IMMUNOPATHOLOGY:

MCQ PREP
Dr David Tran
MBBS FRACP FRCPA
Immunopathologist
Melbourne Health Pathology Service
HAE a) C4
Hereditary angioedema
• Episodic, recurrent subepithelial oedema
• Involving extremities, larynx, face, abdomen & bowel wall
• May present as recurrent abdominal pain ?appendicitis,
cholecystitis
• Precipitants include:
• Physical trauma eg. tooth extraction, surgery
• Emotional stress & anxiety
Pathogenesis
• Type I HAE ( 85% cases):
• Both C1Einh levels and function are  by 5-30%
• Due to  biosynthesis and  catabolic rate

• Type II HAE ( 15% cases):

• Normal or  C1Einh levels
• But  C1Einh function:
• Due to synthesis of dysfunction C1Einh (activity dependent on
confirmation change on binding to serine protease)
• Point mutations involving amino acids at binding site of C1Einh protein
• Note: most “low C1Einh function” results due to degradation of sample
in transit
Hereditary or Acquired angioedema
• C1 Inhibitor Levels & Function used in the investigation of angioedema
without urticarial
• Uncontrolled activation of classical pathway leads to increased activation of
Factor XII and production of bradykinins with increased vascular
permeability and angioedema
HAEI HAEII AAE
C1-INH
Low Normal or ↑ Normal or ↓
quantitative
C1-INH
Low Low Low
functional

C3 Normal Normal Normal

C4 Low Low Low

Normal between
Normal between attacks
C1q attacks (↓ during Low
(↓ during attacks)
attacks)
From: K. Nichols
Treatment Options
• Acute treatment:
• Fresh frozen plasma (6-8 units)
• C1esterase inhibitor concentrate (500-1000 units)
• Purified C1 inhibitor concentrate (Cinryze, Berinert, or Ruconest).
• Ecallantide (Kalbitor) (a kallikrein inhibitor available in the United States).
• Icatibant (Firazyr), a bradykinin-B2-receptor antagonist.

• Preventative treatment:
• Attenuated androgens:
• Danazol
• Stanazolol
• Anti-fibrinolytics:
• Epsilon-amino-caproic acid
• Tranexamic acid
• AAE
• Type I: Rx underlying malignancy
• Type II: immunosuppression +/- plasmapheresis
 7

(Grigoriadou et al, 2009)

Treatment Options
Mechanism for Angioedema
1) Mast cell Mediated
• Allergic reactions to foods, medications or insert stings
• Always other signs of mast cell mediator release (urticaria,
flushing, pruritis, bronchospasm, hypotension etc)
• Reaction begins within minutes of exposure, builds over a few
hours, resolves 24-48hours

2) Bradykinin Mediated
• Not associated with urticarial, hypotension, bronchospasm etc
• More prolonged time course developing over 24-36hours and
resolving in 2-4 days
• Trigger not usually apparent
• E.g. ACE inhibitor, hereditary angioedema
Anaphylaxis

•?B
Anaphylaxis
• Anaphylaxis = life-threatening reaction to a specific
allergen (usually) through IgE.
• Skin (urticaria)
• Angioedema (airway)
• GI (diarrhoea/vomiting)
• CVS (hypotension)
• All true
• But the beginning step is binding of allergen to IgE
attached on mast cells
• A) is the sensitization step, but it cannot initiate
anaphylaxis until B)
• Normal flow: A) -> B) -> E) -> D) -> C) ->
Anaphylaxis
Q87
Which of the following has the highest association with fatal anaphylaxis?
A. Age
B. Chronic urticarial
C. Crustacean seafood
D. Hypertension
E. Poorly controlled asthma
  
Answer: E) poorly controlled asthma
 
From up to date:
The most consistently noted risk factor for fatal anaphylaxis is concomitant asthma
All fatal food reactions in UK in 10 year series were in patients taking daily medications
for asthma
Often misdiagnosed as asthma attack
Also tend to have concomitant allergies
Not clear if better control of asthma would decrease the likelihood of severe anaphylaxis
 
