Immu 1: Autoinflammatory And Autoimmune Diseases 1

Question 1

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

Answer 1

Auto-inflammatory: affects innate immune response
Auto-immune: affects adaptive immune response

Question 2

Give 1 example of a monogenic auto-inflammatory disease ?

Answer 2

Familial Mediterranean fever

Question 3

Which gene is mutated in Familial Mediterranean fever ?

How does this cause the disease ?

Answer 3

MEFV gene (autosomal recessive)

Causes defect in pyrin-marenostrin protein which causes activation of Neutrophils by cryopyrin to become deregulated.

Question 4

How is Familial Mediterranean fever associated with amyloidosis and Nephrotic syndrome ?

Answer 4

The inflammation causes the liver to produce acute phase protein: Amyloid

AMyloid deposits in the kidneys causing proteinuria and hence nephrotic syndrome

Question 5

Name 3 monogenic Auto-immune disease ?

Answer 5

APS1 (auto-immune polyendocrine syndrome type 1) (APECED)
IPEX 
ALPS (auto-immune lymphoproliferative syndrome)

Question 6

What is the main treatment for Familial Mediterranean Fever ?

Answer 6

Colchicine

Question 7

What causes APACED ?

What kind of disease is it?

Answer 7

Causes

Defect in AIRE (autoimmune regulator) transcription factor

(Promotes the apoptosis of auto-reactive T cells in the thymus)

Leads to a loss in central tolerance

What kind of disease

Monogenic Autoimmune Disease

Question 8

Name the 2 most common auto-immune conditions seen in APS1 (APECED)?

Answer 8

Hypoparathyroidism
Addison’s disease

Question 9

What causes IPEX ?

What do pts with this gene also express?

Answer 9

Mutation in Foxp3 gene

Foxp3 is required for development of Treg cells

The lack of Treg cells means that these patients fail to negatively regulate T cell responses, leading to autoantibody formation

Question 10

What are the 3 Ds of conditions seen in IPEX ?

Answer 10

Diarrhoea
Dermatitis
Diabetes

Question 11

What causes ALPS ?

Answer 11

Mutation in FAS pathway

causes defect in apoptosis of Lymphocytes

NB Fas binds to

Question 12

A child is examined and found to have splenomegaly, lymphadenopathy. Her blood tests show a high Lymphocyte count . The professor tells you that this is a monogenic Auto-immune disease and children have an increased risk of Lymphoma. What is the likely diagnosis ?

Answer 12

ALPS

One of the 3 monogenic autoimmune diseases (APECED, IPEX, ALPS)

Question 13

Which genetic mutation has been found to be associated with Crohn’s disease ?

Answer 13

NOD2

This is expressed in the cytoplasm of myeloid cells- macrophages, neutrophils and dendritic cells

Therefore, with the mutation, you get disordered degradation of cellular components which leads to inflammation

Question 14

Give 5 examples of polygenic auto-inflammatory diseases ?

Answer 14

Crohn’s disease
Ulcerative colitis
Osteoarthritis
Giant cell arteritis
Takayasu’s arteritis

Question 15

List 4 drugs used to treat Crohn’s disease ?

Answer 15

Corticosteroids
Azathioprine (steroid sparing)
Anti-TNF alpha antibody
Anti- IL12/23 antibody

Question 16

Give 3 example of mixed pattern diseases (auto inflammatory and auto immune) ?

Answer 16

Ankylosis spondylitis
Psoriatic arthritis
Behcet’s syndrome

Question 17

Which HLA type is associated with Ankylosing spondylitis ?

Answer 17

HLA B27

Question 18

Presentation of ankyloising spondylitis

Answer 18

• It tends to occur at specific sites where there are high tensile forces- ENTHESES (sites where soft tissue (ligament or tendon) insert to bone) e.g. sacroiliac joint
• Can get bone formation- often see bamboo spine
• Low back pain and stiffness
• Enthesitis i.e. plantar fasciitis, Achilles tendonitis
  *

Question 19

What are the main 2 treatments for Ankylosing spondylitis ?

Answer 19

NSAIDS
Anti-TNF alpha antibodies

Question 20

List 6 polygenic Auto-immune diseases ?

Answer 20

Rheumatoid arthritis
Myasthenia gravis
Pernicious anaemia
Addison’s disease
SLE
PBC (primary biliary cirrhosis)

Question 21

Which diseases are associated with HLA-DR3 polymorphisms ?

Answer 21

Graves’ disease
SLE
Type 1 diabetes Mellitus

Question 22

Which diseases are associated with HLA-DR4 polymorphisms ?

Answer 22

Type 1 diabetes Mellitus
Rheumatoid arthritis

Question 23

Which disease is associated with HLA-DR15 polymorphisms ?

Answer 23

Goodpasture’s disease

Question 24

which two genes are involved in regulating T cell function

Answer 24

PTPN 22 (suppresses T cell activity) 
CTLA 4 (expressed by T cells to suppress activity)

Question 25

List 3 areas of immune privilege in the body ?

