Immuno Flashcards
1
Q
A severe asthmatic presents to their GP for the third time in three years complaining of blocked sinuses. However, over the last 6 months, she has also had unintentional weight loss and reports intermittent fevers. She also has an indistinct erythematous macular rash on both her ankles.
A Full Blood Count reveals an eosinophilia (>10% of white blood cells).
What rare immunological condition may be responsible for her symptoms?
A
Eosinophilic Granulomatosis with Polyangiitis
Eosinophilic granulomatosis with Polyangiitis (EGPA) formerly known as Churg Strauss syndrome, is a small-medium vessel vasculitis associated with p-ANCA antibodies and eosinophilia.
Patients affected typically have severe allergies or sinus problems, which progress to severe asthma prior to the systemic vasculitis.
It is treated with corticosteroids.
2
Q
A 5 year old girl is seen by her GP. Her mother says she is unable to sleep at night as her knees, elbows and shoulders are very red and painful, especially to touch. Her mother has also noticed small bumps under her skin. She is currently pyrexic, but the mother says she is still recovering from a bad sore throat two weeks ago.
What is the likely diagnosis?
A
Acute Rheumatic Fever
Rheumatic fever is now a rare type II hypersensitivity reaction that may occur post-streptococcal infection.
The condition is diagnosed using Jones’ criteria:
Major criteria
Polyarthritis Carditis Subcutaneous nodules Erythema marginatum (Rash on the trunk/arms which spread outward. Worse with heat) Sydenham's chorea (Involuntary movements of the face and arms)
Minor criteria
Fever Arthralgia Raised ESR/CRP Leukocytosis
3
Q
What is the causative agent of Progressive Multifocal Leukoencephalopathy?
A
John Cunningham Virus
This rare complication of immunosuppression is a concern particularly with the monoclonal antibody natalizumab used in the treatment of relapsing remitting multiple sclerosis. The pathogenesis of the condition includes the uncovering of dormant JC (John Cunningham) Virus, which is normally suppressed by a functioning immune system.
4
Q
What monoclonal antibody targets IL-17 and is involved in the treatment of psoriasis, psoriatic arthritis and ankylosing spondylitis?
A
Secukinumab
Secukinumab is used in the treatment of psoriasis, psoriatic arthritis and ankylosing spondylitis. It is a monoclonal antibody that targets IL-17, binding to it, rendering it inert and marking it for clearance by phagocytic cells.
5
Q
What monoclonal antibody targets RANKL?
A
Denosumab
Denosumab targets RANKL and therefore prevents the development of osteoclasts. RANKL binds to the RANK receptor on osteoclast precursors and promotes cell differentiation into osteoclasts. Hence, inhibition of RANKL/RANK receptor interaction reduces bone turnover and may increase bone density.
6
Q
What disease is Tofacitinib used in?
A
Rheumatoid Arthritis
Tofacitinib is used in the treatment of rheumatoid arthritis, ulcerative colitis or psoriatic arthritis. It inhibits a tyrosine kinase (JAK) and reduces the expression of pro-inflammatory cytokines that are responsible for cellular damage.
7
Q
A 80 year old lady received 2 units of FFP 4 hours ago due to a severe nosebleed and an INR of 4.8 on admission. She takes wafarin for a metallic heart valve. Over the last hour, she is beginning to feel short of breath, especially when lying down. She is hypotensive at 65/40 and SpO2 of 94% on 5L/min O2. She is pyrexic at 37.8C. What complication of blood transfusion is she suffering from?
A
Transfusion Related Acute Lung Injury
Transfusion related acute lung injury (TRALI) is due to the presence of leukocyte antibodies causing white blood cells to aggregate in the pulmonary circulation as it passes through in the blood. The disease is characterised by acute onset pulmonary oedema, dyspnoea, severe hypoxaemia and hypotension. Treatment is usually supportive with a good resolution within 2 days. However, severe TRALI may lead to acute respiratory distress syndrome.
8
Q
What autoantibody is associated with Granulomatosis with Polyangiitis (Wegner’s Granulomatosis)?
A
Cytoplasmic Anti Neutrophil Cytoplasmic Antibody
Granulomatosis with polyangiitis (formerly Wegener’s Granulomatosis) is a C-ANCA associated small to medium vessel vasculitis.
It may present with sinus problems, nosebleeds, arthritis, conductive hearing loss or pulmonary nodules. However, it is most associated with a rapid, progressive crescentic glomerulonephritis.
9
Q
What is the target of the autoantibodies responsible for pemphigus vulgaris?
A
Cadherin
Type 2 Hypersensitivity is due to antibody directly binding to cells and tissues that leads to cell damage.
Examples include:
Pernicious anaemia (anti parietal cell antibodies) Graves' disease (anti-TSH receptor) Immune thrombocytopenic purpura (anti-platelet antibodies such as anti-glyoprotein IIb/IIIa) Goodpasture's syndrome (Anti-glomerular basement membrane antibodies [specifically anti-type IV collagen antibodies]) Haemolytic disease of the newborn (maternal IgG against fetal erythrocyte antigens) Pemphigus Vulgaris (anti-cadherin)
10
Q
What monoclonal antibody targets IL-23 and IL-12 and is used in the treatment of psoriasis or psoriatic arthritis?
A
Ustekinumab
Antibodies targeting IL-23 or IL-12 are used in the treatment of psoriasis or psoriatic arthritis. IL-23 is made up of the IL-12B subunit - hence why mAbs can target both antibodies. An example of this class of medication is ustekinumab.
11
Q
What intracellular pro-proliferative molecule does cyclosporine and tacrolimus inhibit?
A
Calcineurin
Medications that inhibit Calcineurin, a protein needed for T cell proliferation, include tacrolimus or cyclosporine. Side effects include renal damage, hypertension or in the case of cyclosporine, gingival hyperplasia.
12
Q
What type of vaccine is comprised of a polysaccharide bound to a immunogenic toxin?
A
Conjugate
There is a huge variability in pathogens.
Hence, in order to get the best possible immunity, vaccines vary as well.
There are a few main types of vaccines:
Live attenuated vaccines
These are avoided in pregnancy and immunocompromised patients.
Examples include:
BCG for TB, MMR, Yellow Fever
Subunit (recombinant) Vaccines
Typically for viruses.
The vaccine contains proteins found on the surface of the viruses in addition to an adjuvant. Examples include Hep B and HPV.
Conjugate vaccines
For encapsulated bacteria.
Consist of bacterial polysaccharides conjugated to an immunogenic toxin (diphtheria toxin).
Used for Haemophilus influenzae, meningococcus and pneumococcus.
Inactivated vaccines
These are vaccines where the pathogens have been rendered inert - usually by heat killing or formaldehyde.
Examples include the pertussis vaccine.
As the pathogen cannot replicate, it usually requires multiple booster shots to provide immunity.
13
Q
A 21 year old woman reports weight loss, tiredness, diarrhoea and non-bloody offensive smelling stools. She has had three chest infections requiring antibiotics in the last three years. Blood tests are ordered and reveals a hypochromic, microcytic anaemia with low ferritin. Anti-TTG and anti-endomysial antibodies are negative. There are normal levels of IgG, IgM and IgE. No IgA is found.
What is the most likely cause of her gastrointestinal symptoms?
A
Coeliac Disease
Particular caution should be noted in the diagnosis of coeliac disease, as the common autoantibodies that are used for diagnosis are of the type IgA (Anti-Endomysial and Anti-Tissue Transglutaminase).
Hence, in IgA deficiency (1 in 600 people), they may be falsely negative.
IgA levels should always be assessed at the same time when assessing for coeliac disease.
14
Q
A 31 year old accountant reports an itchy rash over the trunk and back that has been present for the last 7 weeks. On examination, there are smooth erythematous papules with evidence of excoriation. She reports no association with food, time and has changed her washing powder to a “Non-Bio” formulation.
What condition is she suffering from?
A
Chronic Urticaria
Chronic urticaria is urticaria (hives) which is present for at least 6 weeks and has no obvious trigger.
It is difficult to treat and may be related to other conditions, such as dermatographia.
Treatment is with antihistamines.
15
Q
A 74 year old woman presents to the GP with of loss of vision and a severe headache around the sides of their head. In addition, she reports feeling generally tired and has trouble “getting going” in the morning.
An urgent referral to A&E is made. She treated urgently by the team and is admitted to hospital after blood results showed an elevated CRP.
24 hours after admission, a new set of bloods showed a moderate leukocytosis, which was not present on the previous bloods.
In the absence of other symptoms, what is the most likely cause of the leukocytosis?
A
Corticosteroids
Steroid Side Effects
BECLOMETHASONE
Buffalo hump
Easy bruising
Cataracts
Larger appetite
Obesity
Moonface
Euphoria
Thin arms & legs
Hypertension/ Hyperglycaemia
Avascular necrosis of femoral head
Skin thinning
Osteoporosis
Negative nitrogen balance
Emotional lability
In addition, there may be a transient neutrophilia. Approximately 50% of neutrophils in blood are “stuck” to the walls of blood vessels. Steroids inhibit this adhesion and they subsequently circulate in blood.
16
Q
What is the primary target of the antibody C-ANCA?
A
Proteinase 3
Antineutrophil cytoplasmic antibodies are implicated in pauci-immune conditions such as granulomatosis with polyangiitis or goodpasture’s disease.
Their presence suggests a breakdown in immune tolerance as the immune system has become sensitised to intracellular antigens.
p-ANCA = Myeloperoxidase = UC, Eosinophilic Granulomatosis with Polyangiitis, Primary Sclerosing Cholangitis or Microscopic Polyangiitis
c-ANCA = Proteinase-3 = Granulomatosis with polyangiitis (Wegner’s)
17
Q
Mutation in what cell surface receptor may confer immunity from HIV?
A
CCR5
HIV is made up of two main viral envelope proteins:
gp120 - This receptor is responsible for initial binding to CD4 and a co-receptor, such as the CCR5 receptor.
gp41 - Binding of gp120 exposes gp41.
gp41 then leads to fusion with the host cell membrane and viral entry into the cell.
Mutations in the CCR5 receptor confer immunity against HIV as the virus cannot enter cells to replicate.
18
Q
What are the pathogenic antibodies in bullous pemphigoid?
A
Anti-Hemidesmosome
19
Q
HIV belongs to what family of viruses?
A
Retroviridae
HIV is a sexually-transmitted retrovirus.
It expresses an exceedingly error prone reverse transcriptase.
Reverse transcriptase synthesises DNA from viral RNA.
This viral DNA is then incorporated into the cell’s nucleus for the lifetime of the cell. As part of normal cellular protein synthesis, the cell will now produce HIV virions in addition to human proteins.
Typically, HIV infects CD4+ T helper cells, predominantly in the gut. Less commonly it may infect macrophages.
This leads to severe immunosuppression over a period of years and eventually Acquired Immunodeficiency Syndrome (AIDS)
20
Q
What monoclonal antibody can be used in the treatment of osteoporosis?
A
Denosumab
Denosumab targets RANKL and therefore prevents the development of osteoclasts. RANKL binds to the RANK receptor on osteoclast precursors and promotes cell differentiation into osteoclasts. Hence, inhibition of RANKL/RANK receptor interaction reduces bone turnover and may increase bone density.
21
Q
A 80 year old woman was given a blood transfusion yesterday due to low haemoglobin. All observations normal. Infusion site is unremarkable. She feels like she has a fever. What complication of blood transfusion is this patient suffering from?
A
Febrile non-haemolytic transfusion reaction
Febrile non-haemolytic is the most common reaction to whole blood products. It is thought to be caused by white blood cells releasing cytokines such as IL-1 during storage. Symptoms include a fever >38 in mild cases or a high fever >39 with chills and rigors in severe reactions. Mild reactions are not a reason to stop treatment. Paracetamol or other NSAIDs may provide symptomatic relief.
22
Q
How may mast cell degranulation be measured?
A
Tryptase
Tryptase is an enzyme released with histamine granules by mast cells and hence can be used to quantify mast cell activation
23
Q
What primary immunodeficiency is a patient with a negative nitro-blue tetrazolium (NBT) test likely to have?
A
Chronic granulomatous disease
Chronic Granulomatous Disease is an inherited immunodeficiency affecting neutrophil function. A full blood count is likely to be normal, however patients are at increased risk of severe, atypical infections (usually catalase positive bacteria). Often, this means recurrent, severe pneumonia before age 5. It is diagnosed by the Nitroblue-tetrazolium (NBT) or dihydrorhodamine (DHR) tests. In CGD, these tests are negative. In the NBT or DHR tests, the presence of reactive oxygen species will cause a colour change. A positive (normal) NBT test will stain neutrophils blue. A negative (abnormal) test will remain colourless. The only curative treatment is haematopoietic stem cell transplantation. Injections of interferon gamma can be used to reduce infections and augment the immune response.
24
Q
What is the term given to a transplant between two genetically identical individuals?
A
Isograft
There are a number of terms used to describe transplants:
Isograft - Between genetically identical members of the same species (self transplant or from an identical twin)
Allograft - Between genetically distinct members of same species (most human transplants are these)
Xenograft - Between species
25
Congenital absence of C4 (Complement) predisposes to what autoimmune disease?
Systemic Lupus Erythematosus
Deficiencies in complement have many effects.
Any deficiencies the in the complement pathway will inhibit the formation of formation of the membrane attack complex - which is vital for defence against encapsulated bacteria.
However, C5b, C6, C7, C8 and C9 deficiencies are most likely to cause symptoms.
Encapsulated bacteria include meningococcus (Neisseria spp.), Haemophilus spp. or pneumococcus (Streptococcus spp.) [Memory Aid: NHS]
In addition, deficiencies in C2, C3 or C4 (classical pathway) predispose to Systemic Lupus Erythematosus, as cellular debris is not phagocytosed effectively.
Function of the complement system may be quantified using the CH50 or CH100 tests, which test the ability of a serum to lyse sheep erythrocytes.
26
A 30 year old lady presents to her GP. She says she struggles to concentrate at work because she feels like there is sand stuck in her eye. She is also constantly tired despite more than 12 hours of sleep a day and she think she may be losing weight. On examination, her conjunctival mucosa appears erythematous and dry. She also reports a dry mouth and dry skin on her hands, for which she uses E45 lotion. What underlying condition may be responsible for her symptoms?
Sjogren's Syndrome
27
What monoclonal antibody targets CD52 and causes depletion of all lymphocyte subsets?
Alemtuzumab
Alemtuzumab is a monoclonal antibody that targets CD52. CD52 is found on both B and T cell lymphocytes at various stages of development. It may be used in place of radiation to wipe out the immune system for hematopoietic stem cell transplantation.
28
What type of vaccine uses weakened strains of a pathogen?
Live attenuated
There is a huge variability in pathogens.
Hence, in order to get the best possible immunity, vaccines vary as well.
There are a few main types of vaccines:
Live attenuated vaccines
These are avoided in pregnancy and immunocompromised patients.
Examples include:
BCG for TB, MMR, Yellow Fever
Subunit (recombinant) Vaccines
Typically for viruses.
The vaccine contains proteins found on the surface of the viruses in addition to an adjuvant. Examples include Hep B and HPV.
Conjugate vaccines
For encapsulated bacteria.
Consist of bacterial polysaccharides conjugated to an immunogenic toxin (diphtheria toxin).
Used for Haemophilus influenzae, meningococcus and pneumococcus.
Inactivated vaccines
These are vaccines where the pathogens have been rendered inert - usually by heat killing or formaldehyde.
Examples include the pertussis vaccine.
As the pathogen cannot replicate, it usually requires multiple booster shots to provide immunity.
29
What HLA allele is found in 90% of patients with coeliac disease?
HLA-DQ2
Coeliac disease is a due to an aberrant cell-mediated (Th1) response to antigens found in gluten.
Activation of intraepithelial lymphocytes by gluten leads to the production of cytokines which damage the mucosal epithelium, leading to villous atrophy and malabsorption.
Antigens contained within gluten include: gliadin (most commonly) and other antigens that may be found in rye or barley.
More than 90% of patients with coeliac disease express the HLA alleles DQ2 or, less commonly DQ8. (Memory aid: I 8 2 much gluten).
There are also antibodies directed against tissue transglutaminase (IgA), gliadin (IgG) or endomysial antibodies (IgA) which may be used in the diagnosis of the disease.
30
The Meningitis C vaccination is an example of what type of vaccination?
Conjugate
31
A mutation in what protein is the most common cause of Hyper IgM syndrome?
CD40
Hyper IgM is characterised by high levels of IgM in blood and reduction in levels of other immunoglobulin classes. IgM is the first antibody to be created during the immune response - all other classes of antibody require a process called class switching to occur. Class switching requires activation of CD40 on the surface of B lymphocytes to occur. When CD40 is defective, only IgM can be produced. Typically this leads to increased infection risk, particularly Pneumocystis pneumonia.
