CHAPTER 57 Overview of Immunity 481
innate cells, such as phagocytes, are less sensitive to proinflam-
matory cytokines and chemokines. Newborns actually have
higher number of circulating lymphocytes than adults, but the
newborn’s T cells and B cells are individually less effective.
IgG and IgA production begins after birth and only reaches
protective levels at around 1 year. As a consequence, until
around 6 months, most of the circulating IgG is in fact mater-
nal-derived antibody that crossed the placenta before birth, and
the mucosal surface of the gastrointestinal tract is similarly pro-
tected by maternal IgA that is secreted into breast milk.
The precise reason why newborns have reduced immunity is
unknown, but the same phenomenon is observed in all mam-
mals, suggesting that this state confers an evolutionary survival
benefit during the fetus-to-newborn transition. One possible
explanation is that the sudden move from the relatively sterile
uterus to the outside world comes with an enormous increase in
the amount of foreign material the newborn encounters, most
of which is harmless (e.g., commensal microbes). The new-
born immune system needs to take a “tolerant” stance, because
responding to all of these as pathogenic invaders would result
in an overwhelming and inappropriate inflammatory response
that would cause collateral damage to the newborn’s own tissues
(see IPEX syndrome, Chapter 66).
The neonatal window leaves infants highly susceptible to
infections, and vaccines must be timed carefully; they should
be given as early as possible so that the infant gets timely pro-
tection, but if given too soon, then the infant cannot mount an
effective response. For example, the pneumococcal vaccine con-
taining unconjugated polysaccharides does not induce protec-
tive immunity when given prior to 18 months of age, indicating
that these children cannot mount a protective T-independent
response (see Chapter 61), but the pneumococcal vaccine con-
taining the polysaccharides conjugated to a carrier protein is
effective when given as early as 2 months of age.
Because adaptive immunity provides long-term memory,
you might expect that immunity gets increasingly stronger
with age, and this is true up to a point. However, as we become
elderly, immunity declines with age. The thymus, which is the
source of all T cells (see Chapter 59), begins to atrophy after
puberty, and by the time we reach age 60, there is a buildup of
memory cells but almost complete inability to generate new T cells
that recognize new antigens. The age-related effect on B cells
is less dramatic but shows a similar trend toward more expe-
rienced and “exhausted” B cells. This means there is a reduced
IgG response to certain antigens, and the immune responses to
certain vaccines and infections are blunted.
As in the very young, the elderly experience a somewhat
increased frequency and severity of infections, such as influenza.
In addition, the elderly can develop “reactivation” of a latent
infection, caused by, for example, Mycobacterium tuberculosis or
varicella-zoster virus, that was previously held in check by their
“young” immune system. The frequency of autoimmune dis-
eases also increases in the elderly, possibly because of a decline
in the number of regulatory T cells, which allows autoreactive
T cells and B cells to proliferate and cause disease.
SELF-ASSESSMENT QUESTIONS
1. Which one of the following is an attribute of the innate, rather
than the adaptive (acquired), arm of our host defenses?
(A) Is highly specific in its response to individual bacterial species
(B) Responds to viruses and fungi, but not bacteria
(C) Exhibits memory following exposure to bacteria
(D) Is part of our host defense against bacteria but not against fungi
(E) Is as effective the first time it is exposed to bacteria as it is
subsequent times
2. Regarding haptens, which one of the following is the most accurate?
(A) A hapten is the antigen-binding site of an immunoglobulin.
(B) A hapten cannot induce antibody by itself but can do so when
covalently bound to a carrier protein.
(C) A hapten can bind to the antigen receptors of CD4-positive
T cells without being processed by antigen-presenting cells.
(D) A hapten is defined by its ability to bind to the smaller of the
two polypeptides that comprise the class I MHC proteins.
3. Certain components of our immune system are characterized by
two attributes: being able (1) to respond specifically to microbes
and (2) to exhibit memory of having responded to a particular
microbe previously. Which one of the following has BOTH speci-
ficity and memory?
(A) B cells
(B) Natural killer cells
(C) Dendritic cells
(D) Macrophages
(E) Neutrophils
4. Your patient says that she must travel on business 3 days from now
to a country where hepatitis A is endemic. She just read in the news-
paper that there are two types of protection against this disease: one
is a vaccine that contains killed hepatitis A virus, and the other is
a serum globulin preparation that contains antibodies to the virus.
She asks which you would recommend and for what reason?
(A) The vaccine containing killed hepatitis A virus is best because
it induces the most antibody.
(B) The vaccine containing killed hepatitis A virus is best because
it provides the most long-lived immunity.
(C) The serum globulin preparation containing antibodies against
the virus is best because it provides immunity in the shortest
time.
(D) The serum globulin preparation containing antibodies against the
virus is best because it provides the most long-lived immunity.
ANSWERS
(1) (E)
(2) (B)
(3) (A)
(4) (C)
PRACTICE QUESTIONS: USMLE &
COURSE EXAMINATIONS
Questions on the topics discussed in this chapter can be found
in the Immunology section of Part XIII: USMLE (National
Board) Practice Questions starting on page 735. Also see Part
XIV: USMLE (National Board) Practice Examinations starting
on page 753.
 CHAPTER 58 Innate Immunity 493

