Immuno 5: 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 ?

Answer 7

Defect in AIRE transcription factor

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

Leads to a loss in central tolerance

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 ?

Answer 9

Mutation in Foxp3 gene

Foxp3 is required for development of Treg cells

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

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

Question 13

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

Answer 13

NOD2

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

What are the main 2 treatments for Ankylosing spondylitis ?

Answer 18

NSAIDS

Anti-TNF alpha antibodies

Question 19

List 6 polygenic Auto-immune diseases ?

Answer 19

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

Question 20

Which diseases are associated with HLA-DR3 polymorphisms ?

Answer 20

Graves’ disease
SLE
Type 1 diabetes Mellitus

Question 21

Which diseases are associated with HLA-DR4 polymorphisms ?

Answer 21

Type 1 diabetes Mellitus

Rheumatoid arthritis

Question 22

Which disease is associated with HLA-DR15 polymorphisms ?

Answer 22

Goodpasture’s disease

Question 23

List 3 areas of immune privilege in the body ?

Answer 23

Eyes
Testes
CNS

Question 24

Describe type 1 immune reaction ?

Answer 24

Immediate hypersensitivity which is IgE mediated

Question 25

Describe type 2 immune reaction ?

Answer 25

Antibody reacts to cellular antigen

Question 26

Describe type 3 immune reaction ?

Answer 26

Antibody reacts with soluble antigen to form an immune complex

Question 27

Describe type 4 Immune reaction ?

Answer 27

Delayed type hypersensitivity T cell mediated response

Question 28

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

Answer 28

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

Question 29

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

Answer 29

Skin- Cutaneous vasculitis (purpuric rash) Kidneys- glomerulonephritis/renal failure Joints- Arthritis

Question 30

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

Answer 30

SLE

Question 31

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

Answer 31

Type 1 diabetes mellitus MS Rheumatoid arthritis

Question 32

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 32

APACED AIRE gene loss of central immune tolerance of T cells

Question 33

List 4 features of APACED ?

Answer 33

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

Question 34

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

Answer 34

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 35

list monogenic autoinflammatory disease

Answer 35

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 36

what is the inflammasome complex

Answer 36

pathway activated by toxins, pathogens, and urate crystals act via cryopyrin - ASC - procaspase 1 --> IL1, NF kappa B, apoptosis pyrin-marenostrin is a negative regulator of this pathway gain of function mutation in cryopyrin - more inflammation loss of function mutation of pyrin-marenostrin - more inflammation

Question 37

features of familial mediterranean fever

Answer 37

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 38

what is APACED

Answer 38

``` 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 39

features of IPEX

Answer 39

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

Question 40

features of ALPS

Answer 40

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

Question 41

which genes are associated with crohns

Answer 41

IBD1 on chromosome 16 gene = NOD2 same mutations in Blau syndrome and some forms of sarcoidosis NOD2 expressed on cytoplasm of myeloid cells act as a microbial sensor

Question 42

features of ankylosing spondylitis

Answer 42

highly heritable 50% heritability comes down to HLA-B27 tends to colour at entheses low back pain + stiffness, enthesitis, large joint arthritis treat: nsaids, immunosuppression (anti TNF a, anti IL17

Question 43

list some features of polygenic autoimmune disease

Answer 43

HLA associations are common aberrant B and T cell responses lead to the breaking of tolerance auto-antibodies can be found

Question 44

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

Answer 44

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

Question 45

which two genes are involved in regulating T cell function

Answer 45

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

Question 46

how can we classify different hypersensitivity reactions

Answer 46

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

Question 47

give 2 examples of type III hypersensitivity diseases

Answer 47

SLE | rheumatoid arthritis

Question 48

list examples of type 4 hypersensitivity mediated diseases

Answer 48

insulin dependent DM rheumatoid arthritis MS

Question 49

list examples of polygenic autoimmune diseases

Answer 49

``` graves hashimotos thyroiditis pernicious anaemia mysathenia gravis goodpastures T1DM rheumatoid arthritis SLE sjogrens syndrome systemic sclerosis dermato/polymyositis ANCA associated vasculitis ```