, a country widely praised for its clean environment has high rates of asthma, whereas areas of Eastern Europe with high levels of air pollution, for example the coal mining areas of the Czech Republic and southwestern Poland, have relatively low rates of asthma. This misconception is probably based on the observation that air pollution can trigger asthmatic attacks. While this is true, it only occurs in individuals who have already developed asthma. In contrast, pollution itself does not seem to be the primary cause for the development of the disease.
Rather than correlating with pollution, the rise in asthma and allergies correlates better with increasing prosperity. One intriguing hypothesis suggests that it is our hygiene that is to blame – that we have too much of it. In particular, it has been proposed that living in ever cleaner environments we are no longer being exposed to such a wide variety of pathogens during our childhood as in the past, so the immune system does not have enough things to respond to. In the absence of these infections, with nothing better to do, the immune system makes mischief by mounting exaggerated responses to innocuous substances such as pollen or nuts. There is some evidence supporting this idea. The characteristic of the allergic immune response is the generation of IgE, which is normally used to fight infections by parasites such as worms that infect the gut. These kinds of infections have become rare in prosperous developed countries, whereas they are still common in the developing world, where the incidence of allergies is low. Furthermore, within developed countries the risk of asthma and allergy is lowest amongst individuals growing up in close proximity to animals, for example with domestic pets or on a farm with livestock. Perhaps children in these environments are exposed to a wider variety of pathogens than those living in animal-free surroundings. If immunologists can succeed in identifying which microorganisms we need to be exposed to, in order to avoid asthma, it may eventually be possible to inoculate children with a cocktail of such microbes. This would thereby deliberately generate immune reactions and hopefully prevent the immune system from being diverted into mounting useless or even dangerous allergic responses.
The future of immunological research promises to be very exciting. Research now is aimed at trying to understand the detailed mechanisms of how the immune system responds the way it does. Such knowledge may eventually allow us to design subtle therapies to selectively augment or diminish immune responses against particular antigens. As mentioned earlier, this would allow treatment of autoimmune diseases by selectively turning off the response to self antigens without affecting the ability of the immune system to respond to foreign pathogens. Similarly such a selective desensitization might be an effective way to treat allergy or asthma, or to control transplant rejection.
The converse, selectively increasing immune responses, may become a very useful therapeutic tool in other diseases, particularly cancer. A promising new approach to treating cancer is to try and generate an immune response against the cancer itself by vaccinating the patient with their own cancer cells, or with extracts from the tumour. Usually cancer cells are ignored by the immune system, because they are seen as “self”. However, there is good evidence that the tumour may carry antigens that are not present on other cells. If this is the case, it may be possible to force the immune system to mount a response against these antigens and thereby eliminate the cancerous cells. The immune system is an ideal tool for this purpose since it is designed to get access to most, though not all, parts of the body and since it is capable of eliminating every cell carrying an infection, it should be able to do the same to cancer cells. While early clinical trials of “cancer vaccination” have shown some limited success, the method is not yet able to cure cancer. However these are early days and the hope is that in due course research will reveal better ways to effect such therapy.