32
What drug is used to temporarily reverse the symptoms of anaphylaxis?
Adrenaline
Allergic reactions to blood products may range from mild urticaria to anaphylaxis.
In general, mild reactions limited to the skin are not enough to warrant stopping the transfusion - they can be treated with antihistamines.
However, if other symptoms occur such as headache, severe widespread rash or airway involvement, this is an indication to stop the transfusion and potentially consider reassessing using an A to E approach.
The first drug in the management of anaphylaxis is both oxygen and adrenaline. However, oxygen can be applied quickly at the bedside. While in reality you will arrange for both to happen, the first thing you should do in an A-E assessment is secure the airway and then apply oxygen. Especially if there are signs of impending respiratory failure e.g. cyanosis.
33
A 10 year old has severe hayfever. Twice in the last month she has complained to her parents of tingly lips after eating celery. She also says the same thing happens when she eats apples. What allergic condition is the cause of her symptoms?
Oral Allergy Syndrome
Oral allergy syndrome refers to a collection of mild symptoms that occur when a patient eats typically stony fruit or some vegetables.
Common examples include: apples and celery.
Symptoms include: tingly lips, lip swelling, mild hives or itchy eyes.
As it is an IgE mediated condition, there is the possibility that in severe cases it may lead to anaphylaxis. It is due to cross reactivity with pollen antigens.
It is a clinical diagnosis, but specific antigens may be identified using skin prick testing. The gold standard for any allergy, rarely performed, would be a double blind challenge trial. This is normally unnecessary.
Treatment for mild OAS is antihistamines.
34
When evaluating patients for coeliac disease, in addition to serology for anti-TTG and anti-endomyseal antibodies.
What other blood test should be performed to correctly interpret these serological tests?
Serum IgA levels
Particular caution should be noted in the diagnosis of coeliac disease, as the common autoantibodies that are used for diagnosis are of the type IgA (Anti-Endomysial and Anti-Tissue Transglutaminase).
Hence, in IgA deficiency (1 in 600 people), they may be falsely negative.
IgA levels should always be assessed at the same time when assessing for coeliac disease.
35
What immunomodulatory agent may be given to treat chronic granulomatous disease?
Interferon Gamma
Chronic Granulomatous Disease is an inherited immunodeficiency affecting neutrophil function. A full blood count is likely to be normal, however patients are at increased risk of severe, atypical infections (usually catalase positive bacteria). Often, this means recurrent, severe pneumonia before age 5. It is diagnosed by the Nitroblue-tetrazolium (NBT) or dihydrorhodamine (DHR) tests. In CGD, these tests are negative. In the NBT or DHR tests, the presence of reactive oxygen species will cause a colour change. A positive (normal) NBT test will stain neutrophils blue. A negative (abnormal) test will remain colourless. The only curative treatment is haematopoietic stem cell transplantation. Injections of interferon gamma can be used to reduce infections and augment the immune response.
36
A 33 year old man is seen by the rheumatologists for evaluation of his raynaud's syndrome.
He says his hands are becoming more sensitive to changes in temperature. In addition, the skin is cracked and dry.
During the appointment, he is constantly sipping water from a water bottle.
An autoimmune antibody screen reveals positive ANA (Anti-Ro, Anti-La positive).
What autoimmune condition explains his symptoms?
Sjogren's Syndrome
37
What clinical criteria are used for the diagnosis of acute rheumatic fever?
Jones Criteria
Rheumatic fever is now a rare type II hypersensitivity reaction that may occur post-streptococcal infection.
The condition is diagnosed using Jones' criteria:
Major criteria
Polyarthritis
Carditis
Subcutaneous nodules
Erythema marginatum (Rash on the trunk/arms which spread outward. Worse with heat)
Sydenham's chorea (Involuntary movements of the face and arms)
Minor criteria
Fever
Arthralgia
Raised ESR/CRP
Leukocytosis
38
What is the main metabolite of azathiroprine?
6-Mercaptopurine
Azathioprine is a antiproliferative immunosuppressant that particularly inhibits T cells. It is metabolised into the inert 6-mercaptopurine. Mutations in an enzyme, TPMT, can mean that azathioprine is metabolised into a cytotoxic metabolite instead of 6 mercaptopurine. Hence, before starting azathioprine all patients should have activity of the TPMT enzyme checked.
39
An prenatal autoimmune panel of bloods reveals positive anti-Ro antibody in the blood of a pregnant woman with SLE. What cardiological condition is her unborn baby at risk of?
Congenital Heart Block
40
What protein is defective in X linked Severe Combined Immunodeficiency?
Common Gamma Chain
X Linked Severe Combined Immunodeficiency (SCID) is found when there is a defective or deficient gene coding for the common gamma chain (IL-2RG) of the IL-2 receptor. IL-2 is a vital cytokine used for activation and differentiation of the adaptive immune system, particularly T cells. The common gamma chain (IL-2RG), in addition to being part of the IL-2 receptor, also is part of receptors for IL-4, IL-7, IL-9, IL-15 and IL-21. Clinically, X linked SCID presents within the first month of birth typically with sepsis. T cells are often absent (as the lack of IL-2 receptor prevents their growth). Also, there is a deficiency in immunoglobulins as IL-4 is involved in B cell differentiation to plasma cells. An eczema like rash is often present. Failure to thrive or systemic Candida infections may also be present.
41
What subset of T helper cells are associated with the transcription factor FoxP3?
T regulatory cells
T regulatory cells are CD25 positive T helper cells and express the transcription factor FOXP3.
They inhibit the immune response by secreting IL-10, an immunosuppressive cytokine.
Alternatively, T regs express CTLA-4 on their cell surface which can directly inhibit T cell activation.
_________
Anti-CTLA4 antibodies (Ipilimumab) are a novel class of drugs which inhibit T regulatory cells, causing an increase in immune system function.
This is used for some cancers.
Alternatively, hybrid antibodies with CTLA-4 bound to the constant region of IgG (abatacept) are used in the treatment of autoimmune disease.
42
Which is the first type of immunoglobulin secreted in response to viral infection?
IgM
Immunoglobulin M (IgM) is a pentameric immunoglobulin. It is one of the first Ig molecules made in the early response to an infection. Each binding site has a relatively low affinity to antigen - this is compensated by the fact it has 10 binding sites. Structurally, it is 5 immunoglobulin molecules joined together by a J chain. It's especially good at activating complement and agglutination.
43
What mouse monoclonal antibody targets CD3 on the surface of T cells?
Muromonab
Muromonab is a monoclonal antibody that targets CD3, found on all T cells. It was used to prevent transplant rejection. It is now no longer manufactured. It was the first monoclonal antibody approved for use in humans.
44
Immunoglobulins may bind to cell surface receptors on viruses, to prevent viral binding and entry of human cells.
What is this function of immunoglobins known as?
Neutralisation
Neutralisation is the process whereby a target molecule (which may be a toxin, virus or even whole bacteria) is covered in antibodies such that it is unable to bind to its receptors & hence rendering the target inert.
This differs from opsonization, which is where antibodies bind a target to allow more effective phagocytosis.
45
A 20 year old man is screened for primary immunodeficiencies by his GP after a number of recent, severe infections.
A full blood count was normal.
IgA Normal
IgM Low
IgG Low
What immunodeficiency is this patient likely to have?
Common Variable Immunodeficiency
Common Variable Immunodeficiency (CVID) is a diagnosis of exclusion in patients greater than 4 years old. The diagnostic criteria are:
Decrease in serum IgG and a decrease in one of IgM or IgA.
There is a lack of antibody response to antigens or immunisation
More than 4 years old.
Patients will have increased infections with bacteria such as Haemophilus, Strep (usually immunized against) and Staph. There is an increased rate of autoimmune conditions and malignancies. Treatment is with normal human IVIg for life.
46
What enzyme, deficient or defective in chronic granulomatous disease, is responsible for the "respiratory burst" that may kill phagocytosed pathogens?
NADPH oxidase
Neutrophils kill phagocytosed pathogens by creating a respiratory burst. A respiratory burst involves the release of superoxide species, oxygen free radicals and hydrogen peroxide into the phagolysosome. This process is deficient in chronic granulomatous disease due to the lack or dysfunction of the enzyme NADPH oxidase
47
Electrophoresis of CSF for a 23 year old patient with nonspecific neurological symptoms, tiredness and weight loss reveals the presence of oligoclonal bands of IgG. What autoimmune condition is this highly suggestive of?
Multiple Sclerosis
A type IV T cell mediated response directed against Myelin Basic Protein or Proteolipoprotein. Th17, a subtype of T helper cells, that are usually associated with parasites or fungal infections, is involved in the pathogenesis of the condition. Oligoclonal bands of IgG may be found in electrophoresis of Cerebrospinal Fluid of patients with MS.
48
What is the descriptor given to a solution of antibodies that recognise multiple antigens?
Polyclonal
Monoclonal antibody = a solution of identical antibodies Polyclonal antibody = a solution of mutliple antibodies with different affinities for the same antigen (or target molecule)
49
What HLA allele is associated with Rheumatoid Arthritis?
HLA-DR4
50
A 3 year old boy is brought in by ambulance to A&E unconscious. He was having a meal at a friend's birthday party. His lips are swollen, he is wheezing and he has widepsread urticaria. He is hypotensive and has a capilary refill time of 5 seconds. What chemical is predominantly responsible for his symptoms?
Histamine
Histamine is a vasoactive peptide found throughout the body. It signals via H1-H4 receptors, all G protein coupled receptors. H1 receptor activation on endothelial cell surfaces leads to vasodilation and in severe cases, hypotension, that is responsible for anaphylactic shock. The H1 receptor is also responsible for itch perception.
51
The rabies and hepatitis A vaccinations are examples of what type of vaccination?
Inactivated
52
Immunoglobulins may bind to bacteria to allow phagocytosis to occur. What is this process known as?
Opsonisation
Opsonisation is where, as a result of antibodies binding to the surface of a pathogen, an otherwise undigestable pathogen is allowed to be phagocytosed.
Agglutination, on the other hand, is a process where to enhance phagocytosis, an antibody (such as IgM) may bind to multiple pathogens at once to allow for more effective clearance.
53
What is the autoantibody found in myasthenia gravis?
Anti Acetylcholine Receptor Antibody
Type 2 Hypersensitivity is due to antibody directly binding to cells and tissues that leads to cell damage.
Examples include:
Pernicious anaemia (anti parietal cell antibodies)
Graves' disease (anti-TSH receptor)
Immune thrombocytopenic purpura (anti-platelet antibodies such as anti-glyoprotein IIb/IIIa)
Goodpasture's syndrome (Anti-glomerular basement membrane antibodies [specifically anti-type IV collagen antibodies])
Haemolytic disease of the newborn (maternal IgG against fetal erythrocyte antigens)
Pemphigus Vulgaris (anti-cadherin)
54
Which type of immunoglobulin is primarily secreted into breast milk and is responsible for passive immunity in newborns?
Immunoglobulin A
Secretory IgA is a dimeric antibody typically found on mucosal or epithelial surfaces, such as in the mouth or gut. It is also the main antibody found in breast milk. It is made up of two immunoglobulin molecules joined by a J chain. It may also contain a secretory component, which allows for transmigration across epithelial surfaces. As it is a dimeric antibody, there are 4 antigen binding sites. There is also a monomeric form that typically circulates in serum. Its main function is neutralisation - blocking pathogenic ligands from binding to epithelial cell surface receptors.
55
The family of a 13 year old boy with a known latex allergy have kept a food diary after they noticed some foods make his skin itchy. They noticed that bananas, potatoes, tomatoes and mangos may precipitate an outbreak. What specific allergic condition does he suffer from?
Latex Food Syndrome
Latex food syndrome is an IgE mediated type 1 hypersensitivity reaction to fruits and seeds, that is caused by cross-reactivity to latex antigens. To have latex food syndrome, someone must also be allergic to latex. Common fruits that may cause symptoms include: Banana, pineapple or avocado. It is diagnosed via skin prick testing, demonstrating an allergy to latex and other foods.
56
A 50 year old man is seen by the rheumatologists.
The rheumatologists take a thorough history and the symptoms he experiences include: exquisitely painful fingers when entering the chilled aisle of his local supermarket, difficulty swallowing large bites of food, tight skin on his hands and around his mouth. In addition, he is easily fatigable and often feels feverish. His CRP is raised and an autoantibody is detected.
What antibody is associated with this condition?
Anti-Centromere Antibody
57
A patient in SAU has developed angioedema after taking an antibiotic. There blood pressure has dropped to 86/60 mmHg. You suspect anaphylaxis. What route should be used to administer the adrenaline?
Intramuscular
Anaphylaxis is managed using an ABCDE approach.
If there is evidence of hypoxaemia, Oxygen is the first drug that is given.
If there is evidence of wheeze, this suggests airway involvement and hence intramuscular adrenaline (500 micrograms) may be given if there is sufficient blood flow.
If blood pressure is low, IV fluids should be given.
Antihistamines (Chlorphenamine) and corticosteroids should also be given, however they need time to take effect.
A repeat dose of adrenaline may be necessary.
Response to treatment over the next few hours may be monitored by levels of mast cell tryptase - a marker of mast cell activation.
58
What antiretroviral drug is given as IV monotherapy during labour to prevent vertical transmission of HIV-1?
Zidovudine
HIV is treated using Highly Active Antiretroviral Therapy (HAART), sometimes called ART (antiretroviral therapy)
UK guidelines (BHIVA) suggest HAART should consist of three medications:
Two nucleoside reverse transcriptase inhibitors (NRTIs) and another class of drug.
Examples of the common drug classes include:
NRTI: Zidovudine, Abacavir
Non-nucleoside reverse transcriptase inhibitor: Efavirenz
Protease inhibitor: Ritonavir
Integrase inhibitor: Dolutegravir
Zidovudine is considered safe for use in pregnancy
59
CD8 is specifically a marker of what type of immune cell?
T killer cells
CD8 is a co-receptor for the T cell receptor and recognises MHC class 1.
MHC class 1 is found on most nucleated cells and presents random intracellular peptides to CD8+ T cells.
If a T cell recognises a peptide-MHC class 1 complex, then the T cell activates and kills the target cell.
Please note: Simply writing "CD8" is not enough detail for the mark. CD8 is a cell surface protein. We use cell surface markers to classify T cells. Hence, CD8+ T Cells is acceptable - but CD8+ is not.
60
An autoimmune panel of bloods reveals positive anti-Jo-1 antibody in a woman with breast cancer.
What autoimmune condition is associated with this autoantibody?
Dermatomyositis
61
What is the descriptor given to a solution of antibodies that recognise one antigen only?
Monoclonal
Monoclonal antibody = a solution of identical antibodies Polyclonal antibody = a solution of mutliple antibodies with different affinities for the same antigen (or target molecule)
62
A 31 year old woman presents to their GP with tiredness and offensive smelling diarrhoea with no blood. Since the diarrhoea has started, she has complained of recurrent bouts of skin infections and food poisoning like symptoms.
She is anti-TTG and anti-endomysial antibody positive. A full STI screen is negative. FBC is unremarkable. Albumin and Immunoglobulins are very low.
What condition has her uncontrolled coeliac disease caused that has led to her functional immunosuppression?
Protein losing enteropathy
Any condition where there is loss of protein from the blood may lead to a state of immunodeficiency. Immunoglobulins are proteins - hence, the loss of circulating antibodies will reduce immunity. Any GI condition may cause loss of protein from the gut - usually due to damage to the mucosa. Hence it may occur in inflammatory bowel disease, infection (causing lymphatic obstruction), coeliac disease or even SLE. Protein losing enteropathy may be diagnosed by performing faecal alpha-1 antitrypsin levels.
63
A 40 year old woman presents to her GP with hot, tender bilateral wrists and metacarpophalangeal joints for two weeks. She thinks she has lost weight and feels completely run down over the last month.
She is positive for Anti-CCP antibody and has an elevated ESR. Rheumatoid Factor is negative.
What is the diagnosis?
Rheumatoid Arthritis
64
A 34 year old man has severe Crohn's disease. His gastroenterologist wishes to start a biologic drug, infliximab. What infection should be ruled out before commencing the drug?
Tuberculosis
Monoclonal antibodies directed against TNF-alpha are associated with activation and dissemination of latent TB. TNF-alpha is vital for the control of TB infection in the lungs. If it is blocked, TB can grow unchecked. Hence, prior to starting treatment with an anti-TNF-alpha antibody, a mantoux test should be performed to exclude exposure to TB. If the mantoux is positive, an interferon gamma release assay (IGRA) is then performed. If that is also positive, the patient has latent TB and requires treatment before starting the biological therapy.
65
What type of hypersensitivity reaction is Pernicious Anaemia?
Type 2
Type 2 Hypersensitivity is due to antibody directly binding to cells and tissues that leads to cell damage.
