Test Bank for Janeway’s Immunobiology, 9th Edition By Kenneth Murphy, Casey Weaver

Test Bank for Janeway’s Immunobiology, 9th Edition By Kenneth Murphy, Casey Weaver 

JANEWAY'S IMMUNOBIOLOGY, 9

CHAPTER 2: INNATE IMMUNITY: THE FIRST LINES OF DEFENSE 

 

Anatomic barriers and initial chemical defenses 

 

2-1  Infectious diseases are caused by diverse living agents that replicate in their hosts

 

2.1  Multiple choice: Antibodies, complement proteins, and phagocytic cells provide 

effective protection against all of the following types of infections in Figure Q2.1, except: 

Figure Q2.1 

 

2.2  Multiple choice: Pathogenic infections induce damage to the host by a variety of 

mechanisms. While many mechanisms are direct effects of the pathogen, some

damaging mechanisms result from the immune response to the infection, as illustrated in

Figure Q2.2. Examples of damage caused by the host immune response are: 

 

 Page 2 of 19 

Figure Q2.2 

 

 

2.3  True/False: Mucosal surfaces and external epithelia are major routes of pathogenic 

infection. Mucosal surfaces are found in tissues such as the gastrointestinal tract, the

reproductive tract and the mouth and respiratory tract. While the mouth and respiratory

tract are routes of virus but not bacterial infections, the gastrointestinal tract is the route

for bacterial but not virus infections. 

 

2-2  Epithelial surfaces of the body provide the first barrier against infection

 

2.4  Multiple choice: Epithelial surfaces provide the first line of defense against infection by 

the use of several types of mechanisms. One of the chemical mechanisms used by

epithelia is:

A.  Joining of epithelial cells by tight junctions

B.  Secretion of antimicrobial peptides by epithelial cells 

C.  Production of mucus, tears, or saliva in the nose, eyes, and oral cavity

D.  Movement of mucus by cilia

E.  Peristalsis in the gastrointestinal tract 

 

2.5  Multiple choice: Women with urinary tract infections caused by E. coli are generally 

treated with a course of antibiotics. A common complication of the antibiotic treatment is

the occurrence of a vaginal yeast infection caused by Candida albicans, an organism

that is normally present in very low numbers in the human vaginal tract. This

complication occurs because:

A.  The E. coli infection damages the reproductive epithelium, causing a breach in 

the tight junctions and allowing invasion by the Candida albicans.

B.  The E. coli infection induces adhesion molecule expression on the reproductive 

epithelium, allowing attachment of the yeast.

C.  The antibiotic treatment kills all strains of fungi present in the reproductive tract, 

except the Candida albicans.

D.  The E. coli infection causes gastrointestinal distress leading to diarrhea. 

E.  The antibiotics kill many of the commensal organisms in the reproductive tract, 

allowing overgrowth of the fungus.

 

2-3  Infectious agents must overcome innate host defenses to establish a focus of

infection

 

2.6  Short answer: Our environment contains masses of microorganisms, many of which 

reside as commensal organisms on our body’s mucosal and epithelial surfaces without

causing disease. What two features distinguish a pathogenic microbe from these

commensal microbes? 

 

2-4  Epithelial cells and phagocytes produce several kinds of antimicrobial proteins

 

2.7  Multiple choice: Streptococcus pneumoniae is a Gram-positive bacterium that 

colonizes the mucosal surface of the upper respiratory tract in humans. The presence of

this bacterium in the nose and throat is widespread in the population, and in most

people, colonization with Strep. pneumoniae is asymptomatic. Figure Q2.7 shows a

comparison of in vitro growth curves of the wild-type strain of Strep. pneumoniae, as well

as a Strep. pneumoniae mutant strain with a defect in one bacterial gene. The graph on

the right shows the growth curve following addition of lysozyme during the logarithmic

phase of bacterial growth. 

 Page 3 of 19 

 

 Page 4 of 19 

Figure Q2.7 

 

Which statement could account for the data in these graphs? 

A.  Strain B is wild-type Strep. pneumoniae, and strain A is a mutant that cannot 

modify its peptidoglycan to be lysozyme-resistant.

B.  Strain B is wild-type Strep. pneumoniae, and strain A is a mutant that that 

expresses increased levels of LPS.

C.  Strain A is wild-type Strep. pneumoniae, and strain B is a mutant that cannot 

modify its peptidoglycan to be lysozyme-resistant.

D.  Strain A is wild-type Strep. pneumoniae, and strain B is a mutant that secretes an 

enzyme that inactivates lysozyme.

E.  Strain A is wild-type Strep. pneumoniae, and strain B is a mutant that cannot 

grow well in vitro. 

2.8  Multiple choice: The production of antimicrobial peptides is one of the most

evolutionarily ancient mechanisms of defense for multicellular organisms, and most

eukaryotic species make many different forms of these proteins. For instance, human

paneth cells in the gastrointestinal epithelium make 21 different defensins. The reason

for this diversity of antimicrobial peptides is:

A.  Epithelial cells make different forms than those made by neutrophils.

B.  Neutrophils make many different defensins and store them as inactive proteins in 

their secretory granules.

