Immunology SBAs Flashcards
A 10-year-old boy is seen by a paediatrician after suffering recurrent chest
infections. His mother reports purulent sputum production and cough for the
previous 2 years. Genetic testing reveals the child has a ΔF508 mutation on
chromosome 7. Which physical barrier to infection is most likely to be affected
by the child’s condition?
A Skin B Gastric acid C Mucociliary clearance D Tears E Gut flora
C Mucociliary Clearance
Physical barriers to infection which form part of the innate immune
system provide initial protection against disease-causing organisms.
Impaired mucociliary clearance (C) may arise secondary to cystic fibrosis,
which is the most likely answer in this scenario. Cystic fibrosis is
an autosomal dominant disease which primarily affects the lungs but
also the pancreas, liver and gastrointestinal system. The most common
mutation is the ΔF508 mutation on chromosome 7, which codes for the
cystic fibrosis transmembrane conductance regulator (CFTR). Defective
sodium and chloride ion transport across epithelial cells leads to the formation
of viscous secretions. In the respiratory tract increased viscous
secretions produced by goblet cells cause damage to the cilia, as well as
diffuse lung injury, which can result in bronchiectasis. The skin (A) is
perhaps the most important physical barrier to infection. Although covered
by normal flora, these bacteria are unable to penetrate the numerous
layers which make up the skin. However, severe burns which break
down this important barrier to infection may allow bacteria to enter the
body. Small breaks in the skin that allow a small number of pathogens
to enter the body are usually dealt with by other components of the
innate immune system. The low pH of gastric acid (B) produced in the
stomach destroys most bacteria present in food. Bacteria that reach the
large intestines must compete with commensal gut flora (E); extrinsic
bacteria are therefore unable to replicate and cannot survive. Tears (D)
are produced by the lacrimal glands of the eyes. The lysozyme component
reduces the risk of pathogens entering the eye. Keratoconjunctivitis
sicca (‘dry eye’) is a condition that causes reduced production of tears,
subsequently increasing the risk of infection.
A 62-year-old woman sees her GP for a regular check-up. On examination, she
has notable deformities of her hands, including swan-neck and Boutonniere
deformities of her fingers. Blood tests reveal a raised CRP. Which of the following
investigation results will most likely feature?
A Reduced AH50 and normal CH50 B Reduced C1 inhibitor C Reduced C3 and C4 D Reduced C3 and normal C4 E High CH50
E High CH50
The complement system is composed of the classical, lectin and alternative
pathways. These individual pathways culminate in the formation of
the membrane attack complex (MAC), which traverses cell surface membranes
of pathogens, causing cell lysis. Components of the complement
system can be quantified in order to differentiate possible diagnoses.
CH50 (total complement activity) measures the level of factors of the
classical and final pathways (C1–C9). As complement factors are acute
phase proteins, a high CH50 (E) indicates acute or chronic inflammation.
Together with the raised CRP and clinical features, this patient is likely
to suffer from rheumatoid arthritis. Systemic lupus erythematosus (SLE)
is a systemic autoimmune disease characterized by antibody-immune
Book Interior Layout.indb 191 28/11/12 7:20 PM
192 Section 6: Immunology SBAs
complex formation and deposition. The classical complement pathway
is composed of C1, C2 and C4. Reduced C3 and C4 (C) levels are typical
of SLE as a result of complex formation (hence consumption) in
an attempt to eliminate immune complexes. C3 and C4 may also be
reduced in SLE due to immunodeficiency which predisposes to developing
the disease. In membranoproliferative glomerulonephritis (MPGN),
anti-nephritic antibodies cause consumption of complement factors,
especially C3. As a result, complement profiling reveals a reduced C3
but normal C4 (D); MPGN type III reflects this pattern particularly well.
AH50 is a laboratory investigation to test for abnormalities of the alternative
pathway, which involves factors C3, B, D and P. A reduced AH50
and normal CH50 (A) suggest possible deficiency of one or more of the
alternative pathway factors; this predisposes to infection by encapsulated
bacteria.
Reduced C1 inhibitor (B) levels indicate hereditary angioedema, characterized
by facial swelling; in severe cases the airway can become compromised
leading to respiratory distress.
A 25-year-old woman, who has a history of allergy to nuts, is taken to accident
and emergency after eating a dessert containing peanuts. She has an evident
wheeze with an increased respiratory rate, swelling of her lips and itchy skin.
Which cell of the innate immune system is most likely to be responsible for her
symptoms?
A Natural-killer cells B Dendritic cells C Eosinophils D Mast cells E Neutrophils
D Mast cells
Mast cells (D) are involved in the inflammatory process that occurs in
allergy and anaphylaxis (the diagnosis in this case), but also provide
a protective function against pathogens. Mast cells are activated by
one of three mechanisms: direct injury (toxins or drugs), cross-linking
of IgE receptors or by activated complement proteins. Once activated,
mast cells release granules containing histamine and heparin. Histamine
causes vasodilatation leading to the characteristic features of inflammation
(oedema, warmth and redness of the skin). The ‘flare and wheal’
skin reaction is a feature of histamine release by mast cells. Mast cells
play a role in diseases such as asthma, eczema and allergic rhinitis.