Examples include:
Pernicious anaemia (anti parietal cell antibodies)
Graves' disease (anti-TSH receptor)
Immune thrombocytopenic purpura (anti-platelet antibodies such as anti-glyoprotein IIb/IIIa)
Goodpasture's syndrome (Anti-glomerular basement membrane antibodies [specifically anti-type IV collagen antibodies])
Haemolytic disease of the newborn (maternal IgG against fetal erythrocyte antigens)
Pemphigus Vulgaris (anti-cadherin)
66
A 34 year old man has severe Crohn's disease. His gastroenterologist wishes to start an anti-TNF drug to see if it controls his symptoms better. What first-line test should the patient undergo before starting adalimumab?
Mantoux Test
Monoclonal antibodies directed against TNF-alpha are associated with activation and dissemination of latent TB. TNF-alpha is vital for the control of TB infection in the lungs. If it is blocked, TB can grow unchecked. Hence, prior to starting treatment with an anti-TNF-alpha antibody, a mantoux test should be performed to exclude exposure to TB. If the mantoux is positive, an interferon gamma release assay (IGRA) is then performed. If that is also positive, the patient has latent TB and requires treatment before starting the biological therapy.
67
HIV infected CD4+ cells are killed by the immune system. What cell type is responsible for this?
T killer cells
Cytotoxic T Lymphocytes (T killer cells) are CD8+ and involved in intracellular immunity.
Through CD8 and its T cell receptor, it may recognise infected or cancerous cells when viral proteins are expressed on MHC class 1.
Activation of T killer cells leads to the release of perforin and granzyme, inducing apoptosis in the affected cell.
T killer cells also release pro-inflammatory cytokines like IFN-y.
Note: CD8+ is not a "type of cell" - CD8 is a cell surface marker, found on the surface of T (killer) cells. Putting a cell surface marker without specifying the cell it is attached to will not give you the mark in the exam.
68
What antigen is injected intradermally as part of the mantoux screening test for tuberculosis?
Tuberculin Purified Protein Derivative
The mantoux test measures the immune response to tuberculosis antigens.
A Purified Protein Derivative of Tuberculin is injected intradermally.
The size of the induration (not erythema) is measured after 48-72 hours.
Science:
If a patient has previously been exposed to tuberculosis antigens (via any form, including previous mantoux tests or active infection) then they will react vigorously and create an area of induration around the injection site.
Immunosuppressed people will mount a weaker immune response, hence the interpretation thresholds are smaller.
Interpretation:
>5mm is positive in HIV or immunosuppressed patients or people at very high risk of TB (such as living with someone with active TB)
>10mm is positive in IVDU, medium risk populations such as healthcare workers or children <4 years old
>15mm is positive in low risk populations.
Interpretation guidelines differ, but what is provided here is an approximate guide.
69
What autoantibody, sometimes detectable in Graves' disease, is a useful clinical marker in monitoring thyroid cancer?
Anti-thyroglobulin antibodies
70
What is the most common inherited primary immunodeficiency?
Selective IgA Deficiency
IgA deficiency is the most common inherited immunodeficiency, with a prevalence of approximately 1 in 500. A lack of IgA leads to infections of mucosal surfaces. Clinically, this may present as repetitive upper respiratory tract infections, ear infections or sinusitis. In most patients, the disease is mild and it is undiagnosed. There is an increased association with autoimmune diseases in patients with IgA deficiency.
71
What type of hypersensitivity reaction results when circulating antibodies directly react with self antigens leading to tissue damage?
Type 2
Type 2 Hypersensitivity is due to antibody directly binding to cells and tissues that leads to cell damage.
Examples include:
Pernicious anaemia (anti parietal cell antibodies)
Graves' disease (anti-TSH receptor)
Immune thrombocytopenic purpura (anti-platelet antibodies such as anti-glyoprotein IIb/IIIa)
Goodpasture's syndrome (Anti-glomerular basement membrane antibodies [specifically anti-type IV collagen antibodies])
Haemolytic disease of the newborn (maternal IgG against fetal erythrocyte antigens)
Pemphigus Vulgaris (anti-cadherin)
72
What HLA allele is associated with an 87x increased risk of ankylosing spondylitis?
HLA-B27
73
An 9 year old boy has had recurrent chest infections and influenza like illnesses since joining primary school.
Blood tests reveal a low lymphocyte count, with very low B cells but normal T cell levels.
There as very low levels of IgM, IgA and IgG.
What immunodeficiency is this patient likely to have?
Bruton's Agammaglobulinaemia
Bruton's Agammaglobulinaemia is a rare X linked immunodeficiency caused by a mutation in the BTK gene, which codes for a tyrosine kinase required for B cell development. Patients with this condition suffer from recurrent infections, typically from Streptococcal or Haemophilus spp. It often does not manifest until after 6 months, when the child loses passive immunity from the mother when breastfeeding. There is a notable lack of lymphoid tissue (lack of tonsils and adenoids) or lack of lymphadenopathy during infections. There is a decrease in all immunoglobulins, though small amounts may be present. It can usually be managed by injections of normal human IVIg for life.
74
A tumour cell has mutated and no longer expresses endogenous peptides and MHC Class I on the surface. What immune cell would recognise and kill this mutated cell?
Natural Killer cells
Natural killer (NK) cells are lymphoid derived cells of the innate immune system. Phenotypically similar to lymphocytes, however they do not express either of the eponymous T or B cell receptors. NK cells can recognise either lack of MHC (a common tactic of viruses to avoid the immune system, by preventing MHC expression) or an imbalance in numerous cell surface receptors. Imbalances in cell surface receptors suggests that the cell may be infected, cancerous or dying.
75
What subtype of T cells are killed by HIV?
T helper cells
HIV is a sexually-transmitted retrovirus.
It expresses an exceedingly error prone reverse transcriptase.
Reverse transcriptase synthesises DNA from viral RNA.
This viral DNA is then incorporated into the cell's nucleus for the lifetime of the cell. As part of normal cellular protein synthesis, the cell will now produce HIV virions in addition to human proteins.
Typically, HIV infects CD4+ T helper cells, predominantly in the gut. Less commonly it may infect macrophages.
This leads to severe immunosuppression over a period of years and eventually Acquired Immunodeficiency Syndrome (AIDS)
76
A 15 day old infant is brought to A&E by their concerned parents. He has been feeding poorly (<80% of normal) and is producing fewer wet nappies. He is quite sleepy.
On examination there are multiple discharging abscesses approximately half a centimeter in diameter visible around his umbilical cord stump. They are swollen and very red. The child's father says his dad has a problem with white blood cells and takes injections for it. He is unsure what it is. The child is pyrexial at 38c and has a heart rate of 150bpm. A full blood count reveals a low neutrophil count. He was born at full term.
What primary immunodeficiency is this child likely to have?
Kostmann Syndrome
Kostmann Syndrome, otherwise known as severe congenital neutropenia, is characterised by frequent, severe bacterial infections (typically involving Staphylococcus). There is a predilection to abscess formation and life threatening infections. Most suffers will have a severe infection in the first month of life, where a neutropenia will be identified on a full blood count. Genetic testing may be done to identify the mutation. Treatment involves regular injections of granulocyte colony stimulating factor, which increases myelopoiesis and increases neutrophil levels.
77
Ritonavir is an example of what class of antiretroviral drug?
Protease inhibitor
HIV is treated using Highly Active Antiretroviral Therapy (HAART), sometimes called ART (antiretroviral therapy)
UK guidelines (BHIVA) suggest HAART should consist of three medications:
Two nucleoside reverse transcriptase inhibitors (NRTIs) and another class of drug.
Examples of the common drug classes include:
NRTI: Zidovudine, Abacavir
Non-nucleoside reverse transcriptase inhibitor: Efavirenz
Protease inhibitor: Ritonavir
Integrase inhibitor: Dolutegravir
Zidovudine is considered safe for use in pregnancy
78
What class of medication is a contraindication to skin prick testing, unless stopped at least two days prior to testing?
Anti-histamines
Skin prick testing is used to determine allergens in Type 1 (IgE mediated) Hypersensitivity reactions, such as allergic rhinitis.
Histamine is injected as a positive control, saline as a negative.
Antihistamines must be stopped 48 hours prior to the test to allow for an accurate result.
Patch testing is used for the diagnosis of Type 4 (T cell mediated) hypersensitivity reactions, such as contact dermatitis.
Blood tests (such as a radioallergosorbent test) also exist for the detection of allergen specific IgE in blood.
However, the gold standard for diagnosis of food allergy is a double-blind, oral food challenge test. A small quantity of suspected allergen (or placebo) is administered in a hospital environment.
79
What auto-antibody is associated with Eosinophilic Granulomatosis with Polyangiitis (Churg Strauss)?
p-ANCA
Eosinophilic granulomatosis with Polyangiitis (EGPA) formerly known as Churg Strauss syndrome, is a small-medium vessel vasculitis associated with p-ANCA antibodies and eosinophilia.
Patients affected typically have severe allergies or sinus problems, which progress to severe asthma prior to the systemic vasculitis.
It is treated with corticosteroids.
80
A 30 year old nulliparous female is brought to the A&E department. Her haemoglobin is 10. She needs a blood transfusion urgently.
In the emergency management of this patient, what blood type would be most appropriate?
O negative
The best blood type depends on the time available.
If there is sufficient time for a crossmatched blood sample, then the results of these blood tests should guide management. Typically, this process takes at least an hour.
A group and save is a blood test that identifies the blood type and Rh antigen status. It is valid for up to three months (if no blood products have been given before).
Cross match is the direct mixing of donor blood products and recipient serum. It is how blood products are ordered - so ordering a cross match reserves blood for that specific patient. No one else can be given that blood until the cross match expires. A cross match is normally only done when there is an imminent need for blood. Cross matched samples are typically valid for less than a few days.
However, if there is not time for G&S +- crossmatch then:
There are no contraindications to O negative blood.
O positive blood may be given to males or postmenopausal women. If O positive blood is given to women of childbearing age (who are Rh antigen negative) then it may lead to haemolytic disease of the newborn if she has a Rh negative child.
A group and save may be valid for 3 months if a patient has never received a transfusion. However, if a patient has received a transfusion, group and saves are normally only valid for 72 hours. Some hospitals stipulate 72 hours for all samples. This is so that any new antibodies can be detected.
81
What type of hypersensitivity reaction is Type 1 Diabetes?
Type 4
T1DM is a type IV hypersensitivity reaction, mediated by T cell destruction of beta cells.
82
What cell type of the adaptive immune system recognises MHC Class I on epithelial cells?
T killer cells
CD8 is a co-receptor for the T cell receptor and recognises MHC class 1.
MHC class 1 is found on most nucleated cells and presents random intracellular peptides to CD8+ T cells.
If a T cell recognises a peptide-MHC class 1 complex, then the T cell activates and kills the target cell.
Please note: Simply writing "CD8" is not enough detail for the mark. CD8 is a cell surface protein. We use cell surface markers to classify T cells. Hence, CD8+ T Cells is acceptable - but CD8+ is not.
83
What is the term given to proteins, typically produced by the liver in response to infection, that include IL-1, ferritin, IL-6 and CRP.
Acute Phase Proteins
Acute phase proteins include: IL-1, IL-6 and CRP.
They are produced by the liver in response to infection and are involved in the upregulation of many functions of the immune system.
IL-1 and IL-6 are very pyrogenic and cause fever.
CRP binds to the surface of dead or dying cells and activates the classical complement cascade via C1q.
84
What type of vaccine uses pathogens that are unable to replicate?
Inactivated
There is a huge variability in pathogens.
Hence, in order to get the best possible immunity, vaccines vary as well.
There are a few main types of vaccines:
Live attenuated vaccines
These are avoided in pregnancy and immunocompromised patients.
Examples include:
BCG for TB, MMR, Yellow Fever
Subunit (recombinant) Vaccines
Typically for viruses.
The vaccine contains proteins found on the surface of the viruses in addition to an adjuvant. Examples include Hep B and HPV.
Conjugate vaccines
For encapsulated bacteria.
Consist of bacterial polysaccharides conjugated to an immunogenic toxin (diphtheria toxin).
Used for Haemophilus influenzae, meningococcus and pneumococcus.
Inactivated vaccines
These are vaccines where the pathogens have been rendered inert - usually by heat killing or formaldehyde.
Examples include the pertussis vaccine.
As the pathogen cannot replicate, it usually requires multiple booster shots to provide immunity.
85
What immunoglobulin subtype binds to Fc receptors on the surface of mast cells?
IgE
Immunoglobin E, IgE, is structurally very similar to IgG. It has two antigen binding sites. Is main role is in the protection against parasites and helminths. IgE uniquely binds to a special type of Fc receptor on the surface of mast cells. This binding is one of the strongest non-covalent bonds found in biological systems. This binding is therefore essentially irreversible. If two IgE molecules on the surface of mast cells recognise antigen and cross-link, then this will lead to mast cell activation and in servere cases, anaphylaxis.
86
CD14 is typically a marker of what type of immune cell?
Monocytes
CD14 is found on macrophages (or monocytes) and recognises the bacterial endotoxin lipopolysaccharide (LPS). LPS is one of the most immunogenic molecules in existence and is a key molecule involved in the pathophysiology of septic shock.
87
What specific malignancy are people with Sjogren's syndrome at greater risk of?
Mucosa Associated Lymphoid Tissue Lymphoma
88
An autoimmune panel of bloods reveals positive anti-tissue transglutaminase antibody and positive anti-endomysial antibody. What autoimmune condition is associated with these autoantibodies?
Coeliac Disease
Coeliac disease is a due to an aberrant cell-mediated (Th1) response to antigens found in gluten.
Activation of intraepithelial lymphocytes by gluten leads to the production of cytokines which damage the mucosal epithelium, leading to villous atrophy and malabsorption.
Antigens contained within gluten include: gliadin (most commonly) and other antigens that may be found in rye or barley.
More than 90% of patients with coeliac disease express the HLA alleles DQ2 or, less commonly DQ8. (Memory aid: I 8 2 much gluten).
There are also antibodies directed against tissue transglutaminase (IgA), gliadin (IgG) or endomysial antibodies (IgA) which may be used in the diagnosis of the disease.
89
Mastocytosis suggests an infection by what class of organism?
Parasites
Parasites and helminths activate the Th2 arm of the adaptive immune response.
This is a process mediated by cytokines such as IL-4, IL-5 and IL-13.
This axis is also implicated in the development of allergy.
There may also be elevated levels of IgE, due to antibody class switching secondary to the previously mentioned chemokines.
In the innate immune system, parasites and helminths cause a mastocytosis or eosinophillia
90
What is the gold-standard test for diagnosis of food allergy?
Double Blind Oral Food Challenge
Skin prick testing is used to determine allergens in Type 1 (IgE mediated) Hypersensitivity reactions, such as allergic rhinitis.
Histamine is injected as a positive control, saline as a negative.
Antihistamines must be stopped 48 hours prior to the test to allow for an accurate result.
Patch testing is used for the diagnosis of Type 4 (T cell mediated) hypersensitivity reactions, such as contact dermatitis.
Blood tests (such as a radioallergosorbent test) also exist for the detection of allergen specific IgE in blood.
However, the gold standard for diagnosis of food allergy is a double-blind, oral food challenge test. A small quantity of suspected allergen (or placebo) is administered in a hospital environment.
91
What is the long term management of Common Variable Immunodeficiency?
Normal Human Immunoglobulin
Common Variable Immunodeficiency (CVID) is a diagnosis of exclusion in patients greater than 4 years old. The diagnostic criteria are:
Decrease in serum IgG and a decrease in one of IgM or IgA.
There is a lack of antibody response to antigens or immunisation
More than 4 years old.
Patients will have increased infections with bacteria such as Haemophilus, Strep (usually immunized against) and Staph. There is an increased rate of autoimmune conditions and malignancies. Treatment is with normal human IVIg for life.
92
An ANA test using indirect immunofluorescence suggests a homogenous pattern of ANA staining. What autoantibody is this pattern of ANA staining associated with?
anti-dsDNA
ANA is typically detected using indirect immunofluorescence.
A patient's serum is mixed with immortalised HeLa cells. Antibodies in the patient's serum will bind to their target on the immortalised cells. The serum is washed off and a fluorescent tag that binds to human antibodies is added.
The pattern of immunofluorescence under a microscope suggests which antibodies are present.
Homogenous pattern of ANA staining, suggests the presence of anti-dsDNA antibodies.
"Speckled" pattern, suggesting the presence of anti-centromere antibodies and hence CREST syndrome.
ANA and other auto-antibodies are often detectable in patients without evidence of disease. For example, approximately 10% of people are positive for rheumatoid factor - even though 10% of people don't have rheumatoid arthritis. Diagnosis of rheumatological conditions often require a combination of symptoms and immunological evidence of disease.
93
An autoimmune panel of bloods reveals positive anti-Glomerular Basement Membrane antibody. What autoimmune condition is associated with this autoantibody?
