IMMUNOLOGY AND SEROLOGY

CHAPTER 2
INNATE IMMUNITY

OUTLINE
I. External Defense System II. Internal Defense System

● Humans are protected by two systems of immunity—innate

and adaptive—as we discussed in Chapter 1.
● Innate immunity consists of the defenses against
infection that are ready for immediate action when a host
is attacked by a pathogen.
➔ If a pathogen manages to evade these defenses,
there is a coordinated series of interactions between
various cells and molecules to destroy any invading
pathogens before disease can occur.
➔ These defenses are considered nonadaptive or
nonspecific; regardless of the infectious agent to
which the body is exposed, innate immunity produces
the same response.
➔ Components of innate immunity can be thought of as ● First and foremost are the unbroken skin and the mucosal
the first responders because they react immediately membrane surfaces.
to infectious agents. ➔ The outer layer of the skin, the epidermis, contains
● Adaptive immunity, in contrast, is a more tailored several layers of tightly packed epithelial cells.
response. ➔ These cells are coated with a protein called keratin,
➔ It takes a longer time to be activated, but it is more making the skin impermeable to most infectious
specific and longer lasting. agents.
● The two systems, however, are highly interactive and ➔ The outer skin layer is renewed every few days to
interdependent; innate immunity actually sets the stage for keep it intact.
the more specific and longer-lasting adaptive immune ➔ The dermis is a thicker layer just underneath the
response. epidermis that is composed of connective tissue with
● The innate immune system is composed of two parts: the blood vessels, hair follicles, sebaceous glands, sweat
external defense system and the internal defense system. glands, and white blood cells (WBCs), including
● The external defense system consists of anatomical macrophages, dendritic cells, and mast cells.
barriers designed to keep microorganisms from entering ➔ To understand how important a role the skin plays,
the body. one has only to consider how vulnerable victims of
➔ If these defenses are overcome, then the internal severe burns are to infection.
defense system is triggered within minutes and clears ● Not only does the skin serve as a major structural barrier,
invaders as quickly as possible. but the presence of several secretions on the skin
● Internal defenses include cellular responses that discourages the growth of microorganisms.
recognize specific molecular components of pathogens. ● Lactic acid in sweat, for instance, and fatty acids from
● Both of these systems work together to promote sebaceous glands maintain the skin at a pH of
phagocytosis. approximately 5.6.
● The process of phagocytosis, as defined in Chapter 1, is the ➔ This acidic pH keeps most microorganisms from
engulfment and destruction of foreign cells or particles by growing.
leukocytes, macrophages, and other cells. ● In addition, human skin cells produce psoriasin, a small
● Importantly, phagocytosis and resulting inflammation bring protein that has antibacterial effects, especially against
cells and humoral factors to the injured area, orchestrating gram-negative organisms such as Escherichia coli.
the healing process. ● Additionally, each of the various organ systems in the body
● If healing begins and inflammation is resolved as quickly as has its own unique defense mechanisms.
possible, the tissues are less likely to be damaged. ● In the respiratory tract, mucous secretions block the
● The innate immune system is so efficient that most adherence of bacteria to epithelial cells.
pathogens are destroyed before they ever encounter cells ➔ These secretions contain small proteins called
of the adaptive immune response. surfactants that are produced by the epithelial cells
and bind to microorganisms to help move pathogens
I. EXTERNAL DEFENSE SYSTEM out.
● The external defense system is composed of physical, ➔ The motion of the cilia that line the nasopharyngeal
chemical, and biological barriers that function together to passages clears away almost 90% of the deposited
prevent most infectious agents from entering the body material.
(Fig. 2–1). ➔ The simple acts of coughing and sneezing also help to
move pathogens out of the respiratory tract.
● The flushing action of urine, plus its slight acidity, helps to
remove many potential pathogens from the genitourinary
tract.

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 ➔ Lactic acid production in the female genital tract ➔ These receptors are encoded by the host’s genomic
keeps the vagina at a pH of about 5, which is another DNA and act as sensors for extracellular infection.
means of preventing the invasion of pathogens. ➔ PRRs thus play a pivotal role as a second line of
● In the digestive tract, the stomach’s hydrochloric acid defense if microorganisms penetrate the external
keeps the pH as low as 1. barriers.
