Chapter 43: The Immune System

Saliva, tears, and mucous secretions that bathe various exposed epithelia provide a

washing action that also inhibits colonization by fungi and bacteria.

Cycles of signaling and response continue the process of inflammation. Activated complement proteins promote further histamine release, attracting more phagocytic cells to the site of injury and infection. At the same time,

enhanced blood flow to the site helps deliver antimicrobial peptides, which, as in insects, typically kill or inactivate pathogens by disrupting membrane integrity.

Because most of the recent discoveries regarding vertebrate innate immunity have come from studies of mice and humans, we'll

focus here on mammals.

Note that a foreign molecule or cell doesn't have to be pathogenic to elicit an immune response, but we'll

focus on the immune system's role in defending against pathogens.)

In insects, the major immune cells are called

hemocytes.

Beyond their physical role in inhibiting microbial entry, body secretions create an environment that is

hostile to many pathogens.

The innate immune response of insects is specific for particular classes of pathogens. For example,

if a fungus infects an insect, binding of recognition proteins to fungal cell wall molecules activates a transmembrane receptor called Toll.

Fortunately, adaptations have arisen over the course of evolution that protect animals against many pathogens. The body's defenses make up the

immune system, which enables an animal to avoid or limit many infections.

In the case of a severe infection, such as meningitis or appendicitis, the number of white blood cells in the bloodstream may

increase severalfold within only a few hours.

Virus-infected body cells secrete interferon proteins that

induce nearby uninfected cells to produce substances that inhibit viral replication. In this way, these interferons limit the cell-to-cell spread of viruses in the body, helping control viral infections such as colds and influenza.

In the airway, ciliated epithelial cells sweep mucus and any entrapped material upward, helping prevent

infection of the lungs.

Like amoebas, some hemocytes are phagocytic cells: They

ingest and break down microorganisms by a process known as phagocytosis (Figure 43.2).

Once bound to a pathogen molecule, a recognition protein triggers an

innate immune response.

Chitin also

lines the insect intestine, where it blocks infection by many pathogens.

Dendritic cells reside outside the

lymphatic system but migrate to the lymph nodes after interacting with pathogens.

Dendritic cells

mainly populate tissues, such as skin, that contact the environment. They stimulate adaptive immunity against pathogens that they engulf.

Pharmaceutical companies now use recombinant DNA technology to

mass-produce interferons to help treat certain viral infections, such as hepatitis C.

Pathogens in food or water and those in swallowed mucus must also contend with the acidic environment of the stomach (pH 2), which kills

most of them before they can enter the intestines.

The barrier defenses of mammals, which block the entry of many pathogens, include the

mucous membranes and the skin.

In this section, we'll consider the innate defenses that are similar to those found among invertebrates—barrier defenses, phagocytosis, and antimicrobial peptides—as well as some that are unique to vertebrates, such as

natural killer cells, interferons, and the inflammatory response.

The two main types of phagocytic cells in the mammalian body are

neutrophils and macrophages.

Housed within body fluids and tissues, the invader is

no longer an outsider.

As mentioned above, some are very similar to the insect innate immune receptor Toll. Each mammalian Toll-like receptor (TLR) binds to fragments of molecules characteristic of a set of pathogens (Figure 43.4). For example, TLR3, on the inner surface of vesicles formed by endocytosis, binds to

double-stranded RNA, a form of nucleic acid produced by certain viruses.

Any pathogen that breaches an insect's barrier defenses

encounters internal immune defenses.

Small organs called lymph nodes scattered within the lymphatic system contain macrophages, which

engulf pathogens that enter the lymph from the interstitial fluid.

Sealing off the entire body surface is impossible, however, because gas exchange, nutrition, and reproduction require

openings to the environment.

In mammals, as in insects, there are

phagocytic innate immune cells dedicated to detecting, devouring, and destroying pathogens.

Phagocytosis.

phagocytosis..

Similarly, secretions from oil and sweat glands give human skin a pH ranging from 3 to 5, acidic enough to

prevent the growth of many bacteria.

