Path - Immunology Flashcards

1
Q
Investigations show:
ANA+ve
Anti-dsDNA+ve
Low C3 and C4
High ESR
Negative results for:
Ro, La, Sm, RNP
SCL70
Centromere
Jo-1

What is the most likely diagnosis?

A. CREST syndrome
B. Systemic lupus erythematosus
C. Polyangitis with granulomatosis
D. Dermatomyositis
E. Sjogren's syndrome
A

B. Systemic lupus erythematosus

A positive anti-nuclear antibody (ANA) test is a generic indicator of autoimmune disease, and so is not very helpful in narrowing down the options here. However, anti-double stranded DNA (Anti-dsDNA) antibodies are extremely specific for systemic lupus erythematosus (SLE), and so are the only result you strictly need to get the right answer here. Depletion of C3 and C4 gives an idea of how severe the disease is, as although C4 will be depleted in any active SLE, depleted C3 indicates severe disease. High ESR is a very generic marker of inflammation.

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2
Q

Which option best defines auto-inflammatory disease?

A. Aberrant T cell and B cell responses in primary and secondary lymphoid organs lead to breaking of tolerance with development of immune reactivity towards self-antigens
B. Hypersensitivity of the immune system towards otherwise harmless antigens which results in both chronic inflammation and acute episodes
C. Local factors at sites predisposed to disease lead to activation of innate immune cells such as macrophages and neutrophils, with resulting tissue damage
D. Mutations/polymorphisms in genes encoding proteins involved in innate and adaptive T cell function.
E. IgE-mediated local inflammation as a result of cross-linking and subsequent mast cell degranulation

A

C. Local factors at sites predisposed to disease lead to activation of innate immune cells such as macrophages and neutrophils, with resulting tissue damage

The difference between auto-inflammatory and auto-immune is essentially that auto-inflammatory involves the innate immune system, and auto-immune involves the adaptive immune system. As a result, auto-immune diseases are often more systemic than auto-inflammatory diseases, and have associated antibodies.

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3
Q

Which of the following mutations is present in Familial Mediterranean Fever?

A. Loss of function in Pyrin-Marenostrin (MEFV gene)
B. Gain of function in Pyrin-Marenostrin (MEFV gene)
C. Loss of function in Cryopyrin (NALP3 gene)
D. Gain of function in Cryopyrin (NALP3 gene)
E. Mutation of TNF receptor

A

A. Loss of function in Pyrin-Marenostrin (MEFV gene)

The Pyrin-Marenostrin protein acts as a negative regulator within the inflammasome: a complex responsible for activation of inflammatory responses. The inflammasome complex receives input from Pyrin-Manenostrin (negative regulator) and Cryopyrin (positive regulator which reacts to inflamamtory triggers e.g. toxins, pathogens, urate), which then influences activation of apoptosis-associated speck-like proteins (ASC) and Procaspase 1. This then influences expression of IL-1 and NF-kB. It’s worth looking at diagrams for the inflammasome complex.

A loss of function mutation in the Pyrin-Manenostrin gene (MEFV) leads to Mediterranean fever.

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4
Q

Which of the following is not a feature of Familial Mediterranean Fever?

A. Peritonitis and arthritis
B. Periodic fevers lasting 48-96 hours
C. Haemoptysis from alveolar damage
D. Pericarditis or pleuritis causing chest pain
E. Long term dysfunction in the kidneys and liver from Serum Amyloid A deposition

A

C. Haemoptysis from alveolar damage

Familial Mediterranean Fever is a monogenic disease characterised by ‘attacks’ which feature periodic fevers lasting between 48-96 hours in conjunction with inflammation leading to peritonitis, pericarditis, pleuritis, arthritis, and rash. Features may be present in a variety of combinations, making diagnosis tricky.

During inflammatory attacks, the liver produces various acute-phase proteins including Serum Amyloid A, which then deposits in organs, particularly the kidneys, liver and spleen. Deposition of these proteins leads to formations of oligomers and eventually fibrils, which are toxic to the organs in which they deposit. Management of these patients therefore focuses on limiting the number of attacks they have using Colchicine, which disrupts neutrophil migration and chemokine secretion. If Colchicine doesn’t work, Etanercept (TNF alpha inhibitor) or Anakinra (IL-1 antagonist) may be used.