● We take in many microorganisms with food and drink, and ● Once these receptors bind to a pathogen, phagocytic cells
the low pH serves to halt microbial growth. become activated and are better able to engulf and
● Lysozyme: an enzyme found in many bodily secretions, eliminate microorganisms.
such as tears and saliva—attacks the cell walls of ● Activated cells then secrete proinflammatory cytokines and
microorganisms, especially those that are gram-positive. chemokines, chemical messengers that make capillaries
● In many locations of the human body, the presence of more permeable and recruit additional phagocytic cell types
microbiota (formerly known as normal flora) helps to to the area of infection.
keep pathogens from establishing themselves in these ➔ Cytokines and chemokines also trigger the adaptive
areas. immune response.
➔ Microbiota consist of a mix of bacteria that are ● PRRs are able to distinguish self from nonself by
normally found at specific body sites and do not recognizing substances, known as pathogen-associated
typically cause disease. molecular patterns (PAMPs), which are only found in
● The significance of microbiota is readily demonstrated by microorganisms.
looking at the side effects of antimicrobial therapy. ➔ Some examples of PAMPs include peptidoglycan in
➔ For example, women who take an antibiotic for a gram-positive bacteria, lipopolysaccharide in
urinary tract infection (UTI) frequently develop a gram-negative bacteria, zymosan in yeast, and
yeast infection because of the presence of Candida flagellin in bacteria with flagellae.
albicans. ● Charles Janeway’s discovery of the first receptor in
● In this case, antimicrobial therapy depletes not only the humans, the Toll-like receptor (TLR), had a major
pathogenic bacteria but also the microorganisms that impact on the understanding of innate immunity.
ordinarily compete with such opportunists that are ➔ Toll is a protein originally discovered in the fruit fly
normally present in very small numbers. Drosophila, where it plays an important role in innate
● Interestingly, the dynamic and bilateral interaction between immunity in the adult fly.
resident microbes of the digestive tract (the gut ➔ Very similar molecules were found on human
microbiome) and the innate immune system is now a focus leukocytes and some other cell types.
of investigation with regard to therapies for systemic ➔ The highest concentration of TLRs occurs on
diseases such as inflammatory bowel disease and monocytes, macrophages, and dendritic cells (Fig.
metabolic syndrome. 2–2).

II. INTERNAL DEFENSE SYSTEM

● If microorganisms do penetrate the barriers of the external
defense system, the innate immune system has additional
mechanisms to destroy foreign invaders.
● The internal defense system is composed of both cells
and soluble factors that have specific and essential
functions.
● Cells that are capable of phagocytosis play a major role in
the internal defenses (see Chapter 1).
➔ Phagocytic cells engulf and destroy most of the
foreign cells or particles that enter the body; this is
the most important function of the internal defense
system.
➔ Phagocytosis is enhanced by specific receptors on
cells that capture invaders through identification of
unique microbial substances.
● In addition, soluble factors called acute-phase reactants
act by several different mechanisms to facilitate contact ● TLRs make up a large family of receptors strategically
between microbes and phagocytic cells and to bind to and located in various cellular compartments; some are found
recycle important proteins after the process of in the cytoplasm, whereas others are found on cell surfaces
phagocytosis has taken place. (Table 2–1).
● Both cellular receptors and soluble factors are described in
more detail here.

A. Pattern Recognition Receptors

● The internal defense system is designed to recognize
molecules that are unique to infectious organisms.
● Macrophages and dendritic cells constituting between 10%
and 15% of the total cellular population in the tissues are
the most important cells involved in pathogen recognition.
● They are able to distinguish pathogens from normally
present molecules in the body by means of receptors
known as pattern recognition receptors (PRRs), which are
also found on neutrophils, eosinophils, monocytes, mast
cells, and epithelial cells.

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 ● Although the initial signaling pathway differs from TLRs,
the end result is the same—the production of cytokines and
chemokines to eliminate microbes.
● Other families of receptors that recognize pathogens
include retinoic acid–inducible gene-I-like receptors (RLRs)
and nucleotide-binding oligomerization domain (NOD)-like
receptors (NLRs).
● The RLR family recognizes RNA from RNA viruses in the
cytoplasm of infected cells and induces inflammatory
cytokines and type I interferons.
➔ Type I interferons inhibit viral replication and induce
apoptosis (cell death) in infected cells.
● NLRs provide immune surveillance in the cytoplasm, where
they bind ligands from microbial pathogens, such as
peptidoglycan, flagellin, viral RNA, and fungal hyphae.
● NLRs also have the ability to form an inflammasome, a
multiprotein unit that can activate apoptotic
(controlled-cell-death) proteins and proinflammatory
cytokines.