Anaphylaxis

• Answer: A
Exam answers
Answer
• E - Penicillin
• All other options produce anaphylactoid reactions (direct
mast cell release)
Exam questions
Answer
• C - lifelong avoidance of peanuts
• Epipen and avoidance of the causative agent are the only
measures available for food allergy anaphylaxis
• Optimisation of asthma control is also important (but not
an option)
Exam questions
Answer
• E - ACE inhibitors
• Up to 50% of angioedema presenting to ED and used
predominantly in older populations (with hypertension,
heart disease, diabetes)

• ACE inhibitor angioedema, which occurs in ACE inhibitor users at a prevalence greater than 1:1000. Most
cases are much milder than this one.
• Hereditary angioedema is a condition with a prevalence of about 1:10 000 or less.2 There is a deficiency in
C1 esterase inhibitor, or C1 esterase inhibitor is present but not functional, allowing accumulation of active
C1 esterase. This in turn leads to, among other things, a periodic accumulation of bradykinin in tissues that
results in angioedema.
• Acquired C1 esterase inhibitor deficiency is an autoimmune condition in which there is autoimmune
inactivation of C1 esterase inhibitor.4 This renders the C1 esterase inhibitor ineffective and excess C1
esterase activity can develop. This can result in accumulation of bradykinin in tissues. This condition is very
rare with less than 150 described cases.
• Hereditary angioedema without C1 esterase inhibitor deficiency appears to be due to abnormalities in clotting
factor XII and occurs with a prevalence of less than 1:100 000 people.5 The majority of cases are female.

AUSTRALIAN FAMILY PHYSICIAN

VOL. 42, NO. 12, DECEMBER 2013
Exam questions
Answer
• C or D
• Previous speakers thought E, based on ASCIA
recommendation
• ASCIA has been contacted regarding the
recommendation
Anaphylaxis Definition
• Patient features should fit of the following criteria:
1. Skin /mucosal tissue (hives +/- angioedema) and either
Respiratory compromise (dyspnoea, wheeze, hypoxia). Or
Hypotension (syncope, collapse, incontinence).
2. Two or more of following after exposure to likely allergen: 1)
Skin/mucosal 2) Respiratory 3) Hypotension 4)
Gastrointestinal features (cramping, vomiting).
3. Hypotension after exposure to known allergen for patient
(minutes to 2-3 hours): defined in adults as systolic <90 mmHg
or >30% fall from baseline. Infant criteria age based

~90% have skin manifestations (not all)

Skin/mucosa manifestations alone not enough for diagnosis
Serum Tryptase / IgE measures can aid in diagnosis
Mast cell products: Tryptase, Histamine, TNF, IL-4,
IL-13, PAF, prostaglandin D2, leukotrienes, Etc

Cross linking IgE to activate receptor Allergen

specific BUT direct release possible: Vancomycin,
Opiates, contrast
 Mast Cell Mediator Release

Source: Visioncareeducation.com
Histamine Release
 Immune

Thyroid
Life-related
(Stress, Sleep)
Infection
MAST CELL

Too Many Medications

Mast Chemicals
Cells

Hormones
Coeliac

Allergy Alcohol
Physical
(Cold, Heat, Exercise, Pressure, Scratch)
Omalizumab (Xolair®)
• Omalizumab (Xolair®) anti-IgE is approved throughout
the world for the treatment of allergic asthma
• Obviously, IgE is involved in the pathogenesis of many
other atopic conditions beyond asthma

• A Humanized Monoclonal Anti-IgE Antibody IgG1

which binds to the Fc portion of the IgE molecule
blocking IgE binding to FceRI
Omalizumab-Other Conditions
• Allergic rhinitis
• Immunotherapy
• Drug allergy
• Insulin allergy
• Idiopathic anaphylaxis
• Eosinophilic gastrointestinal
diseases
• ABPA
• Mastocytosis Indolent and
systemic
• Nasal polyposis/sinusitis
• Latex allergy
• Chronic
urticaria/angioedema
Idiopathic, autoimmune,
cholinergic, cold induced
• Atopic dermatitis
Penicillin allergy
• Penicillin allergy is the most
commonly reported drug allergy
with a prevalence rate of up to 10%
• Penicillin haptenates lysine
residues on proteins because the β-
lactam ring opens spontaneously,
and forms a stable covalent
conjugate
• Haptenation through carboxy and
thiol groups forms minor Core structure of penicillin is the β-lactam ring with variable side
chain R
determinants Penicillin-derivative antibiotics arise from modifications at the R site