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5
Q

Match each lettered disease with the appropriate numbered description

A. APECED
B. IPEX
C. ALPS
D. Familial Mediterranean Fever

  1. Single gene mutation of the MEFV gene and affecting the inflammasome complex, resulting in recurrent episodes of serositis
  2. Mutation within the Fas pathway associated with lymphocytosis, lymphomas and auto-immune cytopenias
  3. Single gene mutation involving FOXp3 resulting in abnormality of T reg cells
  4. A defect in the AIRE gene leading to a lack of expression of self-antigens in the thymus, which results in survival of autoreactive lymphocytes
A

Each disease is a monogenetic cause of autoimmune or auto-inflammatory (Familial Mediterranean Fever) disease:

APECED - A defect in the AIRE gene leading to a lack of expression of self-antigens in the thymus, which results in survival of autoreactive lymphocytes

IPEX - Single gene mutation involving FOXp3 resulting in abnormality of T reg cells

ALPS - Mutation within the Fas pathway associated with lymphocytosis, lymphomas and auto-immune cytopenias

Familial Mediterranean Fever - Single gene mutation of the MEFV gene and affecting the inflammasome complex, resulting in recurrent episodes of serositis

Auto-immune polyendocrinopathy-candidiasis-ectodermal dystrophy syndrome: APECED
APECED is caused by a defect in the auto-immune regulator gene (AIRE). The AIRE gene transcribes a transcription factor which is able to transcribe any other gene. This is crucial in the thymus where AIRE serves to produce self-antigens to identify lymphocytes which would be self-reactive in circulation, which are then apoptosed. IF this fails, self-reactive lymphocytes are released into circulation resulting in widespread autoimmunity.

Immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome: IPEX
The FOXp3 gene is important for the development of Treg cells, which normally function to negatively regulate autoreactive B-cells. Mutations in FOXp3 lead to dysfunctional Treg cells, and dysregulated B-cell responses.

Auto-immune lymphoproliferative syndrome: ALPS
The FAS pathway usually functions to trigger apoptosis. Mutations in the FAS pathway leads to survival of lymphocytes after infections that have been cleared. The result is chronic lymphocytosis, auto-immunity, and an increased incidence of lymphoma. The manifestation of the disease is fairly heterogenous as it may be caused my multiple mutations within the FAS pathway.

Familial Mediterranean Fever
Familial Mediterranean Fever is a monogenic disease characterised by ‘attacks’ which feature periodic fevers lasting between 48-96 hours in conjunction with inflammation leading to peritonitis, pericarditis, pleuritis, arthritis, and rash. Features may be present in a variety of combinations, making diagnosis tricky.

During inflammatory attacks, the liver produces various acute-phase proteins including Serum Amyloid A, which then deposits in organs, particularly the kidneys, liver and spleen. Deposition of these proteins leads to formations of oligomers and eventually fibrils, which are toxic to the organs they deposit in. Management of these patients therefore focuses on limiting the number of attacks they have using Colchizine, which disrupts neutrophil migration and chemokine secretion. If Colchizine doesn’t work, Etanercept (TNF alpha inhibitor) or Anakinra (IL-1 antagonist) may be used.

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6
Q

A mutation within which gene increases the risk of Crohn’s disease?

A. TNF-alpha
B. Cryopyrin
C. TGF-beta
D. FASL
E. NOD 2
A

E. NOD 2

This gene is only present in ~1/3 of Crohn’s patients but is associated with the disease, especially if there are two copies present.

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7
Q

Match the lettered polymorphisms with the numbered diseases they are associated with

A. HLA DR3
B. HLA B27
C. HLA DR15
D. HLA DR 4
E. Both HLA DR3 and DR4
  1. Goodpasture’s disease
  2. Rheumatoid arthritis
  3. Type I Diabetes Mellitus
  4. Ankylosing spondylitis
  5. Graves’ disease, SLE
A
HLA DR3 - Graves' disease, SLE
HLA B27 - Ankylosing spondylitis
HLA DR15 - Goodpasture's disease
HLA DR 4 - Rheumatoid arthritis
Both HLA DR3 and DR4 - Type I Diabetes Mellitus

HLA associations are most common in polygenic autoimmune diseases, which all of the above are (apart from ankylosing spondylitis, which falls under mixed pattern disease).

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8
Q

Where is inflammation mostly enhanced in ankylosing spondylitis?

A. Areas of high friction between vertebra and cartilage
B. Areas of bone-bone contact
C. Areas where there are high tensile forces
D. Within small joints in the feet and ankles
E. Within small joints in the hands and wrists

A

C. Areas where there are high tensile forces

Enthesitis is a classic feature of ankylosing spondylitis, and occurs where tendons or ligaments insert into bone, which are points of high tensile stress.

