Immuno

Question 1

SUMMARY CARD:

What are the 4 main types of cells in the innate immune system?

Answer 1

1. Granulocytes: neutrophils, eosinophils, basophils
2. Monocytes (in blood) + macrophages (same as monocyte but found in tissue) –> APCs to T-cells
   NOTE: macrophage named differently based on where it is found e.g. liver (Kupffer), kidney (mesangial), spleen (sinusoidal lining), bone (osteoclast), lung (alveolar macrophage), neural (microglia), connective (histiocyte), skin (langerhans)
3. Natural killer (NK) / cytotoxic cells: kill ‘altered’ self cells e.g. those that are malignant or infected with a virus
4. Dendritic cells: reside in peripheral tissues and modulate the innate and adaptive immune system

Question 2

SUMMARY CARD:

How does the innate pathway normally function?

Phagocyte development; migration to infection; non vs oxidative methods

Answer 2

1. Phagocytes produced in bone marrow –> released into blood
2. Types of phagocytes: neutrophils (die afterwards) + macrophages (signal to T-cells after) = phagocytosis; dendritic cells mediate the transition between innate and addaptive immune cells
3. Endothelial cells in blood vessels release / express adhesion molecules e.g. ICAM-1 (make the blood vessel wall stickier)
4. Infection releases cytokines and chemokines, which attracts the phagocytes. Adhesion molecules allow the phagocytes to stick to the blood vessel wall + access the microorganisms
5. Phagocytosis occurs (engulf the pathogen)
6. Pathogen is killed via oxidative and non-oxidative methods
7. Oxidative: Firstly, reduction: O2 –NADPH oxidase–> H2O2; then H2O2 + Cl2 –myeloperoxidase –> 2HClO (hydrocholorous acid)
8. Non-oxidative: lysozymes
9. As phagocytosis can be done by neutrophils OR macrophages:
10. Neutrophils: Phagocytosis depletes glycogen reserve –> results in CELL DEATH and therefore residual enzymes liquify surrounding tissue (PUS!!)
11. Macrophages: become activated + release cytokines to interact with T-cells

Question 3

SUMMARY CARD:

What deficiencies in the phagocyte pathway can lead to which disorders?

Clue: production, maturation, migration, oxidative killing

Answer 3

Primary immune deficiences in PHAGOCYTES can lead to:

1. Failure to produce neutrophils:

• Reticular dysgenesis (auto reccessive = MOST SEVERE SCID) –> mutation in adenylate Kinase 2 (AK2) = NO lymphoid or myeloid cells (LOW B and T cells)
• Kostmann Syndrome (autosomal recessive = severe congenital neutropenia) –> mutation in HCLS1-associated protein X-1 (HAX-1) = LOW neutrophils (and as neutrophils are responsible for pus formation, NO PUS!)
• Cyclical neutropenia (autosomal dominant) –> mutation in Neutrophil Elastase (ELA-2) = fluctuating neutropenia every 4-6 weeks

2. Failure of phagocyte migration:

• Leucocyte adhesion deficiency (autosomal recessive) –> mutation in CD18 Beta-2 integrin subunit = LFA-1 on neutrophils cannot bind to adhesion molecule ICAM-1 so cannot migrate to infection site = very high neutrophil count and NO PUS

3. Failure of oxidative killing:

• Chronic granulomatous disease (X-linked recessive / auto recessive) –> defective NADPH oxidase = lack of ROS = normal cell counts as deficiency is to do with the enzyme, not the granulocytes

4. Deficiency of cytokines:

• Interferon-gamma/IL-12 deficiency = deficiency in IFN-y, IL-12 and their receptors = ↑ susceptibility to mycobaterial infections (e.g. TB, salmonella) AND normal neutrophil count

Question 4

SUMMARY:

What is the normal IL-12 and IFN-gamma pathways?

stimulates oxidative pathways!

Answer 4

• Infected macrophages produce IL-12
• IL-12 induces T-cells to secrete IFN-y
• IFN-y feeds back to macrophages & neutrophils
• Stimulates the production of TNF
• Activates NADPH oxidase = stimulation of the oxidative pathway(s)

Question 5

DISEASE:

SEVERE sepsis few days after birth
Usually do not survive past 1 year in infancy
Sensorineural deafness
LOW T and B cells

1. Diagnosis?
2. Mutation?
3. Inheritance pattern?
4. Management?

Most severe phagocyte deficiency

Answer 5

1. reticular dysgenesis
2. adenylate kinase 2 (AK-2)
3. auto recessive
4. fatal in early life unless corrected with bone marrow transplant

NOTE: AK2 is responsible for devloping certain structures in the ear –> which is why it presents with sensorineural deafness!

Question 6

DISEASE:

ISOLATED low neutrophils
NO PUS formation

1. Diagnosis?
2. Mutation?
3. Inheritance pattern?
4. Management?

Answer 6

1. Kostamann Syndrome (severe congenital neutropenia)
2. HCLS1-associated protein X-1 (HAX-1)
3. auto recessive
4. granulocyte-colony stimulating factor (G-CSF)

Question 7

DISEASE:

Fluctuating neutropenia every 4-6 weeks
e.g. X pt is found to have low neutrophils. 6 weeks later, they are back to normal.

1. Diagnosis?
2. Mutation?
3. Inheritance pattern?
4. Management?

Answer 7

1. cyclic neutropenia
2. neutrophil elastase = enzyme (ELA-2 = gene)
3. auto dom
4. granulocyte-colony stimulating factor (G-CSF)

Question 8

DISEASE:

Delayed umbilical cord separation
Absence of pus formation
VERY HIGH neutrophil counts in blood

1. Diagnosis?
2. Mutation?
3. Inheritance pattern?
4. Management?

Answer 8

1. leukocyte adhesion deficiency
2. CD18 B2 integrin subunit
3. auto recessive
4. neutrophils are deficienct in adhesion receptors therefore are useless –> Mx with haematopoietic stem cell transplant

Question 9

DISEASE:

Increases susceptibilibity to bacterial infections: PLACESS (pseudomonas, listeria, aspergillus, candida, E coli, staph, serratia)
CHRONIC INFLAMMATION
Non-caseating granuloma formation
Lymphadenopathy, hepatosplenomegaly, recurrent skin / fungal infections
NORMAL neutrophil / WBC count

1. Diagnosis?
2. Mutation?
3. Inheritance pattern?
4. Investigations?
5. Management?

(failure of oxidative killing)

Answer 9

1. chronic granulomatous disease
2. mutation in ENZYME NADPH oxidase (so normal WCC)
3. X-linked recessive or autosomal recessive
4. abnormal dihydrorhodamine = no flourescence (normal: flourescence); abnormal nitroblue tetrozolium (NBT) test = remains yellow (normal: colour change yellow –> blue)
5. interferon-gamma therapy

Question 10

DISEASE:

Increased susceptibility to atypical mycobacterial infections e.g. TB, salmonella
Inability to form granulomas
NORMAL neutrophil count

1. Diagnosis?
2. Mutation?

Answer 10

1. Interferon-gamma/IL-12 deficiency
2. IFN-y, IL-12 and their receptors

Question 11

SUMMARY CARD:

What is the purpose of natural killer (cytotoxic) T-cells?

How do they kill cells?

Answer 11

• Present within the blood + migrate to inflamed tissue
• Typically, they express inhibitory receptors for self-HLA molecules to avoid accidental inappropriate action against self cells
• HOWEVER, they express a range of activating receptors that allow it to kill ‘altered’ self cells e.g. those that are malignant or infected with a virus (as these lack the inhibitory signals of normal self antigens) –> so deficiency in this = ↑risk of viral infection

2 main mechanisms of killing ‘altered’ self cells:
1. Perforin (pokes holes in membranes) + granzymes
2. Fas ligand expression –> triggers apoptosis

Question 12

DISEASE:

↑risk of viral infection e.g. HERPES
Typical SBA: child with severe chickenpox or disseminated CMV

Which 2 NK deficiencies could this be and how is it managed?

Answer 12

1. Classical NK deficiency = ABSENCE of NK cells in peripheral blood
2. Functional NK deficiency = NORMAL levels of NK cells in blood BUT non-functional

Mx for both = prophylactic antivirals; IFN-alpha to stimulate NK cells and if severe –> HSCT

Question 13

SUMMARY CARD:

What is the complement cascade and how does it normally function?

How is the complement cascade activated?

Answer 13

Complement cascade = sequence of reactions that complement/enhance the rest of the immune system
They are inactive proteins produced by the liver + exist in the circulation
Triggers e.g. infection = series of enzymes cleave the proteins and initiate a cascade of reactions
This leads to the END POINT: membrane attack complex (MAC) –> attacks pathogen cell membrane (pokes holes)

ALSO: fragments released during cascade leads to:

• ↑ vascular permeability –> immune cells can reach the infected tissue more easily
• Activated phagocytes = ↑ phagocytosis
• Opsonise (make pathogen more susceptible to phagocytosis e.g. by marking it for destruction) pathogens + immune complexes
• Promote mast cell + basophil degranulation

Activation of complement cascade:

1. Classical pathway: C1, C2, C4

• Requires a functioning immune system as they are activated via an antigen-antibody (Ag-Ab) complex
• Conformational change in Ag-Ab complex exposes binding site for C1 activation –> the binding initiates cascade

2. Alternative pathway: C3

• Activated by pathogens of apoptotic tissue

3. Mannose-binding lectin: C4, C2

• Activated by serum lectin binding sugars (which may be found on bacterial cell walls or yeast cells)

The combination of C4b+C2a forms C3 convertase, which converts C3 to C3a (inflammation) and C3b (opsonisation)

Afterwards, this all feeds into a final common pathway composed of C5 convertase and C5-C9 –> this eventually forms the end product: MEMBRANE ATTACK COMPLEX (MAC)

NOTE: a cleaved complement divides into a (smaller) and b (bigger) fragments e.g. C3a + C3b

Question 14

SUMMARY CARD:

What deficiencies in the complement cascade can lead to which disorders?