● TLR1, TLR2, TLR4, TLR5, and TLR6 are found on cell
surfaces, whereas TLR3, TLR7, TLR8, and TLR9 are found B. Pattern Recognition Receptors and Disease
in the endosomal compartment of a cell. ● Although PRRs are essential for protection against
● Each of these receptors recognizes a different microbial pathogens, inappropriate PRR responses have been found
product. to contribute to acute and chronic inflammation as well as
➔ For example: to systemic autoimmune diseases.
◆ TLR2 - recognizes teichoic acid and ➔ For example, mutations in NLRs may result in Crohn’s
peptidoglycan found in gram-positive bacteria disease, a painful inflammatory disease of the bowel.
◆ TLR4 - recognizes lipopolysaccharide, which ● Additionally, in systemic lupus erythematosus, there is a
is found in gram-negative bacteria higher concentration of antibodies to self–nucleic acids,
◆ TLR5 - recognizes bacterial flagellin (Fig. which activate dendritic cells through TLR9.
2–3). ● Therefore, a tight regulatory network of PRR signaling is
◆ TLR10 - anti-inflammatory. critical to ensure the elimination of invading pathogens
while avoiding harmful immune reactions that can cause
pathology.

C. Acute-Phase Reactants
● In addition to the cells and receptors that enhance the
destruction of pathogens, the internal defense system also
consists of soluble factors called acute-phase reactants that
contribute to the innate immune response.
● Acute-phase reactants are normal serum constituents
that rapidly increase or decrease in concentration because
of infection, injury, or trauma to the tissues.
➔ Those that increase are termed positive
acute-phase reactants, whereas those that
decrease, such as albumin and transferrin, are known
as negative acute-phase reactants.
● In this chapter, we will discuss positive acute-phase
● TLRs are membrane-spanning glycoproteins that share a reactants.
common structural element called leucine-rich repeats ● Many of these proteins act by binding to microorganisms
(LRRs). and promoting adherence, the first step in phagocytosis.
● Once TLRs bind to their particular substances, host immune ● Others help to limit destruction caused by the release of
responses are rapidly activated by the production of proteolytic enzymes from WBCs as the process of
cytokines and chemokines. phagocytosis takes place.
● Neutrophils are recruited to the area because of increased ● Some of the most important positive acute-phase reactants
capillary permeability; in addition, macrophages and are C-reactive protein (CRP), serum amyloid A (SAA),
dendritic cells become more efficient because of increased complement components, alpha1- antitrypsin (AAT),
expression of adhesion molecules on their cell surfaces. haptoglobin, fibrinogen, and ceruloplasmin.
● These processes enhance phagocytosis and, importantly, ● They are produced primarily by hepatocytes (liver
provide a vital link between the innate and adaptive parenchymal cells) within 12 to 24 hours in response to an
immune systems, which work together to destroy most increase in cytokines (see Chapter 6 for a complete
pathogens that humans are exposed to before disease sets discussion of cytokines).
in. ● The major cytokines involved in inflammation are
● In addition to TLRs, there are several other families of interleukin-1 (IL-1), interleukin-6 (IL-6), and tumor
receptors that activate innate immune responses. necrosis factor-α (TNF-α), all of which are produced by
➔ One such family is the C-type lectin receptor (CLR). monocytes and macrophages.
● CLRs are plasma membrane receptors found on monocytes, ● Table 2–2 summarizes characteristics of the main positive
macrophages, dendritic cells, neutrophils, B cells, and acute-phase reactants.
T-cell subsets.
● These receptors bind to mannan and β-glucans found in
fungal cell walls (see Chapter 22).
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 follow a disease process and observe the response to
treatment of inflammation and infection.
● It is a nonsurgical means of following the course of
malignancy and organ transplantation because a rise in the
level may mean a return of the malignancy or, in the case
of transplantation, the beginning of organ rejection.
● CRP levels can also be used to monitor the progression or
remission of autoimmune diseases.
➔ Laboratory assays for CRP are sensitive, reproducible,
and relatively inexpensive.
● CRP has also received attention as a risk marker for
cardiovascular disease.
➔ In accord with the finding that atherosclerosis
(coronary artery disease) may be the result of a
chronic inflammatory process, an increased level of
CRP has been shown to be a significant risk factor for
myocardial infarction, ischemic stroke, and peripheral
vascular disease in men and women who are at an
intermediate risk for cardiovascular disease.