• IgE antibodies against penicillins

are directed to the β-lactam ring or
side chains
Pichichero M, Zagursky R. Penicillin and cephalosporin allergy. Ann Allergy Asthma Immunol 2014;112:404-12.
Cephalosporin allergy
• A slower and less efficient
process occurs with
cephalosporins
• IgE antibodies against
cephalosporins are directed
to side chain determinants
rather than the β-lactam ring,
except in first generation
cephalosporins
First generation cephalosporins arise from modifications at the R1
site.
Second generation cephalosporins have modifications at the R1
and R2 site.

Pichichero M, Zagursky R. Penicillin and cephalosporin allergy. Ann Allergy Asthma Immunol 2014;112:404-12.
 Skin Prick Test
• Test for specific IgE to
protein and peptide
antigens (allergens)

• IgE antibodies induce

mast cell degranulation
and wheal formation

Image: ASCIA website

Specific IgE
• Serum collection

• Individual
allergens

• Mixed allergens

• Fluorescence
enzyme
Immunoassay FEIA

Source: Phadia website

 Penicillin Allergy Label
Penicillin Allergy Label

Intermediate/high pre-test
Low pre-test probability
probability

Skin testing with PPL/MDM, BP, AMX, AMP, FLX

Two-dose oral AMX challenge

Negative Selective positive or Positive to

reaction to AMX PPL/MDM/BP
challenge
No Reaction
reaction
Two-dose oral AMX Single dose oral
challenge challenge to Penicillin
VK

Safe to have all Skin testing with PPL/MDM, BP, AMX, No Reaction
penicillin AMP, FLX reaction
antibiotics
Modify allergy
label Safe to
Negativ Selective Positive to have all
accordingly No Reaction
e positive to MDM/PPL/BP penicillin reaction
AMX/AMP antibiotics
Modify
allergy
label
Single dose oral challenge to Penicillin VK Avoid AMX
accordingl
and Abs with an
y Avoid AMX identical side chain and
and single dose oral consider using a
challenge to penicillin with an
Penicillin VK alternate allergenic
epitope
No Reaction Modify allergy label
reaction accordingly

No Reaction
Avoid AMX Avoid all penicillin antibiotics
and Abs with an identical side chain and Modify allergy label accordingly reaction
consider challenge using a penicillin with an
alternate allergenic epitope Avoid AMX
Modify allergy label accordingly and Abs with an
identical side chain and
consider challenge Avoid all penicillin
using a penicillin with antibiotics
an alternate allergenic Modify allergy
epitope label accordingly
Modify allergy label
accordingly
Allergy - Penicillin
QUESTION 71
A 35 year old man with Strept. Pyogenes cellulitis of right foot
and a distant history of penicillin allergy. His mother has told him
he has had an allergic reaction as a child but is unclear as to the
nature of the reaction. What is the best method to test for allergy
status in this man?

A. In vitro Ig E for penicillin ( RAST)

B. In vitro total Ig E
C. Graded oral flucloxacillin challenge
D. Skin prick and intradermal testing for penicillin
E. Skin prick and intradermal testing for cephazolin
C – Low risk, and has an acute indication
Penicillin Allergy
• A) Gives you no indication
• B) Not as specific and sensitive as E
• C) Dangerous, risky
• D) It’s not a penicillin
• E) Answer
• Penicillin skin testing (SPT and IDT) has a very high negative
predictive value (97-99%, 1-3% of negative pt develop mild/self-
limiting reactions). PPV ~50% (lack of data due to ethics)
• Penicillin allergy wanes with time
Penicillin Allergy
Question 80:
50 year old man with Hx of anaphylaxis to cephalexin 20
years ago. Now has strep viridans endocarditis, extremely
sensitive to penicillin
Best management strategy:
A. Oral penicillin challenge
B. Intradermal penicillin challenge
C. Immediate penicillin desensitization
D. Meropenem
E. Vancomycin
 
C – High risk, Urgent Indication for Penicillin treatment.
? Suitable alternatives
Food Allergy
• Question 65
• What is the gold standard test for diagnosis of IgE mediated food allergy?
• A) RAST IgE
• B) Skin prick
• C) Food challenge
• D) Elimination diet
• E) Eosinophil count