Answer 14

1. Classical pathway deficiencies:

• Deficiency in C2 (auto recessive) = most common –> ↑ SLE in childhood + severe skin disease
  NOTE: normally classical pathway is activated by Ag-Ab complexes and it triggers phagocyte mediated clearance of these immune complexes, therefore lack of this = immune complex deposited in organs/joints (SLE)

2. MBL pathway deficiencies:
MBL deficiency (auto recessive) on its own is not an issue (no immunodeficiency), HOWEVER, paired with another immune impairment e.g. HIV, prematurity, chemotherapy, antibody deficiency etc. –> can cause immunodeficiency + ↑infection risk

3. C3 deficiency:
Severe susceptibility to ENCAPSULATED bacterial infections

4. Secondary C3 deficiency:

• C3 deficiency w/ nephritic factors = nephritic factors stabilise C3 convertase which results in ↑activation + consumption of C3 –> associated with membranoproliferative glomerulonephritis + partial lipodystrophy (abnormal fat distribution) –> LOW C3, NORMAL C4
• SLE = production of immune complexes results in consumption of C3 + C4 –> LOW C3 and LOW C4

5. Alternative pathway deficiency:

• Properdin deficiency = RARE: properdin is a protein in the alternative pathway that typically stabilises C3 convertase –> absence = recurrent encapsulated bacterial infection esp. Neisseria
• Other alternative pathway deficiencies = factor B or factor D

6. Terminal pathway deficiency (C5-C9):
Any defect results in inability to form membrane attack complex (MAC) –> recurrent encapsulated bacterial infection esp. recurrent meningococcal disease + FAMILY HISTORY

NOTE: C9 deficiency often asymptomatic

NOTE: NHS for encapsulated bacteria = Neisseria meningitis; Haemophilus influenzae; Streptococcus pneumoniae

Question 15

DISEASE:

How do you differentiate between complement deficiency causing SLE and SLE causing complement deficiency?

Answer 15

Most common complement deficiency to cause SLE = C2 deficiency –> therefore, NORMAL levels of C3 + C4

HOWEVER, if pt has SLE, lupus causes the production and deposition of immune complexes which consumes and consequently depletes C3/C4 levels –> so LOW levels of C3 + C4

Question 16

SUMMARY CARD:

How can you remember the encapsulated bacteria?

Answer 16

NHS
N-eisseria meningitis
H-aemophillus influenzae
S-treptococcus pneumoniae

Question 17

DISEASE:

What are the investigations to test for complement pathway deficiencies?

classical vs alternative?

Answer 17

Measure C3 + C4 levels:

• LOW C3 + LOW C4 = active SLE
• LOW C3, NORMAL C4 = C3 deficiency with nephritic factors (membranoproliferative glomerulonephritis)
• NORMAL C3 + NORMAL C4 but SLE = C2 deficiency

CH50:

• Marker of classical pathway (+ve = normal; -ve/absent = abnormal)

AP50:

• Marker of alternative pathway (+ve = normal; -ve/absent = abnormal)

NOTE: both CH50 + AP50 are markers of C3 to C5-C9

Question 18

DISEASE:

Recurrent neisseria / Hib / strep pneumoniae infections

1. Diagnosis?
2. Management?

Answer 18

1. Presenting with recurrent NHS (encapsulated bacterial infections) –> complement deficiency
2. Mx = vaccinations against NHS, prophylactic abx, treating infections aggressively, screen family members (esp w/ C5-C9 deficiency)

Question 19

DISEASE:

SLE in childhood
vasculitic rash / severe skin disease
glomerulonephritis
arthritis

What is the diagnosis?
What is absent on Ix?

Answer 19

Classical pathway deficiency –> C2 deficiency = most common

Absent CH50

Question 20

DISEASE:

Aymptomatic on its own
Immunodeficient when paired with prematurity / HIV/ chemo therapy –> Pt has recurrent Neisseria infection

What is the diagnosis?

Answer 20

MBL (mannose-binding lectin) complement pathway deficiency

Question 21

DISEASE:

Membranoproliferative glomerulonephritis + partial lipodystrophy (abnormal fat distribution)

What is the diagnosis?

Answer 21

C3 deficiency with nephritic factors –> nephritic factors cause consumption of C3

Therefore LOW C3, normal C4

Question 22

Recurrent Nesseria infection

What is the diagnosis?
What is absent on Ix?

Answer 22

Alternative complement pathway deficiency

• Properdin deficiency = RARE: properdin is a protein in the alternative pathway that typically stabilises C3 convertase –> absence = recurrent encapsulated bacterial infection esp. Neisseria
• Other alternative pathway deficiencies = factor B or factor D

Absent AP50

Question 23

DISEASE:

Recurrent meningococcal disease (e.g. NHS) + FAMILY HISTORY

What is the diagnosis?

Answer 23

Terminal complement pathway deficiency (C5-C9 deficiency)

NOTE: C9 deficiency often asymptomatic

Question 24

SUMMARY CARD:

Development of the T-cell adaptive immune response and how does it normally function?

Answer 24

1. T-cells are produced in the bone marrow + undergo maturation in the thymus
2. Central tolerance: HLA matching in the thymus –> those with a too low OR too high affinity for HLA are not selected for maturation (die as immature T-cells) as they would have inadequate reactivity
3. Only the INTERMEDIATE affinity for HLA are selected for during maturation (~10% of the immature of T cells) –> they can have an affinity to class I or II
4. Those with an affinity for class I develop into CD8+ T-cells (NK) –> important for virus infected cells + tumours:

• Kill cells via perforin (holes in membrane) + granzyme
• Can also kill cells via fas ligand expression

5. Those with an affinity for class II develop into CD4+ T-cells:

• Help with the B-cell response
• Help promote CD8+ (NK) cell action

Question 25

SUMMARY CARD:

What deficiencies in the T-cell pathway can lead to which disorders?

failure of: production, maturation, activation

Answer 25

1. Failure of lymphoid cell production

• Reticular dysgenesis (auto reccessive = MOST SEVERE SCID) –> mutation in adenylate Kinase 2 (AK2) = NO lymphoid or myeloid cells (AKA affects the innate AND immune response) = (LOW B and T cells)
• Severe combined immunodeficiency (SCID) –> 20 possible pathways = unwell by 3 months of age as no longer protected by the maternal IgG that crossed the placenta e.g. failure to thrive, persistent diarrhoea, poorly developed thymus, FHx of early infant death
• X-linked SCID = most common (45% of all SCID) –> mutation in gamma chain of IL-2 receptor on Chromosome Xq13.1 results in poor cytokine response = early arrest of T-cells and NK cell development + production of IMMATURE B-cells = low/absent T cells & NK cells BUT normal (immature) B-cell count
• ADA deficiency –> mutation of adenosine diaminase (ADA), an enzyme required for lymphocyte metabolism, therefore deficiency = low/absent T cells, NK cells & B-cells

NOTE: (definitive) Mx for above = HSCT as all are issues in the bone marrow

2. Failure of maturation/selection in the thymus

• DiGeorge Syndrome (22q11.2 deletion) –> smaller/absent thymus = lack of mature T-cells, which consequently reduces B-cell function (↓IgG) as T-cells normally activate B-cells to produce IgG = NORMAL B-cell count BUT low T-cell
• Bare lymphocyte syndrome (BLS) type I –> defect in MHC class I = deficiency of CD8+ (NK) cells
• Bare lymphocyte syndrome (BLS) type II –> defect in MHC class II = deficiency of CD4+ but normal CD8+ (NK) + B-cell count –> lack of CD4+ = lack of B-cell activation to produce IgG or IgA via class switching

3. Failure of T-cell activation and effector functions

• Interferon-gamma/IL-12 deficiency = deficiency in IFN-y, IL-12 and their receptors = ↑ susceptibility to mycobaterial infections (e.g. TB, salmonella) AND normal neutrophil count
• Hyper IgM syndrome = failure to express CD40L on activated T-cells (normally CD40-ligand on T-cell causes B-cell differentiation from IgM to IgA/G/E) –> therefore absent IgA/G/E + ELEVATED IgM
• Wiskott-Aldrich Syndrome (WAS) = mutation in Wiskott-Aldrich Syndrome Protein (WASP); Xp11.23 –> WASP stabilised T-cell APC interaction therefore mutation in this limits the primary response with IgM = low IgM BUT elevated IgA + IgE as pts present with eczema, thryombocytopenia, ↑ risk of autoimmune disorders and malignancy (lymphomas and leukaemias)

Question 26

DISEASE:

Unwell by 3 months of age with infections of all types
Failure to thrive
Persistent diarrhoea
Poorly developed thymus
FHx of early infant death

What is the diagnosis?

Answer 26

Severe combined immunodeficiency (SCID)

Question 27

DISEASE:

Very low/ absent T cells and NK cell count
Normal B cell count
Sx of immunodeficiency in childhood e.g. failure to thrive, recurrent infections, persistent diarrhoea etc.

What is the diagnosis?

