Chapter 1Elements of the Immune System and Their Roles in Defense

1-1Numerous commensal microorganisms inhabit healthy human bodies

The remit of the immune system is to protect the human body from infectious disease. Most infectious diseases of humans are caused by microorganisms, which are smaller than a human cell. For both benign and dangerous microorganisms, the human body constitutes an extensive resource-rich environment in which to feed, live, and reproduce. More than 1000 different microbial species dwell in a healthy adult human’s gut, and they constitute about 4.5 kg of the body’s weight. They are called commensal microorganisms because they ‘eat at the same table’ as their human host. The entire community of microbial species that inhabits the human body—skin, mouth, gut, or vagina—is called the microbiota. Different ecological niches within the body have distinctive microbiota and are described as the ‘gut microbiota,’ the ‘oral microbiota,’ and so on. The biology of many commensal species has yet to be studied in any depth because they cannot yet be grown in the laboratory. We know they are there, because their distinctive nucleic acid sequences were discovered from analyses of human feces.

Animals coevolve with their commensal species and become both tolerant of them and dependent on them. Commensal organisms enhance human nutrition by processing digested food and making some of our essential vitamins. They also protect against disease, because their presence helps to prevent colonization by disease-causing microorganisms. For example, as well as competing for space, the bacterium Escherichia coli, a major component of the healthy human gut microbiota, secretes antibacterial proteins called colicins that incapacitate other bacterial species and prevent their colonization of the human gut. When a person with a bacterial infection is treated with antibiotics, much of the gut microbiota is killed along with the disease-causing bacteria. After such treatment, the body recolonizes with a new population of commensal bacteria, a situation in which opportunistic bacteria, such as Clostridium difficile, can become established and cause disease. Clostridium difficile is present in small numbers in healthy individuals, but in patients treated with antibiotics it can proliferate (Figure 1.2). It secretes a toxin that inflames the colon. This causes diarrhea and bleeding and can lead to the serious and potentially fatal condition of pseudomembranous colitis.

1-2Pathogens are infectious organisms that cause disease

Any microorganism that causes disease is termed a pathogen. This definition includes microbes such as the influenza virus and the typhoid bacillus that habitually cause disease, and also microorganisms that are usually harmless but cause disease if a person’s immune system and other defenses of the body are weakened. The latter category comprises the opportunistic pathogens. In the early years of the human immunodeficiency virus (HIV) pandemic, when there was no effective therapy, almost all people who became infected died. Their immune systems became worn out by the HIV infection, but their deaths were caused by various opportunistic pathogens.

Pathogens are of four kinds. The viruses, bacteria, and fungi are all groups of related microorganisms. The internal parasites are a heterogeneous group of unicellular protozoa and multicellular invertebrates, mainly worms. In this book we consider the functions of the human immune system principally in the context of controlling infection. For some pathogens this necessitates their complete elimination, but for others it is sufficient to limit the size of the pathogen population and its anatomical location within the human host. Figure 1.3 illustrates the variety in shape and form of the four kinds of pathogen. Figure 1.4 lists common or well-known infectious diseases and the pathogens that cause them. Reference to many of these diseases and the problems they pose for the immune system are made throughout this book.

Over evolutionary time, the relationship between a pathogen and its human host can change in ways that affect disease severity. Pathogenic organisms evolve adaptations that enable them to invade their hosts, replicate within them, and be propagated through a human population. Rapid death of the human host is rarely in a microbe’s interest, because this destroys its home and source of sustenance. Consequently, those organisms with potential to inflict severe and fatal disease often evolve an accommodation with their host. In complementary fashion, human populations evolve a genetic resistance to common disease-causing organisms; the diseases they cause are known as endemic diseases. These diseases, such as measles, chickenpox, and malaria, are ubiquitous in a given population, with most people being exposed during childhood. Because of the interplay between host and pathogen, the nature and severity of infectious diseases in human populations are always changing.

Influenza is an example of a common viral disease that has severe symptoms but is usually overcome by the human immune system. The fever, aches, and lassitude that accompany infection can seem overwhelming, and it is difficult to imagine overcoming foes or predators at the peak of a bout of influenza. Nevertheless, despite the severity of the symptoms, most strains of influenza pose no great danger to healthy people in populations where influenza is endemic. Warm, well-nourished, and otherwise healthy people usually recover within 2 weeks and assume that their immune system will accomplish this task. Contrasting with influenza is Ebola virus, a pathogen new to human populations and which causes a high mortality of 60–75% among those infected. The effects of SARS-CoV-2 on human populations are less severe than those of Ebola but much greater than those of seasonal influenza and the common colds caused by other strains of coronavirus. COVID-19 is killing large numbers of people, but most of them were vulnerable because of other, preexisting conditions.