Answer is C
• Lieberman JA 2011 – Current allergy asthma rep
• “Simple tests such as skin prick testing (SPT) and serum food-specific IgE testing are the most commonly
used diagnostic tests to evaluate for IgE-mediated food reactions. However, these tests, which measure
sensitization and not clinical allergy, are not without pitfalls, and their utility must be appreciated to avoid over-
and underdiagnosis.
• “Although the physician-supervised oral food challenge remains the gold standard for food allergy diagnosis,
• “a careful medical history paired with SPT and serum food-specific IgE testing often can provide a reliable
diagnosis”
• Needs to be conducted as double blind placebo controlled trial
Drug Reaction
2013 Paper B
 
Question 20
A patient with newly diagnosed partial epilepsy is commenced on
carbamazepine. 2 weeks later, she develops a maculopapular rash. What
is the predominant cell type involved in this reaction?
A. T cells
B. IgG
C. Complement
D. IgE
E. B cells
 
SJS/TENS
Answer: A
 Drug hypersensitivity is common and attempts have been made to classify
drug hypersensitivity reactions into the Gell and Coombs classification

Demoly P, et al. International Consensus on drug allergy. Allergy 2014;69:420-37.

Severe mucocutaneous reactions
• Stevens-Johnson syndrome (SJS) and toxic epidermal
necrolysis (TEN) are severe mucocutaneous reactions,
most commonly triggered by medications, characterized
by extensive necrosis and detachment of the epidermis.

• Common Drug causes

• Allopurinol
• Aromatic anticonvulsants
• Antibacterial sulfonamides
• Lamotrigine
• Nevirapine
• NSAIDs
CVID

•D
CVID
•A
CVID

•  Answer: A
• In a large clinical study of 248 patients with CVID, 8 percent of
patients developed NHL over variable periods of time
CVID
•A
Immunodeficiency

•D
Immunodeficiency

•C
Antibody Deficiency
QUESTION 57
What is the most common phenotype in someone who has IgG
subclass deficiency?
A. Autoimmune disease
B. Atopy
C. Normal phenotype
D. Chronic gastrointestinal infections
E. Recurrent sinopulmonary infections

Answer: E
Pneumococcal Infection

• Answer: ?B / ?C
2010B-Question 12
A patient with IgA deficiency is going for a liver transplant.
Which if the following events is most likely to result in
severe adverse reaction:
 
A. Antibiotic administration
B. Blood transfusion
C. Hepatobiliary anastomotic stricture (?)
D. Immunosuppression
E. Post-operative ventilation
A) relatively safe
B) anaphylaxis via anti-IgA antibody
C) they won’t assess you on surgical complications
D) IgA deficiency usually asymptomatic (1/3 comes to
medical attention). So it shouldn’t contribute much to the
infection risk on top of immunosuppression itself
E) Same as D. Perhaps a little bit of increased infection
Common Variable Immunodeficiency
• Commonest symptomatic primary immunodeficiency
• Variable clinical phenotype
• Immunodeficiency: hypogammaglobulinaemia

Definition
• Low levels of immunoglobulins in the serum
• In at least two immunoglobulin classes
• Exclusion of other causes e.g.
• Other primary immunodeficiencies: XLA, XLP1 (SAP)
• Loss of protein from the kidneys / bowel
• Reduced antibody production secondary to chronic lymphocytic
leukemia or multiple myeloma
• Lymphoproliferative disorder
B-cell development

Molecular defects in T- and B-cell primary immunodeficiency diseases

Charlotte Cunningham-Rundles & Prashant P. Ponda
Nature Reviews Immunology 5, 880-892 (November 2005)
CVID
• Infections

• Autoimmune

• Pulmonary

• Granulomatous

• Gastrointestinal

• Neoplasms
Complications in CVID
Predominantly Antibody Defects
• BTK deficiency: X-linked agammaglobulinemia (Bruton syndrome)
• Thymoma with immunodeficiency (Good’s Syndrome)
• Consider thoracic imaging

• Common variable immunodeficiency disorders

• Specific antibody deficiency
• Normal Ig levels and B-cell numbers but with impaired responses
to vaccination (esp. to polysaccharide vaccines)