Answer 27

X-linked SCID

NOTE: normal B-cell count, but B-cells immature as IL2-receptor mutation = poor cytokine response –> early arrest of T + NK cells (low count) and no maturation if B-cells

Question 28

Very low/ absent T cells and NK cell count
AND low B cell count
Sx of immunodeficiency in childhood e.g. failure to thrive, recurrent infections, persistent diarrhoea etc.

What is the diagnosis? (+ Mx?)

Answer 28

Adenosine Deaminase (ADA) deficiency

NOTE: ADA responsible for lymphocyte cell metabolism

Mx = PegADA or HSCT (definitive)

Question 29

DISEASE:

Developmental defect of pharyngeal pouch
Small/absent thymus
Tetralogy of Fallot
Prominent forehead, wide-set eyes, and small chin
Cleft palate
Hypocalcaemia
Recurrent infections in childhood that get less frequent with age

What is the diagnosis & mutation? (+ Mx?)

Answer 29

DiGeorge Syndrome

Sx: CATCH-22

• C-ardiac abnormalities e.g. Tetralogy of Fallot
• A-bnormal facies (high forehead, low set ears)
• T-hymic hypoplasia
• C-left palate
• H-ypocalcaemia (lack of PTG = low Ca2+)
• 22 - 22q.11.2 (remember as 11x2=22)
• Homeostatic proliferation with age = frequency of infections reduce as immune function improves with age

Lack of mature T-cells but normal B-cell count
NOTE: normally T-cells activate B-cell differentiation to produce IgG, however, this is impaired = LOW IgG

Mx = thymic transplant

Question 30

DISEASE:

LOW CD8+ (NK) cell count

Answer 30

Bare lymphocyte syndrome type I = mutation in class I = CD8+ deficiency

Question 31

DISEASE:

Fhx of early infant death
Sclerosing cholangitis
Normal B cells + IgM but low IgA and IgG

What is the diagnosis?

Answer 31

Bare lymphocyte syndrome (BLS) type II = mutation in class II = CD4+ deficiency

NOTE: CD4+ normally promotes B-cell differentiation and class switching to produce IgA and IgG (therefore, normal B-cell + IgM BUT low IgA + IgG)

Question 32

DISEASE:

TRIAD: eczema (raised IgE), thrombocytopenia (low platelet count), + recurrent bacterial infections
Easy bruising
↑ risk of autoimmune disorders and malignant lymphomas

What is the diagnosis + mutation? (+ levels of IgM / IgA / IgE)

Answer 32

Wiskott-Aldrich Syndrome (WAS) = mutation in WAS-protein; Xp11.23

↑ IgE (eczema)
↑ IgA
↓ IgM

Question 33

SUMMARY CARD:

Development of the B-cell adaptive immune response and how does it normally function?

Answer 33

1. B-cell produced and matured in the bone marrow
2. Central tolerance: HLA matching in bone marrow –> those with affinity for self-HLA are not selected for maturation (die as immature B-cells) to avoid autoreactivity
3. ONLY those with NO recognition of self in bone marrow survive and mature!
4. Initially formed B-cells produce IgM response, which is T-CELL INDEPENDENT
5. Germinal centre reaction: dendritic cells prime CD4+ T-cells –> CD4+ help B-cell differentiation via CD40-ligand –> leads to B-cell proliferation + isotype switching e.g. to IgA, IgG, IgE

Question 34

SUMMARY CARD:

What deficiencies in the B-cell pathway can lead to which disorders?

Answer 34

1. Failure of B-cell production

• Reticular dysgenesis (auto reccessive = MOST SEVERE SCID) –> mutation in adenylate Kinase 2 (AK2) = NO lymphoid or myeloid cells (AKA affects the innate AND immune response) = (LOW B and T cells)

2. Failure of B-cell maturation

• Bruton’s X-linked hypogammaglobulinemia (X-linked, BTK gene): only affects Boys –> mutation in Bruton Tyrosine Kinase (BTK) = pre-B-cells cannot develop into mature B-cells, therefore absence of mature B-cells and no circulating Ig after ~3 months –> leads to recurrent infections during childhood + absent lymph nodes & tonsils

3. Failure of class-switching

• Selective IgA deficiency (most COMMON deficiency): unknown genetic component; many individuals asymptomatic, associated with recurrent GI/resp infections (~30%) as IgA present on mucosal surfaces, coeliac and SLE and/or anaphylaxis after blood transfusion (NOTE: so in IgA deficiency use anti-TTG IgG to test for coeliac instead)
• Hyper IgM syndrome (X-linked recessive): mutation in CD40-ligand on T-cell (CD40L normally aids B-cell differentiation + class-switching) = elevated IgM and NO IgE/A/G –> boys esp. present with failure to thrive, recurrent bacterial infections, no germinal centre development within lymph nodes or spleen, etc.
• Common variable immune deficiency = diagnosis of EXCLUSION (make sure B and T cells are normal first) AND >4 y/o–> LOW IgG, IgA and IgM = poor response to immunisation; recurrent bacterial infections with end-organ damage etc.

Question 35

DISEASE:

Affects BOYS
Recurrent bacterial infections during childhood (after 3 months)
Absent/scanty lymph nodes + tonsils
Failure to respond to immunisations;
Ix: NORMAL T cells, ABSENT B cells + Immunoglobulins

What is the diagnosis? (+ Mx?)

Answer 35

Bruton’s X-linked hypogamma globulinemia (only affects boys as X-linked)

NOTE: pre-B cells cannot mature = lack of Ig

Mx = pooled human IG every 3 weeks

Question 36

DISEASE:

Recurrent GI/resp infections
Coeliac / SLE
Anaphylaxis after blood transfusion (anti-IgA Abs)

What is the diagnosis?

Answer 36

IgA deficiency = LOW IgA BUT normal IgM/IgG

Anti-IgA Abs mean pts have anaphylaxis if they get a blood transfusion
GI/resp infections more common because IgA protects mucosal surfaces

Question 37

DISEASE:

First few days of life (typically in BOYS) –> pneumocystis jiroveci pneumonia infection
↑ risk of AI disease + malignancy

What is the diagnosis? (+ Mx?)

Answer 37

Hyper IgM Syndrome

Lack of CD40-ligand on T cell = lack of B-cell class switching –> Normal B and T cells, ↑ IgM (due to failure of isotype switching), ↓ IgA, IgG and IgE

Mx = IVIG

NOTE: Wiskott-Aldrich (WAS) is the opposite, ↑ IgA and IgE BUT ↓ IgM due to excessive class switching

Question 38

DISEASE:

Normal T-cells and B-cells
LOW IgG, IgA and IgM
Poor response to immunisation
Recurrent bacterial infections with end-organ damage
GI and pulmonary disease e.g. bronchiectasis, ILD, IBD
AI disease e.g. RA, pernicious anaemia, thyroiditis

What is the diagnosis?

Clue: diagnosis of exclusion

Answer 38

Common variable immune deficiency

Question 39

QUESTION:

Which Ig is required for effective immunisation?

Answer 39

Require IgG for effective immunisation

Question 40

SUMMARY SLIDE:

What are some examples in the spectrum of autoinflammatory to autoimmmunity?

↑
|Rare monogenic autoinflammatory diseases
|Polygenic autoinflammatory diseases
|Mixed pattern disease
|Polygenic autoimmune diseases
|Rare monogenic autoimmune disease
↓

Answer 40

Autoinflammatory = innate immune response
Autoimmune = adaptive immune response
Mixed innate + adaptive = mixed

↑
|Rare monogenic autoinflammatory diseases: Familial mediterranean fever, Muckle Wells Syndrome
|Polygenic autoinflammatory diseases: Crohns disease, UC, osteoarthritis, GCA (PMR RF for this), Takayasu’s arteritis
|Mixed pattern disease: AS, psoriatic arthritis, Behcet’s
|Polygenic autoimmune diseases: RA, MG, pernicious anaemia, Graves’, SLE, primary biliary cirrhosis, ANCA associated vasculitis, Goodpasture’s disease
|Rare monogenic autoimmune disease: APS-1, APECED, ALPS, IPEX
↓

Question 41

SUMMARY SLIDE:

Monogenic autoinflammatory disease

Guess the diagnosis and mutation (+/- Mx):

1. Flare ups = periods of intense fever lasting 2-4 days, serositis (peritonitis, abdo pain, pleurisy, pericarditis and rash), AA amyloidosis (rare type of amyloidosis)
   e.g. child with unexplained episodic fevers
2. Sensorineural deafness + recurrent episodes of hives, athralgia, conjunctivitis, serositis, ascites (non-tender)

Answer 41

1. Familial mediterranean fever (auto recessive)

• MEFV gene normally responsible for the protein pyrin-marenostrin, which helps control inflammation
• Mutation in MEFV gene = reduced pyrin-marenostrin (thus ↑ IL-1), therefore –> uncontrollable inflammation / pain / fever
• Ix = Tel HaShomer Criteria (1 major or >1 minor criteria)
• Mx 1st line = colchicine (binds to tubules in neutrophils); 2nd line = Anakinra (IL1-receptor antagonist) or Etanercept (TNF-alpha inhibitor)

2. Muckle Wells Syndrome (auto dominant)

• Mutation in NLRP3 gene = ↑ cryopyrin = ↑ IL1-beta = ↑ inflammation
• Sensorineural hearing loss develops overtime due to chronic inflammation of the inner ear
• Mx = Anakinra (IL1-receptor antagonist)

Question 42

SUMMARY CARD:

Monogenic autoimmune

Guess the diagnosis and mutation (+/- Mx):

