Healthy humans have an extremely specific and powerful system for resisting infectious agents. This system is called adaptive or acquired immunity, sometimes known as the third line of defense. It is responsible for the long-term protection we develop through infections or vaccinations. The absolute need for adaptive immunity is impressively documented in children with genetic defects in this system or in patients with AIDS, who have lost it. Even with heroic measures to isolate the patient, combat infections, or restore lymphoid tissue, immunodeficient people are constantly vulnerable to life-threatening infections.
Acquired adaptive immunity is the product of a dual system of specialized leukocytes—the B and T lymphocytes. During fetal development, these lymphocytes undergo a selective process that pre pares them to react only to one specific antigen. During this time, immunocompetence, the ability of the body to interact with a wide spectrum of foreign substances, begins to develop. Through this process, an infant is born with the theoretical potential to produce an immune response to hundreds of millions of different foreign molecules or antigens. But the completion of this immunocompetence takes many years, extending into late puberty.
Antigens are defined as any molecules that can stimulate a response by T and B cells. They consist of protein, polysaccharide, and other compounds from cells and viruses. Environmental chemicals can also be antigens, as we shall see in section 16.2 dealing with allergy. In fact, any exposed or released substance is potentially an antigen, even those from our own cells. For reasons we discuss later, our own antigens do not usually evoke a response from our own immune systems, but they may do so in other people.
In chapter 14, we discussed pathogen-associated molecular patterns (PAMPs) that stimulate responses by phagocytic cells during an innate defense response. PAMPs are molecules shared by many types of microbes that stimulate a nonspecific response. In contrast, antigens are molecules unique to a microbe that stimulate specific immune responses. The two kinds of molecules do share two characteristics: (1) they are “parts” of foreign cells (microbes) and (2) they provoke a reaction by the white blood cells of the host.
Two features that make adaptive immunity very different from innate immunity are specificity and memory. Unlike mechanisms such as anatomical barriers or phagocytosis, acquired immunity is selective. For example, the antibodies produced against the chicken pox virus during an infection will protect against that virus but not against the measles virus. Demonstrating memory means that lymphocytes have been programmed to “recall” their first engagement with an invader and respond rapidly to that same invader during subsequent exposures, which is a critical feature of immunity. These topics will be covered in greater depth in several later sections.
An Overview of Specific Immune Responses
Immune responses are highly complex and regulated, and they rep resent one of the most elegant and coordinated networks of cells and chemicals in the body. To present this system in an organized manner, we have found it helpful to divide it into separate but related sections, each detailing some event in development of the immune response. The sections of coverage are as follows:
I. Development and differentiation of the immune system
II. Lymphocyte maturation and the nature of antigens
III. Immune reactions to antigens and the activities of T cells
IV. Immune activities of B cells and the production and actions of antibodies
As we explore the information contained in these sections, we will be following a “map” of sorts. Process figure 1 lays out the flow of the main stages and will serve to coordinate the presentation. It also includes figure numbers that enlarge on the topics in that section.
Fig1. Overview of the origins and events of adaptive immune responses.
Development of the Immune Response System
Before we examine lymphocyte development and function in greater detail, we must initially review concepts such as the unique structure of molecules (especially proteins), the characteristics of cell surfaces (membranes and envelopes), the ways that genes are expressed, immune recognition, and identification of self and non self. Ultimately the shape and function of protein receptors and markers protruding from the surfaces of certain white blood cells are the result of genetic expression, and these molecules are responsible for specific immune recognition and, thus, immune reactions.
Markers on Cell Surfaces Involved in Recognition of Self and Nonself
Chapter 14 touched on the fundamental idea that cell surface receptors confer specificity and identity. A given cell can express several different receptors, each type playing a distinct and significant role in detection, recognition, and cell communication. Major functions of immune receptors are as follows:
● to recognize and attach to nonself or foreign antigens,
● to promote the recognition of self antigens,
● to receive and transmit chemical messages among other cells of the system, and
● to aid in cellular development.
Because of their importance in the immune response, we concentrate here on the major receptors of lymphocytes and macrophages.
