Immunology. Richard Coico
the hygiene hypothesis. The first six months after birth are considered the window of opportunity during which contact with specific microbe‐associated molecular patterns triggers a cascade of reactions crucial for infant gut maturation, including the developing mucosal immune system.
GENERATION OF DIVERSITY IN THE IMMUNE RESPONSE
The most recent tidal surge in immunological research represents a triumph of the marriage of molecular biology and immunology. While cellular immunology had delineated the cellular basis for the existence of a large and diverse repertoire of responses, as well as the nature of the exquisite specificity that could be achieved, arguments abounded on the exact genetic mechanisms that enabled all these specificities to become part of the repertoire in every individual of the species.
Briefly, the arguments were as follows.
By various calculations, the number of antigenic specificities toward which an immune response can be generated could range upward of 106–107.
If every specific response, in the form of either antibodies or T‐cell receptors, were to be encoded by a single gene, did this mean that more than 107 genes (one for each specific antibody) would be required in every individual? How was this massive amount of DNA carried intact from individual to individual?
The pioneering studies of Susumu Tonegawa (1987 Nobel laureate) and Philip Leder, using molecular biological techniques, finally addressed these issues by describing a unique genetic mechanism by which B‐cell immunological receptors (BCRs) of enormous diversity could be produced with a modest amount of DNA reserved for this purpose.
The technique evolved by nature was one of genetic recombination in which a protein could be encoded by a DNA molecule composed of a set of recombined minigenes that made up a complete gene. Given small sets of these minigenes, which could be randomly combined to make the complete gene, it was possible to produce an enormous repertoire of specificities from a limited number of gene fragments. This is discussed in detail in Chapter 7.
Although this mechanism was first elucidated to explain the enormous diversity of antibodies that are not only released by B cells but that, in fact, constitute the antigen‐ or epitope‐specific receptors on B cells (BCRs), it was subsequently established that the same mechanisms operate in generating diversity of the antigen‐specific TCR. Mechanisms operating in generating diversity of BCRs and antibodies are discussed in Chapter 9. Those operating in generating diversity of TCRs are discussed in Chapter 10. Suffice it to say at this point that various techniques of molecular biology, that permit genes not only to be analyzed but also to be moved around at will from one cell to another, have continued to provide impetus to the onrushing tide of progress in the field of immunology.
BENEFITS OF IMMUNOLOGY
While we have thus far discussed the theoretical aspects of immunology, its practical applications are of paramount importance for survival and must be part of the education of students.
The field of immunology has been in the public limelight since the successful use of polio vaccines in the mid‐twentieth century. Today, vaccines almost completely eliminate a host of childhood diseases in the United States and other industrialized nations, including those that prevent measles, mumps, chickenpox, pertussis (whooping cough), polio, and tetanus. Advances in the field of immunology with expanded knowledge regarding mechanisms of organ and tissue rejection and tolerance have ushered in successful life‐saving efforts in transplantation of major organs such as heart, liver, pancreas, and kidney, just to name a few. More recently, public interest in immunology has intensified with the use of monoclonal antibodies used in a variety of clinical applications including diagnostic, surgical mapping, and direct (e.g., tumor specific) or indirect (immune system targeted) therapy. It is noteworthy that the Nobel Prize was awarded in 1984 to Köhler and Milstein for their technological advances in the development of monoclonal antibodies and them in 2018, James Allison was awarded the Nobel Prize for launching an effective new way to attack cancer by treating the immune system rather than the tumor.
The innate and adaptive immune systems play an integral role in the prevention of and recovery from infectious diseases and are, without question, essential to the survival of the individual. Metchnikoff was the first to propose in the 1800s that phagocytic cells formed the first line of defense against infection and that the inflammatory response could actually serve a protective function for the host. Indeed, innate immune responses are responsible for the detection and rapid destruction of most infectious agents that are encountered in the daily lives of most individuals. We now know that innate immune responses operate in concert with adaptive immune responses to generate antigen‐specific effector mechanisms that lead to the death and elimination of the invading pathogen. Chapter 19 presents information concerning how our immune systems respond to microorganisms and how methods developed to exploit these mechanisms are used as immunoprophylaxis.
Vaccination against infectious diseases has been an effective form of prophylaxis. Immunoprophylaxis against the virus that causes poliomyelitis has significantly reduced the incidence of this dreadful disease. Indeed, the previously widespread disease smallpox has been eliminated from the face of the Earth. The last documented case of natural transmission of smallpox virus was in 1972. Unfortunately, the threat of biological weapons has prompted new concerns regarding the reemergence of certain infectious diseases, including smallpox. Fortunately, public health vaccination initiatives can be applied to prevent or significantly curtail the threat of weaponized microbiological agents.
DAMAGING EFFECTS OF THE IMMUNE RESPONSE
The enormous survival value of the immune response is self‐evident. Adaptive immunity directed against a foreign material has as its ultimate goal the elimination of the invading substance. In the process, some tissue damage may occur as a result of the accumulation of components with nonspecific effects. This damage is generally temporary. As soon as the invader is eliminated, the situation at that site reverts to normal.
There are instances in which the power of the immune response, although directed against foreign substances—some innocuous such as some medications, inhaled pollen particles, or substances deposited by insect bites—produces a response that may result in severe pathological consequences and even death. These responses are known collectively as hypersensitivity reactions or allergic reactions. An understanding of the basic mechanisms underlying these disease processes has been fundamental in their treatment and control and, in addition, has contributed much to our knowledge of the normal immune response. The latter is true because both utilize essentially identical mechanisms; however, in hypersensitivity, these mechanisms are misdirected or out of control (see Chapters ).
Given the complexity of the immune response and its potential for inducing damage, it is self‐evident that it must operate under carefully regulated conditions, as does any other physiological system. These controls are multiple and include feedback inhibition by soluble products as well as cell–cell interactions of many types, which may either heighten or reduce the response. The net result is to maintain a state of homeostasis so that when the system is perturbed by a foreign invader, enough response is generated to control the invader, and then the system returns to equilibrium; in other words, the immune response is shut down. However, its memory of that particular invader is retained so that a more rapid and heightened response will occur should the invader return.
Disturbances in these regulatory mechanisms may be caused by conditions such as congenital defects, hormonal imbalance, or infection, any of which can have disastrous consequences. AIDS may serve as a timely example: it is associated with an infection of T lymphocytes that participate in regulating the immune response. As a result of infection with the human immunodeficiency virus (HIV), which causes AIDS, there is a decrease in occurrence