1. Endocrine disease –> hypoparathyroidism (most common) = hypocalcaemia, Addison’s, hypothyroidism, T1DM
   Chronic mucocutaneous candidiasis, enteropathy (diarrhoea) + mild immune deficiency (recurrent infections)
2. Endocrine disease –> T1DM, hypothyroidism
   Enteropathy (diarrhoea), eczema/dermatitis
   REMEMBER 3Ds: diarrhoea, diabetes, dermatits
3. High lymphocyte count
   Autoimmune cytopenias, lymphoma, splenomegaly, lymphadenopathy

Answer 42

1. Autoimmune polyendocrine syndrome type 1 (APS-1) or Autoimmune polyendocrinopathy-candidiasis-ectodermal dystrophy (APECED)

• Auto recessive condition resulting in abnormal tolerance (AKA autoreactive immune cells DON’T die)
• Mutation in auto-immune regulator protein (AIRE) –> leads to autoreactive T-cells in thymus = auto-reactive B-cells = production of autoantibodies

2. Immune dysregulation, polyendocrinopathy, enteropathy X-linked (IPEX) syndrome

• X-linked condition resulting in failure to regulate T-cell responses
• Mutation in FOXp3 transcription factor, a master protein regulator for the development T-regulatory cells
• Failure to negatively regulate T-cell response = T-cell autoimmunity = B-cell autoimmunity = production of autoantibodies

3. Autoimmune lymphoproliferative syndrome (ALPS)

• Mutation in FAS pathway (death/apoptosis pathway)
• Results in defect of lymphocyte apoptosis –> failure of tolerance
• Thus: ↑ HIGH lymphoctye count + autoimmune cytopenias

Question 43

DISEASE:

Polygenic autoinflammatory disease

Guess the diagnosis + mutation (+/- Mx)

1. Crampy abdominal pain, diarrhoea, mucosal ulcerations
   'Cobblestone mucosa' - skip lesions
   Focal inflammation around crypts + granulomatas

Answer 43

1. Crohn’s disease

• Mutation in NOD-2 or CARD-15 (menumonic: crap ass rectal disease)
• Normally, NOD2 is an intracellular microbial receptor that causes autophagy of dendritic cells when activated
• However, abnormal NOD2 = disordered degradation of immune cells –> inflammation

Question 44

SUMMARY CARD

Which gene is associated with mixed pattern autoinflammatory + autoimmune conditions?

Guess the diagnosis:

1. Enthesitis (achilles tendonitis, sacroilliitis), large joint arthritis, low back pain, joint stiffness relieved by exercise, acute iritis
2. Red, scaly patches, joint pain, dactylitis etc.
3. episodes / flares of: recurrent oral and genital ulcers, uveitis, thrombophlebitis (vasculitis), painful joints

Answer 44

Seronegative arthropathies AKA HLA-B27: Ankylosing spondylitis, psoriatic arthritis

1. Ankylosing spondylitis - HLA-B27 association, highly heritable, associated with uveitis + UC
2. Psoriatic arthritis - HLA-B27
3. Behcet’s disease - HLA-B51

Question 45

SUMMARY CARD:

How do these mutations cause polygenic autoimmune disease + what autoimmune conditions do they cause?

1. PTPN22
2. CTLA4

Answer 45

These are both genetic polymorphisms:

1. PTNP22 codes for a protein tyrosine phosphatase –> important negative T-cell regulator. Mutation in this = development of RA, SLE, T1DM
2. CTLA4 is a is a protein receptor expressed by T-cells that transmits inhibitory signals to control T-cell activation (negative T-cell regulator). Mutation in this = development of SLE, T1DM, autoimmune thyroid disease

Question 46

SUMMARY CARD:

Polygenic autoimmune disease

Guess the diagnosis (type of hypersensitvity) + autoantibodies (+/- Mx)

1. Hyperthyroidism, diffuse goitre, exopthalmos, pretibial myxoedema
2. Hypothyroidism, diffuse goitre, associated with MALT lymphoma
3. Polyuria/nocturia, polydipsia, weight loss OR abdo pain + raised ketones (metabolic acidosis)
4. Macrocytic anaemia + ↑ megaloblasts (RBC precursor)
5. Muscle weakness that worsens with movement; thymoma
6. Muscle weakness improves with movement, NSCLC
7. Glomerulonephritis + pulmonary haemorrhage
8. Symmetrical joint swelling, morning stiffness, swan-neck deformity, boutonniere deformity, ulnar deviation of fingers
9. Villous atrophy, abdominal pain, bloating, steatorrhoea, dermatitis herpetiformis (itchy blisters on elbows / knees / buttocks)

Answer 46

1. Graves’ disease (type 2 / 5) –> anti-TSH receptor antibodies (90%) stimulate thyroid to release more thyroxine; anti-TPO (75%)
2. Hashimoto's (type 2 + 4) –> anti-TPO; anti-thyroglobulin
3. T1DM (type 4) –> anti-islet cell; anti-insulin; anti-GAD (glutamate decarboxylase); anti-tyrosine phosphatase. NOTE: C-peptide is LOW in T1DM but NORMAL in MODY
4. Pernicious anaemia (type 2) –> anti-parietal cell; anti-intrinsic factor
5. Myasthenia gravis (type 2 / 5) –> Anti-nicotinic acetylcholine receptor; anti-MuSK. Mx = Pyridostigmine, if crisis plasmapheresis + IVIG
6. Lambert-Eaton myasthenic syndrome (LEMS) –> anti-voltage-gated calcium-channel antibody
7. Goodpasture's disease / Anti-GBM disease (type 2) –> anti-GBM (type IV collagen)
8. Rheumatoid arthritis (type 3) –> anti-cyclic citrullinated peptide; polymorphisms in PAD2/PAD4 genes cause increased conversion of arginine to citrulline

NOTE: Felty’s = splenomegaly + neutropenia

9. Coeliac disease (type 4) –> anti-tissue transglutaminase IgA; anti-endomysial; anti-gliadin antibodies (NOTE: gliadin deaminated by tTG then deaminated gliadin presented by APC, which triggers immune response to destroy that area of epithelial cells –> gold standard Ix = duodenal biopsy)

Question 47

SUMMARY CARD:

What are the HLA associations with each of these polygenic autoimmune diseases:

1. Ankylosing spondylitis
2. Goodpasture’s syndrome
3. Graves’ disease
4. SLE
5. T1DM
6. RA
7. Coeliac disease

Answer 47

1. Ankylosing spondylitis = HLA-B27
2. Goodpasture’s syndrome = HLA-DR15/DR2
3. Graves’ disease = HLA-DR3
4. SLE = HLA-DR3
5. T1DM = HLA-DR3/4
6. RA = HLA-DR4
7. Coeliac = HLA-DQ2/8

Question 48

SUMMARY CARD:

Polygenic autoimmune diseases: Connective tissue disease (ANA +ve) edition

Guess the diagnosis (type of hypersensitvity) + autoantibodies (+/- Mx)

1. Malar rash + arthralgia + pleurisy after taking procainamide / hydralazine / isoniazid
2. Malar rash, nephritis, pleuritis etc.; associated with anti-phospholipid syndrome, low C3 and C4 in active disease
3. Dry mouth and eyes (confirmed with Schirmer’s test, < 5mm), bilateral parotid enlargement, arthralgia, myalgia, lymphoid malignancy
4. CREST syndrome – Calcinosis (calcium deposition in tissue/skin), Raynaud’s phenomenon, Esophageal dysmotility, Sclerodactyly (localised thickening of skin) and Telangectasia (small dilated blood vessels); skin involvement not below elbows/knees
5. CREST but trunk and proximal limbs predominantly affected, >1 organ system affected (diffuse rather than limited); respiratory involvement most common cause of death
6. Can be associated with underlying malignancy, photosensitive rash w/heliotrope rash in the periorbital region; Gottron’s papules (red papules over extensors); proximal muscle weakness +/- tenderness; high CK + -ve EMG (normal muscle response)
7. Proximal muscle weakness +/- tenderness, ptosis, dysphagia; elevated CK BUT no skin manifestations, EMG might be +ve
8. Renal impairment (↑creatinine), small vessel vasculitis, palpable purpura, cough + dyspnoea, systemic malignancy
9. Saddle nose deformity, URT: epistaxis, sinusitis, LRT: dyspnoea and haemoptysis; pauci-immune glomerulonephritis; renal biopsy: epithelial crescents in Bowman’s capsule
10. Eosinophilia, asthma, mononeuritis multiplex paranasal sinusitis, M>F

Answer 48

1. Drug-induced lupus: anti-histone antibodies; drug causes = procainamide and hydralazine (most common), isoniazid (less common)
2. SLE (type 3): anti-dsDNA (higher titre = more severe disease) OR anti-Smith (most specific but less sensitive); cytology: haematoxylin antibodies, antibody deposition in a granular lumpy-bumpy granules
3. Sjogren's syndrome: anti-Ro and anti-La; ↑ risk of MALT lymphoma; Mx = pilocarpine
4. Limited cutaneous systemic sclerosis: anti-centromere
5. Diffuse systemic sclerosis: anti-topoisomerase (SCL-70) antibody
6. Dermatomyositis: Anti-histidine-tRNA ligase (Jo-1)
7. Polymyositis: Anti-Jo-1
8. Microscopic polyangiitis (type 3): pANCA (70%) + cANCA (45%)
9. Wegener's granulomatosis / granulomatosis w/ polyangiitis (type 3): cANCA (antineutrophil cytoplasmic antibodies)
10. Churg-Strauss syndrome / eosinophilic granulomatosis w/polyangiitis (type 3): pANCA (antineutrophil cytoplasmic antibodies)

Question 49

SUMMARY CARD:

When staining for autoantibodies, a positive nuclear staining result can show which staining patterns?

miscellaenous (can skip)

Answer 49

Positive nuclear staining can show more detailed staining patterns: such as speckled, peripheral, or homogeneous

E.g.