➔ When inflammation is chronic, increased amounts of
C-Reactive Protein CRP react with endothelial cells that line blood vessel
● C-reactive protein (CRP): a trace constituent of serum walls, predisposing them to vasoconstriction, platelet
originally thought to be an antibody to the activation, thrombosis (clot formation), and vascular
C-polysaccharide of pneumococci. inflammation.
➔ It was discovered by Tillet and Francis in 1930 when ● The ability to monitor CRP is significant because
they observed that serum from patients with cardiovascular disease is the number-one cause of
Streptococcus pneumoniae infection precipitated with mortality in the United States and the world today.
a soluble extract of the bacteria. ● The Centers for Disease Control and Prevention (CDC) has
➔ Now CRP is known to have a more generalized role in recommended that a serum CRP concentration of lower
innate immunity. than 1 mg/L is associated with a low risk for cardiovascular
● CRP has a molecular weight of between 118,000 and disease, 1 to 3 mg/L is associated with an average risk,
144,000 daltons and has a structure that consists of five and greater than 3 mg/L is associated with a high risk.
identical subunits held together by noncovalent bonds. ● Normal levels in adults range from approximately 0.47 to
● It is a member of the family known as the pentraxins, all 1.34 mg/L.
of which are proteins with five subunits. ● The mean CRP level for people with no coronary artery
● CRP acts somewhat similar to an antibody because it is disease is 0.87 mg/L.
capable of opsonization (the coating of foreign particles), ➔ Thus, monitoring of CRP is now an established clinical
agglutination, precipitation, and activation of complement tool to evaluate subtle chronic systemic inflammation,
by the classical pathway. and when used in conjunction with traditional clinical
● However, binding is calcium-dependent and nonspecific. laboratory methods, it may be an important
● The main substrate is phosphocholine: a common preventative measure in determining the potential risk
constituent of microbial membranes. of heart attack or stroke.
● CRP also binds to small ribonuclear proteins; ● High-sensitivity CRP testing has the necessary lower level
phospholipids; peptidoglycan; and other constituents of of detection of 0.01 mg/L, which enables measurement of
bacteria, fungi, and parasites. much smaller increases than the traditional latex
● In addition, CRP promotes phagocytosis by binding to agglutination screening test.
specific receptors found on monocytes, macrophages, and ● One clinically relevant property of CRP is that it is easily
neutrophils. destroyed by heating serum to 56°C for 30 minutes.
● Thus, CRP can be thought of as a primitive, nonspecific ● The destruction of CRP is often necessary in the laboratory
form of an antibody molecule that is able to act as a because it may interfere with certain tests for the presence
defense against microorganisms or foreign cells until of antibodies.
specific antibodies can be produced.
➔ CRP is a relatively stable serum protein, with a Serum Amyloid A
half-life of about 18 hours. It increases rapidly, within ● Serum amyloid A (SAA): the other major protein besides
4 to 6 hours following infection, surgery, or other CRP whose concentration can increase almost a
trauma to the body. thousand-fold in response to infection or injury.
➔ Levels increase dramatically, as much as a ➔ It is an apolipoprotein that is synthesized in the liver
hundredfold to a thousand-fold, reaching a peak value and has a molecular weight of 11,685 daltons.
within 48 hours. ➔ Normal circulating levels are approximately 5 to 8
● CRP also declines rapidly with cessation of the stimuli. ug/mL.
● Elevated levels are found in conditions such as bacterial ● In plasma, SAA has a high affinity for high-density
infections, rheumatic fever, viral infections, malignant lipoprotein (HDL) cholesterol and is transported by HDL to
diseases, tuberculosis, and after a heart attack. the site of infection.
● Additionally, the median CRP value for an individual ● SAA appears to act as a chemical messenger, similar to a
increases with age, reflecting an increase in subclinical cytokine, and it activates monocytes and macrophages to
inflammatory conditions. produce products that increase inflammation.
● Because the levels rise and then decline so rapidly, CRP is ● It has been found to increase significantly more in bacterial
the most widely used indicator of acute inflammation. infections than in viral infections.
● Although CRP is a nonspecific indicator of disease or ● Levels reach a peak between 24 and 48 hours after an
trauma, monitoring of its levels can be useful clinically to acute infection.

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● SAA can also be increased because of chronic Haptoglobin
inflammation, atherosclerosis, and cancer. ● Haptoglobin: an alpha2-globulin with a molecular weight
● Because SAA has been found in atherosclerotic lesions, it is of 100,000 daltons.
thought to contribute to localized inflammation in coronary ● It binds irreversibly to free hemoglobin released by
artery disease. intravascular hemolysis.
