Immunology Flashcards
1
Q
What do sebaceous glands produce that has antibacterial effects?
A
Hydrophobic oils – repels water and microorganisms
Lysozyme – destroys the structural integrity of the bacterial cell wall
Ammonia and defensins – anti-bacterial properties
2
Q
How do NK cells determine whether to lyse cells or not?
A
They have inhibitory receptors which recognise self HLA and they have activating receptors that recognise heparan sulphate proteoglycans
The balance of these signals determines the response
They kill ‘altered self’ cells (e.g. malignancy or virus-infected cells)
3
Q
What does a dendritic cell do after phagocytosis?
A
Upregulate expression of HLA molecules
Express co-stimulatory molecules
Migrate via lymphatics to lymph nodes
4
Q
Which receptor is involved in the migration of dendritic cells to lymph nodes?
A
CCR7
5
Q
For each of the following subsets of CD4+ T cell, list their polarising factors and effector factors.
a. Th1
b. Th2
c. Th17
d. Follicular T cell
e. Treg
A
a. Th1 Polarising IL-12 IFN-gamma Effector IL-2 IL-10 IFN-gamma TNF-alpha b. Th2 Polarising IL-4 IL-6 Effector IL-4 IL-5 IL-10 IL-13 c. Th17 Polarising IL-6 TGF-beta Effector IL-17 IL-21 IL-22 d. Follicular T cell Polarising IL-6 IL-1 TNF-alpha Effector IL-2 IL-10 IL-21 e. Treg Polarising TGF-beta Effector IL-10 Foxp3 CD25
6
Q
Outline the mannose binding lectin pathway of complement activation.
A
Activated by the direct binding of MBL to microbial cell surface carbohydrates
This directly stimulates the classical pathway involving C4 and C2 (but NOT C1)
NOTE: this is NOT dependent on the adaptive immune response
7
Q
What are the effects of complement fragments that are released during complement activation?
A
Increase vascular permeability Opsonisation of immune complexes Opsonisation of pathogens Activation of phagocytes Promotes mast cell/basophil degranulation Punches holes in bacterial membranes
8
Q
What are the ligands for the CCR7 receptors on dendritic cells?
A
CCL19
CCL21
This interaction is important in directing dendritic cells towards lymph nodes
9
Q
Give three examples of failure of neutrophil production and outline their mechanism.
A
Reticular dysgenesis
Autosomal recessive severe SCID with no production of lymphoid or myeloid cells
Caused by failure of stem cells to differentiate along lymphoid or myeloid lineage
Kostmann syndrome
Autosomal recessive congenital neutropaenia (mutation in HAX-1)
Cyclic neutropaenia
Autosomal dominant episodic neutropaenia due to mutation in neutrophil elastase (ELA-2)
Occurs every 4-6 weeks
10
Q
Describe the pathophysiology of leucocyte adhesion deficiency.
A
Caused by deficiency of CD18
CD18 normally combined with CD11a to produce LFA-1
LFA-1 normally binds to ICAM-1 on endothelial cells to mediate neutrophil adhesions and transmigration
A lack of CD18 means a lack of LFA-1, so neutrophils cannot enter tissues
During an infection, neutrophils will be mobilised from the bone marrow (HIGH neutrophils in the blood) but they will not be able to cross into the site of infection (NO pus formation)
11
Q
Outline the pathophysiology of chronic granulomatous disease.
A
Absent respiratory burst (deficiency of components of NADPH oxidase leads to inability to generate oxygen free radicals)
Excessive inflammation (persistent neutrophils and macrophage accumulation with failure to degrade antigens)
Granuloma formation
Lymphadenopathy and hepatosplenomegaly
Can be treated with IFN-gamma
12
Q
Describe the cytokine cycle between macrophages and T cells.
A
Macrophages produce IL12 which stimulates T cells, which then produce IFN-gamma
IFN-gamma acts back on the macrophages and stimulates the production of TNF-alpha and free radicals
Deficiencies in IL12, IL12R, IFN-gamma or IFN-gamma receptor can cause immunodeficiency (inability to form granulomas - mycobacterial)
13
Q
Name and describe the colour changes of two tests used to investigate chronic granulomatous disease.
A
Nitroblue Tetrazolium (NBT) – yellow to blue
Dihydrorhodamine (DHR) – fluorescent
NOTE: both of these tests are looking at the ability of neutrophils to produce hydrogen peroxide and oxidative stress
14
Q
What is the main clinical consequence of complement deficiency?
A
Increased susceptibility to infection by encapsulated bacteria
NOTE: Properidin (P) deficiency will also lead to increased risk of meningococcal infection
15
Q
Outline the clinical phenotype of complement deficiency.
A
SLE (if early components involved (e.g. C2)
Usually have severe skin disease
Increased risk of infection (common pathway deficiency)
16
Q
What are nephritic factors?
A
Autoantibodies that are directed against components of the complement pathway
They stabilise C3 convertases (break down C3) resulting in C3 activation and consumption
17
Q
What disease is associated with the presence of nephritic factors?
A
Membranoproliferative glomerulonephritis
It may also be associated with partial lipodystrophy
NOTE: it can cause a ‘tram track’ appearance on microscopy (immune complex and complement proteins deposit in the subendothelium
18
Q
Outline the management of complement deficiencies.
A
Vaccination (especially against encapsulated organisms)
Prophylactic antibiotics
Treat infection aggressively
Screen family members
19
Q
What is basophilic stippling?
A
Basophilic appearance of red blood cells caused by the presence of aggregated ribosomal material
20
Q
In which conditions might you see target cells (codocytes)?
A
Iron deficiency Thalassemia Hyposplenism Liver disease NOTE: target cells have a high SA: V ratio
21
Q
What are Howell-Jolly bodies? Which condition are they associated with?
A
Nuclear remnants present within red blood cells
Present in hyposplenism
22
Q
Which deficiencies are typically seen in Coeliac disease?
A
Iron B12 Folate Fat Calcium
23
Q
Which HLA alleles are particularly common in patients with coeliac disease?
A
HLA-DQ2 (80%) – DQA10501 and DQB102 alleles
HLA-DQ8
24
Q
Describe the T cell response to gluten in coeliac disease.
A
Peptides from gluten (gliadin) are deamidated by tissue transglutaminase
Deamidated gliadin is taken up by antigen-presenting cells and presented via HLA molecules to CD4+ T cells
CD4+ T cell activation results in secretion of IFN-gamma and may increase IL-15 secretion
These cytokines promote activation of intra-epithelial lymphocytes (gamma-delta T cells)
The intraepithelial lymphocytes will kill epithelial cells via the NKG2D receptor (normally recognises the stress protein MICA)
NOTE: anti-gliadin antibodies are the most persistent
25
List some other causes of high intraepithelial lymphocytes.
```
Dermatitis herpetiformis
Giardiasis
Cows’ milk protein sensitivity
IgA deficiency
Tropical sprue
Post-infective malabsorption
Drugs (NSAIDs)
Lymphoma
```
26
How often should a DEXA scan be performed in coeliac patients?
Every 3-5 years
27
Name a defect in stem cells that causes SCID and name the gene that is mutated.
Reticular dysgenesis – adenylate kinase 2 (AK2)
| NOTE: this is a mitochondrial energy metabolism enzyme
28
Which mutation is responsible for X-linked SCID?