Anaphylaxis is characterized by systemic degranulation of mast cells
leading to life-threatening shock. Natural killer cells (NK cells; A) are
responsible for destroying tumour cells and virus-infected cells. NK cells
are unique in that they have the ability to kill such cells in the absence
of antibodies and major histocompatibility complex. Dendritic cells
(B) are antigen-presenting cells (APCs) involved in bridging the gap
between the innate and adaptive immune response. Once dendritic cells
are activated, they migrate to the lymph nodes to facilitate the adaptive
immune system. Eosinophils (C) protect against parasitic infection. Such
pathogens stimulate release of granule contents into the extracellular
space, which surround the parasite and lead to clearance. Neutrophils (E)
are the most common of the granulocytes. Neutrophils are responsible
for the innate protection against bacterial pathogens. Stored within neutrophils
are a host of bactericidal lysosomes which contain lysozyme,
Book Interior Layout.indb 192 28/11/12 7:20 PM
Answers 193
acid hydrolases and myeloperoxidase. Opsonized pathogens are internalized
by neutrophils forming a phagosome. Lysosomal contents enter the
phagosome leading to respiratory burst and lysis of the pathogen.
A 35-year-old man develops diarrhoea with fever and malaise 24 hours after eating
a take-away meal. Stool cultures reveal the source of the infection is Salmonella
spp. Which antibody is responsible for protecting against gastrointestinal infections?
A IgA B IgD C IgG D IgM E IgE
A IgA
Antibodies (also known as immunoglobulins) are glycoproteins produced
by B cells as part of the adaptive immune system. The basic
role of antibodies is to bind to foreign targets, otherwise known as
antigens. Antibody functions are numerous and include host defence
against pathogens by neutralizing toxins or targeting infective organisms,
complement activation and mast cell stimulation. As well as the
physiological role of antibodies, they are also used in the diagnosis of
infectious diseases by measuring anti-viral and anti-bacterial antibodies.
Structurally, antibodies are made up of two heavy chains and two light
chains. Each heavy chain and each light chain has a constant region
as well as a variable region; the variable regions differ significantly
between antibodies and it is this segment that makes antibodies specific
to target antigens.
IgA (A) can exist as a monomer or a dimer (joined by a short peptide
known as the J chain). Its role is primarily related to the protection of
mucosal surfaces via salivary, respiratory, gastrointestinal and lacrimal
secretions. IgA is also present in breast milk, providing passive immunity
in neonates. IgD (B) is an uncommon immunoglobulin in the body
and is found on the cell surface of immature B cells. IgD provides an
essential role in lymphocyte activation. IgG (C) is the most abundant
antibody and occurs in monomer form in the circulation. The various
subclasses of IgG perform different functions, for example IgG2
is important in fighting encapsulated bacteria. IgG also has a role in
activating complement proteins. IgM (D) occurs as a pentamer and has
a role in the primary response against pathogens. IgE (E) is produced in
response to parasitic infections, as well as during type I hypersensitivity
reactions where it is involved in mast cell activation.
A 23-year-old man presents to his GP with recent onset diarrhoea, fatigue and
weight loss. The patient suggests that his symptoms are worsened after eating
bread or rice. Which human leukocyte antigen is most likely to be associated
with his disease process?
A HLA B27 B HLA DR2 C HLA DR3 D HLA DR4 E HLA DQ2
E HLA DQ2
The human major histocompatibility complex (MHC), otherwise
known as human leukocyte antigen (HLA) system, is the collection
of genes that relates to immune system function and is located
on chromosome 6. The HLA system consists of three major classes:
class I (HLA A, B and C), class II (HLA DP, DQ and DR) and class III
(complement components). HLAs have a number of roles in immunology
including defence against pathogens, transplant rejection and
autoimmune disease.
HLA DQ2 (E) represents a risk factor for coeliac disease (HLA DQ8
is also a risk factor but to a lesser extent). The cell surface receptors
formed by HLA DQ2 bind with greater affinity to α-gliadin, a protein
present in wheat, barley and rye which is responsible for the pathogenesis
of coeliac disease. Therefore, receptors formed from HLA DQ2
are more likely to recruit T cells and initiate an autoimmune response
compared to other HLAs. HLA B27 (A) is associated with ankylosing
spondylitis. The association with HLA B27 suggests the involvement of
CD8+ T cells in the pathogenesis of ankylosing spondylitis. HLA DR2
(B) is associated with Goodpasture’s syndrome, an autoimmune disease
triggered by a type II hypersensitivity reaction. It is characterized by
glomerulonephritis and haemoptysis. HLA DR3 (C) is associated with
Graves’ disease, systemic lupus erythematosus (SLE) and myasthenia
gravis. HLA DR4 (D) is associated with type I diabetes mellitus and
rheumatoid arthritis; in these diseases, HLA DR4 recruits T cells with
subsequent production of islet cell antibodies.
A 3-year-old Afro-Caribbean boy is referred to a paediatrician after concerns
about his recurrent chest infections. The child’s hair slowly fell out and there is
evidence of depigmentation of his skin. Blood tests reveal hypocalcaemia and
high TSH levels. Which component of the immune tolerance system is likely to
be dysfunctional?