rate, and loss of appetite that we commonly associate with infec- (C) Macrophages are “professional” APCs that express class II major
tion. As described earlier, macrophages and other cells that are histocompatibility complex (MHC) but not class I MHC.
triggered through their PRRs assemble inflammasomes in their (D) Cytosolic antigens are degraded by the proteasome and dis-
cytoplasm, and these multiprotein complexes cut IL-1 from its played in complex with class II MHC.
4. Which one of the following is NOT a primary function of phagocytes?
inactive precursor into its active form before it is released. IL-6
and TNF-α are also made by macrophages in response to IL-1 (A) Engulfing and killing invading microbes
(B) Expression of proinflammatory cytokines and chemokines
and PRR stimulation.
(C) Attacking cells with perforins and granzymes
IL-1, IL-6, and TNF-α are proinflammatory cytokines,
(D) Production of free oxidative radicals
meaning that they enhance the inflammatory response in vari- (E) Presentation of antigen peptides in complex with MHC to T cells
ous ways (see Table 58–5). They signal to the hypothalamus to 5. Which one of the following describes the immune signals respon-
change the body’s thermostat, causing fever. They also signal sible for fever?
to the liver hepatocytes to increase production of C-reactive (A) Histamine and proteases produced by mast cells
protein, MBL, proteins of the complement cascade (covered in (B) Interleukin-1 (IL-1) and tumor necrosis factor (TNF) pro-
Chapter 63), ferritin, and other acute-phase proteins. Mast cells duced by macrophages
can directly sense microbial patterns through PRRs or through (C) Type I interferons produced by virus-infected cells
receptors for antibodies (i.e., IgE receptors), or can be stimu- (D) Type II interferon and perforin produced by natural killer
lated by IL-1 to release IL-6, leukotrienes, vasoactive signals, (NK) cells
and other proinflammatory mediators. 6. The pathogenesis of chronic granulomatous disease is BEST
Some of the acute-phase proteins are anticoagulants that described as which one of the following?
improve blood flow to inflamed tissues. Other acute-phase pro- (A) A defect of chemokine signaling causing impaired granulocyte
teins, such as ferritin, sequester iron, which bacteria need for exit from the bone marrow
(B) A defect complement receptors causing impaired granulocyte
replication, or bind to the surface of bacteria and activate com-
activation
plement, which can kill the bacteria. For example, C-reactive
(C) A defect in integrin signaling causing impaired granulocyte
protein binds to a carbohydrate in the cell wall of Streptococcus migration into inflamed tissue
pneumoniae, and as mentioned earlier, MBL binds to mannan (D) A defect in oxidative burst causing impaired ability of granu-
(mannose) on the surface of many bacteria, fungi, and proto- locytes to kill microbes
zoa. Finally, many acute-phase proteins signal back to immune 7. Regarding chemokines, which one of the following is the most
cells, increasing the migration of new neutrophils and other accurate?
leukocytes from the bone marrow and enhancing their homing, (A) Chemokines penetrate the membranes of target cells during
phagocytic, and microbicidal functions. attack by cytotoxic T cells.
(B) Chemokines bind to the T-cell receptor outside of the antigen-
binding site and activate many T cells.
SELF-ASSESSMENT QUESTIONS (C) Chemokines attract neutrophils to the site of bacterial infec-
tion, thereby playing a role in the inflammatory response.
1. Which one of the following is the most accurate statement?
(D) Chemokines induce gene switching in B cells, which increases the
(A) Loss of the epithelial barrier predisposes to fungal infections amount of IgE synthesized, thereby predisposing to allergies.
but not bacterial or viral infections.
(B) The main function of mast cells and eosinophils is to engulf
microbes and debris.
(C) Eosinophils and natural killer cells are both innate cells of the ANSWERS
myeloid lineage. (1) (D)
(D) Dendritic cells are the primary cell responsible for initiating an
(2) (B)
adaptive immune response.
2. Local swelling, redness, warmth, and pain associated with inflam-
(3) (A)
mation are primarily due to which one of the following? (4) (C)
(A) Pathogen-associated molecular patterns (PAMPs) recognized
(5) (B)
by neurons and endothelial cells. (6) (D)
(B) Release of preformed mediators such as leukotrienes and his- (7) (C)
tamine and activated complement.
(C) Cytokines such as tumor necrosis factor-alpha released by
T cells. PRACTICE QUESTIONS: USMLE &
(D) IgE bound to the surface of eosinophils. COURSE EXAMINATIONS
3. Which one of the following is an accurate statement about
antigen-presenting cells (APCs)? Questions on the topics discussed in this chapter can be found
(A) Monocytes can enter inflamed tissue and differentiate into in the Immunology section of Part XIII: USMLE (National
macrophages and dendritic cells. Board) Practice Questions starting on page 735. Also see Part
(B) Dendritic cells turn off CCR7 upon recognition of pathogen- XIV: USMLE (National Board) Practice Examination starting
associated molecular patterns. on page 753.
 CHAPTER 59 Adaptive Immunity: Lymphocyte Antigen Receptors
microbial antigens. Mutations in genes that control TCR signaling
or in the gene encoding AIRE can cause autoimmune disease
due to defective thymic selection (see Chapter 66).
In summary, positive and negative selection remove all but
the T-cell clones that react weakly with self-peptides presented
in complexes with MHC proteins. Note that the same MHC
proteins that are required for initial thymic selection of T-cell