1-3Skin and mucosal surfaces are barrier defenses against infection

The skin gives the human body a formidable defense against infection. It is an epithelium protected by a tough, impenetrable outer barrier of layers of keratinized cells. Epithelium is a general name for the layers of cells that line the outer surface and the inner cavities of the body. However, the skin can be breached by physical damage, such as wounds, burns, or surgical procedures, which exposes soft tissues and renders them vulnerable to infection. Until the adoption of antiseptic procedures in the 19th century, surgery was a risky business, largely because of the life-threatening infections that the procedures introduced. Consequently, far more soldiers died from infected wounds than from the direct effects of enemy action. Ironically, the need to conduct increasingly sophisticated and wide-ranging warfare has been the major force driving improvements in surgery and medicine. As an example from immunology, the horrific burns suffered by fighter pilots during the Second World War stimulated the study and application of skin transplantation, which directly led to knowledge of the cellular basis of the immune response.

Continuous with the skin are the epithelia that line the respiratory, gastrointestinal, and urogenital tracts (Figure 1.5). On these internal surfaces, the impermeable skin gives way to specialized tissues that communicate with the environment and are vulnerable to microbial invasion. These tissues, the mucosal surfaces, or mucosae, are coated with the mucus they constitutively secrete. This thick fluid layer contains glycoproteins, proteoglycans, and enzymes that protect the epithelial cells from damage and contribute to limiting infection. In the respiratory tract, mucus is continually removed through the beating action of the cilia that characterize this epithelium. The mucus bathing the epithelium is replenished by goblet cells, specialized in the synthesis and secretion of mucus. In this way the respiratory mucosa is continually cleansed of unwanted material, particularly infectious microorganisms.

Epithelial surfaces also secrete antimicrobial substances. Sebum secreted by the sebaceous glands associated with hair follicles contains fatty acids and lactic acids, which cooperate to inhibit bacterial growth at the skin surface. All epithelia produce antimicrobial peptides that kill bacteria, fungi, and enveloped viruses by the common mechanism of perturbing their membranes. Tears and saliva contain lysozyme, an enzyme that kills bacteria by degrading their cell walls. Also deterring microorganisms are the acidic environments of the stomach, vagina, and skin.

The fixed defenses of skin and mucosa provide well-maintained mechanical, chemical, and microbiological barriers that prevent most pathogens from gaining access to the cells and tissues of the body. When those barriers are breached and pathogens gain entry to the body’s soft tissues, the defense mechanisms of innate immunity are aimed at the invaders.

1-4The innate immune response produces a state of inflammation at sites of infection

Cuts, abrasions, bites, and wounds provide routes for pathogens to get through the skin. Touching, rubbing, picking, and poking the eyes, nose, and mouth help pathogens breach mucosal surfaces, as does breathing polluted air, eating contaminated food, and being around infected people. With few exceptions, the infections remain localized and are extinguished within a few days without incapacitation or illness. Such infections are controlled and terminated by the innate immune response, which is always ready to react. The response consists of two phases (Figure 1.6). The first is recognition that a pathogen is present. This involves soluble proteins and cell-surface receptors that bind either to the pathogen or to human cells and plasma proteins that have been altered by the pathogen’s presence. Once the pathogen has been recognized, the second phase of the response recruits effector mechanisms that kill or eliminate the pathogen. Mediating the effector mechanisms are effector cells that engulf bacteria, kill virus-infected cells, and attack protozoa. Guiding the effector cells is complement, a system of plasma proteins that commands the effector cells by tagging pathogens with molecular flags. Complement proteins can also kill pathogens without assistance from effector cells by perturbing the integrity of the pathogens’ membranes. Collectively, these defenses comprise innate immunity, a genetically programmed set of responses that can act immediately when an infection occurs. Numerous families of receptor proteins contribute to pathogen recognition in the innate immune response. They are of many different structural types and have binding specificities for chemically diverse ligands. These ligands include peptides, proteins, glycoproteins, proteoglycans, peptidoglycans, carbohydrates, glycolipids, phospholipids, nucleic acids, small molecules, and metabolites.

During play and exploration of the local environment, small wounds to the skin can be a daily occurrence for many children. On returning home, the grazes are washed, which removes most of the dirt and the bacteria associated with soil, plants, and wild and domesticated animals, including other humans. Of the bacteria that remain, some divide and start an infection. The receptors of cells in the damaged tissue detect the bacteria, and the cells send out small messenger proteins called cytokines that bind receptors on the effector cells of innate immunity to trigger the innate immune response. The overall effect of the innate immune response is to induce a state of inflammation in the infected tissue. An ancient concept in medicine, inflammation was defined by calor, dolor, rubor, and tumor: the Latin words for heat, pain, redness, and swelling. These symptoms are not caused by the infecting pathogen but by the human innate immune response to the pathogen.

Cytokines induce dilation of nearby blood capillaries, which increases the blood flow, causing the skin to warm and redden. Vascular dilation (vasodilation) creates gaps between the cells of the endothelium, the thin layer of specialized epithelium that lines the interior of blood vessels. This makes the endothelium more permeable, increasing the leakage of blood plasma into connective tissue. Expansion of the local fluid volume, or edema, causes swelling, putting pressure on nerve endings and causing pain. Cytokines alter the adhesive properties of the vascular endothelium, permitting white blood cells to leave the blood and enter the inflamed tissue (Figure 1.7). White blood cells recruited to the infected tissue contribute to the inflammation and in this context are called inflammatory cells. Infiltration of cells into the inflamed tissue increases the swelling, and the cells release chemicals that cause pain. The upside of the discomfort and disfigurement caused by inflammation is that it enables an army of immune-system cells and soluble effector molecules to be brought rapidly and in quantity to the infected tissue.

Historically, the study of immunology (adaptive immunity) and the study of inflammation (innate immunity) were separate medical disciplines, and they began to merge only in the 1980s. Today, the terms inflammation and innate immunity are used interchangeably. The mechanisms of innate immunity are considered in Chapters 2 and 3.

1-5The adaptive immune response builds on the innate immune response

Everybody is exposed to pathogens every day. The intensity of exposure and the diversity of the encountered pathogens increase with crowded city living and the daily exchange of people and pathogens in international airports and other transport hubs. Despite the exposure, innate immunity keeps most people healthy for most of the time. Nevertheless, some infections outrun the innate immune response, an event more frequent in people who are poor, malnourished, badly housed, deprived of sleep, or stressed and insecure in other ways. When this occurs, the innate immune response works to minimize the spread of infection while enlisting white blood cells called lymphocytes to increase the strength and focus of the immune response. The unique contribution that lymphocytes make to the defense of the human body is the adaptive immune response. This is organized around the existing infection and the innate immune response and adapts that response to the unique characteristics of the infecting pathogen. Consequently, the adaptive immunity that is directed at the pathogen is powerful, long lasting, and specific to that pathogen. Adaptive immunity has evolved only in vertebrate animals, where it complements the mechanisms of innate immunity that vertebrates and invertebrates have in common.

The effector mechanisms of adaptive immunity are largely those used in innate immunity. The important differences between innate immunity and adaptive immunity are in the receptors that lymphocytes use to recognize pathogens (Figure 1.8). The receptors of innate immunity are structurally of many different types. Each receptor recognizes molecular features shared by groups of pathogens, and none is specific for a particular pathogen. Conversely, the lymphocytes of adaptive immunity recognize pathogens using only one type of cell-surface receptor, but this is made in billions of different versions. The adaptive immune response becomes specific for a particular pathogen by including only lymphocytes expressing a receptor that recognizes the pathogen. Lymphocyte receptors are not encoded by conventional genes, but by genes that are cut, spliced, and modified during lymphocyte development. By these mechanisms, each lymphocyte is programmed to make one variant of the basic receptor type. Billions of different receptor variants are represented in the lymphocytes of a person’s immune system, which enables all possible pathogens to be recognized by the immune system.

During infection, only lymphocytes bearing receptors that recognize the infecting pathogen are recruited to the adaptive immune response. They then proliferate and differentiate to form an army of pathogen-specific effector cells (Figure 1.9). The processes that select pathogen-specific lymphocytes for proliferation and differentiation are called clonal selection and clonal expansion. Because of the time it takes to expand a few selected lymphocytes into an army, the benefit of the adaptive immune response cannot be felt until 7–10 days after the onset of infection.

The ‘flu’ is a global disease that most people have experienced. It starts when epithelial cells in the lower respiratory tract become infected with influenza virus. The debilitating symptoms emerge 3 or 4 days after the start of infection, when the spread of the virus outruns the innate immune response. The disease persists for 5–7 days while an adaptive immune response is developed and then put to work. As the adaptive immune response gains the upper hand, fever subsides and a gradual convalescence begins in the second week after infection.

Some of the lymphocytes that contributed to a successful adaptive immune response persist in the body and are selected to provide long-term immunological memory of the pathogen. These memory cells enable subsequent encounters with the same pathogen to elicit a stronger and faster adaptive immune response; one that terminates infection before there are any significant symptoms of disease. The adaptive immunity based on immunological memory is also called acquired immunity, or protective immunity. For some pathogens, such as measles virus, one full-blown infection provides immunity for decades, whereas for influenza virus the protection is less effective. This is not due to faulty memory but to the rapid evolution of the virus, which allows it to escape the immunity acquired by its human hosts.

The first time that a person makes an adaptive immune response to a pathogen is called the primary immune response. During the primary response, the person acquires the immunological memory that enables subsequent encounters with the pathogen to be met with a faster and stronger secondary immune response. The purpose of vaccination is to provide people with a good immunological memory of the pathogen without them having to experience the disease. To do this, any vaccine must stimulate strong innate and adaptive immune responses against the pathogen (Figure 1.10). Immunological memory and vaccination are considered in Chapter 11.

1-6Immune-system cells with different functions derive from hematopoietic stem cells

The cells of the immune system are principally the white blood cells, or leukocytes, and tissue cells related to them. They and other blood cells are continually being generated in the body by the process of hematopoiesis. Leukocytes derive from a common progenitor called the pluripotent hematopoietic stem cell, which also gives rise to red blood cells (erythrocytes) and megakaryocytes, the source of platelets. These cells and their developmental precursors are collectively called hematopoietic cells (Figure 1.11). The anatomical site for hematopoiesis changes with age (Figure 1.12). In the early embryo, blood cells are first produced in the yolk sac and later in the fetal liver. From the third to the seventh month of fetal life, the spleen becomes the major site of hematopoiesis. As the bones develop during the fourth and fifth months of fetal growth, hematopoiesis begins to shift to the bone marrow, and by the time of birth practically all hematopoiesis takes place there. In adults, hematopoiesis is concentrated in the marrow of the skull, ribs, sternum, vertebral column, pelvis, and femurs. As blood cells are short-lived, they must continually be renewed, so hematopoiesis remains active throughout life.

Hematopoietic stem cells divide to give daughter cells that are also hematopoietic stem cells, a process of self renewal. Alternatively, daughter cells can differentiate to become more mature stem cells, which commit to one of three cell lineages: the erythroid, myeloid, and lymphoid lineages (Figure 1.13). The megakaryocyte–erythroid precursor cell gives rise to the oxygen-carrying erythrocytes and the platelet-producing megakaryocytes. Megakaryocytes are giant cells that arise from the fusion of multiple precursor cells and have nuclei containing multiple sets of chromosomes (megakaryocyte means ‘cell with giant nucleus’). Megakaryocytes permanently reside in the bone marrow. Platelets are small plate-like packets of membrane-enclosed cytoplasm that break off from a megakaryocyte. Their function is to maintain the integrity of blood vessels. Platelets initiate and participate in the clotting reactions that close off badly damaged blood vessels to reduce blood loss.

The myeloid precursor cell (also called the myeloid progenitor) gives rise to the myeloid cell lineage. One group of myeloid cells is the granulocytes, which comprise neutrophils, eosinophils, and basophils. These effector cells of innate immunity have prominent cytoplasmic granules filled with reactive biochemicals that kill microorganisms and enhance inflammation. The granulocytes are also known as polymorphonuclear leukocytes because of their irregularly shaped nuclei with two to five lobes. The most abundant white blood cell by far is the neutrophil (Figure 1.14), which specializes in the capture and killing of microorganisms; the process is called phagocytosis. Such cells are called phagocytes, with neutrophils being the most lethal. They rapidly mobilize to enter infected tissue and can function under the anaerobic conditions that prevail in damaged tissue. Neutrophils are short-lived and die within the infected tissue, forming pus, the creamy stuff of pimples and boils (Figure 1.15). The eosinophil, a less abundant granulocyte than the neutrophil, specializes in defending the body against intestinal parasites, particularly helminth worms. The basophil, the rarest of the granulocytes, initiates the anti-parasite response and acts more like a regulatory cell than an effector cell. The names of the granulocytes refer to the reactivity of their cytoplasmic granules with histological stains. The eosinophil’s granules contain basic substances that bind the acidic stain eosin, the basophil’s granules contain acidic substances that bind the basic stain hematoxylin, and the neutrophil’s granules bind neither acidic nor basic stains.

A second group of myeloid cells consists of the macrophages, monocytes, and dendritic cells. Tissue macrophages are large, irregularly shaped phagocytic cells having an extensive cytoplasm with numerous vacuoles containing engulfed material in the process of being broken down and digested (Figure 1.16). During early development in utero, tissue macrophages derived from embryonic stem cells move to a tissue, where they become the tissue-resident macrophages. Infection of a tissue is first detected by the resident macrophages, which are activated to kill pathogens and recruit neutrophils to the innate immune response. Numerous neutrophils die in the infected tissue, where the macrophages dispose of them. The name macrophage means ‘large phagocyte,’ and the neutrophil, historically called the microphage, is the ‘small phagocyte.’ Neutrophils are the short-lived infantry of innate immunity, whereas macrophages are the long-lived commanders who orchestrate the local response to infection. As part of their response to the pathogen, macrophages secrete the inflammatory cytokines that recruit neutrophils and other leukocytes into the infected area.

Monocytes are leukocytes that circulate in the blood. They are distinguished from granulocytes by their larger size, distinctive indented nucleus, and uniform appearance: hence the name monocyte. Macrophages recruit monocytes to infected tissue, where the monocytes differentiate into macrophages and reinforce the resident macrophages. Although the resident macrophages of healthy tissue are self renewing, in the presence of infection and extensive tissue damage they can be overwhelmed by the sheer amount of dead pathogens and neutrophils that need to be phagocytosed; at such a point the macrophages too can die. Once the pathogen has been vanquished and is no longer a threat, the tissue will be repaired and repopulated with monocytes, which differentiate in the tissue to become tissue-resident macrophages.

With a distinctive star-shaped morphology, dendritic cells are residents of the body’s tissues and have properties and functions in common with macrophages. The critical function of the dendritic cell is one of decision: to determine whether, and when, the innate immune response needs reinforcement with an adaptive immune response. When adaptive immunity is required, dendritic cells within the infected tissue gather up a cargo of intact and degraded pathogens and take them to lymphoid tissues, where they initiate the adaptive immune response to the pathogen.

The mast cell is resident in all connective tissues. It has granules like those of the basophil but is otherwise not a close relative. The blood-borne progenitor of the mast cell has yet to be discovered and remains a mystery. The mast-cell granules contain chemical mediators that cause violent spasms of smooth muscle that forcefully eject parasites from the respiratory tract and the gut.

The lymphoid precursor cell (also called the lymphoid progenitor) gives rise to the lymphoid lineage of leukocytes. Morphologically, two populations of blood lymphocytes are distinguished: large lymphocytes with a granular cytoplasm, and small lymphocytes with little cytoplasm. The large granular lymphocytes include the natural killer cells (NK cells), which are cytotoxic lymphocytes of innate immunity that respond to viral infections. Macrophages recruit NK cells to infected tissues, where they stop the spread of infection by killing virus-infected cells and secreting cytokines that impede viral replication. Other large lymphocytes of innate immunity are the innate lymphoid cells ILC1, 2, and 3 and LTi (see Figure 1.13). They are resident in tissues and do not circulate between blood and lymph. ILCs secrete cytokines that help to activate the responses of myeloid cells to infection.

The quiescent small lymphocytes mediate all adaptive immune responses. They circulate in an immature and functionally inactive form, hence their small size. Recognition of a pathogen by pathogen-specific receptors on small lymphocytes (see Section 1-5) drives a process of cellular selection, growth, and differentiation that in 1–2 weeks produces a powerful and tailored response aimed at an invading organism.

1-7Immunoglobulins and T-cell receptors are the antigen receptors of adaptive immunity

Although the small lymphocytes are morphologically indistinguishable, they comprise many sublineages that are distinguished by their cell-surface glycoproteins and immunological functions. The fundamental distinction is between B lymphocytes and T lymphocytes, usually called B cells and T cells. The cell-surface pathogen receptors of B cells are called B-cell receptors and are immunoglobulins; those of T cells are called T-cell receptors and are different from, but structurally related to, immunoglobulins. Plasma cells are effector B cells. They secrete a soluble form of the B-cell receptor—the antibody (Figure 1.17). T-cell receptors are only expressed as cell-surface receptors and not as soluble forms.

Immunoglobulins are composed of two identical heavy chains and two identical light chains. T-cell receptors are composed of just two protein chains, an α chain and a β chain. The genes encoding the immunoglobulin heavy and light chains and the T-cell receptor α and β chains are exceptional—qualitatively different from all other human genes. The germline does not contain functional immunoglobulin and T-cell receptor genes, but instead there are arrays of alternative gene segments that must be cut and spliced to produce the functional gene, a process called gene rearrangement. The enzymes involved are error-prone and introduce somatic mutations that further increase the sequence diversity of the immunoglobulin and T-cell receptor chains. Because of the unusual properties of these genes, each B cell expresses only one form of heavy chain and one form of light chain, but within a person’s population of B cells there are billions of different heavy and light combinations. Likewise, each T cell expresses one α and one β chain, but in a person’s T-cell population there are billions of different α- and β-chain combinations. The extent of this diversity enables a specific adaptive immune response to be made against any pathogen, including one such as SARS-CoV-2 that is new to the human species. The structures of these receptors and how they are generated during lymphocyte development are discussed in Chapters 4–7.

Any macromolecule, virus particle, or cell-surface component that is recognized and bound by an immunoglobulin or T-cell receptor is referred to as its antigen. Cell-surface immunoglobulins and T-cell receptors are also referred to as the antigen receptors of their respective lymphocytes. Differences in the amino acid sequences of the variable regions of immunoglobulins and T-cell receptors create a vast variety of binding sites that are specific for different antigens and pathogens. Because each B cell and T cell expresses just one form of antigen receptor, the adaptive immune response made against one pathogen provides no immunity to an unrelated pathogen. Thus antibodies made after measles vaccination bind to measles virus but not to influenza virus, whereas antibodies made after influenza vaccination bind to influenza virus but not to measles virus.

1-8On binding specific antigen, B cells and T cells divide and differentiate into effector cells

When a B cell encounters the specific antigen recognized by its B-cell receptor, the B cell is activated to divide and differentiate into antibody-producing plasma cells. The synthesis and secretion of antibody is the principal effector function of B cells (discussed in Chapter 9). By contrast, antigen-activated effector T cells are of different functional types that are distinguished by their surface glycoproteins, the cytokines they respond to, the cytokines they secrete, and the type of target cell they interact with (discussed in Chapter 8). The main subdivision of effector T cells is defined by the cell-surface expression of either the CD4 or CD8 co-receptor protein (the CD designation is an acronym for ‘cluster of differentiation’ and is a means of unambiguously naming the numerous cell-surface proteins that have historically been given many different names). At the T-cell surface, the co-receptor associates with the T-cell receptor and signaling components to form a complex that recognizes and responds to specific antigen. T cells expressing the CD8 co-receptor are cytotoxic T cells that kill cells infected with a virus or bacterium. These cytotoxic T cells of adaptive immunity have similar effector functions to the NK cells of innate immunity (Figure 1.18). T cells expressing the CD4 co-receptor are known as helper T cells because they secrete cytokines that enable other cells to become fully activated effector cells.

The T_H1 subset of helper T cells activates macrophages to increase phagocytosis and to kill those phagocytosed pathogens that resist the usual processes of intracellular degradation. T_H17 cells activate neutrophils to phagocytose and eliminate extracellular bacteria. The T_H2 subset responds to parasite infections by secreting cytokines that activate mast cells, basophils, and eosinophils. The mediators released by these cells induce contractions of smooth muscle that eject parasitic worms and protozoans from the gut and respiratory tracts. These same mechanisms cause the allergic reactions to pollen, nickel, and other harmless substances. Cytokines secreted by T_FH cells induce the differentiation of antigen-activated B cells to become antibody-secreting plasma cells. Once an infection is terminated, another subset of CD4 T cells, T_reg cells, closes down the effector CD4 and CD8 T-cell responses to prevent further inflammation and tissue damage.

In the past 10 years, subpopulations of innate lymphoid cells have been shown to contribute to innate immunity in ways that parallel the T_H1, T_H2, and T_H17 subsets of helper CD4 T cells. The helper functions of ILCs complement the cytotoxic activity of NK cells. The ILCs reside in tissues, where most infections occur, and do not circulate in the blood like NK cells (see Figure 1.18).

1-9B cells and T cells recognize different categories of microbial antigens

The antigen-binding sites of B-cell receptors and antibodies recognize carbohydrates, glycoproteins, proteoglycans, and glycolipids on the surface of microbial pathogens. In this manner, B-cell receptors and antibodies recognize the native conformations and three-dimensional structures of microbial macromolecules. The part of the outer surface of an antigenic macromolecule that interacts directly with an antibody or B-cell receptor is called the epitope.

T-cell receptors recognize microbial products in a very different way than B-cell receptors and antibodies. The epitopes recognized by T-cell receptors are short peptides of 8–16 amino acids and are produced in phagocytic myeloid cells by the degradation of pathogenic bacteria and in any human cell that is infected with a virus and making viral proteins. T-cell receptors cannot recognize a peptide antigen alone, but require it to be bound by a human glycoprotein called a major histocompatibility complex molecule, or MHC molecule. In this context, the MHC molecule is said to ‘present’ the peptide antigen to the T-cell receptor. There are a number of different types of MHC molecule, and the genes that encode them are the most polymorphic of human genes; that is, each gene exists in many different variants within the human population. The particular set of MHC molecules a person expresses is known as that person’s tissue type, and because of the extensive genetic polymorphism of the MHC genes, the tissue type differs in several respects between individuals. Immune responses against differences in tissue type are the principal cause of rejection in the clinical transplantation of organs and tissues.

Two classes of MHC molecule provide defense against different types of infection (Figure 1.19). MHC class I defends against intracellular infections; that is, all viral and some bacterial infections. MHC class II defends against extracellular infections. Because all human cells are susceptible to viral infection, MHC class I molecules are expressed by all cells. On the other hand, the expression of MHC class II molecules is not needed by most cells, and their expression is restricted to professional antigen-presenting cells: the macrophages, dendritic cells, and B cells. In the interactions between effector T cells and their target cells, CD8 binds to MHC class I but not to MHC class II. Conversely, CD4 binds to MHC class II but not to MHC class I. Consequently, all CD8 cells are cytotoxic T cells, and all CD4 T cells are helper T cells.

1-10Antibodies binding to a pathogen cause its inactivation or elimination

The antibodies secreted by plasma cells circulate in the blood, enter infected tissues, and bind to the surface antigens of pathogens. Such bound antibody can limit infection by interfering with pathogen growth and replication and with pathogen interactions with human cells. Such impedance of a pathogen by an antibody is called neutralization. An essential property of any influenza vaccine is to stimulate the formation of neutralizing antibodies that will coat the virus and prevent it from infecting human cells. With a different strategy, the lethal effects of bacterial toxins can be abrogated with antibody that binds the toxin and covers up its active site (Figure 1.20). The immunity conferred by antibodies is called humoral immunity. Humors are the body fluids, and for many years they were the only source of antibodies for use in medicine and research.

Antibodies can facilitate the engulfment and destruction of extracellular microorganisms and toxins by phagocytes. Because pathogen surfaces consist of a relatively few types of macromolecule, the antigenic macromolecules are present at high density. An antibody specific for one of these antigens can be sufficient to coat the entire pathogen surface. Phagocytes, such as neutrophils and macrophages, have cell-surface receptors that bind the antibody at a site away from its antigen-binding site, which is attached to the pathogen. When numerous receptors on the phagocyte engage an equal number of antibodies bound to the pathogen’s antigens, the pathogen becomes subject to rapid engulfment and death by digestion. Bacteria coated with antibody are far more efficiently phagocytosed than uncoated bacteria. The coating by antibody, leading to enhancement of phagocytosis, is called opsonization (see Figure 1.20).

1-11Most lymphocytes are present in specialized lymphoid tissues

The lymphocytes studied by immunologists have usually been obtained from the peripheral blood of patients and blood donors. However, only a small fraction of lymphocytes are ever in the blood, which they use to travel between tissues. The great majority of lymphocytes are present in specialized lymphoid tissues. The main lymphoid tissues are bone marrow, thymus, spleen, adenoids, tonsils, appendix, lymph nodes, and Peyer’s patches (Figure 1.21). Less-organized lymphoid tissue is also found lining the extensive mucosal surfaces of the respiratory, gastrointestinal, and urogenital tracts. The lymphoid tissues are divided into two functional types. Primary lymphoid tissues (sometimes called central lymphoid tissues) are where lymphocytes develop and mature to the stage at which they are able to recognize and respond to a pathogen. The bone marrow and the thymus are the only primary lymphoid tissues in humans. B and T lymphocytes both originate from lymphoid precursor cells in the bone marrow (see Figure 1.13). B cells complete their maturation in the bone marrow before entering the circulation. By contrast, T cells leave the bone marrow at an early stage in their development and migrate in the blood to the thymus, where they mature. All other lymphoid tissues are secondary lymphoid tissues (sometimes called peripheral lymphoid tissues); these are the sites where mature lymphocytes encounter pathogen-derived antigens and are activated to become effector cells that attack and eliminate the microbial invader.

Lymph nodes are placed at the junctions of an extensive network of lymphatic vessels called the lymphatics, which originate in connective tissues throughout the body and collect the plasma that leaks out of blood vessels to become the extracellular fluid. The lymphatics eventually return this fluid—the lymph—to the blood. The main route for this return is through the thoracic duct, which empties into the left subclavian vein in the neck. Unlike blood, the lymph is not pumped, so its flow is sluggish. One-way valves within lymphatic vessels, and lymph nodes at their junctions, ensure that the net movement of the lymph is always in a direction away from the peripheral tissues and toward the ducts in the upper body where the lymph empties into the blood. The flow of lymph is driven by the constant movements of one part of the body against another. In the absence of these movements, for example, when a person is confined to bed, the flow of lymph slows and fluid accumulates in tissues, causing the swelling known as edema.

B cells and T cells are distinguished from all other blood cells by the way they move around the body using both blood and lymph. Lymphocytes are the only cells present in lymph in any numbers; hence their name. After small lymphocytes have developed in the primary lymphoid tissues, they then enter the bloodstream. On reaching the blood capillaries that invest a lymph node (or other secondary lymphoid tissue), small lymphocytes are able to leave the blood and enter the tissue of the lymph node. If a lymphocyte becomes activated by a pathogen it remains in the lymph node; otherwise it spends some time there, but then leaves in the efferent lymph—the lymph leaving a lymph node—and eventually returns to the blood. With this lifestyle, the population of lymphocytes within a lymph node is in a continual state of flux, with new arrivals from the blood forcing older tenants into the efferent lymph. This pattern of movement between blood and lymph is called lymphocyte recirculation (Figure 1.22). It allows the lymphocyte population to monitor the secondary lymphoid tissues for any evidence of infection. An exception to this pattern is the spleen, which has no lymphatics. Lymphocytes both enter and leave the spleen in the blood.

The secondary lymphoid tissues are dynamic: lymphocytes constantly arrive from the blood and depart in the lymph. At any one time, only a minute fraction of lymphocytes are in the blood and lymph; the large majority of them are in lymphoid tissues.

1-12Adaptive immunity is initiated in secondary lymphoid tissues

Experimental infection of volunteers with cold viruses showed that a large first dose of virus is necessary to create an infection and cause disease. To establish infection, a microorganism must colonize a tissue to the extent that it overwhelms the local innate immune response. Common sites of infection are the connective tissues that pathogens penetrate as a result of skin wounds. From such sites, dendritic cells that are either pathogen-infected or loaded with the pathogen’s antigens are carried in the lymph through the lymphatics to the nearest lymph node. This lymph node is the draining lymph node, which collects all particulate and potentially dangerous materials and prevents them from entering the circulation (Figure 1.23).

The anatomy of the lymph node provides a meeting place where lymphocytes coming from the blood encounter pathogens and antigens brought from the infected connective tissue (Figure 1.24). Arriving lymphocytes are segregated, T cells to T-cell areas and B cells to lymphoid follicles. Pathogens and antigen-laden dendritic cells enter the lymph node in an afferent lymphatic vessel. Several of these converge at the node, and a single efferent lymphatic vessel carries lymph out of the node. As the lymph passes through the node, dendritic cells stay in the node, allowing pathogens and other extraneous materials to be extracted by the resident macrophages. This prevents infectious organisms from reaching the blood and provides the lymph node with pathogen-derived antigens and antigen-bearing dendritic cells.