Mutation in common gamma chain on Xq13.1
This is a component of many cytokine receptors (in particular, IL2) leading to an inability to respond to cytokines, causing arrest in T and NK cell development and the production of immature B cells
29
Describe the typical cell counts you would expect to see in X-linked SCID.
Very low T cells
Very low NK cells
Normal or increased B cells
Low immunoglobulin
30
Describe the typical cell counts you would expect to see in ADA deficiency.
Very low T cells
Very low B cells
Very low NK cells
31
In which group of syndromes does the thymus gland fail to develop properly?
22q11.2 deletion syndromes (e.g. Di George syndrome)
| This is characterised by failure of development of the pharyngeal pouch
32
What are the immunological consequences of an underdeveloped thymus gland?
Normal B cell count
Low T cell count
Homeostatic proliferation with age (T cell numbers increase with age)
Immune function is mildly impaired and tends to improve with age
33
Which defect leads to bare lymphocyte syndrome type 2?
Defects in the regulatory proteins involved in expression of class II genes:
• Regulatory factor X
• Class II transactivator
34
List some investigations that may be used for suspected T cell deficiencies.
Total white cell count and differentials
Lymphocyte subsets
Immunoglobulins
Functional tests of T cell activation and proliferation
HIV test
35
Describe the typical levels of CD4, CD8, B cells, IgM and IgG that you would expect to see in the following diseases:
a. SCID
b. Di George
c. BLS Type 2
```
a. SCID
CD4 low
CD8 low
B cells normal/low
IgM normal/low
IgG low
b. Di George
CD4 low
CD8 low
B cells normal
IgM normal
IgG normal/low
c. BLS Type 2
CD4 low
CD8 normal
B cells normal
IgM normal
IgG low
```
36
Outline the pathophysiology of Bruton’s X-linked hypogammaglobulinaemia.
Prevents the maturation of B cells at that point at which they emerge from the bone marrow
Caused by an abnormal B cell tyrosine kinase (BTK) gene
This results in the absence of mature B cells and, hence, an absence of antibodies
37
Outline the pathophysiology of X-linked hyper IgM syndrome.
Blocks the maturation of IgM B cells through germinal centres into B cells that produce other classes of immunoglobulin (i.e. prevents germinal centre reactions)
Caused by a mutation in the CD40 ligand gene
This is technically a T cell problem, however, it means that CD4+ T helper cells cannot provide help to B cells so they cannot undergo germinal centre reactions
NOTE: CD40 ligand is encoded on Xq26
38
What is common variable immunodeficiency and what are the main features?
A group of disorders caused by some form of failure of differentiation of B lymphocytes
Defined by:
• Marked reduction in IgG, IgA and IgE
• Poor/absent response to immunisation
• Absence of other defined immunodeficiency
39
List some investigations that may be used for suspected B cell deficiencies.
Total white cell count and differential
Lymphocyte subsets
Serum immunoglobulins and protein electrophoresis
Functional tests of B cell function (e.g. measure IgG antibody against a specific pathogen (e.g. S. pneumoniae), if this is low, vaccinate using a killed vaccine and check levels again in 6-8 weeks)
NOTE: IgG production is a surrogate marker for CD4+ T helper cell function
40
Which protein is upregulated in autoinflammatory diseases caused by a gain-of-function mutation in NLRP3? Name 3 diseases that are caused by this mutation.
Cryopyrin (NALP3)
Muckle Wells syndrome
Familial cold autoinflammatory syndrome
Chronic infantile neurological cutaneous articular syndrome
All of these are autosomal dominant
NOTE other examples of monogenic autoinflammatory conditions: TNF receptor associated periodic syndrome (TNF receptor mutation), Hyper IgD with periodic fever syndrome (mevalonate kinase mutation)
41
Which gene mutation causes Familial Mediterranean Fever and which protein does this gene encode?
MEFV gene
| Encodes pyrin-marenostrin which is a negative regulator of the inflammatory pathway
42
Describe how the inflammasome complex functions.
The pathway is activated by toxins, pathogens and urate crystals
These act via cryopyrin and ASC (apoptosis-associated speck-like protein) to activate procaspin 1
Activation of procaspin 1 results in the production of NFB, IL1 and apoptosis
Pyrin-maronestrin is a negative regulator of this pathway
NOTE: pyrin-marenostrin is found in neutrophils
43
What is the inheritance pattern of Familial Mediterranean Fever?
Autosomal recessive
44
Outline the clinical presentation of Familial Mediterranean Fever.
```
Periodic fevers lasting 48-96 hours associated with
• Abdominal pain (peritonitis)
• Chest pain (pleurisy, pericarditis)
• Arthritis
• Rash
```
It can lead to AA amyloidosis
45
Outline the treatment of Familial Mediterranean Fever.
Colchicine 500 µg BD (binds to tubulin and disrupt neutrophil migration and chemokine secretion)
2nd line: blocking cytokines
• Anakinra – IL1 receptor blocker
• Etanercept – TNF-alpha blocker
46
Which autoimmune conditions tend to occur in APECED?
```
Hypoparathyroidism (COMMON)
Addison’s disease (COMMON)
Hypothyroidism
Diabetes mellitus
Vitiligo
```
APECED: autoimmune polyendocrinopathy candidasis ectodermal dystrophy (aka polyglandular autoimmune syndrome type 1)
47
Why are patients with APECED prone to Candida infections?
They produce antibodies against IL17 and IL22
48
What does IPEX stand for?
Immune dysregulation polyendocrinopathy enteropathy X-linked syndrome
Caused by mutation in FoxP3 (Forkhead Box P3)
49
Which mutations cause ALPS?
Mutations in the FAS pathway leading to defects in apoptosis of lymphocytes
This leads to a failure of lymphocyte tolerance (as autoreactive lymphocytes don’t die by apoptosis) and failure of lymphocyte homeostasis (you keep producing lymphocytes)
50
Describe the clinical phenotype of ALPS.
High lymphocyte count
Large spleen and lymph nodes
Autoimmune disease (usually cytopaenias)
Lymphoma
51
What is the best known chromosomal region that is implicated in Crohn’s disease?
IBD1 on chromosome 16 (NOD2/CARD15 gene)
NOTE: NOD2 is found in the cytoplasm of myeloid cells and is a microbial sensor, mutation is also seen in Blau syndrome
```
NOD2 = nucleotide-binding oligomerization domain-containing protein
CARD15 = caspase-activating recruitment domain
```
52
List the autoimmune diseases associated with the following HLA polymorphisms:
a. DR3
b. DR3/4
c. DR4
d. DR15
```
a. DR3
Graves’ disease
SLE
b. DR3/4
Type 1 diabetes mellitus
c. DR4
Rheumatoid arthritis
d. DR15
Goodpasture’s syndrome
```
53
Name and state the function of 2 genes that are involved in T cell activation and are often mutated in polygenic autoimmune disease.
PTPN22 – suppresses T cell activation
CTLA4 – regulates T cell function (expressed by T cells)
```
PTPN = protein tyrosine phosphate non-receptor 22
CTLA = cytotoxic T lymphocyte-associated protein 4
```
54
Name the autoantigen in the following diseases:
a. Goodpasture’s disease
b. Pemphigus vulgaris
a. Goodpasture’s disease
Alpha-3 subunit of non-collagenous domain of collagen IV
b. Pemphigus vulgaris
Epidermal cadherin
55
Describe the difference between immune responses mediated by Th1 and Th2 cells.