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9
Q

Match the lettered diseases with the numbered Gell and Coombs reaction classification

A. Eczema and anaphylaxis
B. Contact dermatitis and Type I Diabetes Mellitus
C. SLE and Rheumatoid arthritis
D. Goodpasture’s disease and Pemphigus Vulgaris

  1. Type I
  2. Type II
  3. Type III
  4. Type IV
A

Eczema and anaphylaxis - Type I
Contact dermatitis and Type I Diabetes Mellitus - Type IV
SLE and Rheumatoid arthritis - Type III
Goodpasture’s disease and Pemphigus Vulgaris - Type II

The Gel and Coombs classification divides all hypersensitivity reactions into four groups:
Type I - IgE mediated (classic allergy)
Type II - antibody reacts with cellular antigen to exert effect
Type III - also antibody-mediated, but the antibody reacts with soluble antigen to form an immune complex which is deposited and leads to further damage
Type IV - delayed-type hypersensitivity (t-cell mediated)

NB: Rheumatoid arthritis may be classified as either type III or IV because it may be immune complex or T-cell mediated

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10
Q

Match the lettered organ-specific disease with the corresponding numbered antibody type

A. Goodpasture's disease
B. Myasthenia Gravis
C. Graves' disease
D. Pernicious anaemia
E. Type I Diabetes Mellitus
F. Hashimoto's thyroiditis
G. Rheumatoid arthritis
  1. Anti-GAD
  2. Anti-thyroglobulin
  3. Anti-basement membrane
  4. Anti-intrinsic factor
  5. Anti-acetylcholine receptor
  6. Anti-cyclic citrullinated peptide
  7. Anti-TSH receptor
A

Goodpasture’s disease - Anti-basement membrane
Myasthenia Gravis - Anti-acetylcholine receptor
Graves’ disease - Anti-TSH receptor
Pernicious anaemia - Anti-intrinsic factor
Type I Diabetes Mellitus - Anti-GAD
Hashimoto’s thyroiditis - Anti-thyroglobulin
Rheumatoid arthritis - Anti-cyclic citrullinated peptide

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11
Q

Which marker is specifically associated with autoimmune connective tissue diseases?

A. Perinuclear anti-neutrophil cytoplasmic antibodies
B. Anti-nuclear antibodies
C. Raised CRP and ESR
D. Rheumatoid factor
E. Anti-neutrophil cytoplasmic antibodies

A

B. Anti-nuclear antibodies

As a rule: ANAs = autoimmune connective tissue disease, and ANCAs = small-vessel vasculitides

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12
Q

Which pattern of antibody deposition seen on indirect immunofluorescence using hep 2 cells (human epithelial cells used to look for autoimmune conditions) is characteristic of SLE?

A. Speckled deposition
B. Homogenous pattern
C. Smooth deposition along the basement membrane
D. Lightning bolt pattern
E. A granular 'lumpy bumpy' pattern
A

B. Homogenous pattern

Homogenous antibody staining almost always indicates the presence of anti-dsDNA antibodies, which are 95% specific for SLE, with a 60-70% sensitivity

Although the granular ‘lumpy bumpy’ pattern does indicate SLE, it is seen on staining of kidney samples with fluorescent conjugated anti human immunoglobulin. Therefore this pattern is not seen on indirect immunofluorescence of Hep 2 cells.

Staining of lupus nephritis classically reveals a granular ‘lumpy bumpy’ pattern which is the result of immune complex deposition (as SLE is a type III hypersensitivity reaction).

Smooth antibody deposition along the basement membrane is indicative of Goodpasture’s disease - the basement membrane is the giveaway.

Speckled staining indicates the presence of antibodies directed against ribonucleoproteins - Ro, La, Sm, or RNP. Ro and La are associated with Sjogren’s syndrome (autoimmune destruction of exocrine glands leading to dry mouth with associated infections, dry eyes, and dyspareunia from lack of vaginal secretions). Sm (Smith) antibodies are extremely specific for SLE.

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13
Q

Which of the following is not a feature of anti-phospholipid syndrome?

A. Recurrent arterial thromboses
B. Serositis
C. A history of recurrent miscarriages
D. Thrombocytopenia
E. Recurrent venous thromboses
A

B. Serositis

Antiphospholipid syndrome may occur in the absence of background disease, but is often associated with other autoimmune disease - classically SLE. Antiphospholipid syndrome can be difficult to detect as its symptoms can be generic, but it causes complications in pregnancy (pre-eclampsia, intra-uterine growth restriction, pre-term delivery, miscarriage) which, in combination with an increased risk of both venous and arterial clotting, can be used to identify the disease.

Thrombocytopenia is a non-specific finding in antiphospholipid syndrome, but serositis does not occur (though it may occur in concurrent SLE).

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14
Q

Which of the following options would be appropriate to test for antiphospholipid syndrome?