➔ Elevated levels may predict a worse outcome for the ● Haptoglobin thus acts as an antioxidant to provide
patient. protection against oxidative damage mediated by free
hemoglobin.
Complement ● Once bound, the complex is cleared rapidly by
● Complement: a series of serum proteins that are normally macrophages in the liver.
present and contribute to inflammation. ● A two- to tenfold increase in haptoglobin can be seen
● Nine complement proteins are activated by bound following inflammation, stress, or tissue necrosis.
antibodies in a sequence known as the classical ● Early in the inflammatory response, however, haptoglobin
pathway; additional numbers are involved in the levels may drop because of intravascular hemolysis,
alternative pathway that is triggered by the presence of consequently masking the protein’s behavior as an
microorganisms. acute-phase reactant.
● The major functions of complement are opsonization, ● Thus, plasma levels must be interpreted in light of other
chemotaxis, and lysis of cells. acute-phase reactants.
● Complement is discussed in detail in Chapter 7. ● Normal plasma concentrations range from 40 to 290
mg/dL.
Alpha1-Antitrypsin
● Alpha1-antitrypsin (AAT): a 52-kD protein that is Fibrinogen
primarily synthesized in the liver. ● Fibrinogen: an acute-phase protein involved in the
● It is the major component of the alpha band when serum is coagulation pathway.
electrophoresed. ● A small portion is cleaved by thrombin to form fibrils that
● Although the name implies that it acts against trypsin, it is make up a fibrin clot.
a general plasma inhibitor of proteases released from ● The molecule is a dimer with a molecular weight of
leukocytes. 340,000 daltons.
● Elastase, one such protease: an enzyme secreted by ● Normal levels range from 200 to 400 mg/dL.
neutrophils during inflammation that can degrade elastin ● The clot increases the strength of a wound and stimulates
and collagen. endothelial cell adhesion and proliferation, which are
➔ In chronic pulmonary inflammation, elastase activity critical to the healing process.
damages lung tissue. ● Formation of a clot creates a barrier that helps prevent the
● Thus, AAT acts to counteract the effects of neutrophil spread of microorganisms further into the body.
invasion during an inflammatory response. ● Fibrinogen makes blood more viscous and serves to
● It also regulates the expression of proinflammatory promote aggregation of red blood cells (RBCs) and
cytokines such as TNF-α, interleukin-1β, and interleukin-6, platelets.
mentioned previously. ● Increased levels may contribute to an increased risk for
● Therefore, activation of monocytes and neutrophils is developing coronary artery disease.
inhibited, limiting the harmful side effects of inflammation.
● AAT deficiency can result in premature emphysema, Ceruloplasmin
especially in individuals who smoke or who have frequent ● Ceruloplasmin consists of a single polypeptide chain with
exposure to noxious chemicals. a molecular weight of 132,000 daltons.
● In such a deficiency, uninhibited proteases remain in the ● It is the principal copper-transporting protein in human
lower respiratory tract, leading to destruction of plasma, binding more than 70% of the copper found in
parenchymal cells in the lungs and to the development of plasma by attaching six cupric ions per molecule.
emphysema or idiopathic pulmonary fibrosis. ● Additionally, ceruloplasmin acts as an enzyme, converting
● It has been estimated that as many as 100,000 Americans the toxic ferrous ion (Fe2+) to the nontoxic ferric form
suffer from this deficiency, although many of them are (Fe3+).
undiagnosed. ● The normal plasma concentration for adults is 20 to 40
● There are at least 75 alleles of the gene coding for AAT, mg/dL.
and 17 of these are associated with low production of the ● A depletion of ceruloplasmin is found in Wilson’s disease,
enzyme. an autosomal recessive genetic disorder characterized by a
➔ One variant gene for AAT is responsible for a complete massive increase of copper in the tissues.
lack of production of the enzyme; individuals who ➔ Normally, circulating copper is absorbed out of the
inherit this gene are at risk of developing liver disease circulation by the liver and either combined with
and emphysema. ceruloplasmin and returned to the plasma or excreted
● Homozygous inheritance of this particular gene may lead to into the bile duct.
the development of cirrhosis, hepatitis, or hepatoma in ➔ In Wilson’s disease, copper accumulates in the liver
early childhood. and subsequently in other tissues, such as the brain,
➔ The only treatment is a liver transplant. corneas, kidneys, and bones.