C.  Most of them are produced only in response to infection.

D.  The production of different peptides is induced following a bacterial infection 

versus a fungal infection.

E.  Each one has distinct activities against Gram-negative bacteria, Gram-positive 

bacteria, or fungi.

 

2.9 True/False: Neutrophils regulate the production of active cathelicidins (a class of 

antimicrobial peptides) by segregating the inactive propeptide from the processing 

enzyme that cleaves and activates it in two different types of cytoplasmic granules.

These two types of granules are induced to fuse with phagosomes after ingestion of

microbes, bringing the processing enzyme and the propeptide together. 

 

The complement system and innate immunity 

 

2-5  The complement system recognizes features of microbial surfaces and marks them

for destruction by coating them with C3b

 

2.10  Multiple choice: Although the complement cascade can be initiated by antibodies 

bound to the surface of a pathogen, complement activation is generally considered to be

an innate immune response. This is because:

A.  Two of the three pathways for complement activation are initiated by 

constitutively produced recognition molecules that directly interact with microbial

surfaces.  

B.  When the complement cascade leads to the formation of a membrane-attack

complex, the pathogen is killed.  

C.  Several of the soluble products generated by complement activation lead

promote the inflammatory response. 

D. Complement proteins bound to the pathogen promote uptake and destruction by

phagocytic cells.  

E.  The C3 convertase is only produced when complement activation is initiated by

antibody binding to a pathogen. 

 

2.11  Multiple choice: The formation of the C3 convertase is a key step in complement 

activation that occurs in all three complement pathways. This enzyme cleaves C3 in

blood plasma, leading to a conformational change in the C3b fragment that exposes its

reactive thioester group. The activated C3b is potentially harmful to the host, if it

becomes covalently attached to a host cell, rather than to the surface of a pathogen.

This deleterious outcome is largely avoided by:

A.  The inability of active C3b to diffuse away in the blood plasma. 

B.  The inability of active C3b to covalently attach to the membranes of eukaryotic 

cells.

C.  The rapid hydrolysis of active C3b in solution, rendering it inactive.

D.  The tight binding of active C3b to the C3 convertase.

E.  The ability of active C3b to recruit phagocytic cells. 

 

2-6  The lectin pathway uses soluble receptors that recognize microbial surfaces to

activate the complement cascade

 

2.12  Short answer: Infants and young children with deficiencies in specific complement 

components present with recurrent respiratory infections caused by extracellular

bacteria. The peak age of susceptibility is between 6 and 12 months after birth. At this

time, as shown in Figure Q2.12, maternal antibodies acquired by the child during fetal

gestation are nearly gone, but the child is not yet generating robust antibody responses

to new infections, as indicated by the low circulating levels of IgG and IgA. As children

with this immunodeficiency get older, they outgrow this disease and show no further

evidence of these recurrent infections. Based on this information, name one likely gene

deficiency (in the complement system) that could cause this primary immunodeficiency,

and the specific complement pathway likely to be affected. Explain your answer. 

 Page 5 of 19 

 Page 6 of 19 

Figure Q2.12 

 

2.13  Multiple choice: Mannose binding lectins (MBL) and ficolins are the two classes of 

proteins that can initiate the lectin pathway of complement activation. These proteins are

selective for activating complement on the surfaces of microbial pathogens rather than

host cells because:

A.  Their higher-order oligomeric structure can be assembled only after the 

monomers first bind to pathogen membranes.

B.  They only recruit MASP (MBL-associated serine proteases) proteins when bound 

to pathogen surfaces and not when bound to host cells.

C.  They only undergo the conformational change needed to activate MASP proteins 

when bound to a pathogen and not when bound to a host cell.

D.  They only bind to carbohydrate side chains and oligosaccharide modifications 

found on pathogen surfaces but not on host cell membranes.

E.  The activated MASP proteins are rapidly inactivated by hydrolysis when present 

on the surface of a host cell.

 

2-7  The classical pathway is initiated by activation of the C1 complex and is homologous

to the lectin pathway

 

2.14  Multiple choice: The classical complement pathway is initiated by C1q binding to the 

surface of a pathogen. In some cases, C1q can directly bind the pathogen, for instance

by recognizing proteins of bacterial cell walls, but in most cases C1q binds to IgM

antibodies that are bound to the pathogen surface. How does this IgM-binding feature of

C1q contribute to rapid, innate immune responses rather than to slow, adaptive

responses?

A.  C1q induces B lymphocytes to begin secreting antibody within hours of pathogen 

exposure.

B.  Natural antibody that binds to many microbial pathogens is produced prior to 

pathogen exposure.

C.  C1q binds to C-reactive protein which then binds to IgM on the pathogen surface.

D.  C1q directly induces inflammation, recruiting phagocytes and antibodies from the 

blood into the infected tissue.

E.  C1q binds to dendritic cells in the infected tissue, inducing them to secrete 

inflammatory cytokines.