NOTE: both are types of CD4 cell
```
Pathogens that have conserved structures (PAMPs) such as bacteria are recognised by Th1 and Th17 cells
Multicellular organisms (e.g. helminths) and allergens don’t have conserved structured but they release mediators that damage epithelial cells. Disturbance of epithelial cells is recognised by the Th2 cells
```
56
List some elective investigations for allergic disease.
```
Skin prick and intradermal tests
Specific IgE measurement
Component resolved diagnostics
Basophil activation test
Challenge test
```
57
What is component resolved diagnostics?
A blood test to detect IgE to single protein components (useful for peanut and hazelnut allergy)
IgE sensitisation to heat and proteolytic labile proteins = minor symptoms
IgE sensitisation to heat and protolytic stable protein = major symptoms
58
List some indications for allergy component testing.
Detect primary sensitisation
Confirm cross-reactivity
Define risk of serious reaction for stable allergens
59
What is a basophil activation test?
Measurement of basophil response to allergen IgE cross-linking
Activated basophils show increased expression of CD63, CD203 and CD300
This is increasingly used in food and drug allergy
60
List some mechanisms of anaphylaxis.
IgE – mast cells and basophils – histamine and PAF (triggered by food, venom, ticks, penicillin)
IgG – macrophages and neutrophils – histamine and PAF (triggered by blood product transfusions)
Complement – mast cells and macrophages – histamine and PAF (triggered by lipid excipients, liposomes, dialysis membranes)
Pharmacological – mast cells – histamine and leukotrienes (triggered by NSAIDs)
61
List some IgE-mediated food allergy syndromes.
Anaphylaxis (e.g. peanut)
Food-associated exercise-induced anaphylaxis (ingestion of food leads to anaphylaxis if the individual exercises within 4-6 hours of ingestion (e.g. wheat, shellfish))
Delayed food-induced anaphylaxis to beef/pork/lamb (symptoms occur 3-6 hours after ingestion, induced by tick bites)
Oral allergy syndrome (limited to oral cavity with swelling and itching, occurs after pollen allergy is established, caused by cross-reaction of IgE antibody to pollen with stone fruits (e.g. apples), vegetables and nuts)
62
Which chromosome is HLA encoded on?
Chromosome 6
63
Describe the basic structure of HLA Class I and Class II.
Class I: have three alpha domains and a beta-2 microglobulin domain, has one transmembrane domain
Class II: has two alpha and two beta domains, had two transmembrane domains
64
Which HLA alleles are most immunogenic?
A, B and DR
65
What are the typical histological features of T-cell mediated rejection?
Lymphocytic interstitial infiltration
Ruptured tubular basement membrane
Tubulitis (inflammatory cells within the tubular epithelium)
66
Name and describe three assays for anti-HLA antibodies before transplants.
```
Cytotoxic Assays (CDC): tests whether patient serum kills donor lymphocytes in the presence of complement
Flow Cytometry (FACS): tests whether patient serum binds donor lymphocytes irrespective of complement
Solid Phase Assays (Luminex): beads containing all the possible HLA epitopes are mixed with the patient’s serum. This determines which HLA types the patient has antibodies against. Having many antibodies against different HLA epitopes suggests that the patient is highly sensitised.
```
67
Name two drugs that target TCR.
Anti-CD3 antibody (OKT3 - also known as muromonab-CD3)
Anti-thymocyte globulin
Used for transplant rejection
68
Name an anti-CD52 antibody and state its effect.
Alemtuzumab (campath) – causes lysis of T cells
Used for solid organ transplantation, multiple sclerosis and NHL, CLL, MS
Side-effects: ITP, Graves disease
69
Name an anti-CD25 antibody and state its effect.
Daclizumab – targets cytokine signalling
70
How to BAFF inhibitors work?
Target cytokines (BAFF) that promote B cell activation and growth
71
Name a proteasome inhibitor and describe how it works.
Bortezomib
| Blocks the production of antibodies by plasma cells
72
Name a complement inhibitor.
Eculizumab
73
Outline the components of modern transplant immunosuppression regimes.
Induction agent (e.g. OKT3, anti-CD52, anti-CD25)
Baseline immunosuppression (e.g. calcineurin inhibitor, mycofenolate mofetil, azathioprine, steroids)
Treatment of acute rejection
• Cellular: steroids, OKT3
• Antibody-Mediated: IVIG, plasma exchange, anti-CD20
74
Which antibodies have a protective role in HIV infection?
Anti-gp120
Anti-gp41 (Nt)
Non-neutralising anti-p24 gag IgG (CD4+ cells recognise these antigens when presented on MHC class II)
NOTE: HIV remains infectious even when coated with antibodies
75
What are the screening and confirmatory tests for HIV?
Screening: HIV antibody ELISA
Confirmatory: HIV antibody Western blot
76
Describe how haemagglutinin inhibition assays work.
If you put normal red blood cells in a petri dish, they will clump at the bottom forming a red spot
If you add influenza virus, the HA makes red cells stick together and causes a diffuse coloration across the well
If you add the serum of someone who has a lot of antibodies against HA, it will inhibit the haemagglutination effects of HA so the red cells remain as a discrete red spot
The higher the dilution of serum at which the red cells remain as a little dot, the more antibodies are present in the serum
NOTE: sialic acid receptors on RBCs bind to HA leading to haemagglutination
77
What is a live attenuated virus vaccine? List some examples.
The organism is alive but modified to limit its pathogenesis
Examples: MMR, typhoid, BCG, yellow fever, polio (Sabin)
78
List some examples of the following types of vaccine:
a. Toxoids
b. Component/Subunit
```
a. Toxoids
Diphtheria
Tetanus
b. Component/Subunit
Hep B (HBsAg)
HPV (capsid)
Influenza (HA)
```
79
Describe how conjugate vaccines work.
Polysaccharide and protein carrier
Polysaccharide induces a T-cell independent B cell response (transient)
Addition of the protein carrier promoted T cell immunity which enhances B cell/antibody responses
80
List some examples of conjugate vaccines.
Haemophilus influenzae type B
Meningococcus
Pneumococcus
81
List some indications for IVIG.
```
Primary antibody defect
• X-linked agammaglobulinaemia
• X-linked hyper IgM syndrome
• Common variable immunodeficiency
Secondary antibody defect
• CLL
• Multiple myeloma
• After bone marrow transplantation
```
82
List four types of T cell adoptive cell transfer.
Virus-specific T cells
Tumour infiltrating T cells (TIL)
T cell receptor T cells (TCR)
Chimeric antigen receptor T cells (CAR T Cell Therapy)
83
Using an example, describe how virus-specific T cells are used.
Used for EBV in patients who are immunosuppressed to prevent the development of lymphoproliferative disease
Blood is taken from the patient or from a donor
Peripheral blood mononuclear cells are isolated and stimulated with EBV peptides
This creates an expansion of EBV-specific T cells which are then reinfused into the patient
NOTE: tumour infiltration T cell therapy follows the same principle but uses tumour antigens
84
Describe how TCR and CAR T cell therapy works.
T cells are taken from the patient and vectors are used to insert gene fragments that encode receptors
In TCR therapy, the gene will encode a specific TCR (e.g. against tumour antigen)
In CAR therapy, the receptors are chimeric (containing both B and T cell components)
85
Describe a use of CAR T cell therapy.