precursors later become the critical signals for activating T cells
through their TCRs.
INNATE-LIKE T CELLS
Approximately 95% of the body’s T cells are CD4-positive or
CD8-positive cells that carry αβ TCRs, as described earlier.
These cells have a highly diverse TCR repertoire, capable of
responding to a wide range of potential infectious agents. A few
other T cells develop in an unusual manner: although they still
pass through the thymus, they have a highly restricted TCR
repertoire, capable of responding quickly but to a narrow range
of antigens. Therefore, because these cells respond more rapidly
and are less diverse than other T cells, they are often called
“innate-like” (see Table 59–2).
One type of innate-like T cell is the natural killer T cell
(NK-T cell). As their name implies, NK-T cells share many
features with innate NK cells, including surface receptors and
markers that are important for NK cell function (see Chapter 58).
But do not confuse the two cell types! NK-T cells are not innate
cells; they have an αβ T-cell receptor and require the thymus
for their development. The best-described NK-T cell, called
the “invariant” NK-T (iNKT) cell, uses a highly limited set of
V, D, and J gene segments to create the α and β receptor chains
of its TCR (see Table 59-2). Instead of recognizing peptides
complexed with MHC, the TCRs of iNKT cells recognize lipids
and glycolipids complexed with an alternate antigen presenta-
tion molecule called CD1d. The precise role of NK-T cells is
unknown, but they may be important in host defense against
organisms that contain certain lipids or in responding to situ-
ations of host tissue stress in which lipids are released from
damaged cells.
Another unusual T cell is the mucosal-associated invari-
ant T (MAIT) cell. Like NK-T cells, MAIT cells develop in the
thymus and use a limited set of α and β gene segments in their
TCRs, but they are restricted to a different antigen presentation
molecule called MR1 (see Table 59-2). Like class I MHC, MR1
is expressed on a large variety of cells. However, rather than
only presenting peptides, MR1 activates MAIT cells with a wide
range of other types of antigens. Not all of the ligands bound
by MR1 that activate MAIT cell have been identified, but at
least some of them are small-molecule metabolites produced by
bacteria. This may explain why MAIT cells populate peripheral
barrier surfaces, such as the lung, intestine, and liver, where
bacterial products are often encountered.
Finally, the γδ (gamma-delta) T cell is perhaps the most
unusual innate-like T cell in that it does not have an αβ TCR.
Instead, for reasons that are not well understood, at the time
when thymic T-cell precursors begin to recombine the α and
503
β chain genes, γδ T cells instead recombine the γ and δ chain
genes (located on human chromosomes 7 and 14, respectively).
The γ chain gene is composed of V, D, and J segments (similar
to the β chain), and the δ chain gene is composed of V and J
segments (similar to the α chain). These alternate TCR chains
then combine with CD3ζ on the cell surface. Little is known
about the antigens recognized by γδ TCRs, but some γδ T cells
may even respond to these antigens in the absence of the usual
antigen-presenting molecules such as MHC, MR1, or CD1d.
Like MAIT cells, γδ T cells primarily reside in mucosal tissues,
but their activating ligands have not been fully characterized,
and their precise role in host defense is unclear.
SELF-ASSESSMENT QUESTIONS
1. Regarding the genes that encode antibodies, which one of the
following is most accurate?
(A) Hypervariable regions are encoded by the genes of both the
light and heavy chains.
(B) The genes for the light and heavy chains are linked on the same
chromosome adjacent to the human leukocyte antigen (HLA)
locus.
(C) During the production of IgG, the light and heavy chains
acquire the same antigen binding sites by translocation of the
same variable genes.
(D) The gene for the constant region of the gamma heavy chain is
first in the sequence of heavy chain genes, and that is why IgG
is made in greatest amounts.
2. Regarding events that occur in the thymus during the maturation
of T cells, which one of the following is the most accurate?
(A) T cells bearing antigen receptors that recognize self-antigens
are deleted, a process known as “negative selection.”
(B) “Positive selection” ensures that CD4-positive T cells and
CD8-positive T cells recognize antigen presented by class I
major histocompatibility complex (MHC) proteins and class II
MHC proteins, respectively.
(C) T cells bearing antigen receptors that recognize antigen in
association with foreign MHC proteins survive, a process
known as “positive selection.”
(D) Most mature T cells have both CD4 and CD8 proteins on their
surface that ensures their ability to react with antigen pre-
sented by either MHC class I or MHC class II proteins.
3. Which one of the following is a mechanism used by B and
T lymphocytes to recognize a diverse range of microbes?
(A) A receptor encoded from birth in the germline
(B) A receptor that recognizes molecular motifs common among
many different microbes
(C) A process of clonal selection that eliminates self-reactive cells
(D) A process of DNA recombination that generates clones with
unique antigen receptors
(E) A process that shuts off alternate alleles
4. Which one of the following lists the components of mRNA that
might be found in a mature naïve B cell in the secondary lymphoid
tissue?
(A) mRNA containing V, D, J, and Cμ segments; mRNA con-
taining V, J, and Cκ segments; and mRNA containing V, J, and
Cλ segments
(B) mRNA containing V, D, J, and Cμ segments and mRNA con-
taining V, J, and Cκ segments
504 PART VII Immunology