A Regulatory T cell B TGF-β C Autoimmune regulator D Dendritic cells E IL-10
C Autoimmune regulator
T-cell tolerance is the process by which the body’s T cells do not attack
self antigens. There are several mechanisms by which this is achieved,
including the selection of answers given above. Autoimmune disease is
defined as the abnormal response to healthy self components; there is
an underlying pathological process which leads to the breakdown of self
tolerance. Autoimmune disease may be organ specific (Graves’ disease)
or non-organ specific (systemic lupus erythematosus).
Central tolerance is the induction of tolerance to self, which is integrated
into T-cell development in the thymus, a major site for the maturation
of T cells. Within the thymus, T-cell receptors are exposed to
self major histocompatibility complexes (MHC). Those binding to these
MHCs with some affinity are positively selected, whereas those with no
affinity (unable to recognize MHC) are neglected and removed. T cells
binding with high affinity are removed by apoptosis, as these cells pose
an autoimmune risk. The autoimmune regulator (AIRE; C) is also present
within the thymus and presents T-cell receptors with a range of
organ-specific antigens. If T-cell receptors bind to such antigens, they
swiftly die via apoptosis. Autoimmune polyendocrine syndrome type 1
(APECED; associated with mild immune deficiency, dysfunctional parathyroid
gland/adrenal gland, hypothyroidism, gonadal failure, alopecia
and vitiligo) results from mutations in the AIRE gene. The child in this
scenario has features of APECED.
The mechanisms of central tolerance are, however, not fail-safe, and
so peripheral systems exist to remove potential auto-reactive T cells.
Regulatory T cells (A) mature in the thymus and are those that express
CD4, CD25 and Foxp3 on the cell surface. Abnormal Foxp3 leads to the
development of immunodysregulation polyendocrinopathy enteropathy
X-linked syndrome. TGF-β (B) is key in the differentiation of regulatory
T cells, while IL-10 (E) has been found to be expressed by regulatory
T cells; TGF-β and IL-10 are considered to be anti-proliferative and
anti-inflammatory signalling molecules. Dendritic cells (D) can present
peripheral T cells with self antigens. Those T cells which react are killed.
Aberrant dendritic cells have been linked to the development of autoimmune
disease.
A 34-year-old man presents to his GP with fever, joint pain and a rash on his
trunk. On examination, a new murmur is auscultated. Blood investigations reveal
a raised anti-streptolysin O titre. What is the most likely mechanism for this
disease process?
A Defective immunoregulation B Molecular mimicry C T-cell bypass D Release of hidden self antigens E Cytokines
B Molecular mimicry
Several mechanisms exist by which autoimmune disease can arise. In
this case, the patient has presented with post-streptococcal rheumatic
fever, for which the pathological mechanism is molecular mimicry
(B). Molecular mimicry is the term used to describe the phenomenon
whereby pathogens produce antigens that are molecularly very similar
to self antigens. The immune response to this pathogenic antigen generates
T cells and B cells which are both anti-pathogen and anti-self;
this process is known as immunological cross-reactivity. In the case of
post-streptococcal rheumatic fever, antibodies to M-proteins present on
the surface of group A streptococci cross-react with cardiac myosin; this
results in the inflammatory features of rheumatic fever (fever, raised
ESR/CRP, leukocytosis, carditis). Defective immunoregulation (A) results
in the reduced number or aberrant function of regulatory T cells which
bear CD4, CD25 and Foxp3 surface markers. These cells are responsible
for maintaining peripheral tolerance. Defective immunoregulation has
been associated with thyroid, islet cell and liver autoimmune diseases.
T-cell bypass (B) involves the generation of a novel autoantigen epitope.
Autoantigens are physiologically internalized by B cells, which are in
turn presented to T-helper cells; the B cell is suppressed from producing
autoantibodies. If the complex autoantigen is modified, a new epitope is
provided for T cells to stimulate antibody production by B cells. Triggers
to this modification include drugs and infection, such as Mycoplasma
pneumoniae inducing autoimmune haemolytic anaemia by modifying
erythrocyte surface proteins. Release of ‘hidden’ self antigens (D) may
occur after damage to an organ and causes release of intracellular proteins
which have never been exposed to the immune system. This is the
case post-myocardial infarction, where release of proteins leads to the
generation of autoantibodies against cardiac myocytes (Dressler’s syndrome),
causing pericarditis. Cytokines (E), such as IL-2, may have an
effect on breakdown of immunological tolerance. There is a strong association
between IL-2 therapy (solid-organ tumours) and autoimmune
thyroid disease.
A 2-year-old girl is seen by an infectious disease paediatrician after suffering
recurrent infections since she was born. Her neutrophil count is normal. A nitroblue-tetrazolium
(NBT) test is performed, which remains colourless. What is the
diagnosis?
A Kostmann syndrome B Cyclic neutropenia C Leukocyte adhesion deficiency D Chronic granulomatous disease E Von Gierke’s disease
D Chronic granulomatous disease
Chronic granulomatous disease (CGD; D) is an X-linked disorder causing
deficiency of NADPH oxidase. As a result, neutrophils cannot produce
the respiratory burst required to clear pathogens. The disease is
characterized by chronic inflammation with non-caseating granulomas.