 

2.15  True/False: The classical and lectin pathways of complement activation converge at the 

step of C3 activation. However, the initiating steps of each pathway use protein

components and enzymatic mechanisms that share no similarity with each other. 

 

 

2-8  Complement activation is largely confined to the surface on which it is initiated 

 

2.16  Multiple choice: Opsonization of pathogens by both antibodies and complement 

proteins (C3b) leads to uptake and destruction of the pathogen by phagocytic cells that

express both Fc receptors and complement receptors. Which of the following in Figure

Q2.16 is the most efficient form of dual opsonization of the pathogen by antibody and 

C3b to maximize phagocytosis?

 

 Page 7 of 19 

Figure Q2.16 

 

2-9  The alternative pathway is an amplification loop for C3b formation that is accelerated

by properdin in the presence of pathogens

 

2.17  Multiple choice: The alternative pathway of complement activation has an important 

role in innate immunity, due to its ability to greatly amplify the amount of C3b deposited

onto the pathogen surface. This amplification occurs because:

A.  The C3 convertase of the alternative pathway is much more active than those of 

the classical and lectin pathways. 

B.  The C3 convertase of the alternative pathway works as a soluble enzyme in the 

plasma.

C.  The C3 convertase of the alternative pathway cannot be inactivated by 

complement regulatory factors in the host.

D.  The C3 convertase of the alternative pathway is more efficiently recruited to 

pathogen surfaces than the C3 convertases of the classical and lectin pathways. 

E.  The C3 convertase of the alternative pathway contains C3b, and can generate 

more of itself. 

 

2.18  True/False: The C3 convertase of the alternative complement pathway amplifies the 

overall magnitude of complement activation regardless of which of the three pathways

initiated the complement activation initially. 

 

2.19  Multiple choice: Patients with recurrent infections of Neisseria meningitidis, an 

 

extracellular bacterial pathogen that causes meningitis, were examined to determine the

underlying cause of their immunodeficiency. A subset of these patients were found to

have defects in complement activation on the bacterial surface, a process that for this

bacterium is dominated by alternative complement activation leading to C3b deposition

on the pathogen surface. When neutrophils from these patients were examined in vitro,

the results in Figure Q2.19 were obtained.  

 

 Page 8 of 19 

 

Figure Q2.19 

Based on these data, the identity of the green neutrophil mediator in Figure Q2.19 is

likely to be:

A.  Complement factor B 

B.  The C3 convertase

C.  Factor P (properdin)

D.  C3b

E.  Mannose-binding lectin (MBL) 

 

2-10  Membrane and plasma proteins that regulate the formation and stability of C3

convertases determine the extent of complement activation

 

2.20  Multiple choice: One form of anemia results when individuals have a deficiency in the 

enzyme phosphatidylinositol glycan A (PIGA). This enzyme is required for the

membrane attachment of proteins anchored by glycolipids to the plasma membrane,

using what is called a ‘GPI-linkage.’ Included in the group of GPI-linked cell surface

proteins is DAF/CD55. These individuals become anemic because:

A.  DAF/CD55 prevents the lysis of red blood cells by infecting pathogens.

B.  DAF/CD55 normally prevents the spleen from clearing healthy red blood cells 

from the circulation.

C.  In the absence of PIGA, the red blood cell membrane is bare of proteins allowing 

increased access of complement activating proteins to attach to the cell

membrane. 

D.  DAF/CD55 is a complement inhibitory protein that inactivates any C3 convertase

that may form on host cell surfaces. 

E.  In the absence of PIGA, red blood cells are unable to synthesize high levels of

hemoglobin. 

 

2-11  Complement developed early in the evolution of multicellular organisms 

 

2.21  Short answer: In vertebrates, complement activation generally involves a pathogen 

recognition step followed by a proteolytic cascade that produces the effector proteins

that function in opsonization, membrane attack, and inflammation. 

a) Which of these is likely to be the most evolutionarily primitive aspect of the

complement system? 

b) Which pathway of complement initiation is likely to be the one that most recently

evolved? 

 

2-12  Surface-bound C3 convertase deposits large numbers of C3b fragments on

pathogen surfaces and generates C5 convertase activity

 

2.22  True/False: The C3 convertase amplifies the process of complement activation by 

generating large amounts of C3b and cleaving large numbers of C5 molecules.