• Transient hypogammaglobulinemia of infancy

• Low Ig levels which spontaneously return to normal within 2 yrs
• Higher rate of viral URTIs
Other Combined Immunodeficiencies
• Immunoglobulin Class Switch Recombination Deficiencies
• Hyper IgM Syndrome
• CD40 ligand deficiency (XL)
• CD40 deficiency (AR)
• Impaired T-cells function
• Opportunistic infections
• P jiroveci, Cryptosporidium,
• Mycobacteria, giardia, Salmonella
• URTIs, LRTIs, diarrhoea,
• Class Switch defect
• Elevate – normal Serum IgM
• Reduce Serum IgG / IgA
• Specific Tests
• Expression of CD40 ligand
• Genetic testing
Combined Immunodeficiencies
• Severe Combined Immunodeficiency (SCID)
• Omenn Syndrome (RAG-1/2)

Severe and recurrent sepsis

Susceptible to viral (EBV, CMV),
fungal and opportunistic infection
e.g. PJP, cryptosporidium,
toxoplasma

Findings
• Impaired lymphocyte proliferation
• Restricted T-cell receptor on flow
or genetic analysis
• Genetic analysis / family hx
• Screening with TREC
• T-cell receptor excision circle
http://www.adagen.com/types_of_SCID.html
Well-defined syndrome with
Immunodeficiencies
• Wiskott–Aldrich syndrome (WASP gene defect)
• XL: Triad of eczema, thrombocytopenia, Immunodysfunction
• Ataxia–telangiectasia
• defect in the ATM gene – impaired DNA repair
• DiGeorge anomaly (chromosome 22q11.2 deletion)
• Thymic defect with congenital anomalies:
• cardiac, cleft plate, hypoparathyroidism, abnormal facies

• Hyper-IgE syndromes(HIES) – “Job syndrome”

• Recurrent eczema, skin abscesses, lung infections, eosinophilia and
high serum levels of IgE.
• AD- STAT 3 mutation; AR- DOCK8 deficiency
Chronic Granulomatous Disease (CGD)
• Recurrent infections – skin, liver and perirectal abscesses,
pneumonia and lymphadenitis
• Staph, Serratia, Burkholderia, Nocardia, Candida, Aspergillus
• Mycobacterial infections
• Granulomatous lesions even in absence of infection

• X-linked CGD caused by X-linked CYBB gene (encoding

gp91phox of NADPH oxidase): 75% of CGD
• AR forms due to defects in p22phox, p47phox and
p67phox.
Question 57
You suspect a patient has a T cell immunodeficiency.
Which recurrent infections would support this suspicion?
A. Candida glabrata oesophagitis
B. Gardnerella vaginalis vulvovaginitis
C. Neisseria meningitides meningitis
D. Staphylococcus aureus furunculosis
E. Streptococcus pneumoniae pneumonia

•  Answer: A) candida glabrata

Lack of B cells/antibodies:
• Infections with Non-intracellular organisms
• Tend to be polysaccharide encapsulated pyogenic organisms
• Strep pneumonia
• Hib
• Strep pyogenes
• Also Staph aureus, giardia, campylobacter
• Tend to affect:
• Sinopulmonary infections
• GI infections

Lack of T cells
• Clinical picture is like HIV
• Difficulty with intracellular organisms
• Fungi eg mucosal candida (not invasive, this would suggest Neut dysfunction)
• Viruses CMV EBV HSV VZV
• Pneumocystis
• Listeria

 
Lack of neutrophils
• High grade bacterial infections, particularly gram negative bacteria
• Invasive fungal infections

Lack of complement
• Classical pathway – autoimmune disease, especially SLE, and pyogenic infections
• Alternative pathway – mostly Neisseria, also other pyogenic bacteria
• Terminal components – disseminated Neisseria
CH50

• Answer D
• Total haemolytic complement level (CH50) is low or
undetectable with complement deficiencies
COMPLEMENT ACTIVATION PATHWAYS

Early
events

Bound covalently
at the pathogen surface

Late
events
Larger fragment b
Smaller fragment a
Exception is C2

Janeway, C, et al, Immunobiology, New York: Garland Science, 2005.