Clinical features include recurrent skin infections (bacterial) as well
as recurrent fungal infections including Candida spp. and Aspergillus
spp. The disease is usually detected by the age of 5 and is diagnosed
using the nitro-blue-tetrazolium (NBT) test, which remains colourless
due to NADPH deficiency (if NADPH is present the solution turns blue).
The NBT test distinguishes CGD from other phagocyte deficiencies. The
patient will have a normal neutrophil count as there is no defect in
neutrophil production. Treatment involves the use of prophylactic antibiotics
and interferon-gamma. Kostmann syndrome (severe congenital
neutropenia; A) is a congenital neutropenia as a result of failure of
neutrophil maturation. This results in a very low neutrophil count and
no pus formation. NBT test is positive. In leukocyte adhesion deficiency
(LAD; C), neutrophils are formed but cannot exit the blood stream
due to a deficit in leukocyte adhesion molecules resulting in reduced
neutrophil chemotaxis. The neutrophil count is very high due to persistence
in the blood stream. NBT test is positive. Cyclic neutropenia
(B) is an autosomal dominant condition caused by a mutation in the
neutrophil elastase gene (ELA2). Neutropenia occurs every 3 weeks and
lasts approximately 6 days at a time. Cyclic neutropenia improves after
puberty. Von Gierke’s disease (E) is a glycogen storage disease caused
by a deficiency of the enzyme glucose-6-phosphatase. Patients may present
with severe hypoglycaemia. Neutropenia is also a manifestation of
the disease.
A 29-year-old woman presents to her GP with recent onset joint pain and tiredness.
On examination she has a malar rash. Further blood tests reveal she is antinuclear
antibody and anti-double stranded DNA positive. Which component of
the complement system is she most likely to be deficient in?
A C3 B C4 C C6 D C9 E C1 inhibitor
B C4
This patient demonstrates symptoms, signs and diagnostic features consistent
with systemic lupus erythematosus (SLE) and is therefore most
likely to have a deficiency of the classical pathway such as C4 deficiency
(B). Other possible deficiencies in this pathway include C1q, C1r and
C1s and C2. The classical pathway is responsible for clearing immune
complexes and apoptotic cells; patients who have deficiencies in this
pathway therefore have a greater risk of developing immune complex
disease such as SLE. C3 (A) is a common factor in both the classical
and alternative pathways. Deficiency of C3 leads to recurrent pyogenic
infections as there is no C3b (produced via C3 convertase) available to
opsinize bacteria. C3 deficiency also leads to decreased C3a production,
an anaphylatoxin that mediates inflammation. C6 (C) forms part of the
terminal complement pathway, together with C5, C7 and C8, which
form the membrane attack complex (MAC) for bacteriolysis. Deficiency
of terminal complement pathway factors leads to increased susceptibility
to encapsulated bacterial infections, such as Neisseria gonorrhoea
and Neisseria meningitides. While C9 (D) also forms part of the MAC,
patients deficient in C9 still retain some ability to clear encapsulated
bacterial infection, albeit at a slower rate. Therefore, patients deficient
in C9 are usually asymptomatic. C1 inhibitor (E) has the physiological
role of inhibiting the kallikrein system and classical pathway. C1 inhibitor
deficiency causes increased production of bradykinin and spontaneous
activation of the complement pathway; deficiency results in the
autosomal dominant condition hereditary angioedema.
A 4-year-old girl is seen by a paediatrician to investigate possible developmental
delay and learning difficulties. Initial blood tests reveal hypocalcaemia, reduced
CD4+ and CD8+ T-cell counts as well as deficiency in IgG and IgA. FISH analysis
reveals the child has a deletion of 22q11. What is the diagnosis?
A Di George’s syndrome B Severe combined immunodeficiency C Bare lymphocyte syndrome D Wiskott–Aldrich syndrome E Interferon-gamma receptor deficiency
A Di George’s syndrome
Di George’s syndrome (A) is caused by an embryological abnormality
in the third and fourth branchial arches (pharyngeal pouches) due to a
22q11 deletion. The result is an absent or hypoplastic thymus, as well
as a deficiency in T cells. There is a reduced level or absence of CD4+
and CD8+ T cells as well as decreased production of IgG and IgA. B-cell
and IgM levels are normal. The features of Di George’s syndrome can
be remembered by the mnemonic ‘CATCH’: cardiac abnormalities, atresia
(oesophageal), thymic aplasia, cleft palate and hypocalcaemia. Two
major subtypes of severe combined immunodeficiency (SCID; B) exist,
which affect both T and B cells: X-linked disease (mutation of IL-2
receptor) and an autosomal recessive condition (mutation of adenosine
deaminase gene which leads to a build-up of toxins and hence compromised
proliferation of lymphocytes). Clinical features include diarrhoea,
failure to thrive and skin disease (graft-versus-host induced, caused by
transplacental maternal T cells, and blood transfusion-related caused by
donor T cells). Blood transfusions are contraindicated in patients with
SCID. Bare lymphocyte syndrome (C) is caused by either deficiency in
MHC I (type 1; all T cells become CD4+ T cells) or MHC II (type 2; all
T cells become CD8+ T cells). Clinical manifestations include sclerosing
cholangitis with hepatomegaly and jaundice. Wiskott–Aldrich syndrome
(WAS; D) is an X-linked condition which is caused by a mutation in
the WASp gene which leads to lymphocytopenia. WAS is linked to the
development of lymphomas, thrombocytopenia and eczema. Interferongamma
(IFN-gamma) released by T cells induces the activation of macrophages.
Therefore, IFN-gamma receptor deficiency (E) leads to the
reduced activation of macrophages and so granulomas cannot form,
resulting in increased susceptibility to intracellular infections such as
Mycobacterium tuberculosis and Salmonella spp.
A 24-year-old man with a history of coeliac disease visits his GP after several
bouts of chest and gastrointestinal infections in the past few years. Although
the infections are mild, the patient is worried about the cause. What is the
diagnosis?
A Severe combined immunodeficiency B Bruton’s agammaglobulinaemia C Hyper IgM syndrome D Selective IgA deficiency E Common variable immunodeficiency
D Selective IgA deficiency
IgA specifically provides mucosal immunity, primarily to the respiratory
and gastrointestinal systems. Selective IgA deficiency (D) results from a
genetic inability to produce IgA and is characterized by recurrent mild
respiratory and gastrointestinal infections. Patients with selective IgA
deficiency are also at risk of anaphylaxis to blood transfusions due to
the presence of donor IgA. This occurs especially after a second transfusion;
antibodies having been created against IgA during the primary
transfusion. Selective IgA deficiency is also linked to autoimmune diseases
such as rheumatoid arthritis, systemic lupus erythematosus and
coeliac disease. The recessive form of severe combined immunodeficiency
(SCID; A) is caused by a mutation of the adenosine deaminase gene
leading to an accumulation of toxins and therefore compromised proliferation
of lymphocytes; CD4+ and CD8+ T-cell levels are decreased.
Reduced proliferation of lymphocytes leads to atrophy of the thymus,
lymph and mucosa-associated lymphoid tissue. Bruton’s agammaglobulinaemia
(B) is an X-linked disease that presents in childhood. It is
caused by a mutation of the BTK gene, which is a tyrosine kinase. This
mutation inhibits B-cell maturation and as a result B-cell and immunoglobulin
levels are diminished. Hyper IgM syndrome (C) is an X-linked
condition that presents in childhood. It is caused by a mutation in
the CD40 ligand on T cells leading to impaired communication with
B cells. B cells are unable to class-switch and therefore only produce
IgM (leading to increased levels in the blood) and patient are deficient
in IgA, IgG and IgE. Patients with hyper IgM syndrome are at risk of
Pneumocystis jerovicci infection. Common variable immunodeficiency
(CVID; E) presents in adulthood. A mutation of MHC III causes aberrant
class switching, increasing the risk of lymphoma and granulomas.
Clinical features include bronchiectasis and sinusitis. Blood tests reveal
a normal IgM level but decreased levels of IgA, IgG and IgE.
A 40-year-old man is referred to an infectious disease specialist after he is
admitted to hospital with Pneumocystis jerovicci pneumonia. On examination the
patient also has multiple Kaposi’s sarcoma lesions on his chest and abdomen.
What is the most likely diagnosis?
A Inflammatory bowel disease B Hyposplenism C Nephrotic syndrome D AIDS E Prematurity
D AIDS
Broadly, secondary immunodeficiency can result from either reduced
production of immune factors, increased loss or catabolism. Human
immunodeficiency virus (HIV) is a double stranded RNA virus that
causes AIDS (E). AIDS is characterized by immune dysfunction, the
primary defect being a reduced CD4+ T-cell count. AIDS patients
are at greater risk of developing opportunistic infections (for example,
Pneumocystis jerovicci and Cryptosporidium spp.) and tumours
(Kaposi’s sarcoma). Inflammatory bowel disease (IBD; A) is an inflammatory
condition of the gastrointestinal tract that may be subdivided
into ulcerative colitis (UC; affects the colon) and Crohn’s disease (CD;
affects anywhere from the mouth to anus). It is mainly CD that causes
protein losing enteropathy as proteins are absorbed in the small bowel.
The reduced absorption of proteins in IBD results in fewer immunoglobulins
being formed which affects the adaptive immune system
response. Hyposplenism (B) may arise due to splenectomy (after trauma)
or sickle-cell disease, for example. Poor spleen function or absence of
a spleen predisposes to encapsulated bacterial infections, for example
Streptococcus pneumoniae, Haemophilus influenzae and Neisseria meningitidis.
Such patients are therefore required to take necessary vaccinations
and antibiotic prophylaxis. Nephrotic syndrome (C) is characterized
by renal dysfunction leading to large amounts of protein leaking
from the blood to the urine. Consequently, immunoglobulins will be lost
as they are passed into the urine, leading to increased risk of infection
by encapsulated bacteria. Prematurity (E) is a cause of secondary immunodeficiency
as IgG is transferred across the placenta during the final
2 months of pregnancy. Premature babies will have had less IgG transferred
as a fetus. As a result, such babies will be at greater risk of infection
before their own immune systems begin to mature (approximately
4 months after birth).
A 12-year-old girl has developed a runny nose, itchy eyes and nasal congestion
during the summer months for the past 4 years. She is prescribed anti-histamines
to help her symptoms. Which of the following cells is responsible for the initial
encounter with the allergen?