● AAT can also react with any serine protease, such as ➔ Treatment involves long-term chelation therapy to
proteases generated by the triggering of the complement remove the copper or a liver transplant.
cascade or fibrinolysis.
● Once bound to AAT, the protease is completely inactivated D. Inflammation
and is subsequently removed from the area of tissue ● When pathogens breach the outer barriers of innate
damage. immunity, both cellular and humoral mechanisms are
involved in a complex, highly orchestrated process known
as inflammation.

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● Inflammation: the body’s overall reaction to injury or ● The failure to remove microorganisms or injured tissue
invasion by an infectious agent. may result in continued tissue damage and loss of function.
● Each individual reactant plays a role in initiating,
amplifying, or sustaining the reaction, and a delicate E. Phagocytosis
balance must be maintained for the process to be quickly ● The main purpose of the inflammatory response is to
and efficiently resolved. attract cells to the site of infection and remove foreign cells
● The four cardinal signs or clinical symptoms of or pathogens by means of phagocytosis.
inflammation: ● Although the acute-phase reactants enhance the process of
➔ redness (erythema) phagocytosis, it is the cellular elements of the internal
➔ swelling (edema) defense system that play the major role.
➔ heat ➔ The cells that are most active in phagocytosis are
➔ pain neutrophils, monocytes, macrophages, and dendritic
● Major events that occur rapidly after tissue injury are as cells, as discussed in Chapter 1.
follows: ● Once the WBCs are attracted to the area, the actual
1. Release of chemical mediators such as histamine from process of phagocytosis consists of seven main steps (Fig.
injured mast cells, which causes dilation of the blood 2–5):
vessels. This results in increased blood flow to the 1. Physical contact between the WBC and the foreign cell
affected area, producing redness and heat. 2. Outflowing of the cytoplasm to surround the
2. Increased capillary permeability caused by contraction microorganism
of the endothelial cells lining the vessels. The 3. Formation of a phagosome
increased permeability of the vessels allows fluids in 4. Fusion of lysosomal granules with the phagosome
the plasma to leak into the tissues, resulting in the 5. Formation of the phagolysosome with release of
swelling and pain associated with inflammation. lysosomal contents
3. Migration of WBCs, mainly neutrophils, from the 6. Digestion of microorganisms by hydrolytic enzymes
capillaries to the surrounding tissue in a process 7. Release of debris to the outside of the cell by
called diapedesis. As the endothelial cells of the exocytosis
vessels contract, neutrophils move through the
endothelial cells of the vessel and out into the tissues.
Soluble mediators, which include acute-phase
reactants, chemokines, and cytokines, act as
chemoattractants to initiate and control the response.
Neutrophils are mobilized within 30 to 60 minutes
after the injury, and their emigration may last 24 to
48 hours.
4. Migration of macrophages to the injured area.
Migration of macrophages and dendritic cells from
surrounding tissue occurs several hours later and
peaks at 16 to 48 hours.
5. Acute-phase reactants stimulate phagocytosis of
microorganisms. Macrophages, neutrophils, and
dendritic cells all attempt to clear the area through
phagocytosis; in most cases, the healing process is
completed with a return to normal tissue structure
(Fig. 2–4). ● Physical contact occurs as neutrophils bind loosely to
adhesion molecules called selectins on the endothelial
cells lining the blood vessels.
➔ This causes the neutrophils to roll along the vascular
wall in a random pattern until they encounter the site
of injury or infection.
➔ They adhere firmly to adhesion molecules on the
endothelial cell wall called integrins and penetrate
through to the tissue by means of diapedesis.
➔ This adhering process is aided by chemotaxis,
whereby cells are attracted to the site of inflammation
by chemical substances such as soluble bacterial
factors or acute-phase reactants, including
complement components and CRP.
● Macrophages and dendritic cells already reside in the
tissues.
● Receptors on neutrophils, macrophages, and dendritic cells
bind to certain molecular patterns on a foreign particle
surface, as discussed previously.
● This binding process is enhanced by opsonins, a term
derived from the Greek word meaning “to prepare for
eating.”
● Opsonins: serum proteins that attach to a foreign cell or
● The acute inflammatory response acts to combat the early pathogen and help prepare it for phagocytosis.
stages of infection and also begins a process that repairs ➔ CRP, complement components, and antibodies are all
tissue damage. important opsonins.
➔ However, when the inflammatory process becomes
prolonged, it is said to be chronic.
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● Opsonins may act by neutralizing the surface charge on the
foreign particle, making it easier for the cells to approach
one another.