 66

From: S. Perel
Immunosuppression
Question 73
Patients who undergo allogeneic stem cell transplants are susceptible to
invasive mould infections including Aspergillus fumigatus, Rhizopus and
Scedosporium. Which host factor is most responsible for susceptibility
to these invasive infections?
A. Corticosteroids
B. Previous pulmonary infections
C. Graft versus host disease
D. Diabetes mellitus
E. Prolonged neutropenia
Neutropenia and impaired cell mediated immunity are the most prominent
defects in the immune system that predispose individuals to mould infections
 
Answer is E
GVHD
Question 35
What is the key cell type involved in GVHD in an allogenic
stem cell transplant
A) B cells
B) NK cells
C) Dendritic cells
D) T cells
E) Macrophage
GVHD
• Graft cells attacking normal host cells
A) Antibody normally recog pathogen, not self-proteins
usually
B) NK cells: kills via ADCC/loss of MHC. Normal host
cells has no foreign antigen for ADCC, and also has
MHC
C) Dendritic cells: presents antigen (Host MHC) to T cells
(graft). Active CD4 -> ab formation
D) Answer: recognize host cells as foreign due to different
MHC. Kills via perforin/fas
Mycobacterium tuberculosis
QUESTION 55
What is the mechanism of reactivation of Mycobacterium
tuberculosis in patients undergoing anti-TNF-alpha
therapy?
A. Increased regulatory T cell function
B. Decreased T cell function
C. Decreased immunoglobulin levels
D. Decreased natural killer cell function
E. Decreased extravasation of T cells into lungs

Answer: ?B
TB reactivation with TNFa (UTD)
• TB clearance are not killed, but sequestered by granulomas, which comprise M0,
multinuleated giant cells, necortic debri, surrounded by macrophage and lymphocyte.
TNFa required for orderly recruitment of these cells and maintenance of structure
• A study: TNFa inh reduced TB-responsive CD4 T cells, and suppressed antigen-
induced interferon-g production.
• Risk is greater with infliximab and adalimumab

• A) ?
• B) ? (potentially, as it affects T cell function)
• C) NK cells are involved in viral immunity
• D) Ig not a major component of TB immunity
• E) Probably answer, most encompassing

• Reference: Tumor necrosis factor-alpha inhibitors and mycobacterial

infections, Up-to-Date
• Tumour necrosis factor (TNF) blockers and immunity to tuberculosis (TB): potential points of interference. After ingestion
of Mycobacterium tuberculosis, the ability of the macrophage phago-lysosomal compartment to acidify is TNF-dependent
and phagosome maturation is inhibited by TNF blockers. TNF-induced autophagy may also play a role in phagosome
maturation. Some TNF blockers also induce killing of T cells (and monocytes) by apoptosis, complement-dependent
cytotoxicity (CDC) and antibody-dependent cell-mediated cytotoxicity (ADCC), while allowing expansion of
immunosuppressive regulatory T cells. The net result may be reduced interferon-γ responses, coupled with increased
interleukin-10 which, with other direct anti-TNF effects, may explain some of the observed increase in susceptibility to TB
reactivation in patients treated with TNF blockers.
Mendelian Susceptibility to Mycobacterial Disease

• Recurrent and severe infection due to weakly virulent

mycobacterial species
• Non-TB mycobacteria
• BCG
• Numerous AD and AR mutations have been described in the IL-
12; IL-23 and IFN-γ axis leading to MSMD
• Also an X-linked form
• Mutation in NEMO
• (NF-κB essential modifier; inhibitor of NF-κB kinase; or IKK)
• Regulator of the NF-κB
• Hypomorphic mutations lead to
• Antibody deficiency
• Susceptibility to viral and bacterial infection; particularly mycobacteria
• Ectodermal dysplasisa and hypohydrosis (variable)
• Null mutation lethal
MSMD
Atopic dermatitis
2010
QUESTION 9
In a 25 year old female with atopic dermatitis, what is the most likely finding?
 
