Autoinflammatory and autoimmune

Question 1

What occurs in monogenic auto-inflammatory conditions?

Answer 1

Mutation in a gene encoding a protein involved in a pathway associated with innate immune cell function. Abnormal signalling via TNF and/or IL-1 is common

Question 2

What occurs in the pathogenesis of Familial Mediterranean fever?

Answer 2

Autosomal recessive, mutation in MEFV gene which encodes Pyrin-marenostrin.
Pyrin-marenostrin is mainly expressed in neutrophils
There is a failure to regulate cryopyrin driven action of neutrophils

Question 3

Describe the clinical features of familial Mediterranean fever.

Answer 3

Periodic fevers lasting 48-96 hours.

Associated with abdominal pain, chest pain due to pleurisy and pericarditis, arthritis, rash.

Question 4

Why is there a long term risk of AA amyloidosis in Familial Mediterranean fever? Where does amyloid deposition occur? What are main problems due to deposition?

Answer 4

Liver produces serum amyloid A as acute phase protein, which deposits in kidneys, liver and spleen. Deposition in kidneys can cause proteinuria/ nephrotic syndrome and renal failure.

Question 5

Give 3 treatments for Familial Mediterranean fever?

Answer 5

Colchicine 500ug bd. Binds to tubulin in neutrophils and disrupts neutrophil functions of migration and chemokine secretion.
Anakinra- interleukin 1 receptor antagonist
Etanercept- TNF alpha inhibitor.

Question 6

What occurs in polygenic auto-inflammatory conditions? Describe the HLA associations and autoantibody features of these conditions.

Answer 6

Mutations in genes encoding proteins involved in innate immune cell functions e.g. macrophages and neutrophils.
HLA associations are less strong
Not characterised by presence of auto-antibodies.

Question 7

Name 5 polygenic auto-inflammatory conditions

Answer 7

Crohn’s, UC, Osteoarthritis, giant cell arteritis, takayasu’s arteritis.

In Crohn’s, IBD1 gene on chromosome 16 identified as NOD2, mutations associated with Crohn’s

Question 8

What is relevance of NOD2 in Crohn’s disease

Answer 8

IBD1 gene on chromosome 16 identified as NOD2, mutations associated with Crohn’s.
NOD 2 expressed in cytoplasm of myeloid cells= intracellular receptor for bacterial products- recognises muramyl dipeptide and stimulates NFKb- activation induces auto-phagy in dendritic cells.

Question 9

What happens in mixed pattern diseases? Describe HLA associations and auto-antibody features of these diseases.

Answer 9

• Mutations occur in genes encoding proteins involved in pathways of innate and adaptive immune cell functions
• HLA associations may be present
• Autoantibodies are not usually a feature.

Question 10

What happens in polygenic autoimmune conditions? Describe the HLA and autoantibody features of these diseases.

Answer 10

Mutations occur in genes encoding proteins involved in adaptive immune cell function.
- HLA associations are common
- Autoantibodies are found
Aberrant B and T cell responses in primary and secondary lymphoid organs lead to breaking of tolerance with development of immune reactivity to self-antigens.

Question 11

Name 2 genetic polymorphisms associated with autoimmune diseases.

Answer 11

PTPN22: RA, SLE, T1DM- lymphocyte specific tyrosine phosphatase which suppresses T cell activation.

CTLA4: SLE, T1DM, autoimmune thyroid disease. Receptor for CD80/ CD86 expressed by T cells which transmits inhibitory signal to control T cell activation.

Question 12

What occurs in monogenic autoimmune conditions?

Answer 12

Mutation of a gene encoding a protein involved in a pathway associated with adaptive immune cell function.

Question 13

What occurs in Auto-immune polyendocrine syndrome type 1 (aka APECED)? What is the inheritance pattern?

Answer 13

• Abnormality in tolerance
• Autosomal recessive inheritance
• Defect in autoimmune regulator (AIRE)- a transcription factor involved in development go T cell tolerance in thymus- upregulates expression of self-antigens by thyme cells and promotes T cell apoptosis.

Question 14

What clinical features are caused by auto-immune polyendocrine syndrome type 1 (APECED).

Answer 14

Multiple autoimmune diseases:

• Hypoparathyroidism, Addison’s, hypothyroidism, diabetes, vitiligo, enteropathy.
• Candidiasis- due to IL17 and IL22 autoantibodies.

Question 15

What occurs in immune dysregulation, polyendocrinopathy, enteropathy (IPEX)? What is the inheritance pattern?

Answer 15

• Autoