The immune system is exceedingly complex in its constituent cells, molecules, and signaling pathways. Each major component of the immune system is critical for survival; immune activity

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THE CLINICAL CONTEXT

The immune system is exceedingly complex in its constituent cells, molecules, and signaling

pathways. Each major component of the immune system is critical for survival; immune activity protects against infections that would quickly be lethal without immune defenses and eliminates cells in the stages of cancerous transformation.

The most common and major disorders of the immune system are related to immune activity that exceeds physiological needs. Hypersensitivity in the form of allergies occurs in 10% to 20% of the population. The prevalence of allergies increased in the developed world from the 1960s through the early 2000s, after which it began to plateau. Allergies were less common in the developing world but are now increasing in prevalence. Autoimmune disorders affect 2% to 5% of peo- ple, with a similar pattern of greater prevalence in developed countries but a trend of increasing numbers of cases in the developing world. 1

Although less common than immune hyperac- tivity, disorders in which immune activity is below normal leave an individual susceptible to dangerous infections. In some individuals, immune activity is compromised to an extent that those affected are at risk for major illness or even death. Primary immu- nodefi ciency disorders, which generally present in childhood as a result of genetic mutations, are rare but very severe. In 2012, the U.S. prevalence of primary immunodefi ciency disorders was 126.8 per 100,000. 2 The most common immunodefi ciency disorder occurs secondary to HIV infection. In the United States, an estimated 1.1 million people were

living with HIV infection at the end of 2015, about 0.3% of the population. 3 Globally, in 2017, it was esti- mated that 36.9 million people were living with HIV, almost 0.5% of the population. 4

ROLE OF THE IMMUNE SYSTEM

The human body is warm, moist, and full of nutrients, with a stable pH—all optimal living conditions for many microorganisms. There are at least as many bacterial cells as human cells in the human body, as well as count- less viruses, protozoa, and fungi. Collectively, these organisms are known as the human microbiota , and for the most part they consist of commensal organisms that coexist with humans without causing overt disease— even providing physiological benefi ts such as protec- tion against pathogens and aiding digestion and nutrient absorption. However, the human body constantly faces attack by disease-causing microorganisms known as pathogens. Pathogens express virulence factors that allow them to outcompete their commensal counter- parts and, in doing so, cause damage and disease.

To defend ourselves against pathogenic microbial attack, and to maintain homeostasis with commensal organisms, humans have evolved a complex and highly orchestrated system of cells, tissues, and organs that are collectively referred to as the immune system . Cytokines are circulating protein molecules produced and secreted by immune cells to promote proliferation and activation of other immune cells. Among the cytokines, there are dozens of interleukins (ILs), so-named because they were originally identifi ed as secreted products of leuko- cytes (white blood cells). Cells of the immune system are equipped with cell-surface receptors and secreted

THE IMMUNE SYSTEM AND LEUKOCYTE FUNCTION

Jo Kirman and Raff aela Ghittoni

6

Copyright Springer Publishing Company. All Rights Reserved. From: Advanced Physiology and Pathophysiology DOI: 10.1891/9780826177087.0006

156 Advanced Physiology and Pathophysiology: Essentials for Clinical Practice

molecules that act as environmental sensors to detect and respond to foreign or non-self molecules and to molecules that are commonly associated with patho- gens. The potent immune response systems are held in check by many inhibitory signals and mechanisms, which prevent undue hyperresponsiveness.

In addition to external threats, the immune system is capable of responding to abnormal self molecules, such as mutated self-proteins expressed by tumor cells, or organs received from a donor in the case of transplan- tation. Therefore, the immune system is a multifaceted defense force that serves to protect the human body from infection, toxins, cancer, and any tissue that is detected as an invader or non-self. The cells of the immune sys- tem circulate in the bloodstream to the body tissues and via the lymphatic system back to the bloodstream, con- ducting constant surveillance and attacking invaders.

Like other body systems, in some individuals, the immune system fails to function normally. This can occur from inherited or spontaneous mutations in crit- ical genes encoding molecules of the immune system, or it can be acquired from infectious or environmental exposures. Failure of the immune system to function appropriately can result in aberrant immune responses to harmless molecules in the environments (such as food or pollen, causing allergy or hypersensitivity) or to self-molecules (leading to autoimmune disease). Alternatively, the impaired immune system might fail to respond to pathogens or fail to maintain homeosta- sis with harmless microbes or commensal organisms, which can lead to severe disease (immunodeficiency).

This chapter summarizes the basic concepts of immunology, which is the biomedical science that stud- ies all aspects of the immune system: its cells, mole- cules, and functions in health and disease. Unlike the other organ systems covered in this text, tools to study the intricacies of immune cell function took many years to develop, and many aspects of immune function are still being elucidated. The complexity and rapid pace of discovery in immunology are exciting and clinically promising, even as they present challenges in staying current in this fast-moving field.

INTRODUCTION TO HOST DEFENSES

Similar to an army that defends its host country by establishing multiple specialized branches, each with highly trained soldiers and equipment, the immune system has three different layers of defense, each with its own specialized cells and molecules. These layers of defense are (a) the physical and chemical barriers, (b) the innate immune system, and (c) the adaptive immune system (Figure 6.1). General mechanisms of each of these layers are described in this section,

followed by more detailed descriptions of innate and adaptive immune cells and functions.

OVERVIEW OF PHYSICAL AND CHEMICAL BARRIERS The first layer of immune defense encountered by a pathogen comprises the physical and chemical barriers of the skin and mucosal surfaces (Figure 6.2).

• Skin covers the outside of the human body, with an outer layer of dead cells and underlying layers of densely packed living cells (the epidermis and dermis) that provide a strong physical barrier against penetra- tion by pathogenic microorganisms. Regular shedding of the outer, dead cells of the epidermal layer further contributes to the physical removal of microbes.

• Skin also produces chemical defenses against inva- sion and colonization through the secretion of sebum (a low-pH, oily, waxy substance) and sweat (high in salt, with antimicrobial enzymes) by sebaceous glands and sweat glands in the dermal layer. Antimicrobial peptides secreted by the skin, such as cathelicidins, can be directly antimicrobial and also can activate production of other effector immune molecules. The acidic, salty environment, as well as the production of antimicrobial peptides and enzymes, function together to limit or prevent microbial growth on the skin.

Physical and chemical barriers

PATHOGENS Viruses, bacteria, fungi, protozoa, helminths

Innate immunity

Adaptive immunity

FIGURE 6.1 Levels of protection against microorganisms. There are three levels of protection against pathogens: physical and chemical barriers include surface protections intrinsic to skin and mucous membranes, innate immunity that is nonspecific and results in acute inflammation while also initiating the next step of protection, and adaptive immunity that is specific and long-lasting.

Chapter 6 • The Immune System and Leukocyte Function 157

• Mucosal surfaces line the cavities of the body that are exposed to air and ingested substances. In contrast to the skin, the outer layer of the mucosa is alive and contains specialized cells that pro- duce mucus, a thick, viscous fl uid that coats the outer layer of cells and functions to trap and expel microbes.

• Cells that line the respiratory tract have short hair- like projections on their surface called cilia . In

healthy individuals, the cilia beat in tandem to expel particles trapped in the mucus up and out of the upper and lower respiratory tract. Failure of the mucociliary transport system can lead to lung dis- ease, such as chronic obstructive pulmonary dis- ease, pneumonia, and increased risk of infection. Cigarette smoking impairs the structure and func- tion of cilia, contributing to the development of smoking-induced respiratory disease.

Hair shaft

Sebaceous gland

Blood vessels

Hair follicle

Mucus layer

Goblet cell

Basal cell

Basement membraneFibroblast Lamina propria

Cilia

Columnar epithelial cell

Nucleus

Blood vessel

Subcutaneous (hypodermis) adipose tissue

(a) Skin

(b) Mucosal membrane (respiratory mucosa)

Opening of sweat duct

Epidermis

Dermis

Sweat duct

Sweat gland

FIGURE 6.2 Physical barriers of skin and mucosa. These regions physically interact with substances and microorganisms in the environment and commensals.

158 Advanced Physiology and Pathophysiology: Essentials for Clinical Practice

• The antimicrobial enzyme lysozyme is abundant in mucus and tears, acting as a chemical barrier for mucosal surfaces. Lysozyme functions by disrupting the cell walls of certain bacteria, causing the bacte- rial cells to rupture and die.

The gastrointestinal tract has its own extensive immune system, summarized briefly here and described in more detail in Chapter 13, Gastrointestinal Tract.

The initial defenses of the immune system effectively parry a vast array of microbial assaults. Nonetheless, at times pathogenic microbes are able to bypass or avoid these physical and chemical barriers, taking advantage of damage or abrasions to enter through the physical barriers or by producing substances that allow them to resist chemical defenses.

OVERVIEW OF THE INNATE IMMUNE RESPONSE The second layer of immune defense is the innate arm of the immune system. The innate immune system comprises fast-acting cells and molecules that recog- nize common features of pathogens, rather than spe- cific types of pathogens.

• This broad response is orchestrated by circulat- ing white blood cells and tissue-resident scavenger cells, which act quickly to recruit additional immune cells to sites of infection and trauma using chemi- cal gradients and signals from molecules known as cytokines and chemokines. The innate immune cells become activated to ingest and destroy any invading microorganisms.

• Cells of the innate immune response are generated continuously from multipotent bone marrow stem cells and can rapidly proliferate in response to appro- priate signals of infection and pathogen invasion.

• Molecules of innate immunity include proteins of the complement cascade, a system that directly attacks and lyses bacteria, while promoting other aspects of innate and adaptive immunity. The timing of the cell and molecular innate responses is crucial to con- tain the replication of pathogens and to prevent the spread of the disease in the host.

Innate immunity is generally very efficient, and is not specific to a particular pathogen. Importantly, the cells of the innate arm of the immune response are able to interact and communicate with cells of the third layer of immune defense—the adaptive immune response (Figure 6.3).

OVERVIEW OF THE ADAPTIVE IMMUNE RESPONSE Although slower to respond than the innate arm of the immune system, the adaptive immune response is highly specific for a particular pathogen and qualita- tively and quantitatively improves during the course of the response. Upon resolution of the immune response,

a small number of these highly specialized cells are retained in the body and can persist for decades. Some of these cells, such as T-helper lymphocytes, are modu- latory and function to promote the activity of other cells. Other adaptive immune cells, such as B lymphocytes and cytotoxic T lymphocytes (CTLs), are effector cells that are directly involved in targeting and destroying antigens and foreign cells. Upon any future encounters, these memory cells are able to efficiently promote pathogen neutralization or elimination so quickly that there may not be clinical signs of infection. This remarkable feature of the adaptive response is known as immunological memory. Immunological memory by adaptive immune cells is the mechanism upon which vaccination is based.

• B and T lymphocytes mediate adaptive immune responses. Both B and T cells recognize highly spe- cific parts of pathogens, called antigens. B cells recognize free antigen located in extracellular com- partments of the body, whereas T cells can recognize both intracellular and extracellular peptide antigen but require other cells to present the peptides to them on cell-surface molecules called the major his- tocompatibility complex (MHC). A given B or T cell always only recognizes one type of antigen; there- fore, each B or T cell has a single specificity.

• When activated, B cells synthesize and secrete highly specific Y-shaped molecules called antibodies that can inactivate, neutralize, or label pathogens or tox- ins. B cells express the same antibody on their cell surface, which forms the antigen-recognition compo- nent of the B-cell receptor (BCR). Signaling a naive or antigen-inexperienced B cell through the BCR enables that B cell to become activated and produce

Antibodies

Macrophage

NK cell or ILC

DC CD8 T cell

CD4 T cell

B cell

Neutrophil

Granulocyte

AdaptiveInnate

Chemokines and cytokines

Antigen presentation

Co-stimulation

FIGURE 6.3 Cellular and molecular communication between innate and adaptive immune cells. Both arms of the immune system have signals that modulate the responses of the other. DC, dendritic cell; ILC, innate lymphoid cell; NK, natural killer (cell).

Chapter 6 • The Immune System and Leukocyte Function 159

antibodies. Activated B-cell clones start to divide, leading to clonal expansion . This expansion can result in many, many thousands of B cells, which all recognize and produce antibody for the same antigen. The antibody-mediated immune response is some- times referred to as the humoral immune response .

• T cells recognize antigen through highly specifi c receptors, known as T-cell receptors (TCRs), expressed on their cell surface. Although many cop- ies of the TCR are present on the surface of an indi- vidual T cell, the TCRs of that cell are all of the same specifi city. However, owing to the genetic variation introduced through somatic gene recombination events in the thymus, there are millions of different T cells present in the body, each with their own TCR specifi city and the capacity to proliferate upon rec- ognition of their specifi c antigen.

• There are two types of T cells: the CD4 T cell , which is sometimes referred to as a T-helper cell ( Th cell ), and the CD8 T cell , sometimes referred to as a CTL. CD4 T cells primarily function to produce cyto- kines, which can activate innate cells and support B-cell and CD8 T-cell responses. CD8 T cells func- tion to lyse cells infected by intracellular bacteria,

virus-infected cells, or tumor cells. CD refers to cluster of differentiation, and signifi es specifi c mem- brane proteins found on the surface of lymphocytes and many immune cells.

Although the innate and adaptive immune responses have distinct characteristics (summarized in Table 6.1 ), their functions overlap and are interconnected. The innate and adaptive immune cells cooperate through a mutual exchange of signals and mediators to provide effi cient protection from pathogens, toxins, and can- cer (see Figure 6.3 ). These processes are described in more detail in the next sections.

Thought Questions

1. What is the “big picture” of the role of the immune system in maintaining homeostasis?

2. What are the general principles involved in protection provided by the innate and adaptive immune systems?

TABLE 6.1 Characteristics of Innate and Adaptive Immunity

Feature Innate Adaptive

Pathogen recognition Broad—pathogen recognition receptors for: • PAMPs

❍ Pathogen surface markers: lipopolysaccharide, fl agellin, di- and tri-acyl-lipopeptides, peptidoglycan, zymosan, mannose

❍ Intracellular pathogen markers—dsRNA, ssRNA, unmethylated CpG, DNA

• DAMPs—tissue injury signals (sterile infl ammation)

Highly specifi c—epitopes of microorganisms, foreign proteins, modifi ed self-proteins, modifi ed self-cells

Initiation time Fast; minutes to hours Slow; days to weeks

Memory Absent or broad enhancement “ trained immunity ”

Specifi c enhanced (faster and better quality) responses to subsequent exposure

Diversity of response Low Extremely high; increases during the course of the response

Major molecules and mechanisms Physical and chemical barriers; antimicrobial molecules; phagocytosis; complement; cytokines; chemokines

Antigen-specifi c receptors: BCR and TCR, antibodies, cytokines, cytolysis

Major cell types Phagocytes (macrophages, dendritic cells); granulocytes (neutrophils, eosinophils, mast cells, basophils); innate lymphoid cells (NK cells and ILCs)

B and T lymphocytes

BCR, B-cell receptor; unmethylated CpG, dinucleotide cytosine-guanine sequences common to microbes; DAMP, danger-associated molecular pattern; dsDNA, double-stranded DNA; ILC, innate lymphoid cell; NK, natural killer; PAMP, pathogen-associated molecular pattern; ssRNA, single-stranded RNA; TCR, T-cell receptor.

160 Advanced Physiology and Pathophysiology: Essentials for Clinical Practice

FUNCTIONAL ANATOMY OF THE IMMUNE SYSTEM

The specialized organs and tissues of the immune system are termed lymphoid organs and lymphoid tissues. They are separated into primary and sec- ondary lymphoid organs and tissues based on their function (Figure 6.4). Primary lymphoid organs and tissues are the site of immune cell development and include the thymus, where T cells develop, and the bone marrow, where B cells develop. Both T and B cells, as well as cells of the innate immune system, develop from multipotent precursor stem cells that reside in the bone marrow. The secondary lymphoid organs and tissues are the sites of adaptive immune cell activation and include the lymph nodes and lym- phatic vessels, in which cells respond to damage and infection of the tissues, and the spleen, where immune responses to blood-borne pathogens are ini- tiated. The lymphatic network provides T and B cells

Thoracic duct

Spleen

Intestinal lymph nodes

Peyer’s patches in intestinal wall

Tonsils

Cervical lymph node

Entrance of thoracic duct into subclavian vein

Axillary lymph node

Right lymphatic duct

Inguinal lymph nodes

Thymus

Bone marrow

FIGURE 6.4 Anatomy of the immune system. Cells of the immune system circulate from the bone marrow to primary and secondary lymphoid tissues, moving through blood and lymph vessels, and sometimes stationary in primary and secondary lymphoid tissues.

with the ability to recirculate through the tissues, lymph, and blood, allowing them to constantly patrol and survey the body for signs of infection.

HEMATOPOIESIS In humans, hematopoiesis occurs in the bone mar- row, where multipotent precursor stem cells, known as hematopoietic stem cells (HSCs), are supported to survive, proliferate, and differentiate by mesenchymal stem cells. HSCs are self-renewing, meaning that they can divide to make more precursor cells. The HSCs can develop into the major cellular constituents of blood: red blood cells, platelets, and white blood cells of the innate and adaptive immune system (Table 6.2).

The three blood lineages that develop from HSCs are the erythroid lineage, which develops into red blood cells (also referred to as erythrocytes) and platelet-pro- ducing megakaryocytes, and the myeloid and lymphoid lineages, which both can develop into white blood cells (also referred to as leukocytes). The myeloid lineage

Chapter 6 • The Immune System and Leukocyte Function 161

originates from a specialized progenitor cell derived from the HSC, known as the common myeloid progen- itor, which can differentiate into granulocytes (neutro- phils, eosinophils, basophils, and mast cells) as well as mononuclear cells, including monocytes, macrophages, and certain dendritic cells. The lymphoid lineage devel- ops from the common lymphoid progenitor and gives rise to T and B lymphocytes, natural killer (NK) cells, innate lymphoid cells (ILCs), and some types of den- dritic cell ( Figure 6.5 ).

CELLS AND TISSUES OF THE IMMUNE SYSTEM B Cells Develop in the Bone Marrow To recognize the vast array of different carbohy- drates and proteins expressed by different pathogens with a high degree of specifi city, an equally vast range of B cells, each with its own unique antigen specifi c- ity, must exist. As previously noted, B cells recognize antigen through their BCR. The BCR has the same structure and specifi city as the antibody it goes on to secrete during an immune response. Each B cell expresses ~10 5 BCRs on its cell surface, all with the same antigen specifi city. Therefore, billions of differ- ent B cells exist in the body, each able to respond to a unique specifi c antigen.

To encode such a vast range of different BCRs, the human genome, which encodes only ~20,000 proteins, would need to be orders of magnitude larger. To cir- cumvent this, the genes that encode the antigen-binding (variable) region of the BCR are expressed in segments ( Box 6.1 and Figure 6.6 ). Dozens of different options for each gene segment combine together in a kind of mix-and-match fashion to create the great BCR diver- sity required with very few genes. This process, called

somatic gene rearrangement , occurs in B-cell precur- sors in the bone marrow. Because the BCR has two chains, heavy and light, and each rearranges its genes encoding the variable region independently, this pro- cess increases the possibility of generating different unique antigen-binding sites on the receptor.

Gene rearrangement does not depend on antigen, so an antigen-specifi c B cell can develop well before exposure to a given pathogen. As the gene rearrange- ment process occurs, the new BCRs are tested. During development, B cells with nonproductive BCRs or self- reactive BCRs are deleted or made nonresponsive so that the B cells that survive are functional and unlikely to lead to autoimmune disease. Each day bil- lions of new B cells enter the circulation from bone marrow. Naive B cells survive for only a few weeks if they do not encounter antigen. Therefore, the process of developing new B cells continues in the bone mar- row throughout life.

T Cells Develop in the Thymus The thymus is a primary lymphoid organ critical for T-cell development early in life. At birth, the human thymus is fully developed; however, after 1 year of age, the thymus begins to involute (shrink) and its function reduces. Naive (antigen-inexperienced) T cells gener- ated by the thymus are long-lived or self-renewing in the periphery, meaning that loss of thymic function with age does not impair T-cell driven immunity over a lifetime.

Progenitor cells from the bone marrow enter the thymus, becoming thymocytes —cells that are com- mitted to the T-cell lineage. In a manner similar to the way B-cell precursors in the bone marrow rearrange the antibody variable genes, thymocytes in the thymus undergo a process of somatic gene rearrangement that leads to the development of an antigen-specifi c TCR.

TABLE 6.2 Concentration and Frequency of Cells in Human Blood

Cell Type Cells/mm 3 Total Leukocytes (%)

Red blood cells 5.0 × 10 6

Platelets 2.5 × 10 5

Leukocytes 7.3 × 10 3

Neutrophil 3.7–5.1 × 10 3 50–70

Lymphocyte 1.5–3.0 × 10 3 20–40

Monocyte 1–4.4 × 10 2 1–6

Eosinophil 1–2.2 × 10 2 1–3

Basophil <1.3 × 10 2 <1

Source: From Owen JA, Punt J, Stranford SA. Kuby Immunology. 7th ed. W.H. Freeman Company; 2013, Table 2-1.

162 Advanced Physiology and Pathophysiology: Essentials for Clinical Practice

The TCR is made up of two polypeptide chains: most commonly, the TCR α  chain and the TCR β  chain (Box 6.2 and Figure 6.7). Each chain has a variable region and a constant region. The variable domain includes the region that recognizes peptide antigens that are bound to MHC molecules. Similar to the gene segments that encode the antigen-binding regions of BCRs, the TCR variable region is also encoded by gene segments, and for each segment of the TCR there are multiple distinct alternatives encoded in the germline genome. In a developing T cell, one option for each gene segment is selected to recombine with the other selected segments to create a unique TCR. In this way,

enormous diversity in the TCRs expressed in the human body is achieved with a limited number of genes.

Each developing T cell will express multiple TCRs of a single specificity on its cell surface. Therefore, each T cell will recognize only one type of antigenic peptide. Most T cells will express an α β  TCR, which is made up of the α  and β  chains. However, a small number of T cells express a different type of receptor made up of γ  and δ  chains; these cells are referred to as γ δ  T cells. The γ δ  TCR is encoded by a different set of gene segments, and this dif- ferent type of TCR leads to different cellular functions.

Developing T cells commit to becoming a CD4 T cell or a CD8 T cell in the thymus, by expressing

After division, some cells remain stem cells (self-renewing)

Multipotent hematopoietic stem cell (hemocytoblast)

The remaining cell goes down one of two paths depending on the chemical signals received

Common lymphoid progenitor

Lymphoid stem cell

Common myeloid progenitor

Myeloid stem cell

Megakaryoblast Proerythroblast Myeloblast Monoblast

Reticulocyte

Erythrocyte Basophil

Mast cell Macrophage Dendritic cell

Neutrophil Eosinophil Monocyte

T lymphocyte

Lymphoblast

Natural killer cell (large granular

lymphocyte) or innate lymphoid cell (ILC)

B lymphocyte

Megakaryocyte

Platelets

FIGURE 6.5 Hematopoiesis. Generation of red and white blood cells occurs in the bone marrow. A multipotent stem cell can follow a myeloid or lymphoid path before further differentiating to final forms of the cells shown.

Chapter 6 • The Immune System and Leukocyte Function 163

either the CD4 or the CD8 co-receptor along with the TCR on their cell surface. Although these co-receptors do not directly bind antigen, they do bind to the MHC molecules that present the antigen to the TCR. Because CD4 T cells recognize only MHC class II and CD8

T cells recognize only MHC class I, the type of peptide antigens recognized by CD4 T cells and CD8 T cells is different. Once mature, CD4 and CD8 T cells go on to play distinct roles in the immune response, described later in this chapter.

BOX 6.1 B-Cell Receptor Gene Rearrangement

• B-cell receptors and

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