Homogenous: anti-histone (drug induced SLE)
Peripheral: anti-dsDNA (SLE)
Speckled: Anti-Jo-1 (dermatomyositis), anti-Ro/anti-La (Sjogren’s), anti-Smith (SLE), anti-RNP (mixed connective tissue disease)
Nucleolar: anti-RNA polymerase (systemic sclerosis)

Question 50

SUMMARY CARD:

What is the auto-antibody for:

1. Drug-induced lupus
2. SLE
3. Sjogren's syndrome
4. Limited cutaneous systemic sclerosis
5. Diffuse systemic sclerosis:
6. Dermatomyositis:
7. Polymyositis:
8. Microscopic polyangiitis:
9. Wegener's granulomatosis / granulomatosis w/ polyangiitis:
10. Churg-Strauss syndrome / eosinophilic granulomatosis w/polyangiitis:

Answer 50

1. Homogenous anti-histone antibodies
2. Homogenous anti-dsDNA (higher titre = more severe disease) OR speckled anti-Smith (most specific but less sensitive)
3. Speckled anti-Ro + anti-La
4. Anti-centromere
5. Anti-SCL-70 (topoisomerase) antibody
6. Anti-Jo-1 (histidine-tRNA ligase)
7. Anti-Jo-1
8. pANCA + cANCA
9. cANCA (cytoplasmic antineutrophil cytoplasmic antibodies)
10. pANCA (perinuclear antineutrophil cytoplasmic antibodies)

Question 51

SUMMARY CARD:

What are the 4 (or 5) types of hypersensitivity reactions?

Answer 51

1. Type 1 = IgE mediated

• Primary exposure results in sensitisation
• Plasma cells produce IgE abs
• IgE abs bind to antigens
• IgE crosslinks with mast cells / basophils –> triggers degranulation of these cells
• Results in release of histamines
• e.g. atopy, anaphylaxis

2. Type 2 = antibodies bind to antifens on cell surface

• Binding of ab to ag = activation of phagocytes + NK cells via the Fc portion
• Causes autoimmune conditions (as autoantibodies result in destruction of self cells) e.g. Goodpasture’s

3. Type 3 = antibodies bind to antigens in the blood to form immune complexes

• Immune complexes deposit in blood vessels / joints / organs and may cause inflammatory conditions e.g. SLE

4. Type 4 = delayed reaction driven by T-cells

• CD4+ cells release cytokines + CD8+ kills targetted cells
• Symptoms progress over a period of time e.g. T1DM, contact dermatitis, MS

5. Type 5 = Type 2 BUT when antibody binds to antigen on cell surface, it causes MODULATION of cell function e.g. Graves’

Question 52

SUMMARY CARD:

How does a type 1 hypersentivity reaction develop?

Sesitisation then allergy

Answer 52

Sensitisation:

• TH2 cells primed by APCs in lymph nodes –> cytokine release
• IL-4 promotes B-cell class switching to IgE
• IgE binds to mast cells and primes them via the Fc region
• IL-5 promotes eosinophils

Allergy:

• Months later, primed mast cells degranulate –> release of histamines, which cause smooth muscle contraction

Question 53

SUMMARY CARD:

Type 1 hypersensitivity reaction

Guess the diagnosis (+/- Ix / Mx):

1. Angioedema + urticaria; SOB, stridor, upper airway oedema/swelling
2. Allergic to e.g. pears but not if cooked (heat liable allergens); urticaria / Sx limited to mouth
3. Ate wheat / shellfish / celery, then went to gym a few hours later –> develops SOB, urticaria, angioedema etc.

Answer 53

1. Anaphylaxis: Mx = IM adrenaline 0.5mg 1:1000 (in paeds: < 6 years = 0.15mg, 6-12 years = 0.3mg, 12+ = 0.5mg); serial mast cell tryptase = biomarker for anaphylaxis (peaks at 1-2 hrs)
2. Oral allergy syndrome: inhaled pollen generates IgE abs that are similar to antigens on other foors e.g. pears –> results in cross reaction
3. Food associated exercise induced anaphylaxis: anaphylaxis that only occurs if exercise is done 4-6 hours after food ingestion

Question 54

SUMMARY CARD:

What are some conditions that can mimic anaphylaxis?

ACEi, hereditary angioedema

Answer 54

1. Hereditary angioedema: caused by C1 inhibitor deficiency –> recurrent episodes of throat swelling, FHx, hepatomegaly
2. ACEi induced angioedema: significant upper airway angioedema associated with ACEi use, does NOT respond to anti-histamines

Question 55

SUMMARY CARD:

What are the allergy investigations?

derm, IgE blood test, basophil, serum tryptase, allergen challenge

Answer 55

1. Allergen specific tests –> look for sensitisation:

a) Dermatological e.g. skin prick testing:

• Easy but ↑risk of false +ves; better than RAST (IgE measurements)
• GOLD STANDARD for pollen + food allergies
• Prick allergen into skin, alongside histamine (+ve control) and placebo (-ve control)
• Positive test result if allergen wheel >3mm wider than -ve control wheel

NOTE: intra-dermal = like skin-prick testing but deeper injection of allergen into skin –> ↑ sensitivity but ↑ risk of anaphylaxis (only done if skin prick -ve but HIGH clinical suspicion of allergy)

NOTE: patch test is for contact dermatitis (Delayed reaction)

b) Blood tests e.g. RAST

• Measures allergen-specific IgE
• Add patient’s serum to allergen –> add flourescently labelled IgE –> measure levels of anti-IgE
• Does NOT predict severity of reaction

NOTE: component resolved diagnostics is the same thing but blood test detects IgE against single protein rather than whole allergen (e.g. dfferentiate between peanut / hazelnut allergy)

2. Functional tests –> done in vitro:

a) Basophil activation test:

• Expose basophils to allergen –> measure cell surface markers
• Difficult to standardise (so rarely used in clinical practice)
• Indicated as a surrogate for oral challenge

b) Serial mast cell tryptase = marker for analyphlaxis (peaks at 1-2 hrs)

c) Allergen challenge:

• Usually blinded
• GOLD STANDARD for food / drug allergy diagnosis
• Supervised exposure to increasing amounts of allergen
• ↑ risk of anaphylaxis; only done is doubt about diagnosis after skin test / RAST

Question 56

SUMMARY CARD:

How does a Type 2 hypersensitivity reaction develop?

Answer 56

Error in central tolerance process –> results in self-reactive B lymphocytes against cell surface antigens
IgM (RARE); IgG (COMMON)

Reaction can be intrinsic (self antigen) or extrinsic (reaction only occurs if taking medication during infection etc.)

Question 57

SUMMARY CARD:

Diagnose the Type 2 hypersensitivity condition:

1. Glomerulonephritis + pulmonary haemorrhage, anti-GBM
2. Non-tense skin blistering, antibody against epidermal cadherin
3. Bruising / purpura, anti-platelet antibody

Others in prev. flashcards e.g. Churg-Strauss (pANCA), Wegener’s (cANCA), MG (Anti ACh-R ab), Graves’ (Anti TSH-R ab), pernicious anaemia (anti parietal cell)

Answer 57

1. Goodpasture’s
2. Pemphigus Vulgaris
3. Autoimmune thrombocytopenic purpura

Question 58

SUMMARY CARD:

How does a Type 3 hypersensitivity reaction develop?

Answer 58

Self-reactive B-cell lymphocyte (IgG) against SOLUBLE antigen (in the blood) –> therefore formation of Ag-Ab complexes

These immune complexes are deposited in vessels / tissues = INFLAMMATION +/- fibrinoid (tissue) necrosis + destruction

Question 59

SUMMARY CARD:

Diagnose the Type 3 hypersensitivity reaction:

1. Nephritis, athritis, skin lesions; anti-histone or anti-dsDNA
2. Systemic vasculitis, fever, fatigue, weakness, arthralgia, Hep B, pericarditis, skin/renal involvement; antibody against Hep B/C; HIGH WCC / ESR / CRP
3. Develop rashes, itching, athralgia, fever, lymphadenopathy over 7-12 days; reaction to proteins in anti-serum (penicillin); LOW C3

Answer 59

1. anti-histone = drug induced lupus –> Mx = discontinue precipitation drug +/- administer steroid, anti-dsDNA = SLE –> Mx = analgesia + steroids + cyclophosphamides
2. Polyarteritis nodosa (PAN) –> Mx = prednisolone + cyclophosphamide
3. Serum sickness = discontinue precipitant, administer steroids + antihistamines

Question 60

SUMMARY CARD:

How does a Type IV hypersensitivity reaction develop?

Answer 60

Delayed reaction, T-cell mediated

Similar to how body responds to virus or cancer, foreign antigen is picked up by dendritic cell + presented to naive T-cells –> triggers either:

1. CD4+ (macrophage recruitment) = ROS generation, lysozymes, inflammatory cytokines
2. OR CD8+ = apoptosis + programmed cell death w/ perforin / granzymes

Question 61

SUMMARY CARD:

Guess the Type 4 hypersensitivity reaction:

1. Two or more CNS lesions with corresponding symptoms, separated in time and space (MacDonald Criteria) - demyelinating disease, optic neuritis, neurological Sx (muscle weakness, sensory disturbance, GI, autonomic etc.), relapsing-remitting; MRI: white matter lesions
2. Tuberculin –> skin induration + erythema

Others in previous flashcards: T1DM (anti-islet, anti-insulin), RA (anti-CCP), Hashimoto’s (anti-TPO, anti-thyroglobulin), contact dermatitis, Crohn’s disease

Answer 61

1. Multiple sclerosis
2. Mantoux test

Question 62

SUMMARY CARD:

How are transplant donors and recipients matched?