A. Anti-thyroid peroxidase and anti-thyroglobulin
B. Anti-Smith and Anti-dsDNA
C. ESR and platelet count
D. Schirmer’s test
E. Anti-cardiolipin and lupus anticoagulant

A

E. Anti-cardiolipin and lupus anticoagulant

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15
Q

The presence of which of the following features would indicate a diagnosis of diffuse rather than limited cutaneous systemic sclerosis?

A. Telangectasia
B. Primary pulmonary hypertension
C. Sclerodactyly
D. Skin tightening on the trunk
E. Calcinosis
A

D. Skin tightening on the trunk

Limited cutaneous systemic sclerosis, by definition, only involves skin on the hands and forearms, and around the mouth. If involvement progresses beyond the forearms, it is diffuse systemic sclerosis.

Limited cutaneous systemic sclerosis is the same thing as CREST syndrome, which is an acronym:
C - Calcinosis
R - Raynaud's phenomenon
E - Esophageal dysmotility
S - Sclerodactyly
T - Telangectasia

One of the most severe manifestations of CREST syndrome, which is not included in the acronym, is primary pulmonary hypertension.

Diffuse cutaneous systemic sclerosis is characterised by the presence of the CREST features, plus extensive GI involvement, renal impairment and/or crisis, and interstitial pulmonary disease. Furthermore, skin is not affected in CREST beyond the hands, forearms, and skin around the mouth; in diffuse cutaneous systemic sclerosis, the skin involvement progresses further than this.

The two diseases can also be distinguished using antibody tests:
CREST syndrome: anti-centromere antibodies
DIffuse cutaneous systemic sclerosis: anti-Scl70 antibodies (directed against topoisomerase enzyme)

NB: Scleroderma refers to both forms of systemic sclerosis

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16
Q

An 45 year-old woman presents with chronic muscle weakness. You notice a red rash over her eyelids and the knuckles of her hands. ANA tests reveal a raised anti-Jo1 titre.

What is the most likely diagnosis?

A. Sjogren's syndrome
B. Psoriatic arthritis
C. Dermatomyositis
D. SLE
E. Polymyositis
A

C. Dermatomyositis

Chronic muscle weakness in this case arises from myositis. This is confirmed by the presence of anti-Jo1 antibodies, which are directed against tRNA synthetase enzymes in the cytoplasm. The presence of anti-Jo1 antibodies doesn’t distinguish between polymyositis and dermatomyositis, but the presence of the skin rash (the rash over the eyelids is classic and is known as a heliotrope rash) indicates dermatomyositis.

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17
Q

The presence of cANCA antibodies would most strongly suggest which disease?

A. Granulomatosis with polyangitis
B. Microscopic polyangitis
C. Eosinophilic granulomatosis with polyangitis
D. Sarcoidosis
E. Sjogren's disease
A

A. Granulomatosis with polyangitis

ANCA is antibodies activating neutrophils
cANCA are associated with GPA (formerly known as Wegener’s). GPA is a small-vessel vasculitis characterised by upper respiratory, lower respiratory, and renal involvement. Questions may ask you to differentiate between GPA and Goodpasture’s as both affect the lungs and kidneys, but only GPA affects the upper respiratory system; a question will often include nosebleeds to point towards GPA.

There are two other small-vessel vasculitides associated with ANCA: microscopic polyangitis, and eosinophillic GPA. However, both of these are associated with perinuclear ANCA (pANCA) rather than cANCA. cANCA are directed against proteinase 3 in neutrophils, and are very sensitive for GPA, whereas pANCA are directed at myeloperoxidase and are less sensitive and specific for eGPA and microscopic polyangitis

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18
Q

A young child presents with recurrent infections. An FBC shows a high neutrophil count, but no abscess formation.

What is the most likely diagnosis?

A. Chronic granulomatous disease
B. Classical NK cell deficiency
C. Interferon gamma receptor deficiency
D. Kostmann syndrome
E. Leuococyte adhesion deficiency
A

E. Leukocyte adhesion deficiency

Caused by CD18 deficiency - a subunit of beta 2 integrin. Neutrophils cannot adhere to endothelium and exit blood stream

19
Q

A child presents with recurrent infections, hepatosplenomegaly, and an abnormal (non-fluorescent) dihydrorhodamine test.

What is the most likely diagnosis?

A. Chronic granulomatous disease
B. Classical NK cell deficiency
C. Interferon gamma receptor deficiency
D. Kostmann syndrome
E. Leuococyte adhesion deficiency
A

A. Chronic granulomatous disease

Chronic granulomatous disease is caused by a failure of neutrophil oxidative killing mechanisms. One of the components of NADPH oxidase is absent, leading to persistent neutrophil and macrophage accumulation and granuloma formation. A negative dihydrorhodamine test is indicative.