A Mast cell B B cell C Macrophage D TH1 cell E TH2 cell
C Macrophage
Type I hypersensitivity reactions are mediated by IgE and are associated
with allergy and anaphylaxis. The mechanism behind the development
of type I hypersensitivity reactions begins with the presentation of the
allergen to professional antigen presenting cells. Professional antigen
presenting cells include macrophages (C), dendritic cells and B cells. For
example, if an allergen is taken up by a macrophage, it is processed
intracellularly and peptides are presented via major histocompatibility
complex on the cell surface to T cells of the TH2-cell (E) subclass. TH2-
cell secrete IL-4, which stimulates B cell (B) proliferation. TH1-cells (D)
do not play a role in the pathogenesis of type I hypersensitivity but do
contribute to type IV hypersensitivity reactions. B cells in turn produce
allergen-specific antibodies of the IgE variety. IgE binds to mast cells
(A) via the Fc receptor. During a second exposure, when the allergen
encounters the sensitized mast cell, the surface IgE cross-links which
leads to an increased intracellular calcium concentration, facilitating
the release of pre-formed mediators (histamine, proteases, serotonin and
heparin) as well as newly formed lipid mediators (thromboxane, prostaglandin,
leukotriene and platelet activating factor). These mediators correlate
with the clinical features of allergic reactions. For example, histamine,
leukotrienes and prostaglandins are vasodilators and contribute
to the warmth, oedema and redness which are associated with allergic
inflammation. Examples of diseases caused by type I hypersensitivity
reactions include allergic rhinitis, food allergy and urticaria.
A 14-year-old girl with a history of eczema presents to accident and emergency
with itching and tingling of her lips and tongue. The girl’s lips are evidently
swollen. All observations are normal. The doctor believes her condition is due to
cross-reactivity of allergens. What is the most likely trigger for her allergy?
A Penicillin B Eggs C Nickel D Dust mite E Fruit
E Fruit
This patient has signs and symptoms confined to her mouth. Together
with the doctor’s suspicions regarding the underlying pathogenesis, oral
allergy syndrome (OAS) is the most likely diagnosis. OAS occurs secondary
to cross-reactivity of antigens inhaled in the mouth, otherwise
known as pollen–food allergy. For example, a patient may be sensitized
to birch pollen; when pollen is breathed in, IgE is created which
cross-reacts with fruit (E) which has been ingested causing release of
histamine from mast cells resulting in local inflammation. Known crossreactants
include birch pollen/stone fruits, mugwort pollen/celery and
ragweed pollen/melon. All symptoms are confined to the mouth only
and include swelling, itching and tingling of the tongue, lips and uvula.
There is often a history of atopic disease. Management includes avoiding
ingestion of the allergen, anti-histamines and prophylactically carrying
an EpiPen in patients who have a history of anaphylaxis. Allergy
to penicillin (A) may result in either acute urticaria or in severe cases,
anaphylaxis. Acute urticaria lasts for less than 6 weeks, characterized
by intermittent rashes which last less than 24 hours at a single site.
Systemic IgE activation results in anaphylaxis characterized by swelling
of the lips, shortness of breath and signs of shock in severe cases.
Eggs (B) are a primary cause of food allergy in children; egg allergy
usually resolves by the age of 8 years. Most food allergies are IgE mediated;
as some are not, the gold standard to test for food allergies is the
double-blind food challenge. Other causes of food allergy include nuts,
shellfish, milk and wheat. Nickel (C) causes contact dermatitis, a type IV
hypersensitivity reaction. A reaction takes 1–2 days to develop (delayed)
leading to desquamation of the skin. As histamines are not involved in
type IV reactions, there is no response to anti-histamines. Dust mites (D)
cause allergic rhinitis, symptomatically characterized by loss of smell,
rhinorrhoea and nasal/eye itchiness.
A 21-year-old woman is at a Thai restaurant, eating her main course when she suddenly
develops shortness of breath, wheeze and swelling of her lips. The patient
has a known peanut allergy. What is the most appropriate treatment in the first
instance?
A Allergen avoidance B Adrenaline C Oral anti-histamines D Doxepin E Nasal steroids
B Adrenaline
This patient is suffering an anaphylactic attack as a result of peanut
allergy. Other potential causes of anaphylaxis include penicillin, animal
venom and latex. The pathophysiology of anaphylaxis involves
IgE binding to the allergen with subsequent systemic release of histamine
causing vasodilation and contraction of bronchial smooth muscle.
Clinical features include swollen lips, shortness of breath, wheeze and
signs of shock. Anaphylaxis is therefore a medical emergency and intramuscular
(IM) adrenaline (B) is the primary treatment; many patients
who suffer from severe allergy are educated in the use of an EpiPen.
IM adrenaline is the best (and life-saving) choice due to its fast acting
vasocontrictive and bronchodilator effects. Non-IgE mediated systemic
histamine release by mast cells is known as an anaphylactoid reaction.
Causes include opioids, NSAIDs, contrast agents and exercise. Clinical
features are similar to anaphylaxis reaction.