 

2-13  Ingestion of complement-tagged pathogens by phagocytes is mediated by

receptors for the bound complement proteins

 

2.23  Multiple choice: Even when the complement cascade fails to proceed beyond 

generating the C3 convertase, complement activation is effective at inducing pathogen

uptake and destruction. This process of immune protection is mediated by:

A.  Activation of complement inhibitory receptors on phagocytes that promote 

pathogen uptake

B.  Activation of soluble proteases in the serum that disrupt pathogen membranes

C.  Engagement of complement receptors on phagocytes by C3b and its cleavage 

products which promotes phagocytosis

D.  Engagement of complement receptors on B cells that promotes antibody 

production

E.  Stimulation of antimicrobial peptide secretion by phagocytes 

 

2.24  Multiple choice: B cells express a complement receptor that binds to C3b cleavage 

products, such as iC3b and C3dg. When a B cell with an antigen receptor that

specifically recognizes that pathogen also has its complement receptor stimulated

because the pathogen is opsonized with these C3 fragments, B cell activation is greatly

enhanced. Due to this mechanism, B cells can be activated by much lower

concentrations of antigen (in this case, the pathogen) than if the antigen is devoid of

complement components. This mechanism functions to:

A.  Ensure that pathogens are readily detected by the adaptive immune system 

before they replicate to high levels in the host

B.  Prevent B cells from being activated in response to antigens that are not 

pathogens

C.  Allow B cells to phagocytose the pathogen and help destroy it

D.  Induce increased rounds of B cell replication to make more pathogen-specific B 

cells

E.  Allow the B cell to block pathogen replication by interfering with multiple 

pathogen surface functions

 

2-14  The small fragments of some complement proteins initiate a local inflammatory

response

 

2.25  Short answer: Recent studies using mouse models of pulmonary inflammation (a model 

 Page 9 of 19 

for human asthma) have found that mice deficient in the C3a receptor have greatly

reduced disease symptoms when challenged with inhaled preparations containing

extracts of the fungal pathogen Aspergillus fumigatus. Specifically, the C3a receptordeficient

mice

showed

reduced

influx

of

granulocytes

and

lymphocytes

into

the

lung

and

reduced

fluid

in

the

lung

after

challenge.

What

is

the

explanation

for

these

findings?

 

 

2-15  The terminal complement proteins polymerize to form pores in membranes that can

kill certain pathogens

 

2.26  Multiple choice: The terminal components of the complement pathway assemble to 

form a membrane attack complex that can induce pathogen lysis and death. Yet,

evidence indicates that this feature of complement is less important than the earlier

steps that promote pathogen opsonization and induce inflammation. This conclusion is

based on:

A.  In vitro experiments showing that very few species of bacteria are susceptible to 

lysis by the membrane attack complex

B.  Experiments indicating that only bacteria, but not viruses or fungi, are susceptible 

to lysis by the membrane attack complex

C.  The very low levels of terminal complement components in the serum

D.  The fact that other mammalian species lack the terminal components of the 

complement pathway needed to form the membrane attack complex

E.  The limited susceptibility to infections of patients with deficiencies in terminal 

complement components

 

2-16  Complement control proteins regulate all three pathways of complement activation

and protect the host from their destructive effects

 

2.27  Multiple choice: Multiple pathways for regulating complement activation limit the 

potential damage caused by complement deposition on host cells or caused by the

spontaneous activation of complement proteins in the plasma. Genetic deficiencies in

these mechanisms often lead to chronic inflammatory diseases, but in some cases can

paradoxically lead to increased susceptibility to bacterial infections. This latter outcome

may occur because:

A.  Complement regulatory proteins have dual functions in inhibiting and promoting 

complement activation.

B.  Uncontrolled complement activation leads to the depletion of serum complement 

proteins.

C.  The inhibition of the membrane attack complex by complement regulatory 

proteins normally leads to enhanced activation of the early steps of the

complement pathway. 

D.  Complement regulatory proteins normally cause the rapid depletion of plasma

complement factors. 

E.  Uncontrolled complement activation recruits the majority of phagocytic cells,

leaving few remaining to fight infections in the tissues. 

 

2.28  Short answer: Although homozygous deficiencies in complement regulatory proteins 

 

cause serious diseases, more subtle alterations in the balance of complement activation

versus inhibition have been found to contribute to disease susceptibility. Describe the

genetic evidence linking subtle alterations in complement regulatory proteins to disease

susceptibility. 

 Page 10 of 19 

2-17  Pathogens produce several types of proteins that can inhibit complement activation

 

2.29  Multiple choice: The importance of complement activation as an innate immune 

defense against infections is illustrated by:

A.  The evolution of complement avoidance strategies by many pathogens

B.  The large number of proteins involved in the complement pathway

C.  The large number of complement regulatory pathways expressed by the host

D.  The existence of three different mechanisms for initiating complement activation

E.  The ability of the membrane attack complex to lyse some pathogens 

 

2.30  True/False: Several pathogens produce proteins, either membrane-bound or secreted, 

that inactivate C3b that might be deposited on the pathogen surface. C3b is specifically

targeted due to its central position in all three complement pathways. 

 

2.31  Synthesis question: Four different clinical isolates of the Gram-positive bacterium, 

Staphylococcus aureus, are tested for their abilities to resist innate immune defense

mechanisms. For these experiments, each bacterial strain is first grown in culture to

achieve log-phase replication, and then cultures are supplemented with dilutions of

human serum containing normal serum proteins as well as antibodies capable of binding

to S. aureus. One hour later, the cultures are analyzed and the numbers of live bacteria

are quantitated. The data from this experiment are shown in Figure Q2.31A. 