Used to target CD19 (present on B cells)
Receptors on the CAR cell have an immunoglobulin variable domain and is joined to a TCR
This means that it recognises CD19 through an immunoglobulin domain but signals through the TCR pathway
NOTE: this is used in ALL and NHL
86
What is ipilimumab and how does it work?
CTLA4 and CD28 are both expressed by T cells and they recognise antigens (CD80 and CD86) on APCs
Signalling through CD28 results in a stimulatory response
Signalling through CTLA4 results in an inhibitory response
Ipilimumab is a monoclonal antibody that blocks CTLA4 thereby removing this inhibitory response
It is used in advanced melanoma
87
Explain the use of antibodies against PD-1 in treating cancer.
PD-1 and PD-2 ligands are present on APCs and interact via PD-1 receptors on T cells to cause an inhibitory response
They can also be expressed by some tumour cells
Pembrolizumab and nivolumab are antibodies that are specific to PD-1, thereby blocking this effect
This is also used in advanced melanoma
88
List some examples of the therapeutic use of recombinant cytokines.
Interferon alpha – used as an adjunct in the treatment of Hep B, Hep C, Kaposi sarcoma, CML and multiple myeloma
Interferon beta – Behcet’s disease, relapsing MS
Interferon gamma – chronic granulomatous disease
89
Describe the effects of steroids on:
a. Prostaglandins
b. Phagocytes
c. Lymphocyte Function
a. Prostaglandins
Inhibits phospholipase A2
Phospholipase A2 is responsible for the conversion of phospholipids into arachidonic acid (which will then be converted to eicosanoids by COX)
Inhibiting phospholipase A2 leads to a reduction in arachidonic acid and prostaglandin formation and, hence, a reduction in inflammation
b. Phagocytes
Decrease traffic of phagocytes to inflamed tissue (reduces the expression of adhesion molecules on the endothelium)
This leads to a transient increase in neutrophil count
Decreased phagocytosis
Decreases proteolytic enzymes
c. Lymphocyte Function
Lymphopaenia (sequestration in lymphoid tissue)
Blocks cytokine gene expression
Decreased antibody production
Promotes apoptosis
90
List some examples of anti-proliferative agents.
Cyclophosphamide
Mycophenolate
Azathioprine
Methotrexate
91
What is the mechanism of action of cyclophosphamide?
Alkylates the guanine base of DNA which damages the DNA and prevents replication
Affects B cells more than T cells
92
List some side-effects of cyclophosphamide.
Toxic to proliferating cells – bone marrow suppression, sterility (mainly males), hair loss
Haemorrhagic cystitis – due to toxic metabolic (acrolein) in the urine
Malignancy – bladder cancer, haematological malignancy, non-melanoma skin cancer
Teratogenic
Infection (e.g. PCP)
93
Outline the mechanism of action of azathioprine.
Metabolised by the liver to 6-mercaptopurine
Blocks de novo purine synthesis (e.g. adenine and guanine)
Prevents DNA replication
Preferentially inhibits T cell activation and proliferation
94
Which precaution must you take before starting a patient on azathioprine?
Check TPMT activity – 1 in 300 individuals have a TPMT polymorphism which means that they are unable to metabolise azathioprine leading to bone marrow suppression
95
Outline the mechanism of action of mycophenolate mofetil.
Blocks de novo nucleotide synthesis
Prevents replication of DNA
Affects T cell proliferation more than B cells
Non-competitive inhibitor of IMPDH (inosine-5-monophosphate dehydrogenase)
96
List some side-effects of mycophenolate mofetil.
Bone marrow suppression
Teratogenic
Infection (particularly HSV reactivation and PML (JC virus))
97
Describe the mechanism of action of calcineurin inhibitors.
Normally, TCR engagement leads to increased cytoplasmic calcium which binds to calmodulin leading to the activation of calcineurin
Calcineurin then activates NFATc resulting in the upregulation of IL2
Calcineurin inhibitors block this pathway, thereby blocking IL2 production
98
What are the main side-effects of calcineurin inhibitors?
Hypertension and nephrotoxicity
Diabetes
Neurotoxic
Gingival hypertrophy (ciclosporin)
99
Give an example of a JAK inhibitor. State which disease it is used to treat.
Tofacitinib (JAK1 and JAK2 inhibitor)
Rheumatoid arthritis
100
Give an example of a PDE4 inhibitor. State which disease it is used to treat.
Apremilast
Psoriasis
101
Describe the mechanism of action of PDE4 inhibitors.
PDE4 is important in the metabolism of cAMP
PDE4 inhibitors result in increased levels of cAMP which activates PKA and prevents the activation of transcription factors
This leads to a decrease in cytokine production
Effective in psoriasis and psoriatic arthritis
102
For each of the following monoclonal antibodies, state the antigen that they are targeting:
a. Basiliximab
b. Abatacept
c. Rituximab
d. Natalizumab
e. Tocilizumab
```
a. Basiliximab
Anti-CD25
b. Abatacept
CTLA4-Ig
c. Rituximab
Anti-CD20
d. Natalizumab
Anti-4 integrin
e. Tocilizumab
Anti-IL6 receptor
```
103
List some side-effects of anti-thymocyte globulin.
Infusion reactions
Leukopaenia
Infection
Malignancy
104
Describe the mechanism of action and the use of basiliximab.
Targets IL2 receptor alpha chain (aka CD25)
This part of the receptor is specific for IL2 receptors
Results in inhibition of T cell proliferation
Uses: allograft rejection
105
Describe the mechanism of action of abatacept.
It is made from the fusion of CTLA4 and IgG Fc
APCs bind to CTLA4 (inhibitory) and CD28 via CD80 and CD86 receptors
Abatacept binds to CD80 and CD86 receptors and prevents engagement with T cells thereby reducing T cell activation
It is effective in rheumatoid arthritis
106
List some indications for rituximab.
Lymphoma
Rheumatoid arthritis
SLE
NOTE: it is given as two IV doses every 6-12 months
107
Describe the mechanism of action of natalizumab.
Antibody against alpha-4 integrin
Alpha-4 integrin is expressed with beta-1 or beta-7
This complex binds to VCAM1 or MadCAM1 to mediate rolling and arrest of leukocytes
Blocking this integrin inhibits leukocyte migration
Uses: multiple sclerosis, Crohn's disease
108
Describe the mechanism of action of tocilizumab.
Antibody against IL6 receptor
| Results in reduced activation of macrophages, T cells, B cells and neutrophils
109
What are the main indications of tocilizumab?
Castleman’s disease (IL6-producing tumour)
| Rheumatoid arthritis
110
Which antigens are targeted by the following monoclonal antibodies:
a. Ustekinumab
b. Secukinumab
c. Denosumab
```
a. Ustekinumab
IL12
IL23
b. Secukinumab
IL17
c. Denosumab
RANKL
```
NOTE: menopause stimulates RANKL production
111
Describe the mechanism of action of etanercept.
It is a decoy receptor that mops up TNF alpha thereby inhibiting its action
It is given as an SC injection
Used in rheumatoid arthritis, psoriasis and ankylosing spondylitis
112
Describe the mechanism of action of ustekinumab.
Antibody against the p40 subunit that is found in IL12 and IL23
This affects Th17 activation and IL17 signalling
These cytokines mainly act on NK cells and T cells thereby modulating their activity
Used in psoriasis and Crohn’s disease
113
Describe the mechanism of action and uses of secukinumab.