As allergies such as allergic rhinitis, oral allergy syndrome and urticaria
are IgE mediated causing release of histamine by mast cells, oral antihistamines
(C) are the main-stay treatment for such conditions. Antihistamines
used in allergic disease are H1 receptor antagonists which
negate the effects of histamine. Although effective in treating mild
symptoms, oral anti-histamines take longer to have an effect than IM
adrenaline. Nasal steroids (E) may also be prescribed to alleviate symptoms
of rhinorrhoea, itching and nasal congestion. Patients with known
triggers to allergy, such as specific foods, irritants or environmental
conditions, are also encouraged to practice allergen avoidance (A) as a
conservative measure in managing their symptoms. Doxepin (D) is indicated
in the management of chronic urticaria.
A demanding mother takes her 6-year-old son to see the GP. She is concerned by
his numerous allergies, including pollen and various foods. She is keen for her
son to have allergy testing to determine the substances he is allergic to. Which of
the following would be the best test for investigating allergy in this child?
A Radioallergosorbent test B Skin prick test C Double-blind challenge D Serum tryptase levels E Total serum IgE
B Skin prick test
There are a battery of tests available for the investigation of IgE mediated
hypersensitivity and the triggers which might be causative of such
a reaction. This patient has an allergy to pollen and food: the skin prick
test (B) is the gold standard for investigating such type I hypersensitivity
reactions. The test involves a few drops of purified allergen being
pricked onto the skin. Allergens which are tested for include foods, dust
mites, pollen and dust. A positive test is indicated by wheal formation,
caused by cross-linking of IgE on the mast cell surface leading to
histamine release. Radioallergosorbent test (RAST test; A) is also used
to test for a variety of potential allergens. The test involves patient
serum being added to a range of insoluble allergens. If antibodies are
present to the allergen, these will bind. Radio-labelled anti-human IgE
antibody is then added, which binds to the IgE bound to the insoluble
allergen. Once the unbound IgE is washed away the radioactivity is
measured; the greater the radioactivity the stronger the reaction to the
allergen. Radioactivity-based tests have been replaced by enzyme- and
fluorescence-based assays. The difficulty with RAST testing is that low
IgE levels may be present in the serum which could lead to false negative
results. Double-blind challenges (C) are reserved for food allergies
where there is some doubt after a skin prick or RAST test. This must be
conducted at a centre where necessary equipment is available in case of
anaphylaxis. Serum tryptase levels (D) are useful in diagnosing anaphylaxis
reaction. Measuring total serum IgE (E) is not very informative in
investigating allergy.
A 56-year-old diabetic man is undergoing a kidney transplant as a result of
chronic renal failure. After the operation, the man immediately develops fever
and has no urine production. Background checks reveal there was an error in
ABO matching of the donor and recipient; the donor’s blood group was A, while
the recipient’s is O. Which of the following immune components is the first to
initiate a response in this case?
A Natural-killer cells B C1 C Neutrophil D Mannose binding lectin E Macrophages
B C1
This patient has suffered hyperacute rejection of his graft as a result
of ABO incompatibility; secondary to a previous sensitizing event, the
recipient has developed antibodies that have attacked the allograft. This
is an example of a type II hypersensitivity reaction. Type II hypersensitivity
reactions are IgG and IgM antibody mediated; the antigen is
fixed to tissues or cell surface. Tissue or organ damage is restricted to
those areas where the antibody target exists. Binding of the antibody
to the target antigen causes activation of the classical complement
pathway, beginning with C1 (B); activation of C1 has a number of
effects. Fragments C3a and C5a are subsequently generated and attract
macrophages (E). The final common pathway of complement activation
involves factors C5–C9 forming the membrane attack complex (MAC)
which inserts into the target cell membrane, causing lysis. The classical
pathway also leads to binding of C3b onto the target cell surface membrane,
which causes recruitment of effector cells such as macrophages,
natural-killer cells (NK cells; A) and neutrophils (C). Effector cells cause
significant damage by lysing target cells by an antibody-dependent
cell-mediated cytotoxicity (ADCC) mechanism. Mannose binding lectin
(MBL; D) is part of the lectin complement pathway, which is not
involved in type II hypersensitivity reactions. Further examples of type
II hypersensitivity reactions include myasthenia gravis, pemphigus vulgaris,
haemolytic anaemia and haemolytic disease of the newborn.
A 54-year-old woman is referred to a dermatologist after developing blisters
which she first noticed in her mouth but have now appeared on her right arm.
On examination, Nikolsky’s sign is positive and immunofluorescent staining
demonstrates the presence of acantholytic cells. What is the most likely target for
antibodies in this case?
A Gastric parietal cell B Rhesus antigen C Acetylcholine receptor D Demoglein 1 E M proteins on group A streptococci
D Demoglein 1
Type II hypersensitivity reactions involve the presence of antibodies
that target antigens fixed to the target cell surface membrane. The
patient in question has clinical features of pemphigus vulgaris. Such
features include blistering of the skin and Nikolsky’s sign is positive
(slight rubbing of the skin results in separation of the outermost layer).
Pemphigus vulgaris results from antibodies directed towards demoglein
1 (D) and demoglein 3, which are epidermal cadherins of the epidermis.