(C) mRNA containing V, D, J, and Cγ segments and mRNA con- ANSWERS

taining V, D, J, and Cκ segments.
(D) mRNA containing V, J, and Cγ segments and mRNA contain- (1) (A)
ing V, D, J, and Cλ segments (2) (A)
(E) mRNA containing V, D, J, and Cγ segments; mRNA contain- (3) (D)
ing V, J, and Cκ segments; and mRNA containing V, J, and Cλ (4) (B)
segments (5) (A)
(F) mRNA containing V, J, and Cκ segments and mRNA contain-
ing V, J, and Cλ segments.
5. You are seeing a child with a suspected immunodeficiency, and PRACTICE QUESTIONS: USMLE &
on testing, you find that he has absent B cells and undetectable
antibody levels but slightly elevated numbers of T cells and NK COURSE EXAMINATIONS
cells. What component of lymphocyte development is most likely Questions on the topics discussed in this chapter can be found
defective?
in the Immunology section of Part XIII: USMLE (National
(A) Abnormal assembly of the lambda and kappa light chains Board) Practice Questions starting on page 735. Also see Part
(B) Abnormal function of the recombinase enzymes encoded by
XIV: USMLE (National Board) Practice Examination starting
recombinase activating genes
on page 753.
(C) Abnormal development of the thymus
(D) Abnormal survival and differentiation of common lymphoid
progenitor cells
(E) Abnormal expression of MHC proteins
516 PART VII Immunology
syndrome toxin-1 (TSST-1) binds class II MHC proteins
directly to the variable portion of the β chain of the TCR,
specifically Vβ2. This causes unrestrained activation of any
CD4-positive T cells that use this Vβ in their TCR, regardless
of that TCR’s antigen specificity and regardless of the peptide
complexed with the MHC protein.
Because a large percentage of human T cells use Vβ2
(up to 30%), if all of these T cells are activated, it causes massive
amounts of IL-2 released from the T cells and IL-1 and TNF
from macrophages. These cytokines account for many of the
findings seen in toxin-mediated staphylococcal diseases, such
as toxic shock syndrome. Certain viral proteins (e.g., those of
mouse mammary tumor virus [a retrovirus]) also possess supe-
rantigen activity. (Although not all superantigens bind Vβ2,
they all cause pathology by activating an excessive number of
T cells irrespective of those cells’ TCR specificities.)
TESTS FOR EVALUATION OF CELL-
MEDIATED IMMUNITY
Evaluation of “immunocompetence” often depends on dem-
onstrating intact T-cell–mediated immune responses to com-
monly present “harmless” antigens (i.e., a T-cell–mediated
hypersensitivity reaction) or, more specifically, on laboratory
assessments of T-cell numbers and function.
Enumeration of T Cells & Subpopulations
The number of each type of immune cell can be precisely
counted by use of a flow cytometer (see Chapter 64). Cells are
labeled with antibodies tagged with fluorescent dyes. These
dyes have properties that give them specific light excitation
and emission wavelengths. The various antibodies specifically
bind to proteins on the surface of cells. Single cells are passed
through the beam of a laser, exciting the fluorescent dyes,
and the number of cells that emit light of a particular color is
registered. Specific antibodies directed against T-cell markers
permit the enumeration of total T cells and the percentage that
are CD4-positive, CD8-positive, regulatory, etc. The normal
number of CD4-positive cells in adults is between 500 and
1500 cells/μL, whereas in patients with advanced HIV/AIDS,
this number drops to less than 200 cells/μL. (In Chapter 59, we
described the polymerase chain reaction [PCR] assay for T-cell
receptor excision circles [TRECs], which is an inexpensive new-
born screening test to identify T-cell deficiencies.)
In Vivo Tests for T-Cell Competence
(Skin Tests)
Skin Tests for Preexisting (Memory) T-Cell–Mediated
Hypersensitivity
Most normal persons respond with inflammatory reactions to
skin test antigens of Candida and other benign environmental
antigens because of immune memory of past exposure to these
antigens. After pricking the skin with a small quantity of these
protein antigens, normal memory T-cell responses take 2 to
3 days to develop, causing an area of skin induration and red-
ness. Absence of this immune response suggests impairment
of T-cell–mediated immunity. This is also the principle behind
skin testing for latent tuberculosis infection.
Skin Tests for Newly Developed T-Cell–Mediated
Hypersensitivity
Most normal persons readily develop reactivity to simple chem-
icals (e.g., dinitrochlorobenzene [DNCB]) applied to their skin
in lipid solvents. When the same chemical is applied to the same
area 7 to 14 days later, the host’s newly primed T cells generate
a skin reaction. Immunocompromised persons with inadequate
development of T-cell–mediated responses fail to generate a
reaction on DNCB rechallenge.
In Vitro Tests for T-Cell Proliferation &
Function
As described earlier, flow cytometry can be used to count spe-
cific cell populations from a pool of the patient’s cells. It can
also be used to identify cell proliferation by determining the
percentage of cells that incorporate alkyne-modified nucleo-
tides added to a cell culture. Uptake and incorporation of these
nucleotides only occur in dividing cells.
Similarly, flow cytometry can be used to assay cell activa-
tion by determining the level of certain surface markers or
measuring the production of certain cytokines. These tests
can be used in conjunction with a variety of stimuli to test
either antigen-specific T-cell responses, as in the case of IFN-γ
release assays (IGRAs) used to diagnose latent tuberculosis,
or nonspecific T-cell responses, as in the case of assays that
use “mitogens” such as phytohemagglutinin or concanavalin A,
which are plant extracts that bypass the TCR to stimulate T cells.
Finally, CTL cytotoxic function can be assayed by culturing
CD8-positive cells with MHC-matched cells displaying foreign
(e.g., viral) peptides. Some fraction of the CD8-positive cells
should recognize these foreign peptides, and if they function
normally, they should increase their expression of activation
markers and cell-killing effector proteins and should cause
widespread death of the target cells in the culture.
SELF-ASSESSMENT QUESTIONS
1. T-cell–mediated immunity is the main host defense against which
one of the following organisms?
(A) Escherichia coli
(B) Mycobacterium leprae
(C) Pseudomonas aeruginosa
(D) Staphylococcus aureus
(E) Streptococcus pneumoniae
2. You would like to target one of the cells involved in a certain auto-
immune disease, described as a CD3-positive CD4-positive cell.
Which one of the following is the most accurate about this cell’s
function?
(A) Produces IgG
(B) Produces interleukin-2
(C) Kills virus-infected cells
 CHAPTER 60 Adaptive Immunity: T-Cell–Mediated Immunity 517

