Immunology

Question 1

What is the difference between Auto-inflammatory and Auto-immune disease?

Answer 1

Auto-inflammatory is driven by the innate immune system leading to activation of macrophages and neutrophils resulting in tissue damage

Auto-immune is driven by the adaptive immune response and leads to aberrant T and B cells in primary and secondary lymphoid organs

Question 2

Which gene mutation causes Familial Mediterranean Fever and which protein does this gene encode? And Muckle well syndrome and the inheritance pattern

Answer 2

MEFV gene
Encodes pyrin-marenostrin which is a negative regulator of the inflammatory pathway
Autosomal recessive

Cryopyrin (NALP3)
Muckle Wells syndrome
Autosomal Dominant

Question 3

Describe how the inflammasome complex functions.

Answer 3

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 NFKappa B, IL1 and apoptosis
Pyrin-maronestrin is a negative regulator of this pathway

NOTE: pyrin-marenostrin is found in neutrophils

o A gain of function mutation in cryopyrin will lead to more inflammation
o A loss of function mutation in Pyrin-Marenostrin will lead to more inflammation

Question 4

Outline the clinical presentation of Familial Mediterranean Fever.

Answer 4

Periodic fevers lasting 48-96 hours associated with
* Abdominal pain (peritonitis)
* Chest pain (pleurisy, pericarditis)
* Arthritis
* Rash

It can lead to AA amyloidosis

Question 5

Outline the treatment of Familial Mediterranean Fever.

Answer 5

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

Question 6

What examples are rare monogenic auto-immune and their mutations and presentations?

Answer 6

IPEX- Immune dysregulation, polyendocrinopathy, enteropathy X-linked syndrome

Mutation in Foxp3 –> required for treg cells –> imp in peripheral tolerance –> cant regulate t and b cells so autoreactive t and b cells.

Sxx: Diarrhoea, Diabetes and Dermatitis (eczema)

ALPS- auto-immune lymphoproliferative syndrome
Mutation in FAS pathway
FAS encodes death –> cell death
Mutation means auto-reactive b and t cells remain and you get lots of lymphocyte production

Sxx: High lymphocyte count
Large spleen and large lymph nodes
Lymphoma

Question 7

What is the best known chromosomal region that is implicated in Crohn’s disease?

Answer 7

IBD1 on chromosome 16 (NOD2/CARD15 gene)

NOTE: NOD2 is found in the cytoplasm of myeloid cells (macrophages, neutrophils) and is a microbial sensor recognises muramyl dipeptide –> mutation affects capacity of cells in the gut to sense intracellular microbes which then leads to an abnormal inflammatory response.

NOD2 = nucleotide-binding oligomerization domain-containing protein.

Question 8

Give an example of a mixed pattern disease and its presentation and tx

Answer 8

Involves innate and adaptive immune cell function
Auto-antibodies are not usually feature

Ankylosing spondylarthritis–> spondylitis (severe)
IL23 –> Th17 (adaptive)
ILR2–>controls IL-1 (innate)

Occurs at specific sites where ligaments and tendons insert –> enthesitis

Presentation:
low back pain
affects large joints

Tx:
NSAIDs
immunosuppression : Anti-TNF and Anti-IL17

Question 9

List the autoimmune diseases associated with the following HLA polymorphisms:
a. DR3
b. DR3/4
c. DR4
d. DR15

Answer 9

a. DR3
Graves’ disease
SLE

b. DR3/4
Type 1 diabetes mellitus

c. DR4
Rheumatoid arthritis

d. DR15
Goodpasture’s syndrome

Question 10

Name and state the function of 2 genes that are involved in T cell activation and are often mutated in polygenic autoimmune disease.

Answer 10

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

Question 11

Name the autoantigen in the following diseases:
a. Goodpasture’s disease
b. Pemphigus vulgaris

Answer 11

a. Goodpasture’s disease
Alpha-3 subunit of non-collagenous domain of collagen IV
b. Pemphigus vulgaris
Epidermal cadherin

Question 12

What is the Gel and Coombs classification?

Answer 12

Type I: immediate hypersensitivity which is IgE mediated
Type II: antibody reacts with cellular antigen
Type III: antibody reacts with soluble antigen to form an immune complex
Type IV: delayed-type hypersensitivity. T cell mediated response

Question 13

Describe the antibodies in graves and hashimoto?

Answer 13

Graves: mediated by IgG antibodies that stimulate TSH receptor. This is a type 2 hypersensitivity

Hashimoto: anti-thyroid peroxidase antibodies. T and B cells infiltrate the thyroid gland

Don’t need to measure anti-thyroid antibodies asa these antibodies are present in a lot of normal people

Question 14

Which antibodies are associated with autoimmune hepatitis and primary biliary cholangitis?

Answer 14

Anti-nuclear antibodies : autoimmune hepatitis and PBC

Smooth muscle antibodies: Autoimmune

Antibodies vs liver kidney microsomal proteins: autoimmune

anti-mitochondrial antibody: Primary biliary cholangitis

p-ANCA :autoimmune andPBC

Question 15

How is good pasture presented and why

Answer 15

antibodies against glomerular basement membrane which are present in lungs and kidneys

auto antibodies deposit in kidneys

Question 16

Describe the role of PAD in the pathogenesis of rheumatoid arthritis. and HLA

Answer 16

HLA DR4 and DR1 subtypes ass with RA.
HLA bind to particular peptide –> citrullinated peptide and predispose to RA.

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 therefore measuring anti-citrullinated proteins is very specific. to. RA

Question 17

List some environmental factors that contribute to the pathogenesis of rheumatoid arthritis.

Answer 17

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

Question 18

Describe B cell involvement in the pathophysiology of rheumatoid arthritis.

Answer 18

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

Question 19

Which type of hypersensitivity reaction is SLE?

What else should be checked in SLE?

Answer 19

SLE- abnormality clearing apoptotic cells

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. Measure c3. and c4 in SLE and c4 goes down first. if c3 +c4 low then severe SLE

check c3,c4
check ESR- high
CRP - usually low, if high suspect infection

These antibodies can also stimulate cells that express Fc receptors

Question 20

What are the two types of ANA and what are their immunofluorescence patterns?

Answer 20

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

Question 21

What other antibodies should be tested in SLE?

Answer 21

Anti-cardiolipin antibody – immunoglobulins directed against phospholipids and alpha beta 2 glycoprotein-1

and 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

Question 22

What is the diagnosis of sjogrens and what do you need to be careful of?

Answer 22

ANA+ speckled pattern due to Ro,La positive

when Ro, La positive they can cross placenta and cross react with conductive tissue of baby cardiac which can cause neonatal block

Question 23

Which cells are particularly important in the pathophysiology of systemic sclerosis?

what is the difference between CREST and diffuse cutaneous systemic sclerosis and in terms of antibodies?

Answer 23

Th2 and Th17
difficulty swallowing
tightening of skin

NOTE: TGF-beta, produced by macrophages and T cells, is important in stimulating the deposition of collagen

CREST: skin involvement does not progress beyond forearms but diffuse does.

Antibodies: diffuse anti-topoisomerase antibodiesSCL70

Limited: anti-centromere antibodies

Question 24

Describe the differences between the histology of dermatomyositis and polymyositis.

What should you ask for if suspecting this

Answer 24

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)

ask for. full myositis panel
anti-jo1 antibodies may be present

Question 25

Outline the pathophysiology of ANCA.

Answer 25

ANCA- not ANA but anti-neutrophil cytoplasmic antibody

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

Question 26

Describe the key difference between cANCA and pANCA.

Answer 26

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