Alternative RNA splicing

produces multiple proteins from a single coding gene.

The increased blood vessel leakiness common to all forms of sepsis allows fluid to leak out of blood into tissues, resulting in both swelling and low blood pressure. If not controlled, sepsis can

progress to septic shock, in which blood pressure drops precipitously and the blood supply to organs is significantly reduced. The mortality rate for septic shock is above 40%.

Insects also have specific defenses that

protect against infection by viruses.

Interferons are

proteins that provide innate defense by interfering with viral infections.

Remarkably, phagocytic mammalian cells use receptor proteins very similar to the Toll receptor to

recognize viral, fungal, and bacterial components, a discovery that was recognized with the Nobel Prize in Physiology or Medicine in 2011.

Histamine triggers nearby blood vessels to dilate and become more permeable. The resulting increase in local blood supply produces the

redness and increased skin temperature typical of the inflammatory response (from the Latin inflammare, to set on fire).

The tertiary structure of a protein is

relies on multiple weak bonds between side chains.

For example, some macrophages are located in the spleen, where pathogens in the blood are often

trapped.

Many viruses that infect insects have a genome consisting of a single strand of RNA. When the virus replicates in the host cell, this RNA strand is the template for the synthesis of double-stranded RNA. Because animals do not produce double-stranded RNA, its presence can

trigger a specific defense against the invading virus, as illustrated in Figure 43.3.

In mammals, pathogen recognition triggers the production and release of a variety of peptides and proteins that attack pathogens or impede their reproduction. A number of these, including the interferons and complement proteins, are

unique to vertebrate immune systems.

Chronic (ongoing) inflammation can also threaten human health. For example, millions of individuals worldwide are affected by Crohn's disease and ulcerative colitis, often debilitating disorders in which an

unregulated inflammatory response disrupts intestinal function.

To fight infections, an animal's immune system must detect foreign particles and cells within the body. In other words, a properly functioning immune system

distinguishes nonself from self.

In innate immunity, recognition and response rely on

traits common to groups of pathogens

In addition to these cells, a number of more specialized cell types also contribute to innate immune defenses:

1. Dendritic cells 2. Eosinophils 3. Natural killer cells 4. Mast cells

Two types of immune defenses are found among animals.

1. Innate Immunity 2. Adaptive Immunity

Pus is both a sign of infection and an indicator of immune defenses in action. Explain.

Because pus contains white blood cells, fluid, and cell debris, it indicates an active and at least partially successful inflammatory response against invading pathogens.

VISUAL SKILLS Observe the locations of the TLR proteins and then suggest a possible benefit of their distribution.

Cell-surface TLRs recognize molecules on the surface of pathogens, whereas TLRs in vesicles recognize internal molecules of pathogens after the pathogens are broken down.

TLR signaling.

Each mammalian Toll-like receptor (TLR) recognizes a molecular pattern shared by a group of pathogens. Lipopolysaccharide, flagellin, CpG DNA (DNA containing unmethylated CG sequences), and double-stranded (ds) RNA are found in bacteria, fungi, or viruses but not in animal cells. Once bound to such a pathogen molecule, TLR proteins trigger internal innate immune defenses, including production of cytokines and antimicrobial peptides.

How is this accomplished?

Immune cells produce receptor molecules that bind specifically to molecules from foreign cells or viruses and activate defense responses.

Figure 43.3 Antiviral defense in insects.

In defending against an infecting RNA virus, an insect cell turns the viral genome against itself, cutting the viral genome into small fragments that it then uses as guide molecules to find and destroy viral messenger RNAs (mRNAs).

WHAT IF? Parasitic wasps inject their eggs into host larvae of other insects. If the host immune system doesn't kill the wasp egg, the egg hatches and the wasp larva devours the host larva as food. Suggest an explanation for why some insect species initiate an innate immune response to a wasp egg, but others cannot.

Mounting an immune response would require recognition of some molecular feature of the wasp egg not found in the host. It might be that only some potential hosts have a receptor with the necessary specificity.