Answer 62

Important to match human leucocyte antigen (HLA)

HLA class 1: A / B / C = found on ALL cells
HLA class 2: DR / DQ / DP = found on APC only

HLA mismatch can lead to potential rejection of transplanted organ

Donor + recipient HLA matched at pre-op; order of importance:
DR > B > A
(so HLA-C and HLA-DP groups aren’t as important in terms of rejection outcomes)

Question 63

SUMMARY CARD:

What are the 5 types of transplant rejections?

hyperacute, T-cell, Ab, chronic, GvHD

Answer 63

1. Hyperacute (mins-hrs): typically if there are pre-formed antibodies to HLA or ABO (due to prior sensitisation event e.g. pregnancy, transfusion, etc.); Sx = thrombosis, necrosis, fever
2. Acute T-cell mediated (wks-months): type 4 hypersensitivity reaction, donor HLA presented on host APCs –> T-cell activation; Sx = interstitial inflammation
3. Acute antibody mediated (months-yrs): recipient MHC picks up donor proteins –> anti-HLA antibodies formation –> antibodies bind to graft endothelium = intravascular disease + organ damage; Sx = capillaritis
4. Chronic (months-yrs): immune + non-immune mechanisms = blockage of graft vessel lumens –> ischaemia + fibrosis
5. GvHD w/ SCT (days-wks): donor lymphocytes target host tissue; prophylaxis = methotrexate / ciclosporin; Sx = diarrhoea, bloody stool, abdo pain, N&V, rash, jaundice, Mx = steroids

Question 64

DISEASE:

Thrombosis + necrosis + fever an hour after transplant

• What is the diagnosis?
• What type of hypersensitivity reaction is this?
• Mx?

Answer 64

Hyperacute: develops within mins-hrs

Typically there are pre-formed antibodies to HLA or ABO due to prior sensitisation event e.g. pregnancy, transfusion, etc.

Type 2 mediated reaction - recipient antibodies bind to antigens on graft

PREVENT by HLA & ABO matching

Question 65

DISEASE:

Interstitial inflammation 1 month after transplant –> eventually organ damage
Rise in Cr
Histology: lymphocytic interstitial infiltration + ruptured tubular BM + tubulitis

• What is the diagnosis?
• What are the 3 pathways to develop this reaction?
• Mx?

Answer 65

Acute T-cell mediated: develops over weeks to months

Type 4 hypersensitivity reaction

3 pathways:
1. Direct pathway = donor APC (e.g. dendritic cell) and donor MHC presenting donor protein is presented to recipient’s immune cells, which stimulates immune response
2. Indirect pathway = proteins from donor released (e.g. when the cells naturally die) –> recipient immune system picks them up and presents them on recipient’s APC, which stimulates immune response
3. Semi-direct pathway = donor MHC presenting donor protein is picked up by recipient APC, which stimulates immune response

Cytotoxic T-cells cause organ damage and interstital inflammation

Mx = T-cell immunosuppression with steroids, tacrolimus / cyclosporin (calcineurin inhibitors)

Question 66

DISEASE:

Vascular rejection (endothelial damage) after weeks / months
Pro-coagulation + graft fibrosis
Histology: vasculitis (capillaritis)

• What is the diagnosis?
• Pathophysiology?
• Mx?

Answer 66

Acute antibody mediated: develops over weeks to months

B-cell activation = antibody attacks vessels

Mx = Ab removal (e.g. plasmapheresis) + B-cell suppression e.g. rituximab = anti-CD20

Question 67

DISEASE:

What is plasmapheresis and what are its indications?

Answer 67

Treat patient’s plasma to remove Igs then re-infuse back into patient

Indications: Type II hypersentivity reaction (e.g. Goodpasture’s, MG), antibody mediated transplant rejection (e.g. anti-HLA abs)

SEs: rebound Ab production afterwards (therefore typically given with anti-proliferative agent)

Question 68

DISEASE:

Smooth muscle growth + blockage of graft vessel lumens, ischaemia, fibrosis >6 months after transplant
RFs: multiple acute rejections, HTN, hyperlipidaemia, HLA mismatches
Histology: fibrosis, ischaemia, glomerulopathy (kidney) or bronchiolitis obliterans (lungs)

• What is the diagnosis +/- underlying mechanism?

Answer 68

Chronic rejection –> typically occurs >6 months after transplant

Due to immune and non-immune mechanisms –> leads to fibrosis of transplanted organ

Question 69

DISEASE:

Sx following transplant:
Skin desquamation / rash
GI disturbance (N&V, abdominal pain, diarrhoea, bloody stool)
Liver failure
Bone marrow failure

• What is the diagnosis?
• What is the underlying mechanism?
• Mx? (BONUS: prophylaxis medications?)

IMPORTANT!

Answer 69

Graft vs Host Disease (GvHD) = ONLY occurs after HSCT

Irreversible attack of donor lymphocytes on recipient HLA
Related to degree of HLA incompatibility

Prophylaxis: methotrexate / ciclosporin, irradiate blood components for immunosuppressed pts
Mx = corticosteroids

Question 70

SUMMARY CARD:

What is immune modulation?

Answer 70

Can either:
Boost immune response:
* Vaccination +/- adjuvants
* Replacement of missing components
* Cytokine therapy
* Blocking immune checkpoints (e.g. for advanced melanoma)

OR suppress the immune response:
* Steroids
* Anti-proliferative agents
* Plasmapheresis
* Inhibitors of cell signalling
* mAbs directed at cell surface antigens
* mAbs directed at cytokines +/- their receptors

Question 71

SUMMARY CARD:

What are passive vaccines?
Examples of passive vaccines:

Answer 71

Vaccine containing pre-formed Abs / Igs
Lasts for ~3 weeks
* HNIG (human normal Ig) = Hep A, measles
* HBIG (hep B Ig) = hep B
* HRIG (human rabies Ig) = rabies
* VZIG (varicella zoster Ig) = varicella
* Paviluzumab = mAb for RSV

Question 72

SUMMARY CARD:

What are the different types of active vaccines?

1. Live attenuated vaccines
2. Subunit (recombinant) vaccines
3. Conjugate vaccines
4. Inactivated vaccines

Answer 72

1. Live attenuated vaccines = e.g. BCG for TB, MMR, Yellow Fever; these are avoided in pregnancy and immunocompromised patients
2. Subunit (recombinant) vaccines = typically for viruses e.g. Hep B and HPV; vaccine contains proteins found on the surface of the viruses in addition to an adjuvant
3. Conjugate vaccines = for encapsulated bacteria e.g. haemophilus influenzae, meningococcus and pneumococcus; consists of bacterial polysaccharides conjugated to an immunogenic toxin
4. Inactivated vaccines = e.g. pertussis; vaccine where the pathogen had been rendered inert - usually by heat killing or formaldehyde; pathogen cannot replicate, it usually requires multiple booster shots to provide immunity

Question 73

DISEASE:

What are the ideal vaccine requirements? (for active vaccines)

Answer 73

1. Generates immunological memory
2. Practical - single injection, easy storage, inexpensive
3. No adverse effects

Question 74

SUMMARY CARD:

What is the UK vaccine programme?

Answer 74

2 months: 6 in 1 (diptheria, polio, tetanus, pertussis, HiB, Hep B); rotavirus; Men B

3 months: 6 in 1 2nd dose (diptheria, polio, tetanus, pertussis, HiB, Hep B); rotavirus 2nd dose; pneumococcal (PCV)

4 months: 6 in 1 3rd dose (diptheria, polio, tetanus, pertussis, HiB, Hep B); Men B 2nd dose

1 year: HiB/MenC; Men B 3rd dose; pneumoccocal vaccine 2nd dose; MMR

3 years 4 months: 4 in 1 booster (diptheria, pertussis, polio, tetanus); MMR

12-13 years: HPV

14 years: 3 in 1 booster (diptheria, tetanus, polio)

Question 75

SUMMARY CARD:

What are the adult vaccines?

Answer 75

18 years: MenACWY
50 years onwards: flu vaccine
65 years: pneumococcal (PCV) vaccine
70 years: shingles
Pregnancy (any age): flu vaccine, 4 in 1 (diptheria/tetanus/pertussis/polio) from16/40 gestation

Question 76

SUMMARY CARD:

Which are the live attenuated vaccines?

Which are the inactivated / component vaccines?

Answer 76

Live attenuated = MMR-VBOY

• MMR
• VZV
• BCG
• Oral - polio, typhoid
• Yellow fever
• Influenza

Inactivated = influenza, polio, cholera, bubonic plague, Hep A, rabies, pertussis, anthrax

Component/subunit = Heb B (HbS antigen), HPV (capsid), influenza recombinant

Question 77

DISEASE:

How to adjuvants / depots work (to enhance vaccine response)?

Answer 77

More persistent antigen (slow release antigen = prolonged response)
+ stimulant assists immune activation

Question 78

SUMMARY CARD:

What are different immunsuppressive drugs?