Goodpasture's Syndrome
Type 2 Hypersensitivity is due to antibody directly binding to cells and tissues that leads to cell damage.
Examples include:
Pernicious anaemia (anti parietal cell antibodies)
Graves' disease (anti-TSH receptor)
Immune thrombocytopenic purpura (anti-platelet antibodies such as anti-glyoprotein IIb/IIIa)
Goodpasture's syndrome (Anti-glomerular basement membrane antibodies [specifically anti-type IV collagen antibodies])
Haemolytic disease of the newborn (maternal IgG against fetal erythrocyte antigens)
Pemphigus Vulgaris (anti-cadherin)
94
What is the chance that a male child born to a mother heterozygous for Bruton's agammaglobulinaemia will have the condition?
50%
Bruton's Agammaglobulinaemia is a rare X linked immunodeficiency caused by a mutation in the BTK gene, which codes for a tyrosine kinase required for B cell development. Patients with this condition suffer from recurrent infections, typically from Streptococcal or Haemophilus spp. It often does not manifest until after 6 months, when the child loses passive immunity from the mother when breastfeeding. There is a notable lack of lymphoid tissue (lack of tonsils and adenoids) or lack of lymphadenopathy during infections. There is a decrease in all immunoglobulins, though small amounts may be present. It can usually be managed by injections of normal human IVIg for life.
95
How long before skin prick testing must antihistamines be stopped to allow for accurate interpretation?
48 hours
Skin prick testing is used to determine allergens in Type 1 (IgE mediated) Hypersensitivity reactions, such as allergic rhinitis.
Histamine is injected as a positive control, saline as a negative.
Antihistamines must be stopped 48 hours prior to the test to allow for an accurate result.
Patch testing is used for the diagnosis of Type 4 (T cell mediated) hypersensitivity reactions, such as contact dermatitis.
Blood tests (such as a radioallergosorbent test) also exist for the detection of allergen specific IgE in blood.
However, the gold standard for diagnosis of food allergy is a double-blind, oral food challenge test. A small quantity of suspected allergen (or placebo) is administered in a hospital environment.
96
In skin prick testing, what is used as a positive control?
Histamine
Skin prick testing is used to determine allergens in Type 1 (IgE mediated) Hypersensitivity reactions, such as allergic rhinitis.
Histamine is injected as a positive control, saline as a negative.
Antihistamines must be stopped 48 hours prior to the test to allow for an accurate result.
Patch testing is used for the diagnosis of Type 4 (T cell mediated) hypersensitivity reactions, such as contact dermatitis.
Blood tests (such as a radioallergosorbent test) also exist for the detection of allergen specific IgE in blood.
However, the gold standard for diagnosis of food allergy is a double-blind, oral food challenge test. A small quantity of suspected allergen (or placebo) is administered in a hospital environment.
97
A 34 year old woman was given a blood transfusion yesterday due to low haemoglobin. She is pyrexic with a fever of 38c and feels slightly under the weather. All other observations normal. Infusion site is unremarkable. What is the first line treatment of this complication of transplant?
Paracetamol
Febrile non-haemolytic is the most common reaction to whole blood products. It is thought to be caused by white blood cells releasing cytokines such as IL-1 during storage. Symptoms include a fever >38 in mild cases or a high fever >39 with chills and rigors in severe reactions. Mild reactions are not a reason to stop treatment. Paracetamol or other NSAIDs may provide symptomatic relief.
98
An alcoholic patient presents to their GP for the first time following years of excessive drinking and poor self care.
The GP undertakes a number of investigations, including a blood film.
What neutrophil abnormality would you expect to see?
Hypersegmented
99
What type of hypersensitivity reaction is Granulomatosis with Polyangiitis (Wegner's)?
Type II
Type 2 Hypersensitivity is due to antibody directly binding to cells and tissues that leads to cell damage.
Examples include:
Pernicious anaemia (anti parietal cell antibodies)
Graves' disease (anti-TSH receptor)
Immune thrombocytopenic purpura (anti-platelet antibodies such as anti-glyoprotein IIb/IIIa)
Goodpasture's syndrome (Anti-glomerular basement membrane antibodies [specifically anti-type IV collagen antibodies])
Haemolytic disease of the newborn (maternal IgG against fetal erythrocyte antigens)
Pemphigus Vulgaris (anti-cadherin)
100
What cell type gives pus its yellow/white appearance?
Neutrophils
Neutrophils, the most abundant white blood cell in peripheral blood, are the hallmark of acute inflammation. They transmigrate through vascular endothelium to sites of inflammation. They have a limited capacity for phagocytosis and die quite quickly. They are responsible for the whitish cellular material in pus. They may also release alarm cytokines, such as IL-1, to attract other cells such as macrophages. Furthermore, through a process known as degranulation, bactericidal molecules and enzymes can augment the immune response.
101
CD19 is typically a marker of what immune cell?
B cells
CD19 is classically a marker of B cells at all stages of maturation
102
An autoimmune panel of bloods reveals positive anti-gastric parietal cell antibodies. What autoimmune condition is associated with this autoantibody?
Pernicious Anaemia
Pernicious anaemia is the most common cause of B12 deficiency. Autoantibodies directed against parietal cells (which secrete intrinsic factor) or intrinsic factor itself are responsible for the condition. Anti-intrinsic factor antibodies are much more specific to the disease compared to anti-parietal cell antibodies, which are found in up to 10% of the population without the disease.
103
HLA types A, B and C are what class of the major histocompatibility complex?
1
Human Leukocyte Antigen (HLA) is the human specific term for the Major Histocompatibility Complex (MHC).
HLA classes A, B and C are MHC Class 1 (one letter = class one)
HLA classes DR, DQ, DR are MHC Class 2 (two letters = class two).
The most important HLA classes with respect to transplant are DR > B > A
Up to 6 HLA subtypes may be inherited, 3 from each parent.
They are expressed in a co-dominant fashion, meaning all will be expressed.
104
What autoantibody is associated with Microscopic Polyangitis?
P-ANCA
Antineutrophil cytoplasmic antibodies are implicated in pauci-immune conditions such as granulomatosis with polyangiitis or goodpasture's disease.
Their presence suggests a breakdown in immune tolerance as the immune system has become sensitised to intracellular antigens.
p-ANCA = Myeloperoxidase = UC, Eosinophilic Granulomatosis with Polyangiitis, Primary Sclerosing Cholangitis or Microscopic Polyangiitis
c-ANCA = Proteinase-3 = Granulomatosis with polyangiitis (Wegner's)
105
What primary immunodeficiency is a patient with a negative dihydrorhodamine (DHR) test likely to have?
Chronic granulomatous disease
Chronic Granulomatous Disease is an inherited immunodeficiency affecting neutrophil function. A full blood count is likely to be normal, however patients are at increased risk of severe, atypical infections (usually catalase positive bacteria). Often, this means recurrent, severe pneumonia before age 5. It is diagnosed by the Nitroblue-tetrazolium (NBT) or dihydrorhodamine (DHR) tests. In CGD, these tests are negative. In the NBT or DHR tests, the presence of reactive oxygen species will cause a colour change. A positive (normal) NBT test will stain neutrophils blue. A negative (abnormal) test will remain colourless. The only curative treatment is haematopoietic stem cell transplantation. Injections of interferon gamma can be used to reduce infections and augment the immune response.
106
What is the full chromosomal abnormality found in DiGeorge syndrome?
22q11.2 deletion
DiGeorge syndrome results from a deletion of part of chromosome 22 (22q11.2) (Question feedback: you must be specific to what has happened to the chromosome, ie a deletion, not simply state the locus affected)
This results in a number of abnormalities which can be remembered with the acronym CATCH 22 (with the 22 referring to the chromosomal deletion):
```
Cardiac anomalies
Abnormal facies
Thymic aplasia
Cleft palate
Hypoparathyroidism
```
Individuals with DiGeorge syndrome are born without the 3rd and 4th branchial arches and so do not have parathyroid glands.
107
Infections by what type of bacteria are more common in patients deficient in the complement protein C3?
Encapsulated
The complement system is a system of many serine proteases produced by the liver. There are three main methods of complement activation: the classical, alternative and mannose binding lectin pathways. The classical pathway is associated with the serine protease C1q binding to antibodies and leading to subsequent complement activation. Dysfunction of the classical pathway may lead to Lupus.
108
How is Latex Food Syndrome diagnosed?
Skin Prick Testing
Latex food syndrome is an IgE mediated type 1 hypersensitivity reaction to fruits and seeds, that is caused by cross-reactivity to latex antigens. To have latex food syndrome, someone must also be allergic to latex. Common fruits that may cause symptoms include: Banana, pineapple or avocado. It is diagnosed via skin prick testing, demonstrating an allergy to latex and other foods.
109
What hematological cells create a "respiratory burst" in order to kill phagocytosed pathogens?
Neutrophils
Neutrophils kill phagocytosed pathogens by creating a respiratory burst. A respiratory burst involves the release of superoxide species, oxygen free radicals and hydrogen peroxide into the phagolysosome. This process is deficient in chronic granulomatous disease due to the lack or dysfunction of the enzyme NADPH oxidase
110
A 3 year old girl with Turner's syndrome has recurrent chest infections. On examination, she has no visible tonsilar tissue. Blood tests reveal a low lymphocyte count, with very low B cells but normal T cell levels. There is very low levels of IgM, IgA and IgG. What primary immunodeficiency is this patient likely to have?
Bruton's Agammaglobulinaemia
Bruton's Agammaglobulinaemia is a rare X linked immunodeficiency caused by a mutation in the BTK gene, which codes for a tyrosine kinase required for B cell development. Patients with this condition suffer from recurrent infections, typically from Streptococcal or Haemophilus spp. It often does not manifest until after 6 months, when the child loses passive immunity from the mother when breastfeeding. There is a notable lack of lymphoid tissue (lack of tonsils and adenoids) or lack of lymphadenopathy during infections. There is a decrease in all immunoglobulins, though small amounts may be present. It can usually be managed by injections of normal human IVIg for life.
111
A 31 year old woman presents to her GP complaining of an itchy, runny nose in springtime. It is worse when she walks the dog at a local park. What allergic condition is she likely to have?
Allergic Rhinitis
Allergic rhinitis, or hayfever, is a Type 1 hypersensitivity reaction to antigens found in pollen. Typical symptoms include: itchy, runny nose or eyes and sneezing. On examination, pale, blue hypertrophied nasal turbinates may be visualised. Specific allergens can be identified using skin prick testing. Treatment is with nasal corticosteroids or oral antihistamines, typically cetirizine, due to its relatively long half life (approx 6 hours).
112
A woman is undergoing investigation for a suspected primary immunodeficiency. An initial blood test revealed a markedly low neutrophil count. However, a repeat blood test two weeks later was normal. What primary immunodeficiency is this patient likely to have?
Cyclic neutropenia
Cyclic neutropenia is an inherited condition characterised by neutropenia approximately every three weeks. It becomes milder with age and may self resolve in adulthood. It is difficult to diagnose due to the lag between neutropenia and symptoms. The neutropenia may predate any symptoms. In severe disease, it will typically be picked up in the first year of life with recurrent oral, throat or skin infections. It may be treated with Granulocyte Colony Stimulating Factor. It is due to a defect in the gene coding for neutrophil elastase resulting in failure of neutrophil maturation.
113
What lymphocyte lineage does cyclophosphamide predominantly inhibit?
B lymphocytes
Cyclophosphamide is an antiproliferative immunosuppressant that predominantly inhibits B cells. It is used in the treatment of vasculitis or as an a chemotherapy agent. It is a relatively toxic medication, with a risk of bone marrow damage. In exams, it may be a cause of haemorrhagic cystitis.
114
What type of hypersensitivity reaction is Systemic Lupus Erythematosus?
Type 3
SLE is a type III hypersensitivity reaction. The aetiology is multifactorial, but simply is due to the ineffective clearance of dead or dying cells from the body, leading to antibody complex formation. When cells die, they are removed from the body by phagocytosis. If cells are not removed quickly, an immune response against antigens inside the cell may be mounted. Typically, this immune response may involve anti-dsDNA or anti-histone antibodies. When they bind to their targets, they may circulate in the blood and deposit in tissues - leading to inflammation. This is particularly relevant in the kidneys. Complement is involved as the classical pathway of complement (through C1q) binds to dying cells to help remove them. A lack of C3 or C4 means this process is deficient, cells are not cleared effectively and it is much more likely an immune response will develop leading to SLE.
115
What is the minimum number of Fc receptors on the surface of mast cells that must bind to an antigen to cause mast cell degranulation?
2
Immunoglobin E, IgE, is structurally very similar to IgG. It has two antigen binding sites. Is main role is in the protection against parasites and helminths. IgE uniquely binds to a special type of Fc receptor on the surface of mast cells. This binding is one of the strongest non-covalent bonds found in biological systems. This binding is therefore essentially irreversible. If two IgE molecules on the surface of mast cells recognise antigen and cross-link, then this will lead to mast cell activation and in servere cases, anaphylaxis.
116
A 40 year old woman with Hashimoto's Disease visits the GP for routine review of medication.
She reported feeling particularly tired recently and visited a private rheumatologist on the advice of friends.
The private rheumatologist ran an autoimmune panel of blood tests showing that she is positive for ANA, anti-TPO antibody positive and positive for rheumatoid factor. Other bloods were unremarkable except for low T3 and T4.
What condition is responsible for her symptoms?
Hashimoto's thyroiditis
ANA is typically detected using indirect immunofluorescence.
A patient's serum is mixed with immortalised HeLa cells. Antibodies in the patient's serum will bind to their target on the immortalised cells. The serum is washed off and a fluorescent tag that binds to human antibodies is added.
The pattern of immunofluorescence under a microscope suggests which antibodies are present.
Homogenous pattern of ANA staining, suggests the presence of anti-dsDNA antibodies.
"Speckled" pattern, suggesting the presence of anti-centromere antibodies and hence CREST syndrome.
ANA and other auto-antibodies are often detectable in patients without evidence of disease. For example, approximately 10% of people are positive for rheumatoid factor - even though 10% of people don't have rheumatoid arthritis. Diagnosis of rheumatological conditions often require a combination of symptoms and immunological evidence of disease.
117
A 38 year old lady with known polycystic kidney disease received 3 units of blood over the last day due to a post-partum haemorrhage. She is complaining of shortness of breath. Chest X ray reveals bilateral pulmonary infiltrates. What complication of blood transfusion is she suffering from?
Transfusion Related Acute Lung Injury
Transfusion related acute lung injury (TRALI) is due to the presence of leukocyte antibodies causing white blood cells to aggregate in the pulmonary circulation as it passes through in the blood. The disease is characterised by acute onset pulmonary oedema, dyspnoea, severe hypoxaemia and hypotension. Treatment is usually supportive with a good resolution within 2 days. However, severe TRALI may lead to acute respiratory distress syndrome.
118
What is the maximum number of viral capsids that a molecule of IgM may bind to?
10
Immunoglobulin M (IgM) is a pentameric immunoglobulin. It is one of the first Ig molecules made in the early response to an infection. Each binding site has a relatively low affinity to antigen - this is compensated by the fact it has 10 binding sites. Structurally, it is 5 immunoglobulin molecules joined together by a J chain. It's especially good at activating complement and agglutination.
119
A 50 year old man is seen by the rheumatologists. The rheumatologists take a thorough history and the symptoms he experiences include: exquisitely painful fingers when entering the chilled aisle of his local supermarket, difficulty swallowing large bites of food, tight skin on his hands and around his mouth. In addition, he is easily fatigable and often feels feverish. His CRP is raised and an autoantibody is detected.
In the absence of other signs, what is the most likely diagnosis?
CREST syndrome
120
What drug is given prophylactically to infants at high risk of developing life threatening RSV infection?
Palivizumab
nfection with RSV carries a very high risk of mortality in children with preexisting lung disease, low physiological reserve, premature or immunocompromised children. A monoclonal antibody directed against RSV, palivizumab, may be used in these populations to protect against infection. It is delivered intramuscularly and has a half life of approximately 20 days.
121
Before commencing what immunosuppressive drug must levels of the enzyme TPMT be measured?
Azathioprine
Azathioprine is a antiproliferative immunosuppressant that particularly inhibits T cells. It is metabolised into the inert 6-mercaptopurine. Mutations in an enzyme, TPMT, can mean that azathioprine is metabolised into a cytotoxic metabolite instead of 6 mercaptopurine. Hence, before starting azathioprine all patients should have activity of the TPMT enzyme checked.
122
What class of medication may alleviate the symptoms of transfusion associated circulatory overload?
Diuretics
Transfusion associated circulatory overload is a state of hypervolaemia secondary to transfusion of blood products (and hence fluid) greater than the capacity of the body to return to euvolaemia.
Renal failure may predispose to TACO.