Innate Immunity of Invertebrates

One part of this defense system is a set of barrier defenses, including the insect exoskeleton. Composed largely of the polysaccharide chitin, the exoskeleton provides a physical barrier against most pathogens.

For instance, sepsis associated with COVID-19 (the disease caused by the coronavirus called SARS-CoV-2) can injure blood vessels, resulting in

abnormal clotting, and damage lung tissue, resulting in respiratory failure.

Figure 43.6 The human lymphatic system.

The lymphatic system consists of lymphatic vessels (shown in green), through which lymph travels, and structures that trap foreign substances. These structures include lymph nodes (orange) and lymphoid organs (yellow): the adenoids, tonsils, thymus, spleen, Peyer's patches, and appendix. Steps 1-4 trace the flow of lymph and illustrate the role of lymph nodes in activating adaptive immunity. (Concept 42.3 describes the relationship between the lymphatic and circulatory systems.)

Some white blood cells secrete a different type of interferon that helps

activate macrophages, enhancing their phagocytic ability.

Within the lymph nodes, dendritic cells interact with other immune cells, stimulating

adaptive immunity.

Secretions that trap or kill pathogens guard the body's entrances and exits, while the linings of the digestive tract, airway, and other exchange surfaces provide

additional barriers to infection.

MAKE CONNECTIONS How do the molecules that activate the vertebrate TLR signal transduction pathway differ from the ligands in most other signaling pathways (see Concept 11.2)?

Whereas the ligand for the TLR receptor is a foreign molecule, the ligand for many signal transduction pathways is a molecule produced by the organism itself.

In the digestive system, lysozyme, an enzyme that breaks down bacterial cell walls, acts as

a chemical barrier against any pathogens ingested with food.

The result is an accumulation of pus,

a fluid rich in white blood cells, dead pathogens, and debris from damaged tissue.

When a splinter lodges under your skin, the surrounding area becomes swollen and warm. As Figure 43.5 depicts, both changes reflect a local inflammatory response,

a set of events triggered by signaling molecules released upon injury or infection.

adaptive immunity,

a set of molecular and cellular defense found only among vertebrates.

The specific binding of immune receptors to foreign molecules is

a type of molecular recognition and is the central event in identifying nonself molecules, particles, and cells.

The mucous membranes that line the digestive, respiratory, urinary, and reproductive tracts produce mucus,

a viscous fluid that traps pathogens and other particles.

A systemic inflammatory response sometimes involves fever. In response to certain pathogens, substances released by activated macrophages cause the body's thermostat to reset to a higher temperature (see Concept 40.3). The benefits of the resulting fever are still a subject of debate. One hypothesis is that

an elevated body temperature may enhance phagocytosis and, by speeding up chemical reactions, accelerate tissue repair

The infection-fighting complement system consists of roughly 30 proteins in blood plasma. These proteins circulate in

an inactive state and are activated by substances on the surface of many pathogens.

The first lines of defense offered by immune systems help prevent pathogens from gaining entrance to the body. For example,

an outer covering, such as skin or a shell, blocks entry by many pathogens.

The term "cytokine storm" is sometimes used to describe

any situation (including sepsis) in which dramatic elevations in cytokine levels lead to tissue damage. This term is also used to describe the elevated level of cytokines.

Macrophages and neutrophils are both key components of the inflammatory response,

as discussed shortly.

Certain viral, bacterial, or fungal infections can induce sepsis, an overwhelming inflammatory response that

causes organ damage.

If a pathogen breaches barrier defenses and enters the body, the problem of how to fend off attack

changes substantially.

Natural killer cells

circulate through the body and detect the abnormal surface proteins found on some virus-infected and cancerous cells. Natural killer cells do not engulf stricken cells. Instead, they release chemicals that lead to cell death, inhibiting spread of the virus or cancer.

Many other hemocytes release antimicrobial peptides, which

circulate throughout the body of the insect and inactivate or kill bacteria or fungi by disrupting their plasma membranes.