➔ In addition to receptors for pathogens themselves,
phagocytic cells also have receptors for
immunoglobulins and complement components, which
aid in contact and in initiating ingestion (see Chapters
5 and 7).
● Once contact with surface receptors occurs, phagocytic
cells secrete chemoattractants such as cytokines and
chemokines that recruit additional cells to the site of
infection.
● Neutrophils are followed by monocytes, after which
macrophages and dendritic cells arrive at the site.
● Macrophages and dendritic cells are not only able to ingest
whole microorganisms, but they can also remove injured or
dead host cells.
● After attachment to a foreign cell or pathogen has
occurred, the cell membrane invaginates, and pseudopodia
(outflowing of cytoplasm) surround the pathogen.
● The pseudopodia fuse to completely enclose the pathogen,
forming a structure known as a phagosome. ● NADPH oxidase also plays a major role in the
➔ The phagosome is moved toward the center of the oxygen-independent pathway.
cell. Lysosomal granules quickly migrate to the ● NADPH oxidase depolarizes the membrane when fusion
phagosome, and fusion between granules and the with the phagosome occurs, allowing hydrogen and
phagosome occurs. potassium ions to enter the vacuole.
➔ At this point, the fused elements are known as a ● This alters the pH, which in turn activates proteases that
phagolysosome. contribute to microbial elimination.
● The granules contain lysozyme, myeloperoxidase, and ● Some of these lytic enzymes include small cationic proteins
other proteolytic enzymes. called defensins.
● The contents of the granules are released into the ➔ When defensins are released from lysosomal
phagolysosome, and digestion occurs. granules, they are able to cleave segments of
● Any undigested material is excreted from the cells by bacterial cell walls without the benefit of oxygen.
exocytosis. ➔ Defensins kill a wide spectrum of organisms, including
● Heavily opsonized particles are taken up in as little as 20 both gram-positive and gram-negative bacteria, many
seconds, and killing is almost immediate. fungi, and some viruses.
● The elimination of pathogens actually occurs by two ● Cathepsin G is another example of a protein that is able to
different processes: an oxygen-dependent pathway and an damage bacterial cell membranes.
oxygen-independent pathway. ● Chapter 1 lists some of the contents of neutrophil granules.
● In the oxygen-dependent process, an increase in oxygen ● The importance of NADPH oxidase in the elimination of
consumption, known as the oxidative burst, occurs within microbes is demonstrated by the fact that a lack of it may
the cell as the pseudopodia enclose the particle within a lead to an increased susceptibility to infection.
vacuole. ● Patients with chronic granulomatous disease have a genetic
● This mechanism generates considerable energy through mutation that causes a defect in NADPH oxidase, resulting
oxidative metabolism. in an inability to kill bacteria during the process of
● The hexose monophosphate shunt is used to change phagocytosis.
nicotinamide adenine dinucleotide phosphate (NADP) to its ● Individuals with this disease suffer from recurring, severe
reduced form by adding a hydrogen atom. bacterial infections (see Chapter 19).
● Electrons then pass from NADPH to oxygen in the presence ● Following phagocytosis, macrophages and dendritic cells
of NADPH oxidase, a membrane-bound enzyme that is only mature and are able to process peptides from pathogens
activated through conformational change triggered by for presentation to T cells. T cells then interact with B cells
microbes themselves. to produce antibodies (see Chapter 4 for details).
➔ A radical known as superoxide (O2–) is then formed. ➔ Because T cells are not able to respond to intact
➔ Superoxide is highly toxic but can be rapidly pathogens, phagocytosis is a crucial link between the
converted to even more lethal products. innate and the adaptive immune systems.
➔ By adding hydrogen ions, the enzyme superoxide
dismutase (SD) converts superoxide to hydrogen F. Action of Natural Killer Cells
peroxide or the hydroxyl radical •OH. ● Another important cellular defense that is part of innate
● Hydrogen peroxide has long been considered an important immunity is the action of natural killer (NK) cells.
bactericidal agent and is more stable than any of the free ● Although phagocytosis is important in eliminating infectious
radicals. agents, NK cells represent the first line of defense against
● Its antimicrobial effect is further enhanced by the virally infected cells, tumor cells, and cells infected with
formation of hypochlorite ions through the action of the other intracellular pathogens.
enzyme myeloperoxidase in the presence of chloride ions. ● NK cells have the ability to recognize damaged cells and to
● Hypochlorite is a powerful oxidizing agent and is highly eliminate such target cells without prior exposure to them.
toxic for microorganisms. ● The fact that they lack specificity in their response is
● It is the main component of household bleach used to essential to their function as early defenders against
disinfect surfaces (Fig. 2–6). pathogens.