Answer 78

1. Steroids = phospholipase A2 inhibitors = ↓ prostaglandins = ↓ inflammation
2. Anti-proliferative agents = e.g. cyclophosphamide (alkylates guanine), azathioprine (metabolised to 6 metacaptopurine, bone marrow suppression if TPMT polymorphism), mycophenolate mofetil (JC virus = PML), methotrexate (inhibits dihydrofolate reductase)
3. Anti-cell signalling agents = e.g. calcineurin inhibitors (e.g. tacrolimus, ciclosporin), tofacitinib (JAKi), aprelimast (PDE4i =↑ cAMP), IL-2 pathway inhibitor (e.g. sirolimus, rapamycin)
4. mAbs against cell surface antigens = e.g. Rituximab (MHL, RA), Vedolizumab (IBD), Natalizumab (MS), Tocilizumab (RA, Castleman’s disease), Basiliximab/Daclizumab (organ transplant rejection prophylaxis)
5. mAbs against cytokines+/- their receptors = e.g. anti-TNFa (e.g. infliximab, adalimumab, certolizumab, golimumab, SE = reactivation of TB), etanercept (anti-TNFa receptor - RA, AS), psoriasis/psoriatic arthritis (e.g. usteki/guselk/secukin -umab), denosumab (osteoporosis, SE = avascular necrosis of jaw), anakinra (IL-1 antagonist, FMF)

Question 79

SUMMARY CARD:

Steroids e.g. prednisolone

• Mechanism of action?
• Indications?
• SEs?

Answer 79

• Inhibition of phospholipase A2 –> no breakdown of phospholipids to arachidonic acid = prostaglandin synthesis blocked = reduced inflammation
• Indicated in: allergy, renal disorders, malignancy
• S/Es: transient neutrophilia, Cushing’s syndrome / steroid induced diabetes mellitus

Question 80

SUMMARY CARD:

What are some anti-proliferative agents?

Answer 80

1. Cyclophosphamide
2. Azathioprine
3. Mycophenolate mofetil
4. Methotrexate

Question 81

SUMMARY CARD:

State the mechanism of action, indications and side effects of each of the anti-proliferative agents:

1. Cyclophosphamide
2. Azathioprine
3. Mycophenolate mofetil
4. Methotrexate

Answer 81

1. Cyclophosphamide: alkylating agent (alkylates guanine in DNA) = damages DNA and prevents cell replication

• Affects B cells > T cells
• Indications: connective tissue disease, vasculitis w/end-organ damage, anti-cancer agent
• SEs: sterility (M>F), hair loss, bladder cancer, haematological malignancy, haemorrhagic cystitis (Due to toxic drug metabolite in urine)

2. Azathioprine: anti-metabolite, metabolised by liver to 6 mercaptopurine and blocks de novo purine synthesis, which prevents DNA replication

• Affects T cells > B cells
• Indications: transplants, AI disease, autoinflammatory disease
• SEs: bone marrow suppression in those with thiopurine methyltransferase (TPMT) polymorphism as they cannot metabolise the drug; pancreatitis, hepatotoxicity

3. Mycophenolate mofetil: Inhibits inosine monophosphate dehydrogenase (IM PDH), which prevents guanine synthesis synthesis = prevents DNA replication

• Affects T-cells > B-cells
• Indications: transplantation, vasculitis (as an alternative to cyclophosphamide)
• Reactivation of herpes, progressive multifocal encephalopathy (John-Cunningham virus)

4. Methotrexate: Inhibits dihydrofolate reductase = decreases DNA synthesis

• Indications: RA, SLE, psoriasis, Crohn’s, ectopic pregnancy abortions, chemotherapy
• SEs: macrocytic megaloblastic anaemia, bone marrow suppression, loss of appetite, depression

Question 82

SUMMARY CARD:

What are some medications that inhibit cell signalling?

Answer 82

1. Calcineurin inhibitors e.g. Tacrolimus, ciclosporin
2. Tofacitinib
3. Aprelimast
4. IL-2 pathway inhibitor e.g. sirolimus, rapamycin

Question 83

SUMMARY CARD:

State the mechanism of action, indications and side effects of each of the anti-cell signalling agents:

1. Tacrolimus, ciclosporin
2. Tofacitinib
3. Aprelimast
4. Sirolimus, rapamycin

Answer 83

1. Tacrolimus: calcineurin inhibitor = ↓ IL-2 function = ↓ T-cell proliferation

• Indications: rejection prophylaxis (transplant), SLE, psoriatic arthritis
• SEs: nephrotoxic, hypertension, neurotoxic, diabetogenic

2. Ciclosporin: calcineurin inhibitor = ↓ IL-2 function = ↓ T-cell proliferation

• Indications: transplantation
• SEs: nephrotoxic, hypertension, gum hyperplasia, dysmorphic features

2. Tofacitinib: JAK 1/3 inhibitor = ↓ JAK-STAT signalling pathway = ↓ production of inflammatory molecules

• Indications: arthritides (rheum, psoriatic)

3. Aprelimast: phosphodiesterase 4 inhibitor (phosphodiesterase normally breaks down cAMP) = ↑ cAMP = inhibits activation of transcription factors

• Indications: psoriasis +/- psoriatic arthritis

4. Sirolimus, rapamycin: IL-2 pathway inhibitor e.g. sirolimus, rapamycin: mTOR inhibitor = inhibits IL-2 pathway = ↓ T-cell proliferation

• Indications: transplant
• SEs: hypertension (but LESS nephrotoxic than the calcineurin inhibitors)

Question 84

SUMMARY CARD:

What do these suffixes of the mAbs mean?
1. -umab
2. -ximab
3. xumab
4. bonus: ‘tu’
5. bonus: ‘os’

Answer 84

• -umab = fully human
• -zumab = humanised
• -ximab = chimeric
• if the drug name has ‘tu’ before the suffix, it acts agains a tumour
• if the drug name has ‘os’ before the suffix, it acts against bone (osteopororis?)

Question 85

SUMMARY CARD:

What are some mAbs directed against cell surface antigens (AKA block cell signalling)?

Answer 85

1. Basiliximab = antiCD25 –> organ transplant rejection prophylaxis
2. Daclizumab = anti-CD25 + IL-2 receptor Ab –> organ transplant rejection prophylaxis
3. Rituximab = anti-CD20 –> non-Hodgkin’s lymphoma, RA
4. Vedolizumab = anti-a4-b7 integrin –> IBD
5. Natalizumab = anti-a4-b1 integrin –> remitting relapsing MS
6. Tocilizumab, Sarilumab = anti-IL-6 receptor –> Castleman’s disease (IL-6 producing tumour)
7. Muromonab = mouse anti-CD3 –> active cell-mediated rejection of transplant
8. Anti-thymocyte globulin = lymphocyte depletion –> heart/renal transplant rejections
9. Abatecept = anti-CTLA4 –> RA
10. Efalizumab = Anti-CD11a –> psoriasis
11. Alentuzumab = anti-CD52 –> chronic lymphoid myeloma (CLL), MS

Question 86

SUMMARY CARD:

State the mechanism of action, indications and side effects of each of the mAbs directed against cell surface antigens:

1. Basiliximab
2. Daclizumab
3. Rituximab
4. Vedolizumab
5. Natalizumab
6. Tocilizumab, Sarilumab
7. Muromonab
8. Anti-thymocyte globulin
9. Abatecept
10. Efalizumab
11. Alentuzumab

Answer 86

1. Basiliximab: antiCD25 (alpha chain of IL-2 receptor) = inhibits T-cell proliferation

• Indications: organ transplant rejection prophylaxis
• SEs: infusion reaction, infection, potential malignancy

2. Daclizumab = anti-CD25 (alpha chain of IL-2 receptor) AKA IL-2 receptor Ab –> organ transplant rejection prophylaxis

• Indications: organ transplant rejection prophylaxis
• SEs: infusion reaction, infection, potential malignancy

3. Rituximab: anti-CD20 = depletes mature B cells

• Indications: Non-Hodgkin’s lymphoma, RA
• SEs: infusion reaction, reactivation of hep B, exacerbation of CV disease

4. Vedolizumab: anti-a4-b7 inegrin = prevents T-cell migration

• Indications: IBD
• SEs: infusion reaction, hepatotoxicity

5. Natalizumab: anti-a4-b1 integrin = prevents T cell migration

• Indications: active / remitting relapsing MS
• SEs: John Cunningham Virus –> PML (progressive multifocal leukoencephalopathy)

6. Tocilizumab, Sarilumab: anti-IL-6 receptor = reduced macrophage / T-cell / B-cell / neutrophil activation

• Indications: Castleman’s disease (IL-6 producing tumour), RA
• SEs: elevated lipids and hepatotoxicity (so LFTs and cholesterol has to be measured regularly)

7. Muromonab: mouse anti-CD3

• Indications: active cell-mediated rejection of transplant
• SEs: fever, leucopenia, anaphylaxis

8. Anti-thymocyte globulin: lymphocyte depletion via modulation of T-cell activation + migration

• Indications: heart/renal transplant rejections
• SEs: fever, leucopenia

9. Abatecept = anti-CTLA4-Ig fusion protein = reduced T cell activation

• Indications: RA w/ resistance to DMARDS
• SEs: infusion reaction, infection, potential malignancy

10. Efalizumab: Anti-CD11a = inhibits migration of T-cells

• Indications: psoriasis

11. Alentuzumab = anti-CD52 (CD52 found on lymphocytes) = depletion of lymphocytes

• Indications: chronic lymphoid myeloma (CLL), MS
• SEs: CMV infection

Question 87

DISEASE:

Which mAb is used in RA?

Which mAb is used in RA resistant to DMARDs?

Answer 87

Rituximab

DMARD-resistant RA = abatacept

Question 88

DISEASE:

Which mAbs are organ transplant rejection prophylactic?

