Immuno 5: Autoinflammatory And Autoimmune Diseases 1 Flashcards
What is the difference between auto-inflammatory and auto-immune disease ?
Auto-inflammatory: affects innate immune response
Auto-immune: affects adaptive immune response
Give 1 example of a monogenic auto-inflammatory disease ?
Familial Mediterranean fever
Which gene is mutated in Familial Mediterranean fever ?
How does this cause the disease ?
MEFV gene (autosomal recessive)
Causes defect in pyrin-marenostrin protein which causes activation of Neutrophils by cryopyrin to become deregulated.
How is Familial Mediterranean fever associated with amyloidosis and Nephrotic syndrome ?
The inflammation causes the liver to produce acute phase protein: Amyloid
AMyloid deposits in the kidneys causing proteinuria and hence nephrotic syndrome
Name 3 monogenic Auto-immune disease ?
APS1 (auto-immune polyendocrine syndrome type 1) (APECED) IPEX ALPS (auto-immune lymphoproliferative syndrome)
What is the main treatment for Familial Mediterranean Fever ?
Colchicine
What causes APACED ?
Defect in AIRE transcription factor
(Promotes the apoptosis of auto-reactive T cells in the thymus)
Leads to a loss in central tolerance
Name the 2 most common auto-immune conditions seen in APS1 (APECED)?
Hypoparathyroidism
Addison’s disease
What causes IPEX ?
Mutation in Foxp3 gene
Foxp3 is required for development of Treg cells
What are the 3 Ds of conditions seen in IPEX ?
Diarrhoea
Dermatitis
Diabetes
What causes ALPS ?
Mutation in Fas pathway
causes defect in apoptosis of Lymphocytes
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 ?
ALPS
Which genetic mutation has been found to be associated with Crohn’s disease ?
NOD2
Give 5 examples of polygenic auto-inflammatory diseases ?
Crohn’s disease Ulcerative colitis Osteoarthritis Giant cell arteritis Takayasu’s arteritis
List 4 drugs used to treat Crohn’s disease ?
Corticosteroids
Azathioprine (steroid sparing)
Anti-TNF alpha antibody
Anti- IL12/23 antibody
Give 3 example of mixed pattern diseases (auto inflammatory and auto immune) ?
Ankylosis spondylitis
Psoriatic arthritis
Behcet’s syndrome
Which HLA type is associated with Ankylosing spondylitis ?
HLA B27
What are the main 2 treatments for Ankylosing spondylitis ?
NSAIDS
Anti-TNF alpha antibodies
List 6 polygenic Auto-immune diseases ?
Rheumatoid arthritis Myasthenia gravis Pernicious anaemia Addison’s disease SLE PBC (primary biliary cirrhosis)
Which diseases are associated with HLA-DR3 polymorphisms ?
Graves’ disease
SLE
Type 1 diabetes Mellitus
Which diseases are associated with HLA-DR4 polymorphisms ?
Type 1 diabetes Mellitus
Rheumatoid arthritis
Which disease is associated with HLA-DR15 polymorphisms ?
Goodpasture’s disease
List 3 areas of immune privilege in the body ?
Eyes
Testes
CNS
Describe type 1 immune reaction ?
Immediate hypersensitivity which is IgE mediated
Describe type 2 immune reaction ?
Antibody reacts to cellular antigen
Describe type 3 immune reaction ?
Antibody reacts with soluble antigen to form an immune complex
Describe type 4 Immune reaction ?
Delayed type hypersensitivity
T cell mediated response
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
Goodpasture disease:::::basement membrane collagen type IV
Myasthenia Gravis:::::acetylcholine receptor
Pemphigus Vulgaris:::::epidermal Cadherin
Grave’s disease:::::TSH receptor
Give examples of regions where Immune complexes deposit and the pathology they cause ?
Skin- Cutaneous vasculitis (purpuric rash)
Kidneys- glomerulonephritis/renal failure
Joints- Arthritis
Which disease is considered to cause a type 3 hypersensitivity reaction ?
SLE
Name 2 disease is considered to cause a type 4 hypersensitivity reaction ?
Type 1 diabetes mellitus
MS
Rheumatoid arthritis
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 ?
APACED
AIRE gene
loss of central immune tolerance of T cells
List 4 features of APACED ?
- Hypoparathyroidism
- Hypothyroidism
- Addisons
- DM type 1
- Vitiligo
- Alopecia
- Hypogonadism
what is the difference between the mechanisms of autoimmune and auto-inflammatory disease
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
list monogenic autoinflammatory disease
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)
what is the inflammasome complex
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
features of familial mediterranean fever
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
what is APACED
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
features of IPEX
immune dysregulation, polyendocrinopathy, enteropathy, X-linked syndrome
mutation in Foxp3
needed for development of T reg cells
autoantibody formation
- enteropathy
- diabetes
- hypothyroidism
- dermatitis
features of ALPS
autoimmune lymphoproliferative syndrome
mutation in the FAS pathway
defect in apoptosis of lymphocytes
high lymphocyte count
large spleen and LN
AI diseases
lymphoma
which genes are associated with crohns
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
features of ankylosing spondylitis
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
list some features of polygenic autoimmune disease
HLA associations are common
aberrant B and T cell responses lead to the breaking of tolerance
auto-antibodies can be found
match the susceptibility allele with the disease:
goodpastures graves SLE T1 DM rheumatoid arthritis
goodpastures - HLA DR 15 graves - HLA DR 3 SLE - HLA DR 3 T1 DM - HLA DR 3/4 rheumatoid arthritis - HLA DR4
which two genes are involved in regulating T cell function
PTPN 22 (suppresses T cell activity) CTLA 4 (expressed by T cells to suppress activity)
how can we classify different hypersensitivity reactions
gel and coombs test
looks at whether a response is antibody of T cell mediated
give 2 examples of type III hypersensitivity diseases
SLE
rheumatoid arthritis
list examples of type 4 hypersensitivity mediated diseases
insulin dependent DM
rheumatoid arthritis
MS
list examples of polygenic autoimmune diseases
graves hashimotos thyroiditis pernicious anaemia mysathenia gravis goodpastures T1DM rheumatoid arthritis SLE sjogrens syndrome systemic sclerosis dermato/polymyositis ANCA associated vasculitis