20
Q

A baby presents with recurrent infections. An FBC shows no neutrophils.

What is the most likely diagnosis?

A. Chronic granulomatous disease
B. Classical NK cell deficiency
C. Interferon gamma receptor deficiency
D. Kostmann syndrome
E. Leuococyte adhesion deficiency
A

D. Kostmann syndrome

Kostmann syndrome is another name for severe congenital neutropenia. Other causes of congenital neutropenia include reticular dysgenesis (which causes severe SCID) and cyclic neutropenia

21
Q

A 20 year-old man presents with cough and fever. Pneumonia is diagnosed, and the organism cultured is an atypical mycobacterium. An FBC is normal.

What is the most likely diagnosis?

A. Chronic granulomatous disease
B. Classical NK cell deficiency
C. Interferon gamma receptor deficiency
D. Kostmann syndrome
E. Leuococyte adhesion deficiency
A

C. Interferon gamma receptor deficiency

The interferon gamma receptor is important in activating production of IL-12, which stimulates TNF production, oxidative killing, and control of mycobacterial infections.

22
Q

A child presents with a widespread vesicular rash. Investigation reveals both severe chicken pox and disseminated cytomegalovirus infection.

What is the most likely diagnosis?

A. Chronic granulomatous disease
B. Classical NK cell deficiency
C. Interferon gamma receptor deficiency
D. Kostmann syndrome
E. Leuococyte adhesion deficiency
A

B. Classical NK cell deficiency

23
Q

A patient presents with fatigue, jaundice and pruritis. Blood tests reveal a high titre of anti-mitochondrial antibodies.

What is the most likely diagnosis?

A. Autoimmune hepatitis
B. Primary sclerosing cholangitis
C. Granulomatosus with polyangitis
D. Microscopic polyangitis
E. Primary biliary cholangitis
A

E. Primary biliary cholangitis

Anti-mitochondrial antibodies are a sensitive indicator for primary biliary cholangitis (formerly known as primary biliary cirrhosis) which is an autoimmune disease most prevalent in women, characterised by progressive destruction of the small bile ducts. PBC usually presents with fatigue, jaundice, and pruritis

24
Q

A patient presents to her GP with fatigue. A panel of blood tests reveal the following abnormalities:

Hb - 10.7d/dL
MCV - 78fL
Ca - 2.00umol/L
PTH - 14 (1.1-6.8pmol/L)
ALP - 400U/L

What is the most likely diagnosis?

A. Ulcerative colitis
B. Pancreatic disease
C. Crohn's disease
D. Post-infective malabsorption
E. Coeliac disease
A

E. Coeliac disease

These test results reveal both a microcytic anaemia and a secondary hyperparathyroidism (indicating vitamin D deficiency). Microcytic anaemia is usually caused by either thalassaemia trait or iron deficiency (though can sometimes be caused by anaemia of chronic disease). Put together, these results indicate a malabsorptive issue. The most likely of the options to cause malabsorption of vitamin D and iron is coeliac disease. Whilst all the options can cause malabsorption, coeliac disease most commonly causes it.

25
Q

Which option is used as the definitive investigation for diagnosing coeliac disease?

A. Proximal duodenal biopsy
B. Anti-TTG antibodies
C. Anti-endomysial antibodies
D. Distal duodenal biopsy
E. Colonoscopy with visual inspection only
A

D. Distal duodenal biopsy

Although coeliac disease can all but be confirmed with antibody tests, duodenal biopsy is the gold standard, and should be performed at the time of diagnosis so that a baseline of the patient’s disease is established.

Anti-endomysial and anti-tTG (tissue transglutaminase) tests are very specific (~95%) for coeliac disease and very sensitive, with anti-tTG being a bit more sensitive. Gluten is broken down into gliadin peptides, which is recognised by CD4+ cells which then activate B-cells to produce IgA antibodies against it. tTG enzymes de-amidate gliadin to form the peptides which are taken up by APCs. Since tTG forms a complex with gliadin peptides, it is also taken up by APCs, and presented to CD4+ cells, thereby triggering IgA anti-tTG antibody formation.

The anti-endomysial antibody test is almost the same thing as the anti-tTG test; these are antibodies still directed against tTG, but against enzyme present in the endomysium (a layer of connective tissue ensheathing a muscle fiber).

The biopsy taken must be distal because the proximal part of the duodenum is filled with Brunner’s glands which, if sampled, may distort the villous anatomy which is what must be analysed for a diagnosis.

