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Janeway CA Jr, Travers P, Walport M, et al. Immunobiology: The Immune System in Health and Disease. 5th edition. New York: Garland Science; 2001.

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Immunobiology: The Immune System in Health and Disease. 5th edition.

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The importance of immunological memory in fixing adaptive immunity in the genome

The previously described events that allowed adaptive immunity to occur also made immunological memory possible. However, immunological memory is an invariable feature of all adaptive immune responses in all vertebrates that have evolved beyond the hagfish and the lamprey. The reason is that immunological memory confers a tremendous survival advantage, as it confers the ability to respond more rapidly and more effectively to a second and subsequent challenge by the same pathogen. Moreover, the ability to mount an antibody response, and then to maintain it, protects against many infectious agents. In this part of the chapter, we ask why immunological memory is so important to survival of the organisms that have it, and why it has been preserved throughout the time of the vertebrate radiation, of which we humans consider ourselves the model of the finished product.

Immunological memory is the hallmark of adaptive immunity

Immunological memory is the property of remembering specific adaptive immune responses, and making a greater and more rapid response in the future to the same pathogen (see Fig. 1.20). This property had been noted by Thucidydes in his account of the Peloponnesian war and had been taken advantage of medically by, for example, infecting individuals with dried material taken from smallpox lesions, a process known as variolation, after the smallpox virus Variola major. Today we would interpret this as immunization with an attenuated or killed virus, but at the time the process was known, in most cases, only to produce a mild form of the disease that would protect the sufferer from a subsequent infection with a more virulent form. This was used by the Chinese for many centuries, by the Turks to protect their daughter's beauty, and was communicated to England in the diaries of the Lady Mary Wortly Montague. Jenner subsequently introduced vaccination against smallpox by injecting material from cowpox lesions into the skin. He was counting on the oral reports of milkmaids, who said that their excellent complexions, free of the ravages of smallpox, were due to exposure to cowpox. Of course, he knew nothing of the mechanisms of the protection, but the same basic procedure was used up until the late 1970s, when, thanks to the efforts of a large number of field workers, the last case of smallpox was eradicated. This was a field trial for adaptive immunity and immune memory, and it was a spectacular success.

When we ask why cowpox should protect against smallpox, and what this tells us about the immune system, we learn that cowpox is closely related to the smallpox virus, sharing some of its antigens, and sets up a state of protective immunity to both viruses. The initial infection with cowpox is mild, and can be contained by the primary response of the immune system, but it sets up the conditions for a more potent secondary response that is now able to control the more virulent smallpox infection. The same lesson can be learnt from vaccination against polio with either the Salk vaccine, which is a formalin-killed vaccine, or the later-developed Sabin vaccine, which is a live attenuated poliovirus that establishes a superficial infection that is eradicated. A worldwide effort is underway to eradicate polio by vaccination. It is in its early stages, and the campaign will undoubtedly take longer to accomplish than for smallpox (see Chapter 1), because several different strains of poliovirus have to be eradicated rather than the single strain of smallpox. There are also questions about the best way to carry out vaccination against polio, and about the safety and efficacy of current vaccine stocks. Nonetheless, the World Health Organization (WHO) is pressing forward with its efforts to eradicate polio from the face of the Earth, and we all hope that it succeeds.

Why does vaccination provide long-term immunity to reinfection? Immunological memory provides the answer. What allows the adaptive immune system to make useful responses to attenuated organisms? It is the development of immunological memory that again makes it possible to think of these effects.

Why then does the response to an attenuated pathogen or to a mild infection protect the individual from a fully virulent infection? The answer lies in the nature of immunological memory itself. The adaptive immune response may be thought of in three phases or developmental stages (not to be confused with the three phases of innate immunity, innate induced responses, and the adaptive immune response described in Chapter 1). The first is the naive lymphocyte phase, which accounts for many of the cells in the immune system, and in particular all the newly formed lymphocytes, which have not yet encountered their specific antigens (Fig. 4). The second phase is the phase of the primary immune response, during which the selected lymphocytes expand in numbers very remarkably and differentiate into effector cells. In the response to lymphocytic choriomeningitis virus (LCMV), the numbers of virus-specific CD8 T cells increase more than 105-fold! That is a remarkable expansion, and it happens in a relatively short time, because of rapid cell division. The adaptive immune response is thus a powerful way of markedly increasing by clonal selection, the right combination of gene segments to deal with the particular pathogen, and then to rapidly expand the cell population containing them to mount a primary response that it is hoped has, and usually have, two effects. One is the elimination of the infectious agent, and the other is the generation of memory cells that can rapidly and specifically respond to any reinfection. Memory cells form the third phase of the immune response, and when such LCMV-specific memory T cells are boosted with LCMV, they again undergo rapid proliferation, so that an effective secondary immune response is developed even more rapidly—within a few days. The ability to ‘remember’ a previous response at the cellular level is quite unusual in biology, and represents a remarkable feat of genetic and biological engineering. That is the virtue of a clonal system of host defense. Vertebrates, which have both innate and adaptive immunity, have the combined benefits of nonclonal and clonal immunity, and can therefore survive over a long lifetime in a pathogen-filled environment.