Antibody to IL17A thereby inhibiting its effect
| Indications include psoriasis and ankylosing spondylitis
114
Describe the mechanism of action of denosumab.
RANKL is produced by osteoblasts and it acts on RANK receptors on osteoclasts
It promotes osteoclast differentiation and function, thereby leading to increased bone resorption
Osteoprotegrin is a natural decoy receptor for RANKL which regulates the system
Denosumab binds to RANKL and reduces osteoclast differentiation and function
NOTE: it is used for osteoporosis and is administered as SC injections every 6 months
115
List some autoantibodies that are found in type I diabetes mellitus.
```
Anti-GAD
Anti-IA2
Anti-islet cell
Anti-insulin
NOTE: the detection of these antibodies does not currently play a part in diagnosis of diabetes mellitus
```
116
List some genetic polymorphisms that predispose to rheumatoid arthritis.
```
HLA DR1
HLA DR4
PTPN22
PAD 2 and PAD 4 polymorphisms
Polymorphisms affecting TNF, IL1, IL6 and IL10
```
117
What is a key common feature amongst HLA alleles that are associated with rheumatoid arthritis?
They share a sequence at position 70-74 of the HLA DR-beta chain (shared epitope)
This enables binding of HLA to arthritogenic peptides (particularly citrullinated peptides)
118
Describe the role of PAD in the pathogenesis of rheumatoid arthritis.
```
Peptidylarginine deaminases (2 and 4) are involved in the deamination of arginine to form citrulline
Polymorphisms that are associated with increased citrullination leads to a high load of citrullinated peptides
```
119
List some environmental factors that contribute to the pathogenesis of rheumatoid arthritis.
Smoking is associated with the development of erosive disease (due to increased citrullination)
Gum infection by Porphyromonas gingivalis is associated with rheumatoid arthritis as it expresses PAD, thereby promoting citrullination
120
Describe B cell involvement in the pathophysiology of rheumatoid arthritis.
Type II – antibodies bind to citrullinated peptides leading to activation of macrophages, NK cells and complement
Type III – immune complexes form and get deposited leading to complement activation
121
Outline the roles of T cells in the pathophysiology of rheumatoid arthritis.
APCs present peptides to CD4+ T cells which then produce IFN-gamma and IL17
These cytokines act on fibroblasts and macrophages
This leads to the production of MMPs, IL1 and TNF-alpha
122
Which type of hypersensitivity reaction is SLE?
Type III hypersensitivity – antibodies bind to antigens forming immune complexes which deposit in tissues (e.g. skin, joints, kidneys) and activated complement via the classical pathway
These antibodies can also stimulate cells that express Fc receptors
123
What are the two types of ANA and what are their immunofluorescence patterns?
Anti-dsDNA – homogenous staining pattern, they are highly specific for SLE and high titres are associated with severe disease (useful for disease monitoring)
Anti-ENA4 (extractable nuclear antigens such as ribonucleoproteins (e.g. Ro, La, Sm)) - speckled immunofluorescence
124
Which antibodies are tested for in antiphospholipid syndrome?
Anti-cardiolipin antibody – immunoglobulins directed against phospholipids and 2 glycoprotein-1
Lupus anticoagulant – prolongation of phospholipid-dependent coagulation tests.
NOTE: cannot be assessed if the patient is on anticoagulant therapy
NOTE: both tests should be performed as 40% of patients have disconcordant antibodies
125
Which cells are particularly important in the pathophysiology of systemic sclerosis?
Th2 and Th17
NOTE: TGF-beta, produced by macrophages and T cells, is important in stimulating the deposition of collagen
126
Describe the differences between the histology of dermatomyositis and polymyositis.
Dermatomyositis – perivascular CD4+ T cell and B cells are seen, this can cause an immune complex-mediated vasculitis (type III response)
Polymyositis – CD8+ T cells surround HLA Class I expressing myofibres, CD8+ T cells kill these myofibres via granzyme/perforin (type IV response)
127
Which antibodies are seen in dermatomyositis and polymyositis?
Dermatomyositis: anti-aminoacyl tRNA synthetase (e.g. Jo-1), anti-Mi2
Polymyositis: anti-signal recognition peptide (anti-SRP) antibody
NOTE: anti-aminoacyl tRNA synthetase antibody is cytoplasmic
128
Outline the pathophysiology of ANCA.
These antibodies are specific to antigens located within primary granules within the cytoplasm of neutrophils
Inflammation may lead to expression of these antigens on the surface of neutrophils
Antibody engagement with these antigens may lead to neutrophil activation (type II hypersensitivity)
NOTE: these are different from anti-nuclear antibodies
129
Describe the key difference between cANCA and pANCA.
cANCA
• Cytoplasmic fluorescence
• Associated with antibodies against proteinase 3
• Occurs in > 90% of Wegener’s patients with renal involvement
pANCA
• Perinuclear staining pattern
• Associated with antibodies to myeloperoxidase
• Less sensitive and specific than cANCA
• Associated with MPA and Churg-Strauss syndrome
130
Describe the reactions involved in oxidative killing of pathogens within phagolysosomes.
NADPH oxidase converts oxygen into reactive oxygen species (e.g. superoxide and hydrogen peroxide)
Myeloperoxidase catalyses the production of hydrochlorous acid (from hydrogen peroxide and chloride)
131
What are the polarising and effector factors of Th1?
```
Polarising
IL-12
IFN-gamma
Effector
IL-2
IL-10
IFN-gamma
TNF-alpha
```
132
What are the polarising and effector factors for Th2?
```
Polarising
IL-4
IL-6
Effector
IL-4
IL-5
IL-10
IL-13
```
133
What are the polarising and effector factors for Th17?
```
Polarising
IL-6
TGF-beta
Effector
IL-17
IL-21
IL-22
```
134
What are the polarising and effector factors for follicular T cells?
```
Polarising
IL-6
IL-1 beta
TNF-alpha
Effector
IL-2
IL-10
IL-21
```
135
What are the polarising and effector factors for Tregs?
```
Polarising
TGF-beta
Effector
IL-10
Foxp3
CD25
```
136
Which types of infection tend to occur in patients with phagocyte deficiency?
Recurrent skin and mouth infections
Bacteria – Staphylococcus aureus, enteric bacteria
Fungi – Candida albicans, Aspergillus fumigatus
Mycobacterial infections (particularly with IL12 deficiency)
TB, atypical mycobacteria
137
Outline the treatment of NK cell deficiency.
Prophylactic antiviral drugs (e.g. aciclovir)
Cytokines (e.g. IFN-alpha to stimulate NK cytotoxic function)
Haematopoietic stem cell transplantation
138
What is factor H?
A control protein in the complement cascade
139
What causes hereditary angioedema?
C1 esterase inhibitor deficiency
It is autosomal DOMINANT
140
List some complications of coeliac disease.
Malabsorption
Osteomalacia and osteoporosis
Neurological disease (epilepsy and cerebral calcification)
Lymphoma (causes multi-focal T cell lymphoma)
Hyposplenism
141
What are the main clinical features of 22q11.2 deletion syndromes?