26
Q

Which of the following histological findings would suggest coeliac disease?

A. Presence of anti-tTG antibodies
B. Mucosal ulcers, depletion of goblet cells, and crypt abscesses
C. Crypt hyperplasia with reduced villous height and increased intra-epithelial lymphocyte infilitration
D. Transmural non-caseating granulamtous inflammation
E. Lead pipe mucosa

A

C. Crypt hyperplasia with reduced villous height and increased intra-epithelial lymphocyte infiltration

Anti-tTG antibodies do strongly indicate coeliac disease, but are not a histological finding.

Mucosal ulcers, depletion of goblet cells, and crypt abscesses are histological signs of ulcerative colitis.

Transmural non-caseating granulamtous inflammation are histological signs of Crohn’s disease

Anti-tTG antibodies do strongly indicate coeliac disease, but are not a histological finding.

Lead pipe mucosa is a radiographic sign of ulcerative colitis, where the colon loses its haustral folds.

27
Q

A 60 year old female develops hypotension and an uriticarial skin rash whilst under general anaesthesia.

What is the most appropriate test to diagnose anaphylaxis?

A: Skin prick
B. Drug challenge
C. Blood histamine
D. Serial mast cell tryptase
E. Urine prostaglandin D2
A

D. Serial mast cell tryptase

Tryptase is contained within mast cells and is released when they degranulate (which is how they cause the features of anaphylaxis). Measurement of tryptase can help confirm anaphylaxis in unclear cases, and can be used to monitor its progression over several hours.

28
Q

Which of the following statements is true?

A. Cutaneous exposure to allergen promote immune tolerance
B. IgE degranulation of mast cells promotes delayed clinical responses
C. IL-4 plays a crucial role in development of Th2 immune responses
D. Targeted drug therapy against IgE has not been useful in the treatment of atopic asthma
E. Secretion of IL-22 by epithelial cells induces Th2 immune responses

A

C. IL-4 plays a crucial role in development of Th2 immune responses

29
Q

Which of the following describes an IgE-mediated mast cell degranulation?

A. A woman is woken up in the early hours of the morning by her SOB in reaction to what she ate for dinner.
B. A patient is given oral antibiotics for a standard community-acquired pneumonia, and promptly develops a rash and vomiting
C. A known hypertensive presents to A&E with tongue and lip swelling that is beginning to affect his breathing. His notes show he recently started ACE inhibitors.
D. A patient undergoes a skin prick test and all the pricks are positive, even the negative control
E. A known asthmatic takes aspirin for a headache, and develops acutely worse shortness of breath

A

B. A patient is given oral antibiotics for a standard community-acquired pneumonia, and promptly develops a rash and vomiting

30
Q

Which antibodies are associated with each of the following conditions?

Primary sclerosing cholangitis, Churg-Strauss syndrome, microscopic polyangitis
Polyangitis with granulomatosis
Primary biliary cirrhosis
Diffuse scleroderma
CREST syndrome
Sjogren's syndrome
SLE
Rheumatoid arthritis
Goodpasture's syndrome
Antiphospholipid syndrome
A

pANCA: primary sclerosing cholangitis, Churg-Strauss syndrome, microscopic polyangitis
cANCA: Polyangitis with granulomatosis
Anti-mitochondrial: primary biliary cirrhosis
Anti-Scl70: diffuse scleroderma
Anti-centromere: CREST syndrome
Anti-Rho and Anti-La: Sjogren’s syndrome
Anti-dsDNA: SLE
Anti-Smith: SLE
Anti-CCP: Rheumatoid arthritis
Anti-glomerular basement membrane: Goodpasture’s syndrome
Anti-smooth muscle: autoimmune hepatitis
Lupus anticoagulant: antiphospholipid syndrome
Anti-cardiolipin: antiphospholipid syndrome

31
Q

Which HLA subtypes are routinely analysed for mismatches in transplantation?

A

A, B, and DR

32
Q

Antibody-mediated inhibition of the ADAMTS-13 enzyme would result in which disease?

A. Autoimmune haemolytic anaemia
B. Thrombotic thrombocytopenic purpura
C. Immune thrombocytopenic purpura
D. Polyarteritis nodosa
E. Antiphospholipid syndrome
A

B. Thrombotic thrombocytopenic purpura

TTP is caused by antibodies which prevent the ADAMTS-13 enzyme from working. This enzyme usually breaks up large multimers of VwF into smaller molecules. If VwF multimers are not broken up, they are more prone to clotting which causes all the symptoms of TTP. There may also be an inherited deficiency of ADAMTS-13.