(D) Presents antigen in association with class II major histocom- (C) IL-21 is made by Th-17 cells and enhances the differentiation
patibility complex (MHC) proteins of cells that defend epithelial barrier surfaces.
(E) Presents antigen in association with class I MHC proteins (D) IL-12 is made by Tfh cells and increases the generation of
3. Which one of the following sets of cells is primarily responsible cytotoxic T cells.
for presenting antigen to helper T cells? 7. Your patient is a 20-year-old woman who experienced the sud-
(A) B cells and dendritic cells den onset of fever, vomiting, myalgias, and diarrhea. This was
(B) B cells and cytotoxic T cells followed by hypotension and a sunburn-like rash over most of
(C) Macrophages and eosinophils her body. You make a presumptive diagnosis of toxic shock syn-
(D) Neutrophils and cytotoxic T cells drome. Which one of the following is the most accurate descrip-
(E) Neutrophils and plasma cells tion of the pathogenesis of this disease?
4. In addition to antigen presentation in association with class I (A) It is caused by the release of large amounts of histamine from
MHC proteins, activation of a CD8-positive T cell requires which basophils.
one of the following? (B) It is caused by an insufficient amount of inhibitor of the C1
(A) High levels of co-stimulation and interleukin-2 produced by component of complement.
CD4-positive T cells (C) It is caused by a superantigen that induces an overproduction
(B) High levels of co-stimulation and gamma interferon produced of cytokines from T cells.
by macrophages (D) It is caused by a delayed hypersensitivity response to procain-
(C) Presentation of antigen with class II MHC proteins and inter- amide, which she was taking for her atrial fibrillation.
leukin-1 produced by macrophages (E) It is caused by a gene mutation causing excessive signal trans-
(D) Presentation of antigen with class II MHC proteins and inter- duction through the T-cell receptor.
leukin-4 produced by CD4-positive T cells
5. Regarding Th-1, Th-2, and Th-17 cells, which one of the following
is the most accurate? ANSWERS
(A) Th-17 cells produce interleukin-17, which stimulates the pro- (1) (B)
duction of Th-2 cells. (2) (B)
(B) The production of Th-1 cells is enhanced by interleukin-4,
(3) (A)
whereas the production of Th-2 cells is enhanced by
interleukin-2.
(4) (A)
(C) Th-2 cells synthesize gamma interferon, which is important in (5) (D)
controlling infections caused by Staphylococcus aureus and (6) (C)
other pyogenic bacteria. (7) (C)
(D) Th-1 cells control infections caused by Mycobacterium
tuberculosis.
6. Regarding interleukins, which one of the following is the most PRACTICE QUESTIONS: USMLE &
accurate? COURSE EXAMINATIONS
(A) IL-2 is made by B cells and increases class switching from IgM
to IgG. Questions on the topics discussed in this chapter can be found in
(B) IL-4 is made by cytotoxic T cells and mediates the killing of the Immunology section of Part XIII: USMLE (National Board)
virus-infected cells. Practice Questions starting on page 735. Also see Part XIV: USMLE
(National Board) Practice Examination starting on page 753.
528 PART VII Immunology

Chimeric Antibody Humanized Antibody Fully Human Antibody

Name Suffix -ximab -zumab -umab

Percent Human ~65% ~95% 100%
Advantages High affinity for antigen Less immunogenic Non-immunogenic
Disadvantages Highly immunogenic May have low antigen affinity Technically difficult; expensive

FIGURE 61–8 Summary of therapeutic monoclonal antibodies. Chimeric antibodies are generated by fusing DNA encoding mouse
variable regions (orange) to DNA encoding human constant regions (green light chain and blue heavy chain). Compared with mouse antibod-
ies, these antibodies (-ximab) have much greater effector function potential because their human Fc fragments bind optimally to human Fc
receptors. However these antibodies are highly immunogenic due to the residual mouse components. Humanized antibodies are generated by
replacing all but the DNA encoding the hypervariable (antigen-binding) region (orange) with human immunoglobulin gene DNA (green and
blue). These antibodies (-zumab) are less immunogenic but may require additional mutation to improve the antigen affinity. Fully human
antibodies (-umab) are generated by screening a “phage library” of randomly generated human antigen-binding sites or by immunizing trans-
genic mice that carry the human immunoglobulin gene loci in place of the mouse genes. These antibodies are the least immunogenic but carry
significant technical barriers and cost.