In the lymph node, the small fraction of B and T cells that have receptors specific for the pathogen’s antigens are stimulated to divide and differentiate into effector cells. Activated pathogen-specific B cells proliferate in each follicle, forming a dense spherical structure, the germinal center. The pathogen-specific T cells are activated by antigen-bearing dendritic cells, some of which then move to the associated lymphoid follicle, where they help antigen-activated B cells to become plasma cells secreting antibody. As a consequence of the lymphocyte activation, proliferation, and differentiation, the lymph node swells in size and can be painful. Other effector T cells and the antibodies secreted by plasma cells are carried in the efferent lymph and the blood to the infected tissue (Figure 1.25). There, the effector cells and antibodies of adaptive immunity synergize with the effector cells and proteins of innate immunity to subdue the infection. Recovery from infection involves the clearance of infectious organisms from the body and repair of the damage caused by the pathogen and the immune response. Cure is not always possible. Infection can overwhelm the immune system, with death as the consequence. In the United States, some 36,000 deaths each year are associated with influenza virus infections. For other pathogens, the infection persists, but its pathological effects are controlled by the adaptive immune response, as usually occurs with herpesvirus infections.

1-13The spleen provides adaptive immunity to blood infections

Pathogens can enter the blood directly, as occurs when blood-feeding insects transmit disease or when the lymph nodes draining infected tissue fail to remove all microbes before returning the lymph to the blood. The spleen is the organ that filters the blood to remove damaged and senescent erythrocytes. The spleen’s other function is that of a secondary lymphoid tissue that defends the body against blood-borne pathogens. Any microorganism that gets into the blood is a potential pathogen and source of systemic infection. Microorganisms and microbial products in the blood are taken up by splenic macrophages and dendritic cells, which then stimulate the B and T cells that arrive in the spleen from the blood. The spleen comprises two types of tissue: the red pulp, where red blood cells are monitored and elderly or damaged ones removed, and the white pulp, a secondary lymphoid tissue. The organization and functions of white pulp are like those of a lymph node, the main difference being that the spleen has no lymphatics. Pathogens and lymphocytes both enter and leave the spleen in the blood (Figure 1.26).

Congenital asplenia

Some children are born without a spleen, the condition called asplenia (Figure 1.27). It is caused by mutation of the gene encoding ribosomal protein SA. The mutant allele is dominant, so inheritance of one mutant allele produces asplenia. All other organs appear normal in individuals with the condition. Children with asplenia are highly susceptible to infections, particularly with bacteria such as Streptococcus pneumoniae (see Figure 1.3d) or Haemophilus influenzae that have thick polysaccharide capsules. Children with asplenia can be protected against these life-threatening infections if their condition is diagnosed early in life, and they are vaccinated against S. pneumoniae and H. influenzae. For best effect, the vaccines are injected subcutaneously, which stimulates an immune response in the draining lymph nodes, which are normal in asplenic individuals. Asplenia is an immunodeficiency disease, a condition in which the inheritance of a mutant gene leads to a defect in immunological function (immunodeficiency is discussed in Chapter 13). The discovery and study of immunodeficiency diseases has largely been the work of pediatricians, because these conditions usually appear in early childhood. Unlike asplenia, most immunodeficiencies are recessive and become manifest only in children with two mutant alleles of the relevant gene.

1-14Most of the body’s secondary lymphoid tissue is associated with the gut

The sites in the body that contain the largest and most diverse populations of microorganisms are the respiratory and gastrointestinal tracts. The extensive mucosal surface of these tissues makes them vulnerable to infection. For their defense these mucosal tissues are heavily invested with secondary lymphoid tissue, known collectively as mucosa-associated lymphoid tissue (MALT). The gut-associated lymphoid tissue (GALT) includes the tonsils, adenoids, and the appendix and Peyer’s patches of the gastrointestinal tract. Similar, but less organized, aggregates of secondary lymphoid tissue line the respiratory epithelium, forming bronchial-associated lymphoid tissue (BALT). Additional, more diffuse lymphoid tissues are also found in most mucosae.

Although different from lymph nodes and spleen in outward appearance, the mucosal lymphoid tissues have similar microanatomy (Figure 1.28) and the function of trapping pathogens to activate lymphocytes. The differences are chiefly in the route of pathogen entry and the migration patterns of their lymphocytes (mucosal immunity is discussed in Chapter 10). Pathogens arrive at mucosa-associated lymphoid tissues by direct delivery across the mucosa, mediated by specialized M cells of the mucosal epithelium. Lymphocytes first enter mucosal lymphoid tissue from the blood. If they are not activated by specific antigen, the lymphocytes leave in lymphatics that connect the mucosal tissues to draining lymph nodes. Lymphocytes activated in mucosal tissues tend to stay within the mucosal system. Effector cells can move out of the lymphoid tissue and into the lamina propria and the mucosal epithelium to eliminate pathogens and counter infection. Alternatively, effector cells can recirculate in the blood and then return to mucosal tissue.