TTP is defined by a pentad that rarely occurs together in reality, but does in exam questions:
Fever
Confusion
Renal failure
Anaemia (MAHA)
Thrombocytopenia
33
Q

Match each clinical description to the corresponding innate immune deficiency:

A. Kostmann syndrome
B. Leukocyte adhesion deficiency
C. Chronic granulomatous disease
D. Interferon gamma receptor deficiency
E. NK cell deficiency
  1. Increases risk of severe disseminated viral infection
  2. Causes recurrent abscess formation and infection because phagocytes can’t kill pathogens, indicated by an abnormal dihydrorhodamine test
  3. Particularly increases risk of atypical mycobacterium infection
  4. A congenital absence of neutrophils
  5. Indicated by recurrent and persistent infections, with a high neutrophil count and no abscess formation
A
  1. Increases risk of severe disseminated viral infection - E. NK cell deficiency
  2. Causes recurrent abscess formation and infection because phagocytes can’t kill pathogens, indicated by an abnormal dihydrorhodamine test - C. Chronic granulomatous disease
  3. Particularly increases risk of atypical mycobacterium infection - D. Interferon gamma receptor deficiency
  4. A congenital absence of neutrophils - A. Kostmann syndrome
  5. Indicated by recurrent and persistent infections, with a high neutrophil count and no abscess formation - B. Leukocyte adhesion deficiency

NK cells are an important innate immune response factor for dealing with viral infections, so deficiency leads to disseminated infections e.g. herpes encephalitis, severe Varicella-Zoster infection

Chronic granulomatous disease is caused by a deficiency in the NADPH oxidative killing pathway. This means neutrophils and macrophages cannot kill pathogens, so infections persist and there is abscess formation as more and more phagocytes are recruited to try and kill pathogens.

Leukocyte adhesion deficiency results in an inability of neutrophils to adhere to and exit blood vessel walls to reach infected tissue. This causes recurrent infections without abscesses, with a high blood neutrophil count.

34
Q

Match each clinical description to the corresponding complement immune deficiency:

A. C1q deficiency
B. C3 deficiency with nephritic factor
C. C7 deficiency

  1. Associated with SLE
  2. Increased vulnerability to encapsulated bacteria, especially N. meningitidis
  3. Associated with membranoproliferative glomerulonephritis and abnormal fat distribution
A
  1. Associated with SLE - A. C1q deficiency
  2. Increased vulnerability to encapsulated bacteria, especially N. meningitidis - C. C7 deficiency
  3. Associated with membranoproliferative glomerulonephritis and abnormal fat distribution - B. C3 deficiency with nephritic factor

SLE is often associated with depletion of the early classical complement pathway (C1, C3, C4).

Deficiency in the common pathway (C5-C9) is strongly associated with vulnerability to encapsulated bacteria. There may well be a family history of death at a young age from infection.

Nephritic factor is antibodies against C3 convertase - an important enzyme in complement manufacturing. Presence of C3 depletion and nephritic factor is linked to glomerulonephritis.

35
Q

Match each clinical description to the corresponding T-cell immune deficiency:

A. 22q11.2 deletion/ DiGeorge syndrome
B. Bare lymphocyte syndrome type 2
C. X-linked SCID

  1. Isolated deficiency of CD4 T-cells and IgG due to lack of MHC expression
  2. Features absence of all T-cells, NK cells, and IgG, and renders B-cells immature and non-functional
  3. Often also features hypocalcaemia, cleft palate, congenital heart disease
A
  1. Isolated deficiency of CD4 T-cells and IgG due to lack of MHC expression - B. Bare lymphocyte syndrome type 2
  2. Features absence of T-cells and IgG, and renders B-cells immature and non-functional - C. X-linked SCID
  3. Often also features hypocalcaemia, cleft palate, congenital heart disease - A. 22q11.2 deletion/ DiGeorge syndrome

Bare lymphocyte syndrome type 2 is caused by a lack of MHC II expression on T-cells. As a result, these cells are destroyed in the thymus because they won’t bind to MHC, which results in low T-cells.

X-linked SCID is a recessive disease and is the most common form of severe combined immunodeficiency (SCID). It is caused by a mutation which makes the patient unable to make a variety of interleukins. These interleukins are crucial for lymphocyte growth and differentiation. In the absence of these interleukin signals, the lymphocytes and NK cells never proliferate and mature.

22q11.2 deletion syndromes (usually synonymous with DiGeorge syndrome) cause a variety of abnormalities from forehead to chest including: hypoparathyroidism, congenital heart defects, cleft palate, abnormal facies, and poor thymic development. However the impact on immunity is not as severe as other syndromes named here and improves with age.