 

Figure Q2.31A 

 

a) From these data, what general conclusions can be reached about the four strains of

S. aureus? 

 

To identify the bactericidal mechanisms killing each strain of S. aureus, the serum is

depleted of complement C3 by running it over an anti-complement C3 antibody affinity

column. The experiment above is then repeated and the data are shown in Figure

Q2.31B. 

 Page 11 of 19 

 

Figure Q2.31B 

 

b) What is the most likely mechanism accounting for the killing of strain D in this

experiment? 

 

To determine whether strains A and C are susceptible to the same microbicidal pathway,

the serum is depleted of antibody by running over an anti-human immunoglobulin affinity

column. Following this treatment, it is found that strain A, but not strain C is still killed by

incubation with the serum.

 

c) From these data, what is the most likely mechanism killing S. aureus strain A? What

about strain C? 

 

2.32  Synthesis question: Pseudomonas aeruginosa is a Gram-negative bacterium that 

causes severe, and often life-threatening infections in immunocompromised individuals.

In susceptible individuals, P. aeruginosa can establish infections in a wide range of

tissues, including the lung, the GI tract, the eye, the ear, the urinary tract, the skin, and

the blood. This bacterium is common in the environment, and is found on the skin of

approximately 5% of healthy individuals. It is often found on hospital equipment, such as

ventilators and catheters, and as a consequence, P. aeruginosa accounts for ~10% of

hospital-acquired infections. To study the role of complement in the early innate immune

response to P. aeruginosa, the following studies in mice were performed. Mice deficient

in complement C3 or C5 (C3-/- or C5-/-, respectively) were infected by intratracheal

inoculation with 10

5

 colony forming units (CFU) of P. aeruginosa, and survival was

monitored over the first 72 hrs post-infection. The data from these studies are shown in

Figure Q2.32. Genetic data from human population studies also indicate that Individuals

with genetic deficiencies in one of the collectins or ficolins show increased susceptibility

to P. aeruginosa infections. 

 Page 12 of 19 

 Page 13 of 19 

 

Figure Q2.32 

 

a) Based on these data, evaluate the importance of complement in protection against P.

aeruginosa infection, and describe the most likely complement pathway(s) involved in

pathogen recognition and in pathogen destruction. 

 

Another group of individuals that are highly susceptible to P. aeruginosa infections are

patients with the disease cystic fibrosis. These individuals suffer from the production of a

thick mucus secretion in their lungs, which clogs the bronchial tubes. A similar increase

in viscosity of bodily secretions is seen in these patients’ sweat, digestive fluid, and

gastrointestinal mucus. In these patients, the most common form of lung infection is that

of P. aeruginosa. 

 

b) What is the most likely explanation for the increased susceptibility of cystic fibrosis

patients to P. aeruginosa and other infections? 

 

 

ANSWERS 

 

2.1: B.  

All extracellular forms of pathogens are targets for antibodies, complement, phagocytic cells and

antibody-dependent immune clearance mechanisms. Once a pathogen, such as a virus or

intracellular protozoan, invades a cell and begins replicating in the cell, these mechanisms are

no longer able to clear the infection. These intracellular stages of pathogenic infection require

cellular responses, such as those mediated by T cells or NK cells.

 

2.2: C. 

Pathogens cause direct tissue damage by the production of exotoxins or endotoxins, as well as

by direct cytopathic effects. Tissue damage caused by the host immune response include

damage caused by cell-mediated immunity and by the accumulation of immune complexes.

 

2.3: False. 

Both bacterial and virus infections can use both the mouth and respiratory tract and the

gastrointestinal tract. There is no route of infection that is specific for a single category of

pathogen.

 

2.4: B. 

Anti-microbial peptides are produced by epithelia at all mucosal and epidermal surfaces. These

chemicals are important in immune protection against microbial pathogens. All other choices are

mechanical mechanisms by which surface epithelia protect against infections, not chemical

mechanisms.

 

2.5: E. 

Commensal organisms associated with all epithelial surfaces provide protection against

colonization by pathogenic microbes. One mechanism is by competition for nutrients as well as

for attachment sites on epithelial surfaces. Another mechanism is by producing metabolites that

are toxic to other organisms. When these commensal microorganisms are eliminated by

antibiotic treatment, pathogenic microbes are able to step into the void and establish an

infection.

 

2.6: The first important feature of a pathogenic microbe is that it must establish a replicating

colony of organisms in our body. This can occur by the pathogen crossing an epithelial barrier

and replicating in the tissue, or by attaching to the epithelial surface and establishing a colony

there. The second feature is that the pathogen needs to have special mechanisms to evade the

innate immune response.

 

2.7: C. 

Strep. pneumoniae is a Gram-positive bacterium that readily colonizes the human nose and

mouth, due to the resistance of its peptidoglycan to degradation by lysozyme, an enzyme that is

abundant in tears, saliva, and mucus. Wild-type Strep. pneumoniae is naturally lysozymeresistant

because

a

substantial

proportion

of

GlcNAc

residues

in

its

peptidoglycan

are

 

deacetylated,

and

no

longer

substrates

for

lysozyme-mediated

hydrolysis.