Answer 25

Eyes Testes CNS

Question 26

Describe type 1 immune reaction ?

Answer 26

Immediate hypersensitivity which is IgE mediated

Question 27

Describe type 2 immune reaction ?

Answer 27

Antibody reacts to cellular antigen

Question 28

Describe type 3 immune reaction ?

Answer 28

Antibody reacts with soluble antigen to form an immune complex

Question 29

Describe type 4 Immune reaction ?

Answer 29

Delayed type hypersensitivity T cell mediated response

Question 30

These auto-immune diseases are considered to involve Type 2 cytotoxic hypersensitivity. Match the auto-immune disease with the antigens that they target Goodpasture disease:::::TSH receptor Myasthenia Gravis:::::Epidermal Cadherin Pemphigus Vulgaris:::::basement membrane collagen type IV Grave’s disease:::::acetylcholine receptor

Answer 30

Goodpasture disease:::::basement membrane collagen type IV Myasthenia Gravis:::::acetylcholine receptor Pemphigus Vulgaris:::::epidermal Cadherin Grave’s disease:::::TSH receptor

Question 31

Give examples of regions where Immune complexes deposit and the pathology they cause ?

Answer 31

Skin- Cutaneous vasculitis (purpuric rash) Kidneys- glomerulonephritis/renal failure Joints- Arthritis NB this is type 3 hypersensitivity reactions (

Question 32

4 type 2 Antibody-driven Autoimmune Disease

Answer 32

Goodpasture disease Pemphigus vulgaris Graves disease Myasthenia gravis

Question 33

Which disease is considered to cause a type 3 hypersensitivity reaction ?

Answer 33

SLE

Question 34

Name 2 disease is considered to cause a type 4 hypersensitivity reaction ?

Answer 34

Type 1 diabetes mellitus MS Rheumatoid arthritis

Question 35

Afrocaribbean boy presents after recurrent chest infections with hypothyroidism, alopecia, gonadal failure and vitiligo. Blood tests show hypocalcaemia. Most likely diagnosis ? Which gene is mutated ?

Answer 35

APACED AIRE gene loss of central immune tolerance of T cells

Question 36

List 4 features of APACED ?

Answer 36

- Hypoparathyroidism - Hypothyroidism - Addisons - DM type 1 - Vitiligo - Alopecia - Hypogonadism

Question 37

what is the difference between the mechanisms of autoimmune and auto-inflammatory disease

Answer 37

auto-inflammatory = activation of macrophages and neutrophils --\> tissue damage (usually localised) auto-immune = aberrant T and B cell responses in primary and secondary lymphoid organs leads to breaking of tolerance - development of immune-reactivity towards self-antigens

Question 38

list monogenic autoinflammatory disease

Answer 38

muckle wells syndrome - NLRP3 gain of function familial cold auto-inflammatory syndrome - NALP3 gain of function chronic infantile neurological cutaneous articular syndrome - NLRP3 gain of function (NLRP3 encoded a protein, cryopyrin, which is involved in the inflammatory pathway)

Question 39

features of familial mediterranean fever

Answer 39

autosomal recessive mutation in MEFV gene gene encodes pyrin-marenostrin periodic fevers lasting 48-96 hrs abdo pain, chest pain, arthritis, rash associated with long term risk of AA amyloidosis treat with colchicine 500mg BD if not successful - use anakinra (IL1 receptor antagonist) entanercept - TNF alpha inhibitor

Question 40

what is APACED

Answer 40

autosomal recessive defect in AIRE (promotes apoptosis of auto-reactive T cells) leads to: - hypoparathyroidism - addisons disease - hypothyroidism - diabetes mellitus - vitiligo - enteropathy predisposition to candidiasis

Question 41

features of IPEX

Answer 41

immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome mutation in Foxp3 needed for development of T reg cells autoantibody formation - enteropathy - diabetes - hypothyroidism - dermatitis

Question 42

features of ALPS

Answer 42

autoimmune lymphoproliferative syndrome mutation in the FAS pathway defect in apoptosis of lymphocytes high lymphocyte count large spleen and LN AI diseases lymphoma

Question 43

match the susceptibility allele with the disease: goodpastures graves SLE T1 DM rheumatoid arthritis

Answer 43

goodpastures - HLA DR 15 graves - HLA DR 3 SLE - HLA DR 3 T1 DM - HLA DR 3/4 rheumatoid arthritis - HLA DR4

Question 44

how can we classify different hypersensitivity reactions

Answer 44

gel and coombs test looks at whether a response is antibody of T cell mediated

Question 45

give 2 examples of type III hypersensitivity diseases

Answer 45

SLE rheumatoid arthritis

Question 46

list examples of type 4 hypersensitivity mediated diseases

Answer 46

insulin dependent DM rheumatoid arthritis MS