NB: If T-cells are low, IgG will also be low and B-cells will not function properly. This is because CD4+ cells are crucial for maturing B-cells and stimulating them to produce IgG. Hence an absence of T-cells causes B-cell dysfunction and IgG deficiency

36
Q

Match each description to the corresponding B-cell immune deficiency:

A. Hyper IgM syndrome
B. Bruton’s X-linked Agammaglobulinaemia
C. IgA deficiency
D. Common variable immunodeficiency

  1. Absence of B-cells and all IgM, normal T-cells
  2. Absence of IgG, and an association with autoimmune disease e.g. atypical SLE
A
  1. Absence of B-cells and all IgM, normal T-cells - B. Bruton’s X-linked Agammaglobulinaemia
  2. Absence of IgG, and an association with autoimmune disease e.g. atypical SLE - D. Common variable immunodeficiency

Bruton’s X-linked Agammaglobulinaemia is a cause of SCID. Common variable immunodeficiency is a poorly understood and heterogeneous disease that has an autoimmune association.

The other two important B-cell immune deficiencies are Hyper IgM syndrome and IgA deficiency. However both are fairly self-explanatory. It is worth noting that IgA deficiency is associated with allergy, and hyper IgM syndrome results from a block in class switching so all antibodies are IgM.

37
Q

Which of the following is not associated with SLE?

A. Anti-Sm antibodies
B. Homogenous staining ANAs
C. Elevated C4 levels
D. Nephritis
E. A malar rash
A

C. Elevated C4 levels

C4 will classically be depleted in SLE, as it causes activation of the classical complement system and depletion of its components. C4 will be depleted in most active disease, whereas C3 will only be depleted in a severe flare-up.

38
Q

Which enzyme in the prostaglandin production pathway do steroids act on?

A

Phospholipase A2

39
Q

Why do steroids cause a transient neutrophilia?

A

Because they decrease expression of adhesion factors on the endothelium, and block signals for phagocytes to move from the blood into tissues. This causes concentration of neutrophils within the blood.

40
Q

Which enzyme’s activity should be checked before starting azathioprine

A

Thiopurine methyltransferase (TPMT)

1 in 300 people have a polymorphism in this enzyme that makes them extremely susceptible to bone marrow suppression from azathioprine

41
Q

Which of the following drugs affects B cells more than T cells?

A. Mycophenolate mofetil
B. Azathioprine
C. Rituximab
D. Ciclosporin
E. Tacrolimus
A

C. Rituximab

All the other agents predominately affect T cells.

42
Q

Match each cell type to the appropriate description:

A. Neutrophils
B. NK cells
C. Dendritic cells
D. Macrophages

  1. Derived from monocytes and resident in peripheral tissues
  2. Polymorphonuclear cells capable of phagocytosing pathogens and killing by oxidative and non-oxidative mechanisms
  3. Lymphocytes that express inhibitory receptors capable of recognising HLA class I molecules and have cytotoxic capacity
  4. Immature cells are adapted for pathogen recognition and uptake whilst mature cells are adapted for antigen presentation to prime T cells
A
  1. Derived from monocytes and resident in peripheral tissues - D. Macrophages
  2. Polymorphonuclear cells capable of phagocytosing pathogens and killing by oxidative and non-oxidative mechanisms - A. Neutrophils
  3. Lymphocytes that express inhibitory receptors capable of recognising HLA class I molecules and have cytotoxic capacity - B. NK cells
  4. Immature cells are adapted for pathogen recognition and uptake whilst mature cells are adapted for antigen presentation to prime T cells - C. Dendritic cells
43
Q

Match each cell type to the appropriate description:

A. Th 1 cells
B. CD8+ cells
C. T follicular helper (Tfh) cells
D. T regulatory cells

  1. Express receptors that recognise peptides usually derived from intracellular proteins and expressed on HLA class I molecules
  2. Subset of lymphocytes that express Foxp3 and CD25
  3. Subset of cells that express CD4 and secrete IFN gamma and IL-2
  4. Play an important role in promoting germinal centre reactions and differentiation of B cells into IgG and IgA secreting plasma cells
A
  1. Express receptors that recognise peptides usually derived from intracellular proteins and expressed on HLA class I molecules - B. CD8+ cells
  2. Subset of lymphocytes that express Foxp3 and CD25 - D. T regulatory cells
  3. Subset of cells that express CD4 and secrete IFN gamma and IL-2 - A. Th 1 cells
  4. Play an important role in promoting germinal centre reactions and differentiation of B cells into IgG and IgA secreting plasma cells - C. T follicular helper (Tfh) cells