This

accounts

for

the

 

prevalence

of

Strep.

pneumoniae

in

the

upper

respiratory

tract

of

healthy

humans,

where

 

lysozyme

is present

at

high

concentrations.

When

one

of

these

enzymes

is

missing,

as

in

strain

 

B,

the

bacteria

become

lysozyme-sensitive,

and

are

killed

by

the

lysozyme.

 

 

fungi.

 

 

 

 Page 14 of 19 

2.8: E. 

The diversity of antimicrobial peptides is a reflection of the diversity of microbial pathogens that

they attack. Some antimicrobial peptides are active against Gram-negative bacteria, while

others are only active against Gram-positive bacteria. Other antimicrobial peptides are only

active against fungal pathogens, and some are able to disrupt the membrane envelopes of

some viruses. 

 

2.9: True. 

All antimicrobial peptides, including cathelicidins, are produced as inactive propeptides. The

active forms of the peptides are generated following proteolytic cleavage of the propeptides.

Neutrophils constitutively produce cathelicidins, which are synthesized as inactive propeptides.

The inactive cathelicidin propeptides are stored in secondary granules, whereas the cleavage

enzyme, neutrophil elastase, is stored in primary granules. These two types of granules are

induced to fuse with phagocytic vesicles, called phagosomes, after the neutrophil has engulfed

a pathogen. This fusion brings the cleavage enzyme together with the cathelicidin propeptide,

leading to cathelicidin activation.

 

2.10: A. 

There are three pathways for initiating complement activation. One of them, known as the

classical pathway, occurs when the pathogen has antibodies bound to its surface, leading to

recruitment of C1q. The other two pathways, the lectin pathway and the alternative pathway, are

initiated by mechanisms that do not require antibodies directed against the pathogen surface.

These latter two pathways are dependent on constitutively produced, and therefore ‘innate’

recognition molecules that directly bind to pathogen surfaces, initiating complement activation.

 

2.11: C. 

Active C3b is highly labile, and is rapidly inactivated by hydrolysis. This prevents the C3b from

remaining active should it diffuse away from the pathogen surface where it was activated by the

C3 convertase.

 

2.12: MBL or MASP. 

Infants and small children with defects in MBL or MASP show recurrent upper respiratory

infections by extracellular bacteria. This is due to a defect in the lectin pathway of complement

activation. When maternal antibodies wane and the child is not yet generating robust antibody

responses on its own, complement activation cannot proceed by the classical pathway. During

this time, protection against upper respiratory bacterial infections is highly dependent on the

lectin pathway, initiated by MBL or collectin binding to the pathogen. The information provided

rule out the alternative pathway, which is initiated by spontaneous C3 cleavage. If there was a

defect in C3, or a downstream component of the complement cascade shared by all three

pathways, the recurrent infections would not disappear as children age.

 

2.13: D. 

MBL and ficolins have binding specificity for carbohydrate side chains and oligosaccharide

modifications that are unique to microbial pathogens, and not found on host cells. MBL binds to

mannose, fucose, and GlcNac residues, which are common on microbial glycans; in contrast,

MBL does not bind to sialic residues, which terminate vertebrate glycans. Ficolins have

specificity for binding to oligosaccharides containing acetylated sugars, a structure also only

found on pathogen surfaces, not on host cells.

 

2.14: B. 

Natural antibody, which is primarily of the IgM class, is produced in the body prior to pathogen 

 Page 15 of 19 

exposure. These antibodies are widely reactive with many microbial pathogens, although they

generally have low affinity for the pathogen. However, since IgM is a pentamer of IgM

monomers, each IgM pentamer has 10 binding sites for antigen, allowing even low affinity

antibodies to bind, due to the increased avidity of multiple binding sites. This natural antibody

will then recruit C1q, leading to complement activation. Since the natural antibody pre-exists

prior to pathogen exposure, this response is rapid and is considered part of the innate immune

response.

 

2.15: False. 

The initiating steps of the classical and lectin pathways of complement activation are remarkably

conserved in their mechanisms. The pathogen recognition component of the classical pathway,

C1q, has structural similarity to MBL and the ficolins. The C1r and C1s components of the

classical pathway, that are activated to form the serine protease, are closely related to the

MASP proteins of the lectin pathway.

 

2.16: A. 

The most efficient form of opsonization by antibody plus C3b is when the complement protein is

covalently linked to the antibody molecule. This leads to efficient engagement of both Fc

receptors and complement receptors on phagocytic cells.

 

2.17: E. 

The C3 convertase (C3bBb) of the alternative pathway contains C3b, allowing it to generate

more of itself and amplify the overall level of C3b formed. Once additional molecules of C3b are

made by C3bBb, these can recruit additional molecules of factor B and the plasma protease

factor D. Factor D cleaves factor B, and one of the products, Bb, remains associated with C3b,

forming more active C3 convertase.

 

2.18: True. 