Facial abnormalities (high forehead, low set ears, cleft palate, small mouth and jaw)
Underdeveloped parathyroid gland (resulting in hypocalcaemia)
Oesophageal atresia
Underdeveloped thymus
Complex congenital heart disease
142
What is the most common allergic disease in:
A) Children
B) Adults
A) food allergy (e.g. egg and milk)
| B) allergic rhinitis
143
List some triggers for the following types of mast cell degranulation:
A) IgE-mediated
B) non-IgE mediated
A) peanut, penicillin, wasp/bee venom, latex
| B) NSAIDs, opioids, IV contrast, exercise
144
Which autoimmune conditions are often seen in IPEX?
Enteropathy
Diabetes mellitus (Type 1)
Hypothyroidism
Dermatitis (eczema)
145
What are three forms of peripheral tolerance?
T cell require costimulation to become activates (costimulatory molecules are upregulated in infection and inflammation)
Regulatory T cells
Immune privileged sites
146
How should acute angioedema be treated?
IM adrenaline
147
Which complement factor is important for chemotaxis?
C3a
148
Which protein does the gene mutation that causes X-linked SCID encode?
IL-2 receptor
149
What is Wiskott-Aldrich syndrome and which gene mutation causes it?
X-linked recessive condition characterised by eczema, thrombocytopaenia, immunodeficiency, bloody diarrhoea and nosebleeds
Low IgM, normal IgG, high IgA and IgE
Caused by WASP mutation
150
What does the MHC Class III gene cluster encode?
C2
C4
B
151
Which types of infection are people with IgA deficiency prone to?
Respiratory and gastrointestinal tract infections
NOTE: IgA deficiency is the only B cell maturation defect that responds to vaccines
152
What is a major risk factor for chronic allograft rejection?
Hypertension
| Hyperlipidaemia is also a risk factor
153
How is acute rejection treated?
Antibody-mediated: IVIG and plasmapheresis
Cell-mediated: high dose corticosteroids
Hyperacute (preformed antibody): can only be prevented by accurate HLA-typing
154
Which HLA types are most important in rejection?
HLA DR > B > A
NOTE: CD4 recognises DR; CD8 recognises A
155
What are the main side-effects of methotrexate?
Pneumonitis
Pulmonary fibrosis
Cirrhosis
156
What is the main side-effect of IVIG?
Anaphylaxis
157
Describe the mechanism of action of alum as an adjuvant to vaccines.
Promotes a predominantly antibody response through the release of IL-4 that primes naïve B-cells
158
Name a vaccine that is made up of recombinant protein?
I.e. using recombinant DNA technology
Hepatitis B vaccine
159
Describe the typical presentation of SCID.
```
Unwell by 3 months
Infections of all types
Failure to thrive
Persistent diarrhoea
unusual skin disease
```
160
List some features of Di George syndrome.
```
CATCH-22
Cardiac abnormalities
Abnormal facies (high forehead, low set ears)
Thymic aplasia
Cleft palate
Hypocalcaemia/hypoparathyroidism
22q11.2
```
161
What are the clinical features of common variable immuondeficiency?
Recurrent bacterial infection (e.g. bronchiectasis, persistent sinusitis, recurrent GI infection)
Autoimmune disease
Granulomatous disease
162
Which test result would be consistent with Factor B deficiency?
Low AP50
AP50 tests the activity of B, D, Properidin, C3 and C5-9
163
Which foods are involved in latex food syndrome?
```
Chestnut
Avocado
Banana
Potato
Tomato
Kiwi
```
164
What counts as a positive result on skin prick testing?
Wheal > 2 mm greater than the negative control
NOTE: discontinue antihistamines 48 hours before test, positive control is histamine, negative control is dilutent
Specific IgE is less sensitive but used if unable to stop antihistamines, history of anaphylaxis or extensive eczema
165
What is the gold standard test for diagnosing food allergy?
Challenge test
But this carries a risk of severe reaction
166
What investigation can be useful in patients without a convincing clinical diagnosis of anaphylaxis?
Mast cell tryptase (peaks at 1-2 hours and returns to baseline by 6 hours)
167
What is Evan syndrome?
AIHA + ITP
168
What antigen is targeted in ITP?
Glycoprotein IIb/IIIa
169
Which antigens are antibodies developed against in rheumatic fever?
M proteins on Group A streptococcus
170
What is mixed essential cryoglobulinaemia?
IgM against IgG (and sometimes hepatitis C antigens)
Causes joint pain, splenomegaly, skin, nerve and kidney involvement
Associated with hepatitis C
171
Which antibodies are associated with Sjogren syndrome?
Anti-Ro
Anti-La
Speckled immunofluorescence
NOTE: classically diagnosed using Shirmer's test
172
Which antibodies are seen in autoimmune hepatitis?
Anti-smooth muscle antibodies (ASMA)
Anti-LKM1
Anti-SLA
173
Which antibodies are seen in systemic sclerosis?
Limited: anti-centromere
Diffuse: topoisomerase/Scl70, RNA polymerase I/II/III, fibrillarin (nucleolar pattern)
174
How often does human normal immunoglobulin need to be given as antibody replacement therapy?
Every 3-4 weeks
E.g. used in combined variable immunodeficiency, Bruton's
175
List some uses of interferon alpha, beta and gamma.
Alpha: hepatitis C, hepatitis B, Kaposi sarcoma, Hairy cell leukaemia, CML, myeloma
Beta: Behcet's disease
Interferon gamma: chronic granulomatous disease
176
What are the limitations of plasmapheresis?
Anaphylaxis
| Rebound antibody production
177
What is the mechanism of action of sirolimus?
Inhibits mTOR thereby blocking T cell replication
NOTE: mTOR inhibits IL2 signalling pathways
178
What is the mechanism of action of Efalizumab?
Anti-CD11a
| Inhibits migration of T cells
179
What is the difference between direct and indirect recognition of a transplanted graft?
Direct - DONOR APC presents antigen to recipient T cells (responsible for acute rejection - everything is perceived as 'foreign')
Indirect - RECIPIENT APC presents donor antigen to recipient T cells (responsible for chronic rejection)
180
Describe the symptoms of graft-versus-host disease.
Skin: rash
Gut: nausea, vomiting, abdominal pain, diarrhoea
Liver: jaundice
181
Which cytokines do CD8 T cell produce that can prevent HIV entry into cells?
MIP-1a
MIP-1b
RANTES
These cytokines block co-receptors
182
What is the median time from HIV infection to AIDS?
8-10 years
Rapid progressors: 2-3 years
Long term non-progressors: stable CD4 and asymptomatic after 10 years
183
List some examples of NRTIs.
Zidovudine
Abacavir
Emtricitabine
Lamivudine
NOTE: tenofovir is a nucleoTide reverse transcriptase inhibitor
184
List some examples of NNRTIs.
Nevirapine
| Efavirenz
185
List some examples of integrase inhibitors.
Raltegravir
| Elvitegravir
186
List some examples of protease inhibitors used for HIV.
Indinavir
Lopinavir
Saquinavir
187
What are some key features of central memory cells?
Found in lymph nodes and extravasate in high endothelial venules
CCR7 and CD62L positive
Produce IL2
Central memory predominates in CD4 cells
188
What are some key features of effector memory cells?
Found in liver, lungs and gut
CCR7 and CD62 NEGATIVE (not found in lymph nodes)
Produce perforin and IFN-gamma
Predominates in CD8 cells
189
Why dont vaccines work very well in the elderly?
Immune senescence
190
List some adjuvants that can be used with vaccinations.