Symptoms include: shortness of breath (pulmonary oedema), peripheral oedema and hypertension.
It can be treated with diuretics.
123
What antigen does the immune system erroneously target in autoimmune thrombocytopenic purpura?
Glycoprotein IIb/IIIa
Type 2 Hypersensitivity is due to antibody directly binding to cells and tissues that leads to cell damage.
Examples include:
Pernicious anaemia (anti parietal cell antibodies)
Graves' disease (anti-TSH receptor)
Immune thrombocytopenic purpura (anti-platelet antibodies such as anti-glyoprotein IIb/IIIa)
Goodpasture's syndrome (Anti-glomerular basement membrane antibodies [specifically anti-type IV collagen antibodies])
Haemolytic disease of the newborn (maternal IgG against fetal erythrocyte antigens)
Pemphigus Vulgaris (anti-cadherin)
124
What monoclonal antibody targets CD25 and is used in the prophylaxis and treatment of allograft rejection?
Basiliximab
CD25, or the interleukin 2 receptor chain alpha, is one of the three components of the IL-2 receptor. Antibodies targeting CD25, such as basiliximab or daclizumab, therefore inhibit T cell proliferation. It used to be used in the treatment of allograft rejection, but now may be used for treatment of multiple sclerosis.
125
What assay is used as the first line test for HIV infection?
Enzyme Linked Immunosorbent Assay
HIV is diagnosed using a number of methods: A first line screening test for HIV is a fourth generation Enzyme Linked Immunosorbent Assay (ELISA) test. It may result in a false positive test. If the ELISA is positive, to confirm diagnosis, a Western Blot may be used. The combination of both methods is very accurate. A HIV viral load of less than 40 copies per mL of blood is considered to be undetectable.
126
What lymphocyte lineage does mycophenolate mofetil predominantly inhibit?
T lymphocytes
Mycophenolate mofetil is an antiproliferative immunosuppressant that targets predominantly T lymphocytes.
127
What monoclonal antibody targets alpha4 integrin and is used in the treatment of relapsing remitting multiple sclerosis?
Natalizumab
Natalizumab targets alpha-4 integrin and prevents lymphocyte migration into the central nervous system.
It is used for treatment of multiple sclerosis and is associated with reactivation of latent JC virus .
JC virus reactivation causes a rapidly fatal progressive multifocal leukoencephalopathy in immunosuppressed patients.
Hence all patients are risk assessed for JC virus infection prior to starting treatment with natalizumab.
128
What is the long term management of Bruton's agammagobulinaemia?
Normal Human Immunoglobulin
Bruton's Agammaglobulinaemia is a rare X linked immunodeficiency caused by a mutation in the BTK gene, which codes for a tyrosine kinase required for B cell development. Patients with this condition suffer from recurrent infections, typically from Streptococcal or Haemophilus spp. It often does not manifest until after 6 months, when the child loses passive immunity from the mother when breastfeeding. There is a notable lack of lymphoid tissue (lack of tonsils and adenoids) or lack of lymphadenopathy during infections. There is a decrease in all immunoglobulins, though small amounts may be present. It can usually be managed by injections of normal human IVIg for life.
129
CD3 is typically a marker of what immune cell?
T cells
CD3 is found on all T cells. It forms part of the T cell receptor for MHC and involved in T cell activation
130
A depressed 40 year old vegan presents to their GP with progressive tiredness. She is on treatment for Hashimoto's thyroiditis and has daily multivitamin supplementation. Her sister is also hypothyroid.
A routine blood panel reveals a macrocytic anaemia. Serum B12 levels are low.
What is the most likely cause of the low B12?
Pernicious Anaemia
Pernicious anaemia is the most common cause of B12 deficiency. Autoantibodies directed against parietal cells (which secrete intrinsic factor) or intrinsic factor itself are responsible for the condition. Anti-intrinsic factor antibodies are much more specific to the disease compared to anti-parietal cell antibodies, which are found in up to 10% of the population without the disease.
131
What monoclonal antibody targets the IL-6 receptor and is involved in the treatment of rheumatoid arthritis?
Tocilizumab
Rheumatoid arthritis is a disease mediated by the cytokines TNF-alpha and IL-6. Most biological (mAb) therapies target these pathways. Examples include: anti-TNF-alpha mAbs: Infliximab, Adalimumab, , Golimumab, Certolizumab, anti-TNF fusion proteins such as Etanercept. anti-IL-6 mAb: Tocilizumab Other classes of medications may be used, including: anti-CD20 mAb: Rituximab Glucocorticoids Methotrexate
132
Which subtype of T helper cells are implicated in the development of allergic diseases, such as asthma or eczema
T helper 2 cells
Parasites and helminths activate the Th2 arm of the adaptive immune response.
This is a process mediated by cytokines such as IL-4, IL-5 and IL-13.
This axis is also implicated in the development of allergy.
There may also be elevated levels of IgE, due to antibody class switching secondary to the previously mentioned chemokines.
In the innate immune system, parasites and helminths cause a mastocytosis or eosinophillia
133
Zidovudine is an example of what class of antiretroviral agents?
Nucleoside Reverse Transcriptase Inhibitor
HIV is treated using Highly Active Antiretroviral Therapy (HAART), sometimes called ART (antiretroviral therapy)
UK guidelines (BHIVA) suggest HAART should consist of three medications:
Two nucleoside reverse transcriptase inhibitors (NRTIs) and another class of drug.
Examples of the common drug classes include:
NRTI: Zidovudine, Abacavir
Non-nucleoside reverse transcriptase inhibitor: Efavirenz
Protease inhibitor: Ritonavir
Integrase inhibitor: Dolutegravir
Zidovudine is considered safe for use in pregnancy
134
An autoimmune panel of bloods reveals a positive anti-mitochondrial antibody. What autoimmune condition is associated with this autoantibody?
Primary Biliary Cirrhosis
The classical autoantibody associated with Primary Biliary Cirrhosis (PBC) is Anti-Mitochondrial antibody (AMA). 95% of patients with PBC have a high titre of AMA. Typically PBC will cause damage to liver parenchyma due to cholestasis of bile secondary to destructure of bile ducts. Middle aged women are predominantly affected in a ratio of 9:1 F:M.
135
A neutrophil engulfs a pathogen and contains the pathogen within a membrane bound organelle.
What is this process known as?
Phagocytosis
Neutrophils, the most abundant white blood cell in peripheral blood, are the hallmark of acute inflammation. They transmigrate through vascular endothelium to sites of inflammation. They have a limited capacity for phagocytosis and die quite quickly. They are responsible for the whitish cellular material in pus. They may also release alarm cytokines, such as IL-1, to attract other cells such as macrophages. Furthermore, through a process known as degranulation, bactericidal molecules and enzymes can augment the immune response.
136
Immunoglobulins may bind to multiple pathogens at once in order to enhance phagocytosis.
What is this process known as?
Agglutination
Opsonisation is where, as a result of antibodies binding to the surface of a pathogen, an otherwise undigestable pathogen is allowed to be phagocytosed.
Agglutination, on the other hand, is a process where to enhance phagocytosis, an antibody (such as IgM) may bind to multiple pathogens at once to allow for more effective clearance.
137
Which joints in the hand are classically not affected by rheumatoid arthritis?
Distal Interphalangeal Joints
138
A 19 year old vegan presents to his GP with diarrhoea and vomiting of two days duration. He typically has 4 episodes of gastroenteritis a year and suffers from recurrent sinusitis. Immunoglobulin levels reveal a lack of IgA, IgG normal, IgM mildly elevated, IgE normal. What primary immunodeficiency is this patient likely to have?
Selective IgA Deficiency
IgA deficiency is the most common inherited immunodeficiency, with a prevalence of approximately 1 in 500. A lack of IgA leads to infections of mucosal surfaces. Clinically, this may present as repetitive upper respiratory tract infections, ear infections or sinusitis. In most patients, the disease is mild and it is undiagnosed. There is an increased association with autoimmune diseases in patients with IgA deficiency.
139
The paediatric SpR is called to review a 21 day old infant who is pyrexic and appears unwell. The child has a high forehead, low set ears and a cleft palate. He has a fever of 39C. Blood tests reveal a neutrophil count of 8 (normal range: 1.5-8.0), absent T cells and normal B cells. What primary immunodeficiency is this patient likely to have?
DiGeorge Syndrome
DiGeorge syndrome results from a deletion of part of chromosome 22 (22q11.2) (Question feedback: you must be specific to what has happened to the chromosome, ie a deletion, not simply state the locus affected)
This results in a number of abnormalities which can be remembered with the acronym CATCH 22 (with the 22 referring to the chromosomal deletion):
```
Cardiac anomalies
Abnormal facies
Thymic aplasia
Cleft palate
Hypoparathyroidism
```
Individuals with DiGeorge syndrome are born without the 3rd and 4th branchial arches and so do not have parathyroid glands.
140
What gene is defective in Bruton's agammagobulinaemia?
BTK gene
Bruton's Agammaglobulinaemia is a rare X linked immunodeficiency caused by a mutation in the BTK gene, which codes for a tyrosine kinase required for B cell development. Patients with this condition suffer from recurrent infections, typically from Streptococcal or Haemophilus spp. It often does not manifest until after 6 months, when the child loses passive immunity from the mother when breastfeeding. There is a notable lack of lymphoid tissue (lack of tonsils and adenoids) or lack of lymphadenopathy during infections. There is a decrease in all immunoglobulins, though small amounts may be present. It can usually be managed by injections of normal human IVIg for life.
141
Which arm of the complement pathway is implicated in the pathogenesis of systemic lupus erythematosus?
Classical
The complement system is a system of many serine proteases produced by the liver. There are three main methods of complement activation: the classical, alternative and mannose binding lectin pathways. The classical pathway is associated with the serine protease C1q binding to antibodies and leading to subsequent complement activation. Dysfunction of the classical pathway may lead to Lupus.
142
What test can be used to measure the levels of serum IgE directed against brazil nut antigens?
Radioallergosorbent test
Skin prick testing is used to determine allergens in Type 1 (IgE mediated) Hypersensitivity reactions, such as allergic rhinitis.
Histamine is injected as a positive control, saline as a negative.
Antihistamines must be stopped 48 hours prior to the test to allow for an accurate result.
Patch testing is used for the diagnosis of Type 4 (T cell mediated) hypersensitivity reactions, such as contact dermatitis.
Blood tests (such as a radioallergosorbent test) also exist for the detection of allergen specific IgE in blood.
However, the gold standard for diagnosis of food allergy is a double-blind, oral food challenge test. A small quantity of suspected allergen (or placebo) is administered in a hospital environment.
143
A 23 year old gentleman presents to their GP complaining of difficulty swallowing and feeling generally run down for the last 6 months. On examination, a white pseudomembrane is found covering the the soft palate. When swabbed, the membrane is easily removed but there is pinprick bleeding. What complication of immunodeficiency is this patient suffering from?
Oral candidiasis
The best answer here is oral candidiasis. A white pseudomembrane which can be removed is highly suspicious for candidiasis. Often, it may be itchy, sore or bleed. Oesophageal candidiasis presents differently, usually with a difficulty in swallowing. In any patient with oral or oesophageal candidiasis, it is highly suspicious for an immunodeficiency - indeed oesophageal candidiasis is an AIDs defining illness. Oral candidiasis may be seen in patients with poor inhaler technique using inhaled corticosteroids for asthma or COPD.
144
What is the term used to describe a transplant between genetically distinct individuals of the same species?
Allograft
There are a number of terms used to describe transplants:
Isograft - Between genetically identical members of the same species (self transplant or from an identical twin)
Allograft - Between genetically distinct members of same species (most human transplants are these)
Xenograft - Between species
145
What colour is observed on a negative result on a nitro blue tetrazolium (NBT) test for chronic granulomatous disease?
Yellow
Chronic Granulomatous Disease is an inherited immunodeficiency affecting neutrophil function. A full blood count is likely to be normal, however patients are at increased risk of severe, atypical infections (usually catalase positive bacteria). Often, this means recurrent, severe pneumonia before age 5. It is diagnosed by the Nitroblue-tetrazolium (NBT) or dihydrorhodamine (DHR) tests. In CGD, these tests are negative. In the NBT or DHR tests, the presence of reactive oxygen species will cause a colour change. A positive (normal) NBT test will stain neutrophils blue. A negative (abnormal) test will remain colourless. The only curative treatment is haematopoietic stem cell transplantation. Injections of interferon gamma can be used to reduce infections and augment the immune response.
146
What immune cell releases granzyme and perforin when activated?
T killer cells
CD8 is a co-receptor for the T cell receptor and recognises MHC class 1.
MHC class 1 is found on most nucleated cells and presents random intracellular peptides to CD8+ T cells.
If a T cell recognises a peptide-MHC class 1 complex, then the T cell activates and kills the target cell.
Please note: Simply writing "CD8" is not enough detail for the mark. CD8 is a cell surface protein. We use cell surface markers to classify T cells. Hence, CD8+ T Cells is acceptable - but CD8+ is not.
147
What primary immunodeficiency is suggested in a patient with recurrent infections with E Coli, Staphylococcus Aureus, Listeria spp, Klebiella spp, Serratia marcescens and Candida species?
Chronic Granulomatous Disease
Catalase positive organisms express catalase and therefore are resistant to some methods of hydrogen peroxide based killing. Examples include:
```
E coli
Staphylococcus Aureus
Listeria spp
Klebsiella spp
Serratia marcescens
Candida spp
```
They are a common cause of infections in patients with chronic granulomatous disease.
148
What monoclonal antibody targets CD20 and is used in the treatment of lymphomas?
Rituximab
CD20 is classically a marker of mature (not immature) B cells. Plasma cells do not express CD20. Targeting this cell surface protein therefore can deplete B cells without affecting plasma cell driven immunity. Rituximab is a classic monoclonal antibody that targets CD20 and is used in the treatment of B cell driven diseases, such as some lymphomas.
149
What class of medication is tisagenlecleucel?
Chimeric Antigen Receptor T cells
Chimeric Antigen Receptor (CAR) T cells are a very new class of anticancer medication. T cells from the patient are removed. A gene containing a T cell receptor (CD3) specific to the patient's cancer is inserted into the DNA of the T cells using a virus. The resulting T cell hybrids are grown in a lab and reinfused into the patient. The CAR-T cells meet their target antigen in the cancer, resulting in T cell activation and subsequent killing of the cancer cell. An example is tisagenlecleucel against CD19. Hence it is used for B cell Acute Lymphoblastic Leukaemias or large B cell lymphomas. A single treatment has a wholesale price of approximately $500,000. CAR T cells are associated with Cytokine Release Syndrome.
150
What specific class of antiretroviral medication does abacavir belong to?
Nucleoside Reverse Transcriptase Inhibitors
HIV is treated using Highly Active Antiretroviral Therapy (HAART), sometimes called ART (antiretroviral therapy)
UK guidelines (BHIVA) suggest HAART should consist of three medications:
Two nucleoside reverse transcriptase inhibitors (NRTIs) and another class of drug.
Examples of the common drug classes include:
NRTI: Zidovudine, Abacavir
Non-nucleoside reverse transcriptase inhibitor: Efavirenz
Protease inhibitor: Ritonavir
Integrase inhibitor: Dolutegravir
Zidovudine is considered safe for use in pregnancy
151
Which type of immunoglobulin is highly specific and is produced more than 5 days after an inital infection?
Immunoglobulin G
Immunoglobulin G is the most abundant antibody in serum. It is highly specific and only created late in a response to infection - typically after around 5 days. Its functions include: activation of the classical pathway of complement via C1q, neutralisation or antibody dependent cell-mediated cytotoxicity. It is a monomeric antibody with 2 highly specific antigen binding sites.
152
What HLA allele is associated with Graves disease?
HLA-DR3
153
What is the term used to describe a transplant between different species?
Xenograft
There are a number of terms used to describe transplants:
Isograft - Between genetically identical members of the same species (self transplant or from an identical twin)
Allograft - Between genetically distinct members of same species (most human transplants are these)
Xenograft - Between species
154
What virus is polyarteritis nodosa associated with?
Hepatitis B
Polyarteritis Nodosa is a rare medium vessel vasculitis. It typically affects medium-sized arteries, such as the renal arteries.
The clinical presentation will be signs of end organ damage with constitutional symptoms (fever, tiredness) in a patient with risk factors. There may be other signs present, such as livedo reticularis.
Classically it is associated with Hepatitis B infection.
The effect of the inflammation is to cause a rosary bead appearance of arteries, where small aneurysms in arterial walls appear to look like beads on a string.
If a biopsy is required, a typical site is the Sural nerve (a superficial nerve in the calf of the leg).
155
Which interleukin is classically responsible for inducing fever?
Interleukin 1
Acute phase proteins include: IL-1, IL-6 and CRP.
They are produced by the liver in response to infection and are involved in the upregulation of many functions of the immune system.