A. Skin prick test positive to house dust mites
B. Rash in the flexor surfaces of elbows and knees
C. Skin Biopsy with eosinophils present
D. RAST
E. Serum IgE > 4000
F. photosensitivity
  
Answer: B
Atopic dermatitis is a clinical diagnosis:
1 mandatory plus 3 out of 5 major criteria
Mandatory: pruritic
Major criteria:
Hx of skin crease involvement
Antecubital fossa, popliteal fossa, neck, around eyes, ankles (ie flexural!)
Hx of atopic disease (or in 1st degree relative if child<4 years of age)
Dry skin in last year
Symptoms in a child appearing before they are 2 years old
Visible dermatitis on flexural surfaces (dermatitis on cheeks/forehead or outer aspects of extremities if child <4 years)
No role for skin biopsy/laboratory testing (may be useful to rule out other conditions)
2009B-QUESTION 88
A 30 year old female has a chronic erythematous, crusting,
pruritic rash on her left wrist as pictured above. What is
the next best investigation?

A. Skin biopsy
B. Thiuram patch test
C. Latex skin prick test
D. Nickel patch test
E. Antiendomysial antibodies
Contact Dermatitis
• Medscape (Dermatitis herpatiformis)
• Assocated with gluten-sensitive enteropathy
• Grouped excoriation, erythematous, urticarial plaques; and papule and vesicles
• Exquisitely pruritic
• Elbow, knees, buttocks, back

• A) to make diagnosis (IgA deposition in granular pattern)

• B) An accelerant used for speed up polymerization – wrong area,
should be hands
• C) can cause urticaria, contact dermatitis (itchy, scaly rash +/-
blisters) – wrong area (should be hands)
• D) ? Answer – contact with watch
• Nickel – ubiquitous allergen (jewlery, kitchen tools, silverware, medical device)
• E) area not consistent with common Dermatitis herpatiformis areas
Familial Fever Syndrome
Familial Fever Syndrome
Answer: B
 
These are autoinflammatory conditions
Autoinflammatory diseases arise through inappropriate activation of
antigen-independent inflammatory mechanisms. Thus, they may broadly
be considered to represent primary diseases of innate immunity, although
cells more typically associated with adaptive immunity (eg, lymphocytes)
may also contribute to autoinflammation.
Accordingly, these diseases typically lack autoantibodies or MHC
associations and occur as commonly in males as in females.
Fairly rare except for FMF, periodic fever with apthous stomatitis,
pharyngitis and adenitis (PFAPA)
 
Suspect autoinflammatory disease when recurrent episodes of fever and
serositis not otherwise explained
Leukocytoclastic vasculitis
Question 79
A 20 year old male presents with erythematous rash of trunk and
limbs. He also complains of polyarthralgia, fever, weight loss,
abdominal pain and rigors. Skin biopsy shows a leukocytoclastic
vasculitis, fibroid necrosis with immune complexes on light
microscopy. What is the expected finding on deep dermal
immunoflourescence?

A. Complement C3
B. Fibrinogen
C. IgA
D. IgG
E. IgM
 Henoch Schönlein purpure (HSP)
Reticular dermis
Blood vessels
• Granular deposits of Ig,
complement and fibrin in +
around vessels
• Seen in various cutaneous
vasculitic disorders
• Massive vascular deposits
mixed cryoglobulinaemia
• Capillary wall deposition of
IgA (C3, fibrinogen) (HSP)
ANCA
• Answer: ? A. Unsure Couldn’t find answer anywhere
Clinical associations with ANCA
(Anti-neutrophil cytoplasmic antibodies)
• Small-vessel vasculitis
• Granulomatosis with polyangiitis
• previously Wegener's granulomatosis
• Microscopic polyangiitis
• renal-limited variant pauci-immune crescentic glomerulonephritis
• Eosinophilic granulomatosis with polyangiitis
• formerly Churg-Strauss syndrome