SELF-ASSESSMENT QUESTIONS (A) IgE blocks the binding of viruses to the gut mucosa.
(B) IgA acts as an antigen receptor on the surface of B cells.
1. It’s time to play “Who am I?” I am the first class of antibody to (C) IgD is our most important defense against worm parasites,
appear, so my presence indicates an active infection rather than such as hookworms.
an infection that occurred in the past. I can fix complement, (D) IgG can activate the alternative pathway of complement,
which is an important defense against many bacterial infections. resulting in the production of C3a that degrades the bacterial
I am found in plasma as a pentamer. cell wall.
(A) IgA (E) There are receptors for the heavy chain of IgG on the surface
(B) IgD of neutrophils that mediate a host defense process called
(C) IgE opsonization.
(D) IgG 5. Regarding the genes that encode antibodies, which one of the
(E) IgM following statements is most accurate?
2. Regarding IgG, which one of the following statements is the most (A) Hypervariable regions are encoded by the genes of both the
accurate? light and heavy chains.
(A) Each IgG molecule has one antigen-binding site. (B) The genes for the light and heavy chains are linked on the
(B) It is the most important antigen receptor on the surface of same chromosome adjacent to the human leukocyte antigen
neutrophils. (HLA) locus.
(C) During the primary response, it is made in larger amounts (C) During the production of IgG, the light and the heavy chains
than is IgM. acquire the same antigen-binding sites by translocation of the
(D) The ability of IgG to fix complement resides on the constant same variable genes.
region of the light chain. (D) The gene for the constant region of the gamma heavy chain is
(E) It is the only one of the five immunoglobulins that is trans- first in the sequence of heavy chain genes, and that is why IgG
ferred from mother to fetus in utero. is made in greatest amounts.
3. If a person had a mutation in the gene encoding J (joining) 6. Regarding T-cell–independent activation of B cells, which one of
chains, which of the following classes of antibodies could NOT be the following statements is true?
produced? (A) “Conjugate” vaccines are most effective in this pathway
(A) IgA and IgM because the antigen is conjugated to an ingredient that provides a
(B) IgA and IgG signal 2.
(C) IgG and IgE (B) Polysaccharide vaccines make use of adjuvants in part to
(D) IgD and IgE bypass the requirement for T-cell help in generating
(E) IgM and IgE antibody.
4. Regarding the function of the different classes of antibodies, (C) This pathway is best engaged by short antigens that cross-link
which one of the following statements is the most accurate? relatively few immunoglobulin receptors.
 CHAPTER 61 Adaptive Immunity: B Cells & Antibodies 529

(D) Engagement of the complement system acts to diminish B cell (D) The antibody binds to the surface of a target cell, and this
activation. binding blocks the cell’s ability to receive essential survival
(E) Antigen presentation by dendritic cells is a key step in this signals, causing it to undergo apoptosis.
pathway. (E) The antibody binds to the surface of a target cell, and its Fc
7. Regarding T-cell–dependent activation of B cells, which one of region recruits complement proteins, which are then detected
the following statements is true? by phagocytes that engulf and kill the cell.
(A) B cell competition for T-cell survival factors usually occurs
outside of the B-cell follicle.
(B) In this pathway, B cells perform as professional antigen- ANSWERS
presenting cells that present antigen to activate naïve T cells.
(1) (E)
(C) Chemokines and their receptors are involved in bringing the T
cells and dendritic cells together, but they do not have a role in
(2) (E)
T cell–B cell interactions. (3) (A)
(D) IL-21 is a key cytokine made by T cells that induces B-cell class (4) (E)
switching. (5) (A)
(E) The AID enzyme directs V(D)J recombination, somatic (6) (B)
hypermutation, and class switching. (7) (D)
8. A new monoclonal antibody is being tested in a trial for a type of (8) (C)
leukemia. The antibody is directed against an antigen found on
the leukemia cells. Which one of the following is NOT a possible
mechanism of action of this antibody?
(A) The antibody binds to the surface of a target cell, and its Fc PRACTICE QUESTIONS: USMLE &
region is detected by NK cells, which then kill the target cell. COURSE EXAMINATIONS
(B) The antibody binds to the surface of the target cell, and its Fc
region recruits complement proteins, which are then activated Questions on the topics discussed in this chapter can be found
to kill the cell directly. in the Immunology section of Part XIII: USMLE (National
(C) The antibody is captured by Fc receptors on the target cell, and Board) Practice Questions starting on page 735. Also see Part XIV:
binding of antigen to the Fab region recruits phagocytes to kill USMLE (National Board) Practice Examination starting on
the target cell. page 753.
536 PART VII Immunology