IL-1 and IL-6 are very pyrogenic and cause fever.
CRP binds to the surface of dead or dying cells and activates the classical complement cascade via C1q.
156
What type of hypersensitivity reaction is Goodpasture's disease?
Type II
Type 2 Hypersensitivity is due to antibody directly binding to cells and tissues that leads to cell damage.
Examples include:
Pernicious anaemia (anti parietal cell antibodies)
Graves' disease (anti-TSH receptor)
Immune thrombocytopenic purpura (anti-platelet antibodies such as anti-glyoprotein IIb/IIIa)
Goodpasture's syndrome (Anti-glomerular basement membrane antibodies [specifically anti-type IV collagen antibodies])
Haemolytic disease of the newborn (maternal IgG against fetal erythrocyte antigens)
Pemphigus Vulgaris (anti-cadherin)
157
A 21 year old female presents to her GP after feeling very tired for the last month. She has lost 5% of her body weight unintentionally over this time. She reports going to the toilet more frequently including at night. She also says she is drinking a lot more than usual. What autoimmune disease presents with these symptoms?
Type 1 Diabetes Mellitus
T1DM is a type IV hypersensitivity reaction, mediated by T cell destruction of beta cells.
158
What serine protease released by neutrophils causes hepatitis and emphysema in patients deficient in alpha-1 antitrypsin?
Neutrophil elastase
Neutrophils, the most abundant white blood cell in peripheral blood, are the hallmark of acute inflammation. They transmigrate through vascular endothelium to sites of inflammation. They have a limited capacity for phagocytosis and die quite quickly. They are responsible for the whitish cellular material in pus. They may also release alarm cytokines, such as IL-1, to attract other cells such as macrophages. Furthermore, through a process known as degranulation, bactericidal molecules and enzymes can augment the immune response.
159
What class of medication acts by inhibiting phospholipase A2 and reduces the expression of pro-inflammatory cytokines?
Corticosteroids
Glucocorticoids (Prednisolone, Hydrocortisone etc) are potent immunosuppressants with a large number of side effects. They bind to the glucocorticoid receptor in the nucleus of cells and affect the expression of a large number of genes. Particularly, it inhibits Phospholipase A2 and prevents synthesis of proinflammatory cytokines.
160
HLA types DR, DQ and DP are what class of the major histocompatibility complex?
2
Human Leukocyte Antigen (HLA) is the human specific term for the Major Histocompatibility Complex (MHC).
HLA classes A, B and C are MHC Class 1 (one letter = class one)
HLA classes DR, DQ, DR are MHC Class 2 (two letters = class two).
The most important HLA classes with respect to transplant are DR > B > A
Up to 6 HLA subtypes may be inherited, 3 from each parent.
They are expressed in a co-dominant fashion, meaning all will be expressed.
161
A 26 year old with seasonal allergic rhinitis presents to his GP. He read online that the GP can do a test to find out what pollens he needs to avoid. What test can be used to identify the allergens in allergic rhinitis?
Skin Prick Testing
Allergic rhinitis, or hayfever, is a Type 1 hypersensitivity reaction to antigens found in pollen. Typical symptoms include: itchy, runny nose or eyes and sneezing. On examination, pale, blue hypertrophied nasal turbinates may be visualised. Specific allergens can be identified using skin prick testing. Treatment is with nasal corticosteroids or oral antihistamines, typically cetirizine, due to its relatively long half life (approx 6 hours).
162
What is the target of the antibody P-ANCA?
Myeloperoxidase
Antineutrophil cytoplasmic antibodies are implicated in pauci-immune conditions such as granulomatosis with polyangiitis or goodpasture's disease.
Their presence suggests a breakdown in immune tolerance as the immune system has become sensitised to intracellular antigens.
p-ANCA = Myeloperoxidase = UC, Eosinophilic Granulomatosis with Polyangiitis, Primary Sclerosing Cholangitis or Microscopic Polyangiitis
c-ANCA = Proteinase-3 = Granulomatosis with polyangiitis (Wegner's)
163
What autoimmune condition is associated with demyelination in the central nervous system, caused by an immune response against Myelin Basic Protein?
Multiple Sclerosis
A type IV T cell mediated response directed against Myelin Basic Protein or Proteolipoprotein. Th17, a subtype of T helper cells, that are usually associated with parasites or fungal infections, is involved in the pathogenesis of the condition. Oligoclonal bands of IgG may be found in electrophoresis of Cerebrospinal Fluid of patients with MS.
164
What is the maximum number of viral capsids that a molecule of secretory IgA may bind to?
4
Secretory IgA is a dimeric antibody typically found on mucosal or epithelial surfaces, such as in the mouth or gut. It is also the main antibody found in breast milk. It is made up of two immunoglobulin molecules joined by a J chain. It may also contain a secretory component, which allows for transmigration across epithelial surfaces. As it is a dimeric antibody, there are 4 antigen binding sites. There is also a monomeric form that typically circulates in serum. Its main function is neutralisation - blocking pathogenic ligands from binding to epithelial cell surface receptors.
165
In haemolytic disease of the newborn, what maternal class of immunoglobulin is responsible for destruction of neonatal erythrocytes?
Immunoglobulin G
Type 2 Hypersensitivity is due to antibody directly binding to cells and tissues that leads to cell damage.
Examples include:
Pernicious anaemia (anti parietal cell antibodies)
Graves' disease (anti-TSH receptor)
Immune thrombocytopenic purpura (anti-platelet antibodies such as anti-glyoprotein IIb/IIIa)
Goodpasture's syndrome (Anti-glomerular basement membrane antibodies [specifically anti-type IV collagen antibodies])
Haemolytic disease of the newborn (maternal IgG against fetal erythrocyte antigens)
Pemphigus Vulgaris (anti-cadherin)
166
Autoantibodies directed against Fibrillarin and Scl70 are classically associated with what autoimmune condition?
Diffuse Cutaneous Systemic Sclerosis
Antibodies associated with Diffuse Systemic Sclerosis include:
Anti-Scl70 (anti-topoisomerase)
Anti-Fibrillarin
Anti-centromere antibodies (present in around 10%)
167
Where are IgA antibodies typically found in the body?
Mucosal surfaces
Secretory IgA is a dimeric antibody typically found on mucosal or epithelial surfaces, such as in the mouth or gut. It is also the main antibody found in breast milk. It is made up of two immunoglobulin molecules joined by a J chain. It may also contain a secretory component, which allows for transmigration across epithelial surfaces. As it is a dimeric antibody, there are 4 antigen binding sites. There is also a monomeric form that typically circulates in serum. Its main function is neutralisation - blocking pathogenic ligands from binding to epithelial cell surface receptors.
168
What HLA allele is associated with Systemic Lupus Erythematosus?
HLA-DR3
169
What condition arises when donor lymphocytes, contained within a solid organ, attack the recipient's cells and tissues?
Graft Versus Host Disease
Graft Versus Host Disease (GvHD) arises when lymphocytes from a transplant donor attack cells and tissues of a transplant recipient. Typically, this occurs when the recipient is heavily immunosuppressed (and cannot destroy the donor lymphocytes) or very young. To counteract this, immunosuppressive drugs such as methotrexate may be used. GvHD presents typically with damage to mucosal surfaces in the area of the transplant. In the GI tract, this may present with severe diarrhoea, abdominal pain and vomiting. In the skin, typically a maculopapular rash.
170
A 48 year old female is seen by the dermatologists for "tight, painful skin". She says it is particularly painful on her fingers when it is cold, but otherwise she says it is difficult to move her fingers. On examination, tight, smooth skin is noted on the wrist, arm, trunk and around the mouth. In addition, she is desperately tired and sleeps for 10 hours a day. She also has difficulty eating and so has lost weight. Her ESR is raised. What is the most likely diagnosis?
Diffuse Cutaneous Systemic Sclerosis
171
A 3 year old boy has recurrent chest infections. On examination, he has no visible tonsilar tissue. Blood tests reveal a low lymphocyte count, with very low B cells but normal T cell levels. There is very low levels of IgM, IgA and IgG. What primary immunodeficiency is this patient likely to have?
Bruton's Agammaglobulinaemia
Bruton's Agammaglobulinaemia is a rare X linked immunodeficiency caused by a mutation in the BTK gene, which codes for a tyrosine kinase required for B cell development. Patients with this condition suffer from recurrent infections, typically from Streptococcal or Haemophilus spp. It often does not manifest until after 6 months, when the child loses passive immunity from the mother when breastfeeding. There is a notable lack of lymphoid tissue (lack of tonsils and adenoids) or lack of lymphadenopathy during infections. There is a decrease in all immunoglobulins, though small amounts may be present. It can usually be managed by injections of normal human IVIg for life.
172
What colour is observed on a positive result on a nitro blue tetrazolium (NBT) test for chronic granulomatous disease?
Blue
Chronic Granulomatous Disease is an inherited immunodeficiency affecting neutrophil function. A full blood count is likely to be normal, however patients are at increased risk of severe, atypical infections (usually catalase positive bacteria). Often, this means recurrent, severe pneumonia before age 5. It is diagnosed by the Nitroblue-tetrazolium (NBT) or dihydrorhodamine (DHR) tests. In CGD, these tests are negative. In the NBT or DHR tests, the presence of reactive oxygen species will cause a colour change. A positive (normal) NBT test will stain neutrophils blue. A negative (abnormal) test will remain colourless. The only curative treatment is haematopoietic stem cell transplantation. Injections of interferon gamma can be used to reduce infections and augment the immune response.
173
What type of hypersensitivity is characterised by immune complex mediated tissue damage?
Type 3
Type 3 hypersensitivity is characterised by immune complex deposition in tissues causing a local inflammatory response. An immune complex means an antibody that has bound to its antigen. Immune complexes cause inflammation through activation of complement (hence, complement is used up - reflecting disease activity in SLE) and the release of cytokines which lead to tissue damage.
174
Which cytokine is important in the pathogenesis of rheumatoid arthritis, anyklosing spondylitis and inflammatory bowel disease?
Tumour Necrosis Factor Alpha
TNF-alpha is a acute phase protein that is very immunogenic and causes fevers. It upregulates the immune response against intracellular pathogens. TNF-alpha is implicated in autoimmune diseases such as rheumatoid arthritis, ankylosing spondylitis and inflammatory bowel disease.
175
A 45 year old female is undergoing preparation for an elective cholecystectomy.
As part of the pre-surgery workup, what blood test should be ordered to minimise the risk of complications if a blood transfusion is required?
Group and Save
The best blood type depends on the time available.
If there is sufficient time for a crossmatched blood sample, then the results of these blood tests should guide management. Typically, this process takes at least an hour.
A group and save is a blood test that identifies the blood type and Rh antigen status. It is valid for up to three months (if no blood products have been given before).
Cross match is the direct mixing of donor blood products and recipient serum. It is how blood products are ordered - so ordering a cross match reserves blood for that specific patient. No one else can be given that blood until the cross match expires. A cross match is normally only done when there is an imminent need for blood. Cross matched samples are typically valid for less than a few days.
However, if there is not time for G&S +- crossmatch then:
There are no contraindications to O negative blood.
O positive blood may be given to males or postmenopausal women. If O positive blood is given to women of childbearing age (who are Rh antigen negative) then it may lead to haemolytic disease of the newborn if she has a Rh negative child.
A group and save may be valid for 3 months if a patient has never received a transfusion. However, if a patient has received a transfusion, group and saves are normally only valid for 72 hours. Some hospitals stipulate 72 hours for all samples. This is so that any new antibodies can be detected.
176
A 23 year old female presents to her GP with painful wrists bilaterally. On questioning, she also hasn't been herself for a few months due to being exhausted. She put this down to looking after her 6 year old with suspected ADHD.
On examination, you notice a scaly erythematous rash on the patient's face sparing the nasolabial folds. She says she got badly sunburnt a few weeks ago on holiday and is still recovering from it. She says the joint pain has been particularly bad since receiving the sunburn.
FBCs reveal an elevated White Cell Count, TFTs unremarkable, Coeliac screen negative, Rheumatoid Factor Positive, ANA positive.
What is the diagnosis?
Systemic Lupus Erythematosus
177
The paediatric SpR is called to review a 21 day old infant who is pyrexic and appears unwell. His parents are concerned about his florid diarrhoea since birth and an eczema-like rash that has been present since day 3 after birth. He has a fever of 39C. Blood tests reveal a neutrophil count of 8 (normal range: 1.5-8.0), absent T cells and elevated B cells. What primary immunodeficiency is this patient likely to have?
X Linked Severe Combined Immunodeficiency
X Linked Severe Combined Immunodeficiency (SCID) is found when there is a defective or deficient gene coding for the common gamma chain (IL-2RG) of the IL-2 receptor. IL-2 is a vital cytokine used for activation and differentiation of the adaptive immune system, particularly T cells. The common gamma chain (IL-2RG), in addition to being part of the IL-2 receptor, also is part of receptors for IL-4, IL-7, IL-9, IL-15 and IL-21. Clinically, X linked SCID presents within the first month of birth typically with sepsis. T cells are often absent (as the lack of IL-2 receptor prevents their growth). Also, there is a deficiency in immunoglobulins as IL-4 is involved in B cell differentiation to plasma cells. An eczema like rash is often present. Failure to thrive or systemic Candida infections may also be present.
178
Eosinophillia suggests an infection by what class of organism?
Parasites
Parasites and helminths activate the Th2 arm of the adaptive immune response.
This is a process mediated by cytokines such as IL-4, IL-5 and IL-13.
This axis is also implicated in the development of allergy.
There may also be elevated levels of IgE, due to antibody class switching secondary to the previously mentioned chemokines.
In the innate immune system, parasites and helminths cause a mastocytosis or eosinophillia
179
What lymphocyte lineage does cyclosporine predominantly inhibit?
T lymphocytes
Medications that inhibit Calcineurin, a protein needed for T cell proliferation, include tacrolimus or cyclosporine. Side effects include renal damage, hypertension or in the case of cyclosporine, gingival hyperplasia.
180
What do you measure in a mantoux test?
Diameter of induration
The mantoux test measures the immune response to tuberculosis antigens.
A Purified Protein Derivative of Tuberculin is injected intradermally.
The size of the induration (not erythema) is measured after 48-72 hours.
Science:
If a patient has previously been exposed to tuberculosis antigens (via any form, including previous mantoux tests or active infection) then they will react vigorously and create an area of induration around the injection site.
Immunosuppressed people will mount a weaker immune response, hence the interpretation thresholds are smaller.
Interpretation:
>5mm is positive in HIV or immunosuppressed patients or people at very high risk of TB (such as living with someone with active TB)
>10mm is positive in IVDU, medium risk populations such as healthcare workers or children <4 years old
>15mm is positive in low risk populations.
Interpretation guidelines differ, but what is provided here is an approximate guide.
181
An autoimmune panel of bloods reveals a positive anti-centromere antibody. What autoimmune condition is associated with this autoantibody?
Limited Systemic Sclerosis
Anti-centromere antibody is found in approximately 65% of patients with limited cutaneous systemic sclerosis (CREST syndrome). However, it is 98% specific for the condition. It's also associated with a more benign disease course. The ANA staining pattern of anti-centromere antibody creates a speckled appearance under indirect immunofluorescence.
182
What is the maximum number of viral capsids that a molecule of IgG may bind to?
2
Immunoglobulin G is the most abundant antibody in serum. It is highly specific and only created late in a response to infection - typically after around 5 days. Its functions include: activation of the classical pathway of complement via C1q, neutralisation or antibody dependent cell-mediated cytotoxicity. It is a monomeric antibody with 2 highly specific antigen binding sites.
183
What type of vaccine uses antigenic proteins to induce immunity?
Recombinant vaccine
There is a huge variability in pathogens.
Hence, in order to get the best possible immunity, vaccines vary as well.
There are a few main types of vaccines:
Live attenuated vaccines
These are avoided in pregnancy and immunocompromised patients.
Examples include:
BCG for TB, MMR, Yellow Fever
Subunit (recombinant) Vaccines
Typically for viruses.
The vaccine contains proteins found on the surface of the viruses in addition to an adjuvant. Examples include Hep B and HPV.
Conjugate vaccines
For encapsulated bacteria.
Consist of bacterial polysaccharides conjugated to an immunogenic toxin (diphtheria toxin).
Used for Haemophilus influenzae, meningococcus and pneumococcus.
Inactivated vaccines
These are vaccines where the pathogens have been rendered inert - usually by heat killing or formaldehyde.
Examples include the pertussis vaccine.
As the pathogen cannot replicate, it usually requires multiple booster shots to provide immunity.
184
There is a huge variability in pathogens.
Hence, in order to get the best possible immunity, vaccines vary as well.
There are a few main types of vaccines:
Live attenuated vaccines
These are avoided in pregnancy and immunocompromised patients.
Examples include:
BCG for TB, MMR, Yellow Fever
Subunit (recombinant) Vaccines
Typically for viruses.