Insect immune cells produce a set of recognition proteins, each of which binds to a molecule common to a broad class of pathogens. Many of these molecules are

components of fungal or bacterial cell walls. Because such molecules are not normally found in animal cells, they function as "identity tags" for pathogen recognition.

Eosinophils, often found beneath an epithelium, are important in

defending against multicellular invaders, such as parasitic worms. Upon encountering such parasites, eosinophils discharge destructive enzymes.

Some bacteria are recognized but resist breakdown after being engulfed by a host cell. One example is Mycobacterium tuberculosis, the bacterium shown in Figure 43.1. Rather than being destroyed, this bacterium grows and

reproduces within host cells, effectively hidden from the body's immune defenses. The result of this infection is tuberculosis (TB), a disease that attacks the lungs and other tissues. Worldwide, TB kills more than 1 million people a year.

Macrophages ("big eaters"), like the one shown in Figure 43.1, are larger phagocytic cells. Some migrate throughout the body, whereas others

reside permanently in organs and tissues where they are likely to encounter pathogens.

A minor injury or infection causes a local inflammatory response, but more extensive tissue damage or infection may lead to a

response that is systemic (throughout the body).

A bacterium or other particle taken up by phagocytosis is

routed to lysosomes for degradation.

In recognizing viral, fungal, or bacterial components, phagocytic mammalian cells rely on

several types of receptors.

Neutrophils, which circulate in the blood, are attracted by

signals from infected tissues and then engulf and destroy the infecting pathogens.

A local inflammatory response begins when activated macrophages discharge cytokines,

small peptides that act as signaling molecules.

Toll in turn activates production and secretion of antimicrobial peptides that

specifically kill fungal cells.

Many viruses act at the cellular level in blocking the innate immune response. For instance, viral genomes often encode proteins that generally suppress protein synthesis by the host cell, or specifically

suppress the synthesis of defensive proteins such as interferons.

Cells in injured or infected tissue often secrete molecules

that stimulate the release of additional neutrophils from the bone marrow.

The great success of insects in terrestrial and freshwater habitats teeming with diverse pathogens highlights

the effectiveness of invertebrate innate immunity.

Lysozyme in tears, saliva, and mucous secretions destroys the cell walls of susceptible bacteria as they enter the openings around

the eyes or the upper respiratory tract.

At the end of the local inflammatory response, pus and excess fluid are taken up as lymph,

the fluid transported in the network of vessels known as the lymphatic system (Figure 43.6).

These mechanisms allow the viral infection to become well established before

the host can mount an effective immune response.

Activation results in a cascade of biochemical reactions that can lead to lysis (bursting) of invading cells. The complement system also functions in

the inflammatory response as well as in the adaptive defenses discussed later in the chapter.

and TLR5 recognizes flagellin,

the main protein of flagella.

In jawed vertebrates, innate immune defenses coexist with

the more recently evolved system of adaptive immunity.

Adaptations have evolved in some pathogens that enable them to avoid destruction by phagocytic cells. For example,

the outer capsule that surrounds certain bacteria interferes with molecular recognition and phagocytosis. One such bacterium, Streptococcus pneumoniae, is a major cause of pneumonia and meningitis in humans (see Concept 16.1).

innate immunity,

the set of immune defenses common to all animals.

In addition, mast cells release

the signaling molecule histamine at sites of damage.

One class of hemocytes produces a type of defense molecule that helps entrap larger pathogens, such as Plasmodium,

the single-celled parasite of mosquitoes that causes malaria in humans.

Some of these cytokines recruit neutrophils to

the site of injury or infection.

For a pathogen—a bacterium, fungus, virus, or other disease-causing agent—the internal environment of an animal offers a source of nutrients, a protected setting, and a means of transport to new environments. From the animal's vantage point,

the situation is not so ideal.

Similarly, TLR4, located on immune cell plasma membranes, recognizes lipopolysaccharide, a type of molecule found on

the surface of many bacteria.