Figure 4. The three phases of the adaptive immune response, naive, memory, and effector cells.

Figure 4

The three phases of the adaptive immune response, naive, memory, and effector cells. Lymphocytes of the immune system can exist in one of three phases. All cells initially are naive lymphocytes, until antigenic stimulation changes their fate. Some become (more...)

Immunological memory allows survival in a world filled with pathogens

As a consequence of the more rapid and intensified secondary immune response, second and subsequent infections with potentially pathogenic microorganisms are often asymptomatic or are mild and of limited duration. The advantage of immunological memory, therefore, is that it allows us to survive without recurring debilitating disease even in a world teeming with pathogens. Viruses usually encountered in childhood give rise to protective immunity, which is relatively easy to mimic in a vaccine with either live attenuated viruses or killed virus particles. A complete list of vaccines currently recommended by physicians in the United States is given in Fig. 14.21. The same vaccines are recommended by most physicians in the first and second world, where they have proved highly successful in reducing childhood illness and mortality. It is in the third world that vaccines are crying out to be developed, as shown by the list of diseases that kill mostly third-world children, and where no effective vaccine exists (see Fig. 14.22).

At this time, immunologists need to focus their attention on two tasks. The first is the preparation and distribution of vaccines to third-world countries, so that their children can have a disease-free childhood and a much longer life expectancy. This is the key to population control in the long term, as parents must first have confidence in the survival of their offspring before population control can become acceptable. The second is the study of the natural course of diseases in these countries, in order to discover ways of preventing them from occurring in the first place. Vaccines are at least part of the solution. I am optimistic about this, as mankind is capable of great feats, as shown by the eradication of smallpox by vaccination. But we need leadership and dedication and understanding, which are human qualities that are in short supply.

Immunological memory for self proteins leads to autoimmune disease

Immunological memory also has its down side, which is a propensity to cause autoimmune disease. We have discussed autoimmunity in Chapter 13, but the contribution of memory cells has been given little emphasis. It is our opinion that without immune memory, there would be no autoimmune disease. Many types of autoimmune disease are found especially in older people. There is, however, at least one exception, and that is autoimmune diabetes, which occurs most frequently in teenagers, and can occur in children as young as 3–4 years old. Its occurrence in childhood has led to attempts to prevent diabetes by immunological means, almost all of which have failed. We believe that this failure is much like the failure to prevent hemolytic disease of the newborn in mothers who have already had a Rh+ child; it is too late to close the stable door, because the colt has already bolted, or more scientifically, an antibody or T-cell response has already been induced.

I and my colleagues would like to try primary prevention measures on children from families that have had one or more diabetic child already, and we think we have the correct antigen for this trial in insulin itself. Early on in work on autoimmune diabetes, certain insulin peptides were found that triggered the CD4 T cells that apparently caused diabetes in mice. Subsequently, it was found that the same peptide, in a shortened form, could be recognized by CD8 T cells, which had the ability to attack the pancreatic β cells themselves. Thus, one of the key proteins recognized in insulin-dependent diabetes mellitus is the insulin molecule itself. An initial trial of insulin injections to create a state of tolerance to these insulin peptides is underway. The jury is still out on whether they will work, but already there is a glimmer of hope in the results.

Summary

There is a lot of evidence that immunological memory is one of the cardinal features conferred on the individual by the existence of adaptive immunity. It is seen in all vertebrate groups that have undergone the immunological Big Bang, and it is found in all vertebrate species that have been tested for it. It also has a down side, in that it contributes to autoimmune disease, which, as we learned in Chapter 13, occurs only in species that have adaptive immunity and is a consequence of their adaptive immune responses.

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By agreement with the publisher, this book is accessible by the search feature, but cannot be browsed.

Copyright © 2001, Garland Science.
Bookshelf ID: NBK27087

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