Alum: most common. Allows slow release of antigens. Activates Gr1 cells to produce IL4 (primes B cells)
CpG: linked to DNA motif rich in CpG. Activates TLRs on APCs by stimulating costimulatory molecule expression
Freund's adjuvant: water-in-oil emulsion contain mycobacterial cell wall components (not used clinically)
ISCOMs: experimental, multimeric antigen.
IL2
191
Which medications are used in the treatment of anaphylaxis and at what doses?
```
IM adrenaline (0.5 mg)
IV chlorpheniramine (10 mg)
IV hydrocortisone (200 mg)
```
Also give IV fluids, oxygen and nebulised bronchodilators
192
What are the two types of latex allergy?
Type 1 hypersensitivity: acute onset of classic allergic symptoms
Type 4 hypersensitivity: causes contact dermatitis which arises 24-48 hours after exposure, itchy rash, NOT responsive to antihistamines
193
What are SPUR infection?
Serious
Persistent
Unusual
Recurrent
194
Describe the mechanism of action of serum sickness.
Penicillin binds to cell surface proteins
This acts as a neo-antigen, which stimulates a very strong IgG response
This means that the individual is sensitised to penicillin
Subsequent exposure leads to the formation of immune complexes with the penicillin and the production of more IgG antibodies
Immune complexes deposit in joints, kidneys and skin causing arthralgia, glomerulonephritis and a vasculitic rash
195
How can serum sickness due to penicillin be investigated?
Low serum C3 + C4 (suggests classical pathway activation)
Specific IgG to penicillin
Biopsy of skin or kidneys (showing infiltration of macrophages and neutrophils, deposition of IgG, IgM and complement)
TREATMENT: stop penicillin, give steroids
196
Explain the following clinical manifestations of serum sickness:
a. Deterioration in renal function
b. Disorientation
c. Purpura
a. Deterioration in renal function
Deposition of immune complexes in the glomeruli leads to complement activation and inflammatory cell recruitment
This leads to glomerulonephritis resulting in a rise in creatinine, proteinuria and haematuria
b. Disorientation
Small vessel vasculitis affecting the cerebral vessels can compromise the oxygen supply to the brain
c. Purpura
Inflamed blood vessels are likely to leak resulting in local haemorrhage
197
What is the role of PTPN22 and which polymorphism is associated with rheumatoid arthritis?
It is a lymphocyte-specific tyrosine kinase that suppresses T cell activation
1858T allele increase susceptibility to rheumatoid arthritis, SLE and T1DM
198
List some medications that are used in the treatment of rheumatoid arthritis.
```
Methotrexate
TNF-alpha antagonists (e.g. infliximab)
Rituximab
Abatacept
Tocilizumab
```
199
Which antibody is seen in mixed connective tissue disease?
Anti-U1RNP
200
Which antibody is present in paraneoplastic cerebellar degeneration?
Anti-purkinje cell antibody
201
How is myeloperoxidase deficiency distinguished from chronic granulomatous disease?
Myeloperoxidase deficiency has a normal NBT test and patients are generally asymptomatic, however, they can develop invasive Candida infections
Chronic granulomatous disease would cause a negative NBT test (inability to generate reactive oxygen species)
202
What does RANK stand for?
Receptor activator of nuclear factor kappa B
203
Describe the presenting features of hereditary angioedema.
Autosomal dominant
Affect upper airway, subcutaneous tissues and abdominal organs (e.g. lip swelling, abdominal pain, diarrhoea)
Can be triggered by minor injury (e.g. dental work)
204
How is allergic rhinitis treated?
Intranasal anti-histamine (H1) therapy - if predominant symptom is nasal discharge
Intranasal corticosteroids - if predominant symptom is nasal blockage
205
Which immune modulating agents are associated with PML?
Natalizumab
Efalizumab
Rituximab
Mycophenolate mofetil
206
What are the three types of autoimmune polyendocrinopathy syndromes?
Type 1: APECED
Type 2: Schmidt syndrome
Type 3: IPEX
Schmidt: Addison's disease and hypothyroidism OR T1DM
207
Name three autoimmune diseases that target type IV collagen and specify which part is targeted.
Goodpasture's = non-collagenous domain of alpha-3 unit
Thin membrane disease = alpha-4 unit
Alport = alpha-5 unit
208
How is oral allergy syndrome treated?
Oral antihistamines (provided there is no ABC compromise)
209
The levels of which complement protein decreases first in active lupus?
C4
210
What is a clinical feature of leucocyte adhesion deficiency that may present at birth?
Delayed separation of the umbilical cord
| Also associated with severe skin infections
211
List and describe three mechanisms of type IV delayed hypersensitivity.
Th1 --> macrophage --> TNFa (auto/alloimmunity)
Th2 --> eosinophil --> inflammatory mediators (allergy)
CTL --> granzyme and perforin --> apoptosis (auto/alloimmunity)
212
Which antigen is targeted in multiple sclerosis?
Myelin basic protein
Proteolipid protein
NOTE: CD4 cells are mainly involved in the pathophysiology
213
Which HLA genotype is associated with juvenile idiopathic arthritis?
DR8
214
What is the receptor phenotype of Tregs?
CD4
CD25 (IL-2 receptor)
CTLA4
FoxP3
215
List some examples of anti-TNFa agents and state some indications.
Examples: infliximab (IV), adalimumab, certolizumab, golimumab
Uses: rheumatoid arthritis, ankylosing spondylitis, IBD, psoriasis
216
List some uses of plasmapheresis.
Antibody mediated disease (type II hypersensitivity)
Goodpasture's syndrome
Myasthenia gravis
Antibody-mediated graft rejection
217
Outline a common pre-transplant and post-transplant treatment regimen.
Pre-transplant: suppress T cells with alemtuzumab, basiliximab or anti-thymocyte globulin
Post-transplant: calcineurin inhibitor + mycophenolate with or without steroids
218
Which malignancies are transplant recipients at increased risk of?
```
Viral-associated malignancy
Kaposi sarcoma
Lymphoproliferative (EBV)
Lung
Colon
Skin (x 20)
```
NOTE: they also have a 20 x increased risk of MI
219
```
Briefly describe the pathology of the following types of transplant rejection:
Hyperacute
Acute cellular
Acute antibody-mediated
Chronic
```
Hyperacute - thrombosis and necrosis (preformed antibodies)
Acute cellular - cellular infiltrate (CD4-mediated)
Acute antibody-mediated - vasculitis
Chronic - fibrosis, glomerulonephritis, bronchiolitis obliterans
220
Which diseases may cause a false-negative on the Mantoux test?
HIV
Sarcoidosis
Lymphoma
Current infection
221
Which vaccines are not safe in HIV?
Yellow fever
BCG
IMPORTANT: MMR is safe
222
Which receptors does HIV use to bind and enter T cells?
CD4
CXCR4
CCR5
NOTE: mutation in CCR5 confers innate resistance to HIV
223
Name an entry inhibitor that may be used to treat HIV.
Maraviroc
224
What are the clinical features of Kearns-Sayre syndrome?
```
Ptosis
Ophthalmoplegia
Pigmented retinopathy
Proximal muscle weakness
Cardiac conduction defects
Hearing loss and cerebellar ataxia
Endocrine dysfunction (e.g. hypoparathyroidism, diabetes)
```
225
What is Hirata's disease?
Insulin autoimmune syndrome
Defined by fasting blood glucose and autoantibodies to serum insulin
Prevalent in Japan
226
Which antigen is targeted in Guillain-Barre syndrome?