After binding to their targets on the surfaces of T cells, these 3. Regarding the graft-versus-host reaction, which one of the
antibodies lead to cell death through complement-mediated following is the most accurate?
lysis of the cell (among other potential mechanisms). As a con- (A) It occurs primarily when a kidney is transplanted.
sequence, ATG has a broader immunosuppressive effect than (B) It is caused primarily by mature T cells in the graft.
do the more targeted monoclonal antibodies described in the (C) It occurs primarily when ABO blood groups are matched.
previous paragraph. (D) It occurs primarily when the donor is immunocompromised.
(E) It occurs primarily when the haplotypes of the donor and
Unfortunately, immunosuppression greatly enhances the
recipient are matched.
recipient’s susceptibility to opportunistic infections and neo-
4. Listed below are transplants between individuals with various
plasms. For example, some patients undergoing treatment for genotypes and the outcome of these transplants. The genotypes
multiple sclerosis with the monoclonal antibody natalizumab are designated A and B for simplicity. A person who is AA or
developed progressive multifocal leukoencephalopathy (see BB is homozygous, whereas a person who is AB is heterozygous.
Chapter 44 for a description of this viral disease). The inci- Regarding outcomes X and Y, which one of the following is the
dence of cancer is increased as much as 100-fold in transplant most accurate?
recipients who have been immunosuppressed for a long time.
Common cancers in these patients include squamous cell car-
Genotype of Genotype of Outcome of
cinoma of the skin, adenocarcinoma of the colon and the lung, Donor Recipient Transplant
and lymphoma.
AA AA Accepted
BB BB Accepted
SELF-ASSESSMENT QUESTIONS AA BB Rejected
1. Regarding solid organ transplantation, which one of the following BB AA Rejected
is the most accurate?
AB AA X
(A) An allograft is a graft that transfers tissue or an organ from one
AA AB Y
member of a species to a member of another species.
(B) The mother or father of the patient is typically the best donor
of a graft because they are two-haplotype matches. (A) X is accepted, and Y is accepted.
(C) The ABO blood groups of the donor and recipient do not have (B) X is accepted, and Y is rejected.
to be matched because they do not play a role in allograft (C) X is rejected, and Y is accepted.
rejection. (D) X is rejected, and Y is rejected.
(D) Even when a donor and a recipient are matched at both the
class I and class II MHC loci, rejection can occur and the
recipient should be given immunosuppressive drugs. ANSWERS
(E) If the same donor is the source of tissue for two grafts to a
recipient and the second graft is performed 1 month after the (1) (D)
first graft is rejected, then the second graft will not be rejected. (2) (C)
2. Regarding the MHC proteins and the genes that encode them, (3) (B)
which one of the following is the most accurate? (4) (C)
(A) The genes encoding class II MHC proteins are highly poly-
morphic, whereas the genes encoding class I MHC proteins
are not. PRACTICE QUESTIONS: USMLE &
(B) The genes encoding class I MHC proteins are located on a dif- COURSE EXAMINATIONS
ferent chromosome from the genes encoding class II MHC
proteins. Questions on the topics discussed in this chapter can be found
(C) The genes are codominant, and each person expresses class I in the Immunology section of Part XIII: USMLE (National
and class II MHC genes inherited from both mother and Board) Practice Questions starting on page 735. Also see Part XIV:
father. USMLE (National Board) Practice Examination starting on
(D) Class II MHC proteins are found on the surface of all cells, page 753.
whereas class I MHC proteins are found only on the surface of
phagocytes.
540 PART VII Immunology

anaphylatoxins and membrane attack complexes are generated. 4. Of the following, which one is the most important function of the
The anaphylatoxins cause shock, and the membrane attack complex formed by complement components C5b,6,7,8,9?
complexes cause red cell hemolysis. (A) To enhance antibody production
(5) Immune complexes formed by antigens and antibodies (B) To inhibit immune complex formation
can bind complement, and thus, complement levels are often (C) To opsonize viruses
low in immune complex diseases (e.g., acute glomerulonephritis (D) To perforate bacterial cell membranes
(E) To release histamine from mast cells
and systemic lupus erythematosus). Binding (fixing) of comple-
5. A deficiency of which one of the following complement compo-
ment attracts polymorphonuclear leukocytes, which release
nents predisposes to bacteremia caused by members of the genus
enzymes that damage tissue. Neisseria?
(6) Patients with severe liver disease (e.g., alcoholic cirrhosis
(A) C1
or chronic hepatitis B), who have lost significant liver function (B) C3b
and therefore cannot synthesize sufficient complement proteins, (C) C5a
are predisposed to infections caused by pyogenic bacteria. (D) C5b
(E) C5b,6,7,8,9
6. Your patient is a 20-year-old woman who complains of swellings
on her arms and legs and a feeling of fullness in her throat that
SELF-ASSESSMENT QUESTIONS makes it difficult to breath. The swellings are not red, hot, or ten-
1. Regarding the complement pathway, which one of the following is der. You suspect she may have angioedema caused by a comple-
the most accurate? ment abnormality. Of the following, which one is the most likely
(A) C3 convertase protects normal cells from lysis by complement. explanation?
(B) C3a is a decay-accelerating factor and causes the rapid decay (A) She has too little C1 inhibitor.
and death of bacteria. (B) She has too little C3b.
(C) In general, gram-positive bacteria are more likely to be killed (C) She has too little factor B.
by complement than gram-negative bacteria. (D) She has too much C5a.
(D) The membrane attack complex is formed as a result of activa- (E) She has too much C9.
tion of the classic pathway but not by activation of the alterna-
tive pathway.
(E) The first time a person is exposed to a microorganism, the ANSWERS
alternative pathway of complement is more likely to be acti-
(1) (E)
vated than the classic pathway.
2. Of the following complement components, which one is the most
(2) (C)
important opsonin? (3) (D)
(A) C1
(4) (D)
(B) C3a (5) (E)
(C) C3b (6) (A)
(D) C5a
(E) C5b
3. Of the following complement components, which one is the most PRACTICE QUESTIONS: USMLE &
potent in attracting neutrophils to the site of infection (i.e., acting COURSE EXAMINATIONS
as a chemokine)?
(A) C1
Questions on the topics discussed in this chapter can be found
(B) C2 in the Immunology section of Part XIII: USMLE (National
(C) C3b Board) Practice Questions starting on page 735. Also see Part
(D) C5a XIV: USMLE (National Board) Practice Examination starting
(E) Mannan-binding lectin on page 753.
550 PART VII Immunology

Late in second pregnancy Erythroblasts

Rh– mother of Rh+ child in blood

Placenta breaks
away
Rh factor
on RBCs

Rh+ fetus

Anti-Rh antibody

First Rh+ fetus Second Rh+ fetus

FIGURE 64–13 Hemolytic disease of the newborn (erythroblastosis fetalis). Left panel: Fetal red cells (RBCs) bearing the Rh antigen enter
the mother’s blood when the placenta separates during the birth of the first Rh-positive child. IgG antibodies to Rh antigen are then produced by
the mother. Center panel: During a second pregnancy with an Rh-positive fetus, IgG antibodies pass from the mother into the fetus via the pla-
centa. The antibodies bind to the fetal red cells, complement is activated, and the membrane attack complex lyses the fetal red cells. Right panel:
Anemia and jaundice occur in the fetus/newborn. As a result of the anemia, large numbers of erythroblasts are produced by the bone marrow and
are seen in the blood of the newborn. (Reproduced with permission from Cowan MK, Talaro KP, eds. Microbiology: A Systems Approach. New York, NY: McGraw-Hill; 2009.)