The vaccine contains proteins found on the surface of the viruses in addition to an adjuvant. Examples include Hep B and HPV.
Conjugate vaccines
For encapsulated bacteria.
Consist of bacterial polysaccharides conjugated to an immunogenic toxin (diphtheria toxin).
Used for Haemophilus influenzae, meningococcus and pneumococcus.
Inactivated vaccines
These are vaccines where the pathogens have been rendered inert - usually by heat killing or formaldehyde.
Examples include the pertussis vaccine.
As the pathogen cannot replicate, it usually requires multiple booster shots to provide immunity.
Sensitisation
Sensitisation refers to the immunological process where, after being exposed to an antigen, an immune response is generated against the antigen.
Typically the first exposure will have no symptoms, but the second exposure results in a vigorous response.
Examples include IgE mediated allergic reactions (first exposure activates B cells, which class switch and produce IgE antibodies. These IgE antibodies bind to mast cells). Alternatively, hyperacute transplant rejection is due to preformed antibodies against ABO.
185
An autoimmune panel of bloods reveals positive anti-cardiolipin and anti-B2 glycoprotein. What autoimmune condition is associated with these autoantibodies?
Anti Phospholipid Syndrome
186
A 13 year old girl is diagnosed with type 1 diabetes mellitus following hospital admission for diabetic ketoacidosis.
Her thyroid function and liver function tests are normal.
What other autoimmune disease should she be screened for on this admission?
Coeliac Disease
Most autoimmune disease has an overlapping genetic component.
This is mainly due to shared HLA haplotypes between conditions - the idea that for an autoimmune disease to be present, a self antigen is presented in such a way that tolerance to that antigen is not developed or tolerance is lost. Some HLA haplotypes e.g. HLA-DQ2 are associated with multiple autoimmune conditions.
In practical terms, this means that for new diagnoses of autoimmune conditions, it's good practice to consider the presence of other autoimmune conditions.
All new diagnoses for T1DM should be screened for coeliac antibodies, for instance.
187
CD20 is typically a marker of what type of immune cell?
Mature B cells
CD20 is classically a marker of mature (not immature) B cells. Plasma cells do not express CD20. Targeting this cell surface protein therefore can deplete B cells without affecting plasma cell driven immunity. Rituximab is a classic monoclonal antibody that targets CD20 and is used in the treatment of B cell driven diseases, such as some lymphomas.
188
A nurse calls you over on the ward as a 5 year old girl is beginning to scratch excessively at her arms. She says her head hurts and she feels faint. The nurse says she started a blood transfusion 25 minutes ago. Before this the patient was clinically well. What is the first line management of this complication of blood transfusion?
Stop Transfusion
Allergic reactions to blood products may range from mild urticaria to anaphylaxis.
In general, mild reactions limited to the skin are not enough to warrant stopping the transfusion - they can be treated with antihistamines.
However, if other symptoms occur such as headache, severe widespread rash or airway involvement, this is an indication to stop the transfusion and potentially consider reassessing using an A to E approach.
The first drug in the management of anaphylaxis is both oxygen and adrenaline. However, oxygen can be applied quickly at the bedside. While in reality you will arrange for both to happen, the first thing you should do in an A-E assessment is secure the airway and then apply oxygen. Especially if there are signs of impending respiratory failure e.g. cyanosis.
189
Other than T lymphocytes, what cell type is primarily infected by HIV?
Macrophages
HIV is a sexually-transmitted retrovirus.
It expresses an exceedingly error prone reverse transcriptase.
Reverse transcriptase synthesises DNA from viral RNA.
This viral DNA is then incorporated into the cell's nucleus for the lifetime of the cell. As part of normal cellular protein synthesis, the cell will now produce HIV virions in addition to human proteins.
Typically, HIV infects CD4+ T helper cells, predominantly in the gut. Less commonly it may infect macrophages.
This leads to severe immunosuppression over a period of years and eventually Acquired Immunodeficiency Syndrome (AIDS)
190
What first-line test can be used to quantify the IgE mediated response to specific allergens?
Skin Prick Test
Skin prick testing is used to determine allergens in Type 1 (IgE mediated) Hypersensitivity reactions, such as allergic rhinitis.
Histamine is injected as a positive control, saline as a negative.
Antihistamines must be stopped 48 hours prior to the test to allow for an accurate result.
Patch testing is used for the diagnosis of Type 4 (T cell mediated) hypersensitivity reactions, such as contact dermatitis.
Blood tests (such as a radioallergosorbent test) also exist for the detection of allergen specific IgE in blood.
However, the gold standard for diagnosis of food allergy is a double-blind, oral food challenge test. A small quantity of suspected allergen (or placebo) is administered in a hospital environment.
191
The paediatric SpR is called to review a 16 day old infant who is pyrexic and appears unwell. His umbillical cord stump is still present, non-purulent, red, tender and hot. He has a fever of 39C. Blood tests reveal a neutrophil count of 16 (normal range: 1.5-8.0) What primary immunodeficiency is this patient likely to have?
Leukocyte adhesion defieiency
A rare autosomal recessive immunodeficiency. Neutrophils are unable to adhere to vascular endothelial - hence they cannot transmigrate into tissues to fight infection. This leads to a high level of neutrophils in the blood (neutrophilia). As a result, there is no abscess formation or pus. The neutrophils function normally (so will be be normal in the NBT test) but simply cannot get to where they are needed. Clinically, this may present with delayed umbilical cord sloughing as neutrophils are involved in this process. There is often infections of the skin (particularly omphalitis, infection of the umbilical cord), pneumonia or gums. The only curative therapy is haematopoietic stem cell transplantation.
192
A nurse calls you over on the ward as a 5 year old girl is beginning to scratch at her arms. The nurse says she was started on a blood transfusion 30 minutes ago. Before this the patient was clinically well.
What is the treatment for this complication of blood transfusion?
Non-Sedating Antihistamine
Allergic reactions to blood products may range from mild urticaria to anaphylaxis.
In general, mild reactions limited to the skin are not enough to warrant stopping the transfusion - they can be treated with antihistamines.
However, if other symptoms occur such as headache, severe widespread rash or airway involvement, this is an indication to stop the transfusion and potentially consider reassessing using an A to E approach.
The first drug in the management of anaphylaxis is both oxygen and adrenaline. However, oxygen can be applied quickly at the bedside. While in reality you will arrange for both to happen, the first thing you should do in an A-E assessment is secure the airway and then apply oxygen. Especially if there are signs of impending respiratory failure e.g. cyanosis.
193
What class of hypersensitivity reaction are pemphigus vulgaris and bullous pemphigoid?
Type II
194
Immunoglobulins bound to cells may activate a set of serine proteases, eventually leading to formation of a membrane attack complex. What system is activated?
Complement
The complement system is a system of many serine proteases produced by the liver. There are three main methods of complement activation: the classical, alternative and mannose binding lectin pathways. The classical pathway is associated with the serine protease C1q binding to antibodies and leading to subsequent complement activation. Dysfunction of the classical pathway may lead to Lupus.
195
A neutrophil releases preformed myeloperoxidase, defensins and neutrophil elastase. What is this process known as?
Degranulation
Neutrophils, the most abundant white blood cell in peripheral blood, are the hallmark of acute inflammation. They transmigrate through vascular endothelium to sites of inflammation. They have a limited capacity for phagocytosis and die quite quickly. They are responsible for the whitish cellular material in pus. They may also release alarm cytokines, such as IL-1, to attract other cells such as macrophages. Furthermore, through a process known as degranulation, bactericidal molecules and enzymes can augment the immune response.
196
A nurse pulls the emergency bell on your ward. A 5 year old girl is struggling to breathe with an audible wheeze.
Her lips are swollen and there are urticarial rashes on the visible parts of her face and hands. Her lips are mottled.
She began receiving 1 unit of group O- blood 5 minutes ago for low Hb.
Before this the patient was clinically well.
What complication of blood transfusion is this patient suffering from?
Anaphylaxis
Allergic reactions to blood products may range from mild urticaria to anaphylaxis.
In general, mild reactions limited to the skin are not enough to warrant stopping the transfusion - they can be treated with antihistamines.
However, if other symptoms occur such as headache, severe widespread rash or airway involvement, this is an indication to stop the transfusion and potentially consider reassessing using an A to E approach.
The first drug in the management of anaphylaxis is both oxygen and adrenaline. However, oxygen can be applied quickly at the bedside. While in reality you will arrange for both to happen, the first thing you should do in an A-E assessment is secure the airway and then apply oxygen. Especially if there are signs of impending respiratory failure e.g. cyanosis.
197
What type of bacteria are conjugated vaccines effective against?
Encapsulated
There is a huge variability in pathogens.
Hence, in order to get the best possible immunity, vaccines vary as well.
There are a few main types of vaccines:
Live attenuated vaccines
These are avoided in pregnancy and immunocompromised patients.
Examples include:
BCG for TB, MMR, Yellow Fever
Subunit (recombinant) Vaccines
Typically for viruses.
The vaccine contains proteins found on the surface of the viruses in addition to an adjuvant. Examples include Hep B and HPV.
Conjugate vaccines
For encapsulated bacteria.
Consist of bacterial polysaccharides conjugated to an immunogenic toxin (diphtheria toxin).
Used for Haemophilus influenzae, meningococcus and pneumococcus.
Inactivated vaccines
These are vaccines where the pathogens have been rendered inert - usually by heat killing or formaldehyde.
Examples include the pertussis vaccine.
As the pathogen cannot replicate, it usually requires multiple booster shots to provide immunity.
198
What is the specific antigen recognised by the immune system in Goodpasture's syndrome?
Type IV collagen
Type 2 Hypersensitivity is due to antibody directly binding to cells and tissues that leads to cell damage.
Examples include:
Pernicious anaemia (anti parietal cell antibodies)
Graves' disease (anti-TSH receptor)
Immune thrombocytopenic purpura (anti-platelet antibodies such as anti-glyoprotein IIb/IIIa)
Goodpasture's syndrome (Anti-glomerular basement membrane antibodies [specifically anti-type IV collagen antibodies])
Haemolytic disease of the newborn (maternal IgG against fetal erythrocyte antigens)
Pemphigus Vulgaris (anti-cadherin)
199
A 78 year old gentleman visits his GP. He complains of double vision when reading newspapers in the evenings or when walking his dog late at night. He also reports generalised tiredness and says he struggles to carry his shopping to the car.
He has longstanding well controlled Type 1 Diabetes. On questioning, his sister has coeliac disease.
What is the diagnosis?
Myasthenia Gravis
Type 2 Hypersensitivity is due to antibody directly binding to cells and tissues that leads to cell damage.
Examples include:
Pernicious anaemia (anti parietal cell antibodies)
Graves' disease (anti-TSH receptor)
Immune thrombocytopenic purpura (anti-platelet antibodies such as anti-glyoprotein IIb/IIIa)
Goodpasture's syndrome (Anti-glomerular basement membrane antibodies [specifically anti-type IV collagen antibodies])
Haemolytic disease of the newborn (maternal IgG against fetal erythrocyte antigens)
Pemphigus Vulgaris (anti-cadherin)
200
What HIV protein is involved in initial binding to CD4?
gp120
HIV is made up of two main viral envelope proteins:
gp120 - This receptor is responsible for initial binding to CD4 and a co-receptor, such as the CCR5 receptor.
gp41 - Binding of gp120 exposes gp41.
gp41 then leads to fusion with the host cell membrane and viral entry into the cell.
Mutations in the CCR5 receptor confer immunity against HIV as the virus cannot enter cells to replicate.
201
What type of immune cell upon activation undergoes class switching and somatic hypermutation?
B lymphocytes
B cells are cells of the adaptive immune system and are derived from lymphoid precursors. They mature in the bone marrow (hence the name B cells).
Upon activation, where a B cell expressing its B cell receptor recognises its target antigen, it begins to differentiate into plasma cells (which secrete IgM) or the B cell will undergo somatic hypermutation and class switching, where after a few days high affinity IgG secreting plasma cells will develop.
Note: Plasma cells are derived from B cells - but are not B cells! Hence, rituximab (an antibody against CD20, found on mature B cells) do not kill plasma cells.
202
Levels of what circulating antibody suggest a diagnosis of goodpasture's syndrome?
Anti-Glomerular Basement Membrane
Type 2 Hypersensitivity is due to antibody directly binding to cells and tissues that leads to cell damage.
Examples include:
Pernicious anaemia (anti parietal cell antibodies)
Graves' disease (anti-TSH receptor)
Immune thrombocytopenic purpura (anti-platelet antibodies such as anti-glyoprotein IIb/IIIa)
Goodpasture's syndrome (Anti-glomerular basement membrane antibodies [specifically anti-type IV collagen antibodies])
Haemolytic disease of the newborn (maternal IgG against fetal erythrocyte antigens)
Pemphigus Vulgaris (anti-cadherin)
203
The paediatric SpR is called to review a 2 day old infant who is jaundiced, pyrexic and appears very unwell. The parents think he has a problem with his hearing as he did not cry when the fire alarm went off on the ward. He has a fever of 40.1C. Blood tests reveal an absolute neutropenia and absolute lymphocytopenia. What primary immunodeficiency is this patient likely to have?
Reticular dysgenesis
Reticular dysgenesis is the most severe form of Severe Combined Immunodeficiency (SCID).
It is an autosomal recessive condition characterised by:
Severe, life threatening infections shortly after birth
Profound sensorineural deafness
Deficiency of the myeloid and lymphoid cell lineages
Without rapid bone marrow transplant (hematopoietic stem cell transplant) the condition is invariably fatal.
204
A 75 year old gentleman presents to his GP with recurrent nosebleeds and coughing blood. He now has bloody urine. He has felt generally unwell for a while, but puts this down to his family visiting him less. He has lost weight and reports some loss of sensation in his hands and feet. He is concerned he may have a bleeding problem. His temperature is 38C and CRP is elevated.
Urine dip is positive for protein and blood.
Results of kidney function tests are given below:
Urea Elevated
Creatinine Elevated
eGFR 40 (normal >90)
A previous blood test performed three weeks ago was normal and an eGFR at that time was 80ml.
What underlying immunological condition may this gentleman have?
Granulomatosis with Polyangitis
The key here is to identify causes of a rapidly progressive glomerulonephritis.
The main points are: a rapid decline in kidney function, nosebleeds and coughing blood, constitutional symptoms and peripheral neuropathy.
A rapidly progressive glomerulonephritis in addition to nosebleeds or coughing blood suggests Wegener's granulomatosis. Nosebleeds suggest Wegner's - as this is a site classically affected.
As a small-to-medium vessel vasculitis, it may also cause peripheral neuropathy and the elevated CRP is due to the high levels of inflammation. Wegener's is associated with C-ANCA.
205
A 80 year old lady received 4 units of blood 8 hours ago secondary to excessive bleeding from a minor fall.
Her INR was 3.5 on admission (on warfarin for metallic heart valve). Her GFR was 50ml/min on admission.
Over the last hour, she has felt short of breath, especially when lying down. She is hypertensive at 160/100, usual baseline 140/90.
What complication of blood transfusion is she suffering from?
Transfusion Associated Circulatory Overload
Transfusion associated circulatory overload is a state of hypervolaemia secondary to transfusion of blood products (and hence fluid) greater than the capacity of the body to return to euvolaemia.
Renal failure may predispose to TACO.
Symptoms include: shortness of breath (pulmonary oedema), peripheral oedema and hypertension.
It can be treated with diuretics.
206
What autoantibody can be found in Graves' disease?
Anti Thyroid Stimulating Hormone Receptor
Type 2 Hypersensitivity is due to antibody directly binding to cells and tissues that leads to cell damage.
Examples include:
Pernicious anaemia (anti parietal cell antibodies)
Graves' disease (anti-TSH receptor)
Immune thrombocytopenic purpura (anti-platelet antibodies such as anti-glyoprotein IIb/IIIa)
Goodpasture's syndrome (Anti-glomerular basement membrane antibodies [specifically anti-type IV collagen antibodies])
Haemolytic disease of the newborn (maternal IgG against fetal erythrocyte antigens)
Pemphigus Vulgaris (anti-cadherin)
207
What lymphocyte lineage does tacrolimus predominantly inhibit?
T lymphocytes
Medications that inhibit Calcineurin, a protein needed for T cell proliferation, include tacrolimus or cyclosporine. Side effects include renal damage, hypertension or in the case of cyclosporine, gingival hyperplasia.
208
Which cytokine is predominantly responsible for T cell proliferation and survival?
Interleukin 2
Interleukin 2 (IL-2) is a cytokine that promotes T cell activation. IL-2 is mainly secreted by activated CD4+ T lymphocytes (this being one of the main actions of T helper cells) or activated T killer cells
209
What autoantibody is most commonly associated with Graves' disease?
