suppressing autoimmunity are discussed in Chapter 12.
Cytokine effects. Cytokines produced by each of the T‐cell subsets (principally TH cells) exert numerous effects on many cells, lymphoid and nonlymphoid. Thus directly or indirectly, T cells communicate and collaborate with many cell types.
For many years, immunologists recognized that cells activated by antigen manifest a variety of effector phenomena. It is only in the past few decades that they began to appreciate the complexity of events that take place in activation by antigen and communication with other cells. We know today that just mere contact of the TCR with antigen is not sufficient to activate the cell. In fact, at least two signals must be delivered to the antigen‐specific T cell for activation to occur. Signal 1 involves the binding of the TCR to antigen, which must be presented in the appropriate manner by APCs. Signal 2 involves co‐stimulators that include certain cytokines such as interleukin (IL)‐1, IL‐4, and IL‐6 (Chapter 11) as well as cell‐surface molecules expressed on APCs, such as CD40 and CD86. The term co‐stimulator has been broadened to include stimuli such as microbial products (infectious nonself) and damaged tissue (Matzinger’s “danger hypothesis”) that will enhance signal 1 when that signal is relatively weak.
Once T cells are optimally signaled for activation, a series of events takes place and the activated cell synthesizes and releases cytokines. In turn, these cytokines come in contact with appropriate cell surface receptors on different cells and exert their effect on these cells.
IMMUNE BALANCE
Although the humoral and cellular arms of immune responses have been considered as separate and distinct components, it is important to understand that the response to any particular antigen, be it a pathogen or other foreign molecular structure, may involve a complex interaction between them, as well as the components of innate immunity. All this with the purpose of ensuring a maximal survival advantage for the host by eliminating the antigen and, as we shall see, by protecting the host from mounting an immune response against self. As was pointed out at the beginning of this introductory chapter, the normally tuned immune system continuously aims to maintain homeostasis in the context of host defenses. A complex set of factors influences how our immune system achieves homeostasis or immune balance. These include an individual’s genotype, diet, and environmental conditions, as well as neurological influences related to how we respond to stress and even potential consequences of mental health disorders on immune homeostasis.
The significance of the microbiome on gut–brain–immune system homeostasis has become a major area of study. The community of microbes that reside in our gut significantly impacts the integrity of our mucosal (gut) immune system. For example, when gut barrier integrity is the norm, we live symbiotically with our gut microbiome. In contrast, under abnormal conditions of gut barrier permeability, we can experience gut–brain–immune system dysregulation or microbiome dysbiosis. The latter can occur during periods of high stress, changes in diet, or other lifestyle changes. These conditions lead to immune imbalance that can manifest as chronic inflammation, autoimmunity, and allergic disease. Specific examples of disease associated with increased gut permeability include type 2 diabetes, inflammatory bowl disease, and mood disorders, just to name a few.
It is important to note that in addition to the impact of the gut microbiome on immune homeostasis, we are becoming increasingly aware of the importance of the early gut microbiome for neonatal immune system development and disease pathogenesis. The increase in allergies and other immune‐mediated diseases in industrialized countries has been hypothesized to be a result of deficiencies in early life exposure to microbial organisms and their products, resulting in impaired immune system development. This concept was first introduced as 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