Major Histocompatibility Complex One set of genes that codes for human cell receptors is the major histocompatibility complex (MHC). This gene complex gives rise to a series of glycoproteins (called MHC molecules) found on all cells except red blood cells. The MHC is also known as the human leukocyte antigen (HLA) system. This receptor complex plays a vital role in recognition of self by the immune system and in rejection of transplanted tissues.
The functions of the MHC groups have been identified. Class I MHC genes code for markers that display unique characteristics of self and allow for the recognition of self-molecules and the regulation of immune reactions.
The system is rather complicated in its details, but in general, each person inherits a particular combination of class I MHC (HLA) genes in a relatively predictable fashion. Although millions of different combinations and variations of these genes are possible among humans, the closer two people are related, the greater the probability their MHC profiles will be similar. Individual differences in the exact inheritance of MHC genes, however, make it highly unlikely that even closely related persons will express an identical MHC profile. This fact introduces an important recurring theme: Although humans are genetically the same species, the cells of each individual express molecules that are foreign (antigenic) to other humans. This is where the term histo- (tissue) compatibility (acceptance) originated. This fact necessitates testing for MHC and other antigens when blood is transfused and organs are transplanted.
Class II MHC genes code for immune regulatory receptors. The cells that express class MHC II are grouped together by the term antigen-presenting cells (APCs). This includes macro phages, dendritic cells, and B cells. These are the only “professional” antigen presenters, in that they possess both class I and II receptors necessary for interactions with T cells. See figure 2 for depictions of the two MHC classes.
Fig2. Molecules of the human major histocompatibility complex.
Lymphocyte Receptors and Specificity to Antigen The part lymphocytes play in immune surveillance and recognition is very much a function of their receptors. B-cell receptors bind free anti gens; T-cell receptors bind processed antigens together with the MHC molecules on the cells that present antigens to them. Because antigens are molecules, their chemical structures can vary over a wide range, potentially exhibiting billions of uniquely different structures. The many sources of antigens include microorganisms as well as an awesome array of chemical compounds in the environment. One of the most fascinating questions in immunology is: How can the lymphocyte receptors be varied to react with such a large number of different antigens? After all, it is generally ac cepted that there will have to be a different lymphocyte receptor for each unique antigen. Some additional questions naturally follow: How can a cell accommodate enough genetic information to respond to possibly billions of different antigens? When, where, and how does the capacity to distinguish self from foreign tissue arise? To answer these questions, we must first introduce a central theory of immunity.
The Origin of Diversity and Specificity in the Immune Response
The Clonal Selection Theory and Lymphocyte Development Research findings have shown that lymphocytes use slightly more than 500 genes to produce the tremendous repertoire of specific receptors they must display for antigens. The most widely accepted explanation for how this diversity is generated is called the clonal selection theory. According to this theory, early undifferentiated lymphocytes in the embryo and fetus undergo a continuous series of divisions and genetic changes that generate hundreds of millions of different cell types, each carrying a particular receptor specificity.
The mechanism, generally true for both B and T cells, can be summarized as follows: Certain stem cell lines in the bone marrow will develop into specialized white blood cells such as granulocytes, monocytes, or lymphocytes. The lymphocytic line of stem cells differentiates into either T cells or B cells. Cells destined to become B cells stay in the bone marrow; T cells move to the thy mus. Mature B and T cells then migrate to secondary lymphoid tissues (figure 3). These secondary lymphoid tissues will constantly be resupplied with B and T cells through this series of activities in the primary lymphoid tissues.
Fig3. Major stages in the development of B and T cells.
By the time T and B cells reach the lymphoid tissues, each one is already equipped to respond to a single unique antigen. This amazing diversity is generated by rearrangements of the gene segments that code for the antigen receptors on the T and B cells (process figure 4a). These extensive genetic recombinations give rise to a huge assortment of lymphocytes. Each genetically unique line of lymphocytes arising from this process is termed a clone. All of the cells in a clone display identical protein receptors on their surface, and because of this will react with one specific antigen.