Anti-TSH Receptor
210
An autoimmune panel of bloods reveals positive anti-liver kidney microsomal-1 antibody and anti-smooth muscle antibody. There is also derangement of LFTs. What autoimmune condition is associated with these autoantibodies and deranged LFTs?
Autoimmune Hepatitis
211
What cell type expresses the T cell receptor, CD4 and recognises MHC Class II?
What cell type expresses the T cell receptor, CD4 and recognises MHC Class II?
CD4 is a co-receptor that recognises MHC class II. MHC class II is classically only present on professional antigen presenting cells and presents antigens from outside the cell.
212
An arterial biopsy of a patient with a suspected arteritis reveals a "rosary bead" appearance of small aneurysms.
What vasculitis is associated with this clinical sign?
Polyarteritis Nodosa
Polyarteritis Nodosa is a rare medium vessel vasculitis. It typically affects medium-sized arteries, such as the renal arteries.
The clinical presentation will be signs of end organ damage with constitutional symptoms (fever, tiredness) in a patient with risk factors. There may be other signs present, such as livedo reticularis.
Classically it is associated with Hepatitis B infection.
The effect of the inflammation is to cause a rosary bead appearance of arteries, where small aneurysms in arterial walls appear to look like beads on a string.
If a biopsy is required, a typical site is the Sural nerve (a superficial nerve in the calf of the leg).
213
A 30 year old female is seen by the rheumatologist.
Her mother suffered from rheumatoid arthritis.
She reports an insidious history of tiredness, multiple painful joints and unintentional weight loss. She says the joints most affecting her are her wrists and knuckle joints.
On examination, there is a swan neck deformity of the fingers on both hands. When asked to push her hand against the table, the deformity corrects itself.
She has an elevated CRP and ESR.
Autoimmune screen reveals she is ANA positive, with high titres of Anti-Sm, Anti-Ro and Rheumatoid Factor.
What is the diagnosis?
Systemic Lupus Erythematosus
A correctable/reversible deformity suggests Jaccoud's arthropathy as part of SLE rather than a diagnosis of rheumatoid arthritis.
214
What type of hypersensitivity is T cell mediated?
Type 4
215
What is the most abundant leukocyte found in peripheral blood?
Neutrophils
Neutrophils, the most abundant white blood cell in peripheral blood, are the hallmark of acute inflammation. They transmigrate through vascular endothelium to sites of inflammation. They have a limited capacity for phagocytosis and die quite quickly. They are responsible for the whitish cellular material in pus. They may also release alarm cytokines, such as IL-1, to attract other cells such as macrophages. Furthermore, through a process known as degranulation, bactericidal molecules and enzymes can augment the immune response.
216
The paediatric SpR is called to review a 21 day old infant who is pyrexic and appears unwell. The parents think he has a problem with his hearing as he has been tugging at his ear. There is pain, tenderness and swelling over the mastoid process of his left ear. Blood tests reveal a neutrophil count of 0.1 (normal range: 1.5-8.0) What primary immunodeficiency is this patient likely to have?
Kostmann Syndrome
Kostmann Syndrome, otherwise known as severe congenital neutropenia, is characterised by frequent, severe bacterial infections (typically involving Staphylococcus). There is a predilection to abscess formation and life threatening infections. Most suffers will have a severe infection in the first month of life, where a neutropenia will be identified on a full blood count. Genetic testing may be done to identify the mutation. Treatment involves regular injections of granulocyte colony stimulating factor, which increases myelopoiesis and increases neutrophil levels.
217
IgE antibodies bind semi-permanently to the surface of what cell of the innate immune system?
Mast cells
Immunoglobin E, IgE, is structurally very similar to IgG. It has two antigen binding sites. Is main role is in the protection against parasites and helminths. IgE uniquely binds to a special type of Fc receptor on the surface of mast cells. This binding is one of the strongest non-covalent bonds found in biological systems. This binding is therefore essentially irreversible. If two IgE molecules on the surface of mast cells recognise antigen and cross-link, then this will lead to mast cell activation and in servere cases, anaphylaxis.
218
What is the definitive treatment for reticular dysgenesis (SCID)?
Haematopoeic stem cell transplantation
Reticular dysgenesis is the most severe form of Severe Combined Immunodeficiency (SCID).
It is an autosomal recessive condition characterised by:
Severe, life threatening infections shortly after birth
Profound sensorineural deafness
Deficiency of the myeloid and lymphoid cell lineages
Without rapid bone marrow transplant (hematopoietic stem cell transplant) the condition is invariably fatal.
219
A 38 year old lady with known polycystic kidney disease received 3 units of blood over the last day due to a post-partum haemorrhage. She is complaining of shortness of breath. On examination she has mild pitting oedema of the sacrum and lower limbs. Serum BNP is elevated. She is apyrexic. What complication of blood transfusion is she suffering from?
Transfusion Associated Circulatory Overload
Transfusion associated circulatory overload is a state of hypervolaemia secondary to transfusion of blood products (and hence fluid) greater than the capacity of the body to return to euvolaemia.
Renal failure may predispose to TACO.
Symptoms include: shortness of breath (pulmonary oedema), peripheral oedema and hypertension.
It can be treated with diuretics.
220
What is the only lymphocyte subset considered to be part of the innate immune system?
Natural killer cells
Natural killer (NK) cells are lymphoid derived cells of the innate immune system. Phenotypically similar to lymphocytes, however they do not express either of the eponymous T or B cell receptors. NK cells can recognise either lack of MHC (a common tactic of viruses to avoid the immune system, by preventing MHC expression) or an imbalance in numerous cell surface receptors. Imbalances in cell surface receptors suggests that the cell may be infected, cancerous or dying.
221
Infliximab, adalimumab, certolizumab and golimumab target what cytokine?
Tumour Necrosis Factor Alpha
Rheumatoid arthritis is a disease mediated by the cytokines TNF-alpha and IL-6. Most biological (mAb) therapies target these pathways. Examples include: anti-TNF-alpha mAbs: Infliximab, Adalimumab, , Golimumab, Certolizumab, anti-TNF fusion proteins such as Etanercept. anti-IL-6 mAb: Tocilizumab Other classes of medications may be used, including: anti-CD20 mAb: Rituximab Glucocorticoids Methotrexate
222
An autoimmune panel of bloods reveals positive anti-dsDNA antibody at a titre of 1:1600.
What autoimmune condition is associated with this autoantibody?
Systemic Lupus Erythematosus
Systemic Lupus Erythematosus (SLE) is a complex autoimmune disorder.
It is considered to be primarily a type III (Immune Complex) hypersensitivity disease, however there is debate over the roles of autoantibodies in the condition.
Anti-dsDNA can be used to monitor disease progression in SLE. Anti-dsDNA is highly specific to SLE.
Anti-Sm (Smith), Anti-Ro, Anti-La or Anti-U1 RNP may also be positive in SLE.
Anti-Histone antibodies are typically found in drug induced SLE.
223
The MMR, VZV and yellow fever vaccines are what type of vaccination?
Live attenuated
224
What is the inheritance pattern of reticular dysgenesis?
Autosomal recessive
Reticular dysgenesis is the most severe form of Severe Combined Immunodeficiency (SCID).
It is an autosomal recessive condition characterised by:
Severe, life threatening infections shortly after birth
Profound sensorineural deafness
Deficiency of the myeloid and lymphoid cell lineages
Without rapid bone marrow transplant (hematopoietic stem cell transplant) the condition is invariably fatal.
225
A 70 year old gentleman is referred to the nephrologists for worsening kidney failure and haematuria. Over the last 3 months, he has lost 20% of his body weight, reports intermittent fevers and joint aches. He is also seeing his GP as he recently started coughing blood.
What underlying immunological condition may this patient have?
Goodpasture's Disease
Goodpasture's syndrome is a Type 2 hypersensitivity reaction with antibodies directed against type IV collagen.
Type IV collagen is a major component of the kidney and lung basement membranes.
It may present with constitutional symptoms of autoimmune disease, in addition to glomerulonephritis and lung haemorrhage.
226
What is the name given to a substance that increases the effectiveness of an immune reponse to a vaccination without altering the specificity of the response?
Adjuvant
Adjuvants are molecules that increase the immune response to an antigen without altering the specificity of response. In other words, they boost the immune response to vaccines. Common examples include: Alum or Aluminium Hydroxide Bacterial products such as toxoids Cytokines such as IL-1 or IL-2 In research, Freund's complete adjuvant (dried Mycobacterium tuberculosis) is often used. It is too toxic for use in humans.
227
On what cell is the RANK receptor found?
Osteoclasts
Denosumab targets RANKL and therefore prevents the development of osteoclasts. RANKL binds to the RANK receptor on osteoclast precursors and promotes cell differentiation into osteoclasts. Hence, inhibition of RANKL/RANK receptor interaction reduces bone turnover and may increase bone density.
228
What cell type is the hallmark of acute inflammation?
Neutrophils
Neutrophils, the most abundant white blood cell in peripheral blood, are the hallmark of acute inflammation. They transmigrate through vascular endothelium to sites of inflammation. They have a limited capacity for phagocytosis and die quite quickly. They are responsible for the whitish cellular material in pus. They may also release alarm cytokines, such as IL-1, to attract other cells such as macrophages. Furthermore, through a process known as degranulation, bactericidal molecules and enzymes can augment the immune response.
229
What blood product is most commonly contaminated by bacteria?
Platelets
Blood products, particularly platelets, are at risk of bacterial contamination. This risk is why the time blood products spend out of refrigeration is minimized. Furthermore, the maximum time an infusion can occur for is 4 hours. If the blood product is contaminated, there is a rapid progression to sepsis, septic shock and death.
230
What specific cell subtype expresses both CD3 and CD4?
T Helper cells
CD4 is a co-receptor that recognises MHC class II. MHC class II is classically only present on professional antigen presenting cells and presents antigens from outside the cell.
231
What viral enzyme is predominantly responsible for the high mutation rate of HIV and other RNA viruses?
Reverse Transcriptase
HIV is a sexually-transmitted retrovirus.
It expresses an exceedingly error prone reverse transcriptase.
Reverse transcriptase synthesises DNA from viral RNA.
This viral DNA is then incorporated into the cell's nucleus for the lifetime of the cell. As part of normal cellular protein synthesis, the cell will now produce HIV virions in addition to human proteins.
Typically, HIV infects CD4+ T helper cells, predominantly in the gut. Less commonly it may infect macrophages.
This leads to severe immunosuppression over a period of years and eventually Acquired Immunodeficiency Syndrome (AIDS)
232
What is measured during an anaphylactic reaction to monitor response to treatment?
Mast Cell Tryptase
Anaphylaxis is managed using an ABCDE approach.
If there is evidence of hypoxaemia, Oxygen is the first drug that is given.
If there is evidence of wheeze, this suggests airway involvement and hence intramuscular adrenaline (500 micrograms) may be given if there is sufficient blood flow.
If blood pressure is low, IV fluids should be given.
Antihistamines (Chlorphenamine) and corticosteroids should also be given, however they need time to take effect.
A repeat dose of adrenaline may be necessary.
Response to treatment over the next few hours may be monitored by levels of mast cell tryptase - a marker of mast cell activation.
233
Which cell type secretes immunoglobulins?
Plasma cell
Plasma cells are derived from B cells and are terminally differentiated (they cannot differentiate further). Plasma cells are highly specialised at creating immunoglobulins, with a large golgi apparatus and rough endoplasmic reticulum.
234
What assay is used as the gold-standard for diagnosis of HIV or as a confirmatory test of infection?
Western Blot
HIV is diagnosed using a number of methods: A first line screening test for HIV is a fourth generation Enzyme Linked Immunosorbent Assay (ELISA) test. It may result in a false positive test. If the ELISA is positive, to confirm diagnosis, a Western Blot may be used. The combination of both methods is very accurate. A HIV viral load of less than 40 copies per mL of blood is considered to be undetectable.
235
What lymphocyte lineage does azathioprine predominantly inhibit?
T lymphocytes
Azathioprine is a antiproliferative immunosuppressant that particularly inhibits T cells. It is metabolised into the inert 6-mercaptopurine. Mutations in an enzyme, TPMT, can mean that azathioprine is metabolised into a cytotoxic metabolite instead of 6 mercaptopurine. Hence, before starting azathioprine all patients should have activity of the TPMT enzyme checked.
236
What is the short-term treatment for severe, life threatening antibody mediated damage or dysfunction, for example myasthenic crisis, cyroglobulinaemia or antibody mediated rejection?
Plasmapheresis
Plasmapheresis allows for blood to be cleared of harmful antibodies. This means it may be a short term treatment for Type II hypersensitivity reactions or diseases caused by antibodies.
237
What immunoglobulin mediates type I hypersensitivity reactions?
Immunoglobulin E
Type 1 Hypersensitivity reactions are mediated by IgE cross linking on the surface of mast cells, leading to mast cell degranulation. Prior to mounting a Type 1 hypersensitivity reaction, a patient must be sensitised (exposed) to an antigen, where B cells recognising the antigen differentiate into plasma cells and secrete IgE specific for that antigen. This IgE then binds to the surface of mast cells. Examples include: Allergic conjunctivitis Allergic rhinitis Anaphylaxis Food allergy
238
Infections by what type of bacteria are more common in patients deficient in the complement protein C9?
Encapsulated
Deficiencies in complement have many effects.
Any deficiencies the in the complement pathway will inhibit the formation of formation of the membrane attack complex - which is vital for defence against encapsulated bacteria.
However, C5b, C6, C7, C8 and C9 deficiencies are most likely to cause symptoms.
Encapsulated bacteria include meningococcus (Neisseria spp.), Haemophilus spp. or pneumococcus (Streptococcus spp.) [Memory Aid: NHS]
In addition, deficiencies in C2, C3 or C4 (classical pathway) predispose to Systemic Lupus Erythematosus, as cellular debris is not phagocytosed effectively.
Function of the complement system may be quantified using the CH50 or CH100 tests, which test the ability of a serum to lyse sheep erythrocytes.
239
A patient's autoimmune panel of bloods reveals positive anti-glycoprotein IIb antibodies. On the patient's lower legs, there are pinprick petechiae. The patient's platelet level is very low. What autoimmune condition is associated with this autoantibody and clinical presentation?
Autoimmune Thrombocytopenic Purpura
Type 2 Hypersensitivity is due to antibody directly binding to cells and tissues that leads to cell damage.
Examples include:
Pernicious anaemia (anti parietal cell antibodies)
Graves' disease (anti-TSH receptor)
Immune thrombocytopenic purpura (anti-platelet antibodies such as anti-glyoprotein IIb/IIIa)
Goodpasture's syndrome (Anti-glomerular basement membrane antibodies [specifically anti-type IV collagen antibodies])
Haemolytic disease of the newborn (maternal IgG against fetal erythrocyte antigens)
Pemphigus Vulgaris (anti-cadherin)
240
The paediatric SpR is called to review a 21 day old infant who is pyrexic and appears unwell. He is noted to be hypocalcaemic and has a cleft palate. He has a fever of 39C. Blood tests reveal a neutrophil count of 8 (normal range: 1.5-8.0), absent T cells and normal B cells. What primary immunodeficiency is this patient likely to have?
DiGeorge Syndrome
DiGeorge syndrome results from a deletion of part of chromosome 22 (22q11.2) (Question feedback: you must be specific to what has happened to the chromosome, ie a deletion, not simply state the locus affected)
This results in a number of abnormalities which can be remembered with the acronym CATCH 22 (with the 22 referring to the chromosomal deletion):
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Cardiac anomalies
Abnormal facies
Thymic aplasia
Cleft palate
Hypoparathyroidism
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Individuals with DiGeorge syndrome are born without the 3rd and 4th branchial arches and so do not have parathyroid glands.
241
What drug class does dolutegravir belong to?
Integrase Inhibitor
HIV is treated using Highly Active Antiretroviral Therapy (HAART), sometimes called ART (antiretroviral therapy)
UK guidelines (BHIVA) suggest HAART should consist of three medications:
Two nucleoside reverse transcriptase inhibitors (NRTIs) and another class of drug.
Examples of the common drug classes include:
NRTI: Zidovudine, Abacavir
Non-nucleoside reverse transcriptase inhibitor: Efavirenz
Protease inhibitor: Ritonavir
Integrase inhibitor: Dolutegravir
Zidovudine is considered safe for use in pregnancy
242
A patient is investigated for a primary immunodeficiency. Lymphocyte counts are normal. However, IgG and IgA are low. There is an excess of IgM. What condition is this patient likely to have?
Hyper IgM Syndrome
Hyper IgM is characterised by high levels of IgM in blood and reduction in levels of other immunoglobulin classes. IgM is the first antibody to be created during the immune response - all other classes of antibody require a process called class switching to occur. Class switching requires activation of CD40 on the surface of B lymphocytes to occur. When CD40 is defective, only IgM can be produced. Typically this leads to increased infection risk, particularly Pneumocystis pneumonia.