• Inflammatory bowel disease

• Autoimmune Liver disease

• Other autoimmune disorders

• Not associated with Polyarteritis Nodosa by definition
ANCA Testing
• International Consensus Statement on Testing and
Reporting of Antineutrophil Cytoplasmic Antibodies
• Combination of indirect immunofluorescence (IIF) of normal
peripheral blood neutrophils and
• ELISAs that detect ANCA specific for proteinase 3 (PR3) or
myeloperoxidase (MPO)
• Two step testing
• 1. IIF – serum applied to slide coated with human neutrophils
• C-ANCA: cytoplasmic staining
• P-ANCA: perinuclear staining
• ANA makes pattern uninterpretable
• 2. Confirmatory test (commonly ELISA) looking for Ab targeting
specific clinically relevant neutrophil cytoplasmic granules including
Myeloperoxidase and Proteinase-3.
Savige J, Gillis D, Benson E, et al. International Consensus Statement on Testing and Reporting of Antineutrophil Cytoplasmic
Antibodies (ANCA). Am J Clin Pathol.1999;111:507-513.
ANCA IIF Patterns

Susan B. Perel,
Diagnostic Value of
Distinguishing and
Reporting Different
Perinuclear ANCA
(P-ANCA)
Immunofluorescence
Patterns
Am J Clin Pathol
2013;140:184-
Basic Science
QUESTION 23
In the immune system, what is the role of Toll Like
receptors?
A. Innate Immune system
B. Activation of neutrophils
C. Activation of Treg cells
D. Activation of the membrane attack complex
E. Activation of B-cells.
 
Answer: A
2012A- Question 37
What is the role of the HLA (human leuckocyte
antigen) or MHC (major histocompatibilty
complex) in the immune response?
 
A.   Presentation of antigens to T cells
B.   Co-stimulation between T and B cells
C.   Production of cytokines
D.   Production on pathogenic autoantibodies
E.   Stimulation of natural killer (NK) cells
Role of MHC
A) Answer. DC presents antigen to T cells who drives the
adaptive immune response
B) CD4 T cell present antigen to B cell (T cell help) -> stim
B cells to produce ab/affinitiy maturation/class
switching. But also req co-stimulating factors
CD40/CD40L
C) doesn’t do that
D) No, pathogenic autoantibody when you lose B cell
tolerance to self antigen (not role of MHC)
E) NK cells stim in the absence of MHC
2013- Question 19
The most important event in complement dependent
cytotoxicity is:

A) Fc receptor binding to membrane bound antigens

B) Something about membrane lipid rafts ??
C) Fas-Fas ligand induced apoptosis
D) Formation of membrane attack complex
E) Perforin mediated cytolysis
Different Types of cell killing
• Infected cells (most viral)
• Complement
• Pathways
• Alternate pw (tick over)
• Classical pw (via ab, C1q)
• Lectin pw (MBL, Ficolins)
• MAC  membrane damage + dies
• Fas-FasL
• Pathways (CTL-CD8, NK)
• Signal transduction  caspases -> apoptosis
• Perforin
• Pathway (CTL-CD8, NK)
• Pore -> cell swells + lyse / granzyme (packaged with perforin) ->
activate caspase -> apoptosis
2011A- Question 32
Which of the following best describes the method by which
NK cells kill virally infected cells?
 
A. Complement activation
 
B. Activation of virus specific B cells
 
C. Lysis of cells that have reduced MHC expression
 
D. Direct binding to highly conserved virus structures
 
E. Opsonisation of virus particles
Mechanism of NK cell killing
• A) classica pathways (ab), alternatve pw (tickover), lectin
pw (PAMP)
• B) T cells do that
• C) Yes. Via perforin/granzymes
• D) NK cells attaches viral particles on host cells via ab
linked with Fc receptor
• E) This is the role of antibody, not a killing mechanism
NK cells
• Large granular lymphoid cells
• ~5-15% human PBL
• ~2-3% mouse spleen cells
• Non MHC dependent cytotoxicity
• standard targets - K562 for human
• Produce lots of IFNγ, TNFα
• CD3- CD56+ CD16+ (human)
Cytotoxic T cells and NK cells

Cytotoxic T cells NK cells

• Antigen specific • Antigen non-specific
• MHC-restricted • MHC non-restricted
• Requires priming • Priming not required
(takes days to (rapid response,
respond) hours)
• Memory • No memory
NK killing mechanisms
Direct ADCC TRAIL TNFα
cytotoxicity (Antibody Dependent (TNF-Related
Cell Mediated Apoptosis-
Cytotoxicity) Inducing Ligand)

NK NK NK NK

CD16

target target target target

Acknowledgements

• Dr S Campbell

• Dr K Nichols

• Dr E Lim
Cryoglobulins