Antibodies causing damage to cadherin proteins result in the loss of
linkages between keratinocytes, hence causing the presence of characteristic
acantholytic cells on biopsy. Gastric-parietal cell (A) antibodies
are a feature of pernicious anaemia and lead to parietal cell loss and
hence reduced intrinsic factor production; this causes reduced vitamin
B12 absorption. As a result patients present with vitamin B12 deficiency,
features of which include tiredness (anaemia) as well as sensory or
motor defects. Rhesus antigens (B) are found on the surface of erythrocytes.
As with ABO, the rhesus (Rh) blood group system is a clinically
important system used for matching in blood transfusions. The most
commonly used Rh antigen in matching is the D antigen. Antibodies
directed against the Rh antigen result in autoimmune haemolytic anaemia
(AIHA). The direct Coombs test, which detects antibodies bound
to the surface of erythrocytes, is positive in AIHA. The acetylcholine
receptor (C) located at the neuromuscular junction is the target for autoantibodies
in myasthenia gravis. Myasthenia gravis is a condition which
presents with fatigability of muscles; muscles become fatigued after
periods of movement but recover after rest. In severe cases, muscles of
breathing may become affected, leading to respiratory distress. In poststreptococcal
rheumatic fever, antibodies to M-proteins present on the
surface of group A streptococci (E) cross-react with cardiac myosin; this
results in the inflammatory features of rheumatic fever which include
fever, raised ESR/CRP, leukocytosis and carditis. Rheumatic fever occurs
as a result of molecular mimicry whereby pathogens produce antigens
that are molecularly very similar to self antigens.
A 35-year-old woman presents to her GP with intermittent fatigue and joint
pain which began 1 month previously. On examination, the patient has a malar
rash on her face. Blood tests reveal anaemia. What is the most likely target for
autoantibodies in this disease process?
A Mouldy hay B Chlamydia trachomatis C DNA D Antiserum proteins E Hepatitis B virus antigen
C DNA
In contrast to type II hypersensitivity reactions, type III hypersensitivity
reactions are characterized by antibodies targeting antigens that are not
fixed to a cell surface. This patient has symptoms and signs characteristic
of systemic lupus erythematosus (SLE). SLE is a multisystem disorder
which may manifest in a number of ways, examples of which include
fever, fatigue, loss of appetite, malar rash, mouth ulcers, photosensitivity,
serositis and joint pains. DNA (C) is the target for circulating antidouble
stranded DNA antibodies in SLE. Many of the clinical features
of SLE result from antibody-immune complex deposition. The presence
of anti-Smith antibodies suggests interstitial lung disease involvement.
Chronic exposure to mouldy hay (A) is the cause of farmer’s lung, an
example of an extrinsic allergic alveolitis. Actinomycetes are the most
common pathogens found in hay dust, which are subsequently inhaled.
Inhalation over prolonged periods of time leads to immune complex
formation as antibodies combine with the inhaled allergen; the immune
complexes are deposited in the walls of the alveoli. Chronic exposure
leads to pulmonary fibrosis, with associated shortness of breath, cyanosis
and cor pulmonale. Antibodies directed at Chlamydia trachomatis
(B) may trigger a reactive arthritis (Reiter’s syndrome). Clinical features
include arthritis, dysuria, conjunctivitis and uveitis. As this phenomenon
is autoimmune, synovial fluid cultures are negative. Proteins in
antiserum (D) are the cause of serum sickness, a self-limiting condition
that occurs when antiserum derived from a non-human animal source
is injected intravenously, resulting in immune complex hypersensitivity.
HBsAg (E) may be associated with the development of polyarteritis
nodosa (PAN), a vasculitis of small and medium sized vessels. Immune
complexes are deposited within such vessels leading to fibrinoid necrosis
and neutrophil infiltration; as a result the vessel walls weaken resulting
in the formation of multiple aneurysms.
A 34-year-old woman notices an itchy and desquamating, erythematous rash on
her wrist, which has emerged approximately 3 days after wearing a new bracelet.
Which cytokine is the first to be released during the initial exposure to the
allergen?
A IL-10 B IFN-γ C IL-2 D TNF-α E IL-12
E IL-12
Type IV hypersensitivity (delayed type) reactions are those that are
mediated by T cells of the immune system. These types of reactions
require two exposures to the allergen. During the first encounter,
antigen presenting cells such as macrophages engulf the allergen and
presents peptides on the cell surface via major histocompatibility complex.
CD4+ T cells recognize the peptide and bind to the macrophage.
The macrophage then releases IL-12 (E) which leads to the production
of memory CD4+ T cells of the TH1 variety. During the second exposure,
the macrophage will once again take up the allergen and present
peptide to CD4+ T cells. On this occasion however, the sensitized
memory T cell releases IFN-γ (B), IL-2 (C) and IL-3 thereby activating
macrophages, inducing the production of TNF-α (D); the result is tissue
injury and chronic inflammation. As type IV hypersensitivity reactions
are cell-mediated, there is a lag time of approximately 48–72 hours
before clinical symptoms and signs are visible. IL-10 (E) is not involved
in type IV hypersensitivity reactions; IL-10 is produced by TH2 cells
which causes inhibition of TH1 cells. As a consequence, IFN-γ would
not be produced to activate macrophages and so type IV hypersensitivity
would not occur. An example of a disease process caused by type
IV hypersensitivity is contact dermatitis occurring secondary to nickel
exposure, as is the case in this clinical scenario.