Answer 88

Anti-CD25 (alpha chain of IL-2 receptor) mAbs = basiliximab, daclizumab

Question 89

DISEASE:

Which mAb is used for IBD?

Answer 89

Vedolizumab

Question 90

DISEASE:

Which mAb is used in relapsing-remitting / active MS?

Answer 90

Natalizumab

Or Alemtuzumab

Question 91

DISEASE:

Which mAb is used for Castleman’s disease?

Answer 91

Tocilizumab, sarilumab = anti-IL-6

Question 92

DISEASE:

Which mAb is used in CLL?

Answer 92

Alemtuzumab
SE = CMV infection

Question 93

SUMMARY CARD:

What are some mAbs directed at cytokines / receptors?

Answer 93

1. Infliximab = anti-TNFa –> IBD, RA, psoriasis
2. Adalimumab, Certolizumab, Golimumab = anti-TNFa –> RA, AS, psoriasis / psoriatic arthritis
3. Etanercept: TNF-alpha antagonist
4. Ustekinumab = anti IL-2 / IL-23 (binds to p40 subunit) –> psoriasis / psoriatic arthritis
5. Guselkumab = anti IL-23 (inhibition of p19 subunit) –> psoriasis / psoriatic arthritis
6. Secukinumab = Anti-IL17A –> psoriasis / psoriatic arthritis
7. Denosumab = anti-RANKL antibody = prevention of bone resorption –> osteoporosis, (only medication that increases bone density), MM (multiple myeloma)
8. Anakinra = IL-1 antagonist –> FMF, gout

Question 94

SUMMARY CARD:

State the mechanism of action, indications and side effects of each of the mAbs directed against cytokines +/- receptors:

1. Infliximab
2. Adalimumab, Certolizumab, Golimumab
3. Etanercept
4. Ustekinumab
5. Guselkumab
6. Secukinumab
7. Denosumab
8. Anakinra

Answer 94

1. Infliximab: anti-TNFa

• Indications: IBD, RA, psoriasis
• SEs: Infusion/injection site reactions, TB infection (do Mantoux before starting anti-TNF)

2. Adalimumab (fully human mAb), Certolizumab, Golimumab: anti-TNFa

• Indications: RA, ankylosing spondylitis
• SEs: infusion/injection site reaction, infection (TB, HBV, HCV), demyelination

3. Etanercept: TNF-alpha antagonist

• Indications: RA, ankylosing spondylitis (NOTE: not useful in IBD)
• SEs: Injection site reaction, Infections (TB, HCV, HBV), demyelination

4. Ustekinumab: anti IL-2 / IL-23 (binds to p40 subunit)

• Indications: psoriasis, psoriatic arthritis
• SEs: injection site reaction, infection (TB)

5. Guselkumab: anti IL-23 (inhibition of p19 subunit)

• Indications: psoriasis, psoriatic arthritis
• SEs: injection site reaction, infection (TB)

6. Secukinumab: anti-IL17A

• Indications: psoriasis, psoriatic arthritis
• SEs: injection site reaction, infection (TB)

7. Denosumab: Anti-RANKL antibody = prevention of bone resorption

• Indications: osteoporosis (only medication that increases bone density, multiple myeloma
• SEs: avascular necrosis of jaw

8. Anakinra: IL-1 antagonist

• Indications: familial mediterranean fever (FMF), gout

Question 95

DISEASE:

Which mAb is used to treat osteoporosis?

BONUS: what is the top SE?

Answer 95

Denosumab –> inhibits anti-RANK ligand

SE: avascular necrosis of jaw

Question 96

DISEASE:

Which 3 mAbs are used in psoriasis / psoriatic arthritis?

Answer 96

Ustekinumab
Guselkumab
Secukinumab

Question 97

DISEASE:

Which mAb is a TNF-alpha receptor inhibitor?

Answer 97

Etanercept –> used for RA, AS

Question 98

DISEASE:

Which mAb is used to treat FMF?

Answer 98

Anakinra = IL-1 antagonist

Question 99

DISEASE:

What test is vital before prescribing anti-TNF alpha mAb?

Hint: may reactivate this infection (cough cough)

Answer 99

Mantoux test –> test for TB before prescribing

Question 100

SUMMARY CARD:

What are cytokines?

Answer 100

Cytokines, proteins produced by various cells (e.g. immune, haematopoietic, and endothelial cells) are important for cell signalling.

Examples: chemokines, interferons, interleukins, TNF-α

Question 101

SUMMARY CARD:

What are Type 1 and Type 2 interferons responsible for?

Answer 101

• Type 1 = IFN-alpha + IFN-beta –> produced by immune and non-immune cells
• Type 2 = IFN-gamma –> produced immune cells, primarily T cells, natural killer cells and macrophages
• Role of IFN-gamma = macrophage activation (e.g. in TB, IFN-gamma is elevated)

Question 102

SUMMARY CARD:

Examples of interleukins and their functions:

Answer 102

• IL-1: proinflammatory, activation of T and B lymphocytes, macrophages, endothelium
• IL-2 (T cell growth factor): proliferation/activation of T and B lymphocytes
• IL-4: activation of B lymphocytes, suppression of Th1 lymphocytes, differentiation of CD4 cells to Th2 lymphocytes
• IL-5: activation of eosinophils
• IL-6: proinflammatory, differentiation of T and B cells, activation of haematopoietic stem cells
• IL-8: activation of neutrophils
• IL-10 + IL-12: suppression of macrophages and Th1 lymphocytes, B cell activation

Question 103

DISEASE:

Which interleukins are pro-inflammatory?

Answer 103

IL-1 + IL-6

Question 104

DISEASE:

Which interleukin is responsible for T-cell proliferation?

Answer 104

IL-2

Question 105

DISEASE:

Which interleukins are anti-inflammatory (help counterbalance effects of inflammation)?

Answer 105

IL-10 (+IL-12)

Question 106

SUMMARY CARD:

Which cells produce which interleukins?

Answer 106

• Dendritic cells - IL-1, IL-12
• Th1 cells - IL-2
• Th2 cells - IL-4, IL-5, IL-6, IL-10
• Macrophages - IL-1, IL-4, IL-6, IL-10, IL-12
• Mast cells - IL-5

Question 107

SUMMARY CARD:

1. How does HIV enter cells?
2. What is the immune response to HIV?
3. How is HIV screened and confirmed?

Answer 107

1. HIV is an RNA retrovirus –> glycoprotein 120 binds to CD4+ and co-receptor CCR5/CXCR4 (so mutation in this = HIV resistant)
2. Immune response:

• Innate = macrophage / NK / complement / dendritic cells
• Adaptive = neutralising (bind to antigens on HIV to prevent it from binding + entering CD4+ cells) + non-neutralising antibodies (bind to antigens on virus infected cells to signal to macrophages to phagocytose)
• Neutralising Abs = anti-gp41 IgM (first weeks), anti-gp120 (later)
• Non-neutralising Abs = anti-p24 gag IgG

3. Screening test: ELISA detects anti-HIV antibody (IgG/IgM)
   NOTE: unreliable in babies as Igs may be passed from mum to baby in utero / via breastmilk
   Confirmation test: Western Blot test detects Abs (takes 15-45 days since infection until +ve)

Question 108

SUMMARY CARD:

1. What are the next steps after confirmation of HIV diagnosis?
2. Mx?

Answer 108

1. PCR is used to detect viral load + FACS used to assess CD4 count (< 200 cells/uL in blood = AIDS)
2. ALL HIV +ve patients are to commence HAART immediately (don’t need to rely on CD4+ count)

• Highly active anti-retroviral therapy (HAART) = 2NRTIs + PI (or NNRTI)
• In pregnancy: Zidovudine (PO antepartum; IV during delivery) –> reduced transmission risk from 26% to 8%
• Monitoring: regular viral loads, CD4+ monitoring not needed if > 350 cells/uL of blood, monitor liver/kidney/bone/lipid toxicity

Question 109

DISEASE:

What is the receptor via which HIV enters?

Answer 109

Co-receptor CCR5/CXCR4 (so mutation in this = HIV resistant)

Question 110

DISEASE:

What are the antibodies produced against an HIV infection?

Answer 110

• Neutralising Abs = anti-gp41 IgM (first weeks), anti-gp120 (later)
• Non-neutralising Abs = anti-p24 gag IgG

Question 111

DISEASE:

What is the screening test vs the confirmation test?
BONUS: what are their limitations?

Answer 111

• Screening test: ELISA detects anti-HIV antibody (IgG/IgM)
  Limitation = unreliable in babies as Igs may be passed from mum to baby in utero / via breastmilk
• Confirmation test: Western Blot test detects Abs
  Limitation = takes 15-45 days since infection until +ve

Question 112

DISEASE:

What is the anti-retroviral given in pregnancy?

Answer 112

Zidovudine
PO antepartum, IV during delivery

Question 113

DISEASE:

At what CD4+ count is HIV considered AIDS?

Answer 113

< 200 cells u/L of blood

BONUS - important CD4+ counts and opportunistic infections:

• 75 - mycobacterium avium complex disease; PCP (caused by pneumocystis jirovecii)
• 300-350 - pulmonary TB
• 400 - Kaposi sarcoma (HHV-8)

Question 114

DISEASE:

What antibodies are associated with anti-phospholipid syndrome?

Answer 114

anti-cardiolipin + anti-B2 glycoprotein

Question 115

DISEASE:

Rapidly progressive glomerulonephritis

Nosebleeds

Haemoptysis

• Diagnosis?
• BONUS: which gene?

Answer 115

Wegener’s (Granulomatosis with Polyangitis)

cANCA