Ganglioside LM1
227
List some features of mucosal surfaces that act as a barrier to pathogens.
```
Mucus traps pathogens
Mucus contains secretory IgA
Lactoferrin starves bacteria of iron
Cilia trap pathogens and waft mucus
Lysozyme
```
228
```
Name the macrophages found in the following tissues:
Kidney
Spleen
Neural tissue
Connective tissue
```
Kidney - mesangial cell
Spleen - sinusoidal lining cell
Neural tissue - microglia
Connective tissue - histiocyte
229
Which proteins can opsonise pathogens?
Antibodies
Complement proteins
Acute phase proteins
230
What do the activating receptors on NK cells recognise?
Heparan sulphate proteoglycans
231
Which part of the immunoglobulin molecule determines its effector function?
Constant region (Fc) of the heavy chain
232
Which cell surface proteins are detected via the alternative complement pathway in Gram-positives and Gram-negatives?
```
Gram-positive = teichoic acid
Gram-negative = lipopolysaccharide
```
233
Describe the clinical features of C1q deficiency.
Severe childhood-onset SLE with normal levels of C3 and C4
234
List some causes of basophilic stippling.
Beta thalassemia
Lead poisoning
Alcoholism
Sideroblastic anaemia
235
Which other diseases are strongly associated with coeliac disease?
Dermatitis herpetiformis
Type 1 diabetes mellitus
Autoimmune thyroid disease
Down syndrome
236
What is the main role of T follicular cells?
They help B cells undergo germinal centre reactions (thereby allowing them to become memory cells)
237
In which group of antibody deficiency patients would vaccination be a worthwhile intervention?
IgA deficiency
| Other types of antibody deficiency wont be able to mount a response to the antigen
238
Describe the differences in IgG/C3 staining patterns of the three types of crescentic glomerulonephritis.
Immune complex: granular
Pauci immune: scanty or absent
Anti-GBM: linear
239
What is the difference between immature and mature dendritic cells?
Immature: phagocytose small quantities of surrounding tissue
Mature: capable of migrating to lymph nodes and activating T cells
240
How can hereditary angioedema be distinguished from drug-induced angioedema?
Hereditary angioedema: does NOT respond to antihistamines (may respond to icatibant or C1 esterase)
Drug-induced angioedema: responds to antihistamines and steroids
241
```
Which diseases are caused by mutations in:
Mevlonate kinase (MK) gene
TNF receptor (TNFRSF1)
```
```
Mevalonate kinase (MK) gene - Hyper IgD with periodic fever syndrome
TNF receptor (TNFRSF1) - TNF receptor associated periodic syndrome
```
242
List some mutations that are associated with ankylosing spondylitis.
IL23 receptor - promotes differentiation of Th17
ERAP1 (ARTS1) - trims peptides for presentation on MHC
ANTXR2 - involves in maintaining structure of basement membrane
ILR2 - decoy receptor that inhibits IL1
HLA-B27 - present antigen to CD8 T cell
243
What are the main targets of immunosuppression in ankylosing spondylitis?
TNF-alpha
| IL17
244
Which mediators released by mast cells are pre-formed and which are synthesised?
Pre-formed: histamine, serotonin, proteases
Synthesised: leukotrienes, prostaglandins, bradykinin, cytokines
NOTE: IgE binds to Fc epsilon receptors on mast cells and basophils
245
Which type of hypersensitivity is most commonly implicated in autoimmune disease?
Type 2
246
Describe the typical presentation of progressive multifocal leukoencephalopathy.
Clumsiness
Progressive weakness
Visual, speech, and sometimes personality changes
247
Describe the immune response to allergens, worms and venoms.
Damaged epithelium releases signalling cytokines (e.g. TSLP)
These cytokines act on Th2, Th9 and ILC2 cells to produce IL4, IL5 and IL13
These cytokines act on eosinophils and basophils which are important in expelling parasites and allergens
The cytokines from the damages epithelium can also activate Th2 cells, which release IL4
IL4 stimulates B cells to produce IgE and IgG4
248
What is the maximum number of important HLA mismatches that a organ recipient can have with a donor?
6
| There are three important HLA types (A, B and DR) and there are 2 alleles for each
249
Which cytokine is important for promoting eosinophil growth?
IL5
250
Which interleukin is important in sensitisation to allergic stimuli?
IL12
251
Which medications are used to treat granulomatosis with polyangiitis?
Inducing Remission: rituximab, cyclophosphamide, steroids
Maintaining Remission: azathioprine, methotrexate, rituximab
NOTE: plasma exchange is used in severe cases
252
What could cause a raised CH50?
Inflammation (e.g. rheumatoid arthritis)
253
Which anti-TNF agent is NOT effective in inflammatory bowel disease?
Etanercept (its Fc region is not functional)
254
What are some therapeutic targets in psoriasis?
IL12/23
TNF-alpha
IL17
255
What are some therapeutic targets in rheumatoid arthritis?
IL6
TNF-alpha
B cells
256
Describe an infusion reaction that might occur with the use of biologic agents.
Urticaria, hypotension, tachycardia, wheeze (IgE)
| Headache, myalgia, fever
257
Describe injection site reactions that you might see when using biologic agents.
Peak reaction at 48 hours
Recall reactions - may occur at the site of previous injection
Mixed cellular infiltrate (often with CD8)
Not usually IgE or immune complex-mediated
258
Which infections are patients receiving biologic therapy at increased risk of?
```
TB
HBV and HCV
HIV
CMV
JC Virus
```
259
Which malignancies are patients receiving biologic therapy at risk of?
Lymphoma (EBV)
Non-melanoma skin cancer
Melanoma
260
What do TNF and TGF stand for?
Tumour necrosis factor
| Transforming growth factor
261
Which cell line is used to test for ANA?
Hep-2 (human epidermoid cancer line)
262
Describe the immunofluorescence pattern seen in lupus nephritis.
Granular lumpy bumpy pattern
263
List three ANA staining patterns and the associated antibodies/diseases.
Homogenous - anti-dsDNA
Speckled - Ro, La, Sm, U1RNP
Nucleolar - anti-Scl70 (diffuse systemic sclerosis)
Cytoplasmic - anti-Jo1, anti-SRP (also nuclear)
NOTE: anti-centromere antibodies have a different staining pattern
264
What is typically used as initial therapy in the prevention of allograft rejection?
Azathioprine/sirolimus + prednisolone + mycophenolate mofetil
265
Which conditions are TNF-alpha inhibitors used to treat?
```
Rheumatoid arthritis
Ankylosing spondylitis
Psoriasis
IBD
NOTE: etanercept is ineffective in IBF
```
266
Which conditions are ustekinumab used to treat?
Psoriasis
| Crohn's disease
267
Which conditions are secukinumab used to treat?
Psoriasis
| Ankylosing spondylitis
268
What is abatacept used to treat?
Rheumatoid arthritis
269
What are some consequences of deficiency in the mannose binding lectin pathway?
Does NOT usually cause significant immunodeficiency
May cause increased risk of infection in patients with other reasons for immune deficiency (e.g. chemotherapy, HIV, premature infants, antibody deficiency)
270
How is ACEi-induced angioedema different from other types of drug-induced angioedema?
DOES NOT RESPOND TO ANTIHISTAMINES
Slower progression than histamine-mediated angioedema (over hours)
No urticaria or itching