The problem can be prevented if the mother’s adaptive
immune system is not allowed to be sensitized to red cells
carrying Rh(D) antigens. This is achieved by administration
of high-titer Rh(D) immune globulins (Rho-Gam) to an
Rh(D) mother at 28 weeks of gestation and immediately upon
the delivery of any Rh(D) child. These antibodies promptly
attach to Rh(D) erythrocytes and prevent their acting as
sensitizing antigen. This prophylaxis is widely practiced and
effective.
SELF-ASSESSMENT QUESTIONS
1. Which one of the following laboratory tests would be the best
to determine the number of CD4-positive cells in the blood of a
patient infected with HIV?
(A) Agglutination
(B) Complement fixation
(C) Enzyme-linked immunosorbent assay (ELISA)
(D) Flow cytometry
(E) Immunoelectrophoresis
2. You have just received a lab report that says your patient is
positive for IgM antibody to Borrelia burgdorferi in an enzyme-
linked immunosorbent assay (ELISA). This supports your clini-
cal impression that the patient has Lyme disease. Which one of
the following best describes how the ELISA was performed? (For
brevity, the wash steps have been left out.)
(A) The patient’s serum was reacted with antibody to human mu
heavy chain. Then Borrelia antigens labeled with an enzyme
were added. Then the enzyme substrate was added, and a color
change was observed.
(B) The patient’s serum was reacted with Borrelia antigens. Then
antibody to human mu heavy chain labeled with an enzyme
was added. Then the enzyme substrate was added, and a color
change was observed.
(C) Borrelia antigens were reacted with antibody to human mu
heavy chain. Then the patient’s serum labeled with an enzyme
was added. Then the enzyme substrate was added, and a color
change was observed.
(D) Borrelia antigens were reacted with antibody to human mu
heavy chain labeled with an enzyme. Then the patient’s serum
was added. Then the enzyme substrate was added, and a color
change was observed.
3. Regarding ABO blood groups, which one of the following is the
most accurate?
(A) People who are blood group O have the O antigen on the sur-
face of their red cells.
(B) The A and B blood group antigens are located on the surface
of red cells but not on the surface of other cells.
(C) The differences between the A and B blood group antigens
are dependent on the presence of different D-amino acids on
the cell surface.
(D) People who are blood group O do not have antibodies to A and
B blood group antigens and thus can be given both type A and
type B blood.
(E) The genes that determine ABO blood groups are codominant,
so a person who is blood group AB is expressing both genes
that encode the enzymes that synthesize the A and the B blood
group antigens.
4. Regarding hemolytic disease of the newborn (erythroblastosis
fetalis), which one of the following is the most accurate?
(A) Maternal red cells are the source of the antigen that induces
the antibody.
(B) It typically occurs when the father is Rh-positive and the
mother is Rh-negative.
(C) Maternal IgM anti-Rh antibody enters the fetus and causes
damage to the fetal red cells.
(D) Symptomatic disease is more likely to occur in the first child
than in the subsequent children.
(E) Administration of Rh antigen to the newborn can prevent
symptomatic disease if given early enough.
 CHAPTER 64 Antigen–Antibody Reactions in the Laboratory 551

5. You think your patient has secondary syphilis, and you order a ANSWERS
VDRL serologic test. The lab reports that the test is negative. If
this is a false-negative result due to the “prozone” phenomenon, (1) (D)
which one of the following is the most likely explanation? (2) (B)
(A) The patient’s serum has too much antibody, and the reaction is (3) (E)
in the zone of antibody excess. (4) (B)
(B) The patient’s serum has too much antigen, and the reaction is (5) (A)
in the zone of antigen-excess phase.
(6) (A)
(C) The patient’s serum has too little antibody, and the reaction is
in the zone of antibody-deficient phase.
(D) The patient’s serum has too little antigen, and the reaction is in
the zone of antigen-deficient phase.
PRACTICE QUESTIONS: USMLE &
(E) The patient’s serum has an amount of antibody that puts it in COURSE EXAMINATIONS
the zone of equivalence.
Questions on the topics discussed in this chapter can be found
6. As part of a murder investigation, the blood group of the victim
in the Immunology section of Part XIII: USMLE (National
was determined by analyzing the antibodies in her serum. (Unfor-
tunately, the red cells of the victim were lost by the crime squad, Board) Practice Questions starting on page 735. Also see
so they had to use her serum.) In this test, red cells known to be Part XIV: USMLE (National Board) Practice Examination start-
either O, A, B, or AB were mixed with her serum and agglutina- ing on page 753.
tion observed. Based on the results in the following table, what is
the blood group of the victim?

Agglutination Seen with

Red Blood Cells Used Victim’s Serum

O No
A Yes
B Yes
AB Yes

(A) Type O
(B) Type A
(C) Type B
(D) Type AB
(E) A laboratory error has occurred, and the test should be
repeated