● By quickly engaging infected target cells, NK cells give the
immune system time to activate the adaptive response of
specific T and B cells.
7
● NK cell activity is enhanced by exposure to cytokines such ● These substances are released into the space between the
as interleukin-12, interferon-α, and interferon-β. NK cell and the target cell.
● Because these cytokines rise rapidly during a viral ➔ Perforins: proteins that form channels (pores) in the
infection, NK cells are able to respond early during an target cell membrane.
infection, and their activity peaks in about 3 days, well ➔ Granzymes: packets of enzymes that may enter
before antibody production or a naïve cytotoxic T-cell through the channels and mediate cell lysis.
response. ● The elimination of target cells can occur in as little as 30 to
● They localize in the tissues in areas where inflammation is 60 minutes.
occurring and where dendritic cells are found. ● Thus, depending on the signals, the NK cell either proceeds
● Once activated, NK cells themselves become major to activate cell destruction or detaches and moves on to
producers of cytokines such as interferon-gamma (IFN-γ) search for another target cell.
and TNF-α that help to recruit T cells.
● In addition, NK cells release various colony-stimulating Antibody-Dependent Cellular Cytotoxicity
factors that act on developing granulocytes and ● A second method of destroying target cells is also available
macrophages. to NK cells.
● Thus, the actions of NK cells have a major influence on ● NK cells recognize and lyse antibody-coated target cells
both innate and adaptive immunity. through a process called antibody-dependent cellular
cytotoxicity (ADCC) (see Fig. 2–7).
Mechanism of Cytotoxicity ● Binding occurs through the surface receptors, CD16
● NK cells constantly monitor the body for potential target (FcγIII) and CD32 (FcγRIIC), which bind to the Fc portion
cells by contacting them through two main classes of of human immunoglobulins.
binding receptors on their surface: ● Lysis of the target cell requires contact with the NK cell,
➔ inhibitory receptors - deliver inhibitory signals, and followed by release of cytotoxic granules.
➔ activating receptors - deliver signals to activate the ● Target cell destruction occurs outside of the NK cell and
cytotoxic mechanisms does not involve phagocytosis or complement fixation.
● The balance between activating and inhibitory signals ● ADCC is recognized as an important contributor to the
enables NK cells to distinguish healthy cells from infected anti-tumor activity of many monoclonal antibodies used as
or cancerous ones. tumor immunotherapy (see Chapter 17).
● The inhibitory signal is based on recognition of class I ● However, this method is not unique to NK cells, as
major histocompatibility complex (MHC) proteins, which monocytes, macrophages, and neutrophils also exhibit such
are expressed on all healthy cells (see Chapter 3 for receptors and act in a similar manner.
details). ● Nonetheless, the overall importance of NK cells as a
● If NK cells react with class I MHC proteins, then the natural defense mechanism is demonstrated by the fact that
killing process is inhibited. patients who lack these cells have recurring, serious viral
➔ Examples of this type of inhibitory receptor include infections and an increased incidence of tumors.
killer cell immunoglobulin-like receptors (KIRs) and
CD94/NKG2A receptors, both of which bind class I G. Innate Lymphoid Cells
MHC molecules. ● Innate lymphoid cells (ILCs) are a growing family of
● Diseased and cancerous cells may lose their ability to immune cells that develop from the common lymphoid
produce MHC proteins. progenitor but do not express markers of the lymphocyte
● NK cells are thus triggered by a lack of MHC antigens, lineage.
sometimes referred to as recognition of “missing self.” ● ILCs are found predominantly at mucosal sites and
● This lack of inhibition appears to be combined with an contribute to the innate response to infectious agents at
activating signal switched on by the presence of proteins these sites through the rapid release of immunoregulatory
produced by cells under stress, namely, those cells that are cytokines.
cancerous or infected with a pathogen. ➔ One key example of the role of ILCs in the innate
➔ Examples of activating receptors that bind stress immune response is through their secretion of IFN-γ.
proteins are CD16 and NKG2D. ● This cytokine activates the production of reactive oxygen
● If an inhibitory signal is not received when binding to species, such as superoxide and hydrogen peroxide, in
activating receptors occurs, then NK cells release phagocytic cells to be used in the oxidative burst.
substances called perforins and granzymes (Fig. 2–7).