Fig4. Lymphocyte development and maturation. (a) Antigen-Independent Period. (1) During development of early lymphocytes from stem cells, a given stem cell undergoes rapid cell division to form numerous progeny. As cells differentiate, random rearrangement of the genes that code for cell surface protein receptors results in a large array of genetically distinct cells, called clones. Each clone bears a different receptor that reacts with only a single type of foreign molecule or antigen. (2) Lymphocyte clones with receptors that recognize self-molecules and could be harmful are eliminated (clonal deletion). T cells undergo further selection in the thymus, where cells that do not recognize self MHC (and are therefore nonfunctional) are also deleted. (3) Each surviving lymphocyte that exits the thymus is specific for a single antigen molecule. The result is an enormous pool of mature but naive lymphocytes that are ready to further differentiate under the influence of their “home” organs and immune stimuli. (b) Antigen-Dependent Period. (4) Lymphocytes migrate to the lymphatic organs where they are situated to encounter antigens. Entry of a specific antigen selects only the lymphocyte clone or clones that carry surface receptors matching the antigen. This will trigger an immune response, which varies according to the type of lymphocyte involved.
This proliferative stage of lymphocyte development does not require the presence of foreign antigens. But it does require another important action—namely, the removal of clones of lymphocytes that can react against self MHC antigens. The presence of such “forbidden clones” could cause severe damage if the immune system mistakenly identifies self-molecules as foreign and mounts a response against the host’s own tissues. Thus, part of the clonal selection theory says that some clones are eliminated during development through clonal deletion. The removal of such potentially harmful clones is one basis of immune tolerance or tolerance to self. Some diseases (such as autoimmunity) are thought to be caused by a loss of immune tolerance that can lead to immune reactions directed at self.
The second stage of development—clonal selection and expansion—does require stimulation by antigens, such as those that come from microbes. When an antigen enters the body, it encounters specific lymphocytes ready to recognize it. Such con tact stimulates that clone to undergo mitotic divisions and expands it into a larger population of lymphocytes, all bearing the same specificity. This increases the capacity of the immune response for that antigen.
Two important points one can derive from the clonal selection theory are (1) that lymphocyte specificity exists in the genetic makeup of a lymphocyte before an antigen has ever entered the tis sues; and (2) that each genetically distinct lymphocyte expresses only a single specificity and can react to only one type of antigen. Other important features of the lymphocyte response system are detailed in later sections.
The B-Cell Receptor: An Immunoglobulin Molecule In the case of B lymphocytes, the receptor genes that undergo the recombination process are those governing immunoglobulin (Ig) syn thesis. Immunoglobulins are large glycoprotein molecules that serve as the specific receptors of B cells and as antibodies. The immunoglobulin molecule is a composite of four protein chains: a pair of identical heavy (H) chains and a pair of identical light (L) chains (figure 5a). Each light chain binds to a heavy chain, and the two heavy chains bind to each other with disulfide bonds, creating a symmetrical, Y-shaped arrangement.
Fig5. The basic structure and genetics of immunoglobulins. (a) Simple model of an immunoglobulin molecule. The main components are four polypeptide chains—two identical light chains and two identical heavy chains bound by disulfide bonds as shown. Each chain consists of a variable region (V) and a constant region (C). The variable regions of light and heavy chains form a binding site for antigen. (b) The final gene that codes for a heavy or light chain is assembled by splicing blocks of genetic material from several regions (1, 2, 3). These genes are transcribed and translated into the polypeptides that join to form the final molecule (4). (c) Space-filling model of an immunoglobulin molecule. Heavy chains are blue and light chains are teal. The intricate configuration of the proteins where the light and heavy chains come together at the tips of the “Y” provide each antibody with a unique antigen binding site. (c): Molekuul_be/Shutterstock
The ends of the forks formed by the light and heavy chains contain pockets called the antigen binding sites. These sites can be highly variable in shape to fit a wide range of antigens. This extreme versatility is due to variable (V) regions, where amino acid composition is highly varied from one clone of B lymphocytes to another. The remainder of the light chains and heavy chains consist of constant (C) regions whose amino acid content does not vary greatly from one antibody to another.