The C3 convertase of the alternative pathway contains C3b, allowing it to generate more of itself

and amplify the overall level of C3b formed. Since C3b is a common intermediate for all three

pathways of complement activation, once the initial C3b is generated by any of the pathways,

the recruitment of factor B, and cleavage by factor D can proceed. By this mechanism, the initial

C3b generated forms an amplification loop leading to more C3b, regardless of how the initial

C3b was made.

 

2.19: C. 

Factor P (properdin) is made by neutrophils and stored in their granules. When neutrophils are

activated by the presence of pathogens, factor P is released. Factor P binds to and stabilizes

the reactive form of C3 (C3-H

0) and the C3 convertase C3bBb. In the absence of factor P, the

alternative complement pathway is inefficient, due to the rapid spontaneous inactivation of C3H

2

2

0 and C3bBb. This pathway is particularly important in protection against Neisseria

meningitidis, and patients that are deficient in producing factor P are highly susceptible to

infections with this pathogen.

 

2.20: D. 

Host cells express several complement-regulatory proteins on their surface. These proteins

function to rapidly inactivate any C3bBb (active C3 convertase) that may form on the host cell

membrane. Several of these complement regulatory proteins use GPI-linkages to attach to the

host cell membrane. Included in this group is DAF/CD55, which competes with factor B for

binding to C3b on the cell surface, and displaces Bb from any active C3 convertase that has

already formed. The absence of DAF/CD55 makes host cells susceptible to complement-

 Page 16 of 19 

mediated lysis. For reasons that are not entirely clear, red blood cells are particularly

susceptible to complement-mediated lysis and the absence of the GPI-linked subset of

complement regulatory proteins is sufficient to cause red blood cell lysis leading to anemia.

 

2.21: 

a)  The most primitive form of a complement system is one that resembles our alternative 

complement pathway, with ancestral homologs of C3 and factor B that make a C3

convertase. This provides a mechanism for opsonizing infecting bacteria and increasing

their phagocytosis by phagocytic cells. These ancestral homologs of C3 and factor B

have been found in echinoderms, and may even have existed in even more primitive

organisms such as corals and sea anemones. 

b)  The latest evolutionary development in the complement system is the classical pathway,

which makes use of antibody binding to initiate complement activation. The adaptive

immune system, including the production of antibodies, is only found in vertebrates. 

 

2.22: False.  

The C3 convertase does generate large numbers of C3b molecules which become attached to

the pathogen surface in the vicinity of the convertase. This enzyme can only cleave C5 when

bound to a molecule of C3b, generating the C5 convertase. The generation of the C5

convertase occurs at a much lower level than the C3 convertase, and many fewer molecules of

C5 than C3 are cleaved.

 

2.23: C. 

Phagocytes have a variety of receptors that recognize C3b and fragments of C3b, such as iC3b.

Engagement of these complement receptors stimulates phagocytosis of the C3b-coated

pathogen, leading to pathogen destruction.

 

2.24: A. 

The complement receptor on B cells, CD21, is often referred to as the B cell co-receptor. When

this receptor is engaged together with the B cell antigen receptor, the B cell can be activated by

much lower concentrations of antigen compared to antigen lacking ligands for CD21.

Experiments have indicated that CD21 stimulation can reduce the concentration of antigen

needed to activate the B cell by 100–1000-fold. This allows B cells to detect small numbers of

infecting pathogens, to initiate an adaptive response prior to the occurrence of a high pathogen

load in the host.

 

2.25: When complement is activated in the lung in response to the inhaled preparations of the

fungus, the C3 convertase generates C3a. C3a induces a local inflammatory response in the

lung, by acting on the vascular endothelial cells. This response includes increased vascular

permeability, leading to an increase of fluid in the lung, and also acts to up-regulate adhesion

molecules on the local vascular endothelium. As a result, there is increased recruitment of

granulocytes, monocytes, and lymphocytes into the lung. 

 

2.26: E. 

Patients with genetic deficiencies in terminal complement components show only a limited

increase in susceptibility to infection. These individuals are more susceptible to infection by

Neisseria species that cause gonorrhea or meningitis. Otherwise, these individuals show no

other increased susceptibility to infection, indicating that formation of the membrane attack

complex is a less important aspect of complement activation compared to the earlier steps that

lead to opsonization of the pathogen as well as inducing inflammation.

 

 Page 17 of 19 

2.27: B. 

Individuals with a genetic defect in factor I are subject to recurrent infections with pyogenic (pusforming)

extracellular

bacterial

infections.

This

occurs

because,

in

the

absence

of

factor

I,

 

uncontrolled

complement

activation

ends

up

depleting

the

complement

proteins

from

the

 

plasma.

This

leads

to

impaired

complement

activation

on these

bacteria,

and

therefore,

to

 

diminished

clearance

of

these

infections.

 

 

 

2.28:

Two

types

of

genetic

alterations

in

complement

regulatory

proteins

have

been

linked

to

 

disease

susceptibility.

First,

individuals

heterozygous

for

mutations

in

one

of

several

 

complement

regulatory

proteins

(MCP,

factor

I,

factor

H).

These

individuals

are

predisposed

to

 

develop

a

hemolytic

disease

that

leads

to

damage

to

platelets

and

red

blood

cells,

and

to

kidney

 

inflammation.

Second,

individuals

with

particular

single-nucleotide

polymorphisms

in

the

gene

 

for

factor

H

are

predisposed

to

macular

degeneration,

an

age-related

disease

that

causes

 

blindness.

Furthermore,

polymorphisms

in

other

complement

genes

have

been

found

to

 

contribute

to

the

susceptibility

to

age-related

macular

degeneration.

 

 

 

 

2.29:

A.

 

 

One

of

the

best

indicators

of

the

importance

of

an

immune

protective

mechanism

is

the

 

development

by

pathogens

of

strategies

to

evade

that

mechanism.

In

the

case

of

the

 

complement

pathway,

many

pathogens

have

evolved

strategies

to

avoid

complement

activation

 

on

their

surface.

These

include

the

expression

of

proteins

that

attract

complement

regulatory

 

proteins

to

their

surface,

in

an effort

to

mimic

host

cell

surfaces

that

can

inactivate

complement.

 

An

additional

strategy

is

to

secrete

proteins

that

directly

inhibit

components

of

the

complement

 

pathway.

 

 

 

2.30:

True.

 

 

All

three

pathways

of

complement

activation

converge

on

the

assembly

of

a

C3

convertase

that

 

produces

C3b

bound

to

the

pathogen

surface.

Therefore,

pathogens

that

can

inactivate

bound

 

C3b

can

interfere

with

complement

activation

that

might

be

initiated

by

any

of

the

three

 

pathways.

This

makes

C3b

an

ideal

target

for

an

immune

evasions

strategy.

 

 

 

2.31:

 

a)

 

 

Strain A and strain C are equally sensitive to a serum component (or set of components) 

that can kill S. aureus. Strain B is resistant to all possible serum components that can kill

S. aureus. Strain D is also sensitive to a serum component(s) that can kill S. aureus, but

is killed by a different mechanism than the one(s) killing strains A and C. This latter

conclusion is based on the observation that the factor(s) killing strain D are no longer

active when the serum is diluted 1:16, whereas the activities that kill strains A and C are

still active at this dilution.b)  Strains A and C are no longer killed when complement C3

is depleted from the serum. This indicates that these two strains are susceptible to

complement-mediated lysis. The killing of strain D is not affected by depletion of C3,

indicating a distinct mechanism. Strain D is most likely being killed by defensins, or

another antimicrobial peptide. It is unlikely that strain D is being killed by lysozyme in

these experiments, as lysozyme is predominantly found in tears and saliva, rather than

in serum.  

c)  Since strain A is still killed following depletion of antibody, but not following depletion of

C3, it is likely that strain A is susceptible to the lectin pathway of complement activation,

initiated by binding of ficolin (or collectin) to the bacterial surface. Ficolins are the most

likely initiators of complement activation in this case, as they are at high concentrations

in the serum. Although it is theoretically possible that strain A is killed by the alternative

pathway of complement activation, this possibility is unlikely. The spontaneous 

 Page 18 of 19 

hydrolysis of C3 produces a fluid-phase C3 convertase that is very short-lived. This fluidphase

C3

convertase

is

stabilized

by

properdin

(factor

P),

which

is only

produced

by

 

neutrophils

when

they

are

activated

by

pathogens.

Therefore,

there

is

unlikely

to

be

factor

P

in

the

serum

used

in

this

study,

and

therefore,

the

alternative

pathway

of

 

complement

activation

would

be very

inefficient.

 

 

Strain C is no longer killed following depletion of antibody. Therefore, strain C is likely

susceptible to the classical pathway of complement activation. 

 

2.32:

a)  Complement is essential for early protection against this dose of P. aeruginosa in mice. 

In the absence of either C3 or C5, all of the infected mice succumb to the infection by 2

days post-infection. Based on the human population studies indicating that individuals

deficient in collectins or ficolins are also more susceptible to this bacterial infection, it is

likely that the lectin pathway of complement activation is the primary mechanism for

initiating the complement cascade. Since C5 is required, this points to an important role

for the membrane attack complex in pathogen destruction. However, it is also possible

that the requirement for C5 is due to the role of C5a in promoting inflammation, leading

to the recruitment of phagocytic cells to the site of infection. In this latter case, pathogen

destruction would be due to uptake by phagocytic cells. 

b) Due to their defect in regulating the viscosity of bodily secretions, the mechanical and

chemical mechanisms of immune resistance at the body’s epithelial barriers do not

function normally. Instead of serving as a fluid that flushes away potential pathogens at

these barriers, the mucus of cystic fibrosis patients functions as a stagnant reservoir

ideal for bacterial colonization. Furthermore, the thick mucus prevents the normal

diffusion of antimicrobial enzymes and peptides that are secreted into the mucus.