Development of B-Lymphocyte Receptors During Maturation The genes that code for immunoglobulins lie on three different chromosomes. An undifferentiated lymphocyte has about 150 different genes that code for the variable region of light chains and about 250 genes for the variable (V) and diversity (D) regions of the heavy chains. The constant (C) regions and the joining (J) regions that link segments of the final molecule are represented by only a small number of genes. A result of the extensive genetic recombination that occurs during development is that only a single V and D gene segments are active in the mature cell, and all the other V and D genes have been deleted (process figure 5b).
One can envision this process by comparing it to a molecular “cut and paste.” The gene segments lie in an established sequence along a chromosome. A complex enzyme system randomly selects and cuts out particular blocks of DNA and splices them together. All remaining unused gene segments are permanently removed from the genome of this cell, leaving only the selected segments, which will code for a specific polypeptide receptor. A summary of the steps in the process is as follows:
● For a heavy chain, a variable region gene segment and diversity region gene segment are selected from among the hundreds available and spliced to one joining region gene and one constant region gene.
● For a light chain, one variable, one joining, and one constant gene segment are spliced together.
● After transcription and translation of each gene complex into a polypeptide, a heavy chain combines with a light chain to form half an immunoglobulin; two of these combine to form a completed protein (process figure 5b).
Once synthesized, the immunoglobulin product is transported to the cell membrane and inserted there to act as a receptor that expresses the specificity of that cell and to react with an antigen, as shown in process figure 5. It is notable that for each lymphocyte, the genes that were selected for the variable region, and thus for its specificity, will be locked in for the rest of the life of that lymphocyte and its progeny. But the constant region may be altered to provide different functional properties.
T-Cell Receptors for Antigen The T-cell receptor for antigen belongs to the same protein family as the B-cell receptor. It is simi lar to B cells in being formed by genetic modification, having variable and constant regions, being inserted into the membrane, and having an antigen binding site formed from two parallel polypeptide chains (figure 6). Unlike the immunoglobulins, the T-cell receptor is relatively small and is not secreted.
Fig6. Structure of the T-cell receptor (TCR) for Membrane antigen and CD receptors. The structure of the TCR is similar to that of an immunoglobulin. It consists of two polypeptides that mimic the structure of one “arm” of an immunoglobulin. The TCR has variable regions that can show high levels of diversity for antigens, and constant regions that do not greatly vary. Another class of T-cell receptors, called CD receptors, function in cell signaling. The CD4 and CD8 receptors will be discussed in section 15.3.
With a working knowledge of some factors in the development of immune specificity, we can now continue our coverage of the immune response as outlined in process figure 1.
Specific Events in T-Cell Maturation
The further development and maturation of T cells are directed by the thymus gland and its hormones. The complexity of T-cell function, is partly due to different classes of T-cell surface molecules termed clusters of differentiation or CD receptors added during maturation. CD molecules serve multiple roles as cell receptors and may be involved in cell adhesion and communication in a variety of cells. They are denoted with a number—CD1, CD2, and so on. Our focus will be primarily on two CD groups found on T cells:
CD4 receptors on T helper cells and CD8 receptors on T cytotoxic cells. These CD receptors interact with a particular MHC marker on other white blood cells during immune reactions. As was shown in figure 3, mature T cells migrate to specific sites in lymphoid organs and constantly circulate from there. It is estimated that 25 × 109 T cells pass between the lymphatic and general circulation per day.
Specific Events in B-Cell Maturation
The sites of B-cell maturation exist in certain bone marrow regions that harbor stromal cells. These huge cells nurture the lymphocyte stem cells and provide chemical signals that initiate B-cell development. The result of gene modification and selection is the development of hundreds of millions of distinct B cells (see process figure 4a). Just as T cells do, these naive B lymphocytes travel to specific sites in the lymph nodes, spleen, and mucosal-associated lymphoid tissue (MALT), where they adhere to specific binding molecules. Here they will come into contact with antigens throughout life. B cells display immunoglobulins as surface receptors for antigens.
Table 1 summarizes the main differences in the structure, functions, and actions of B cells and T cells.
Table1. Contrasting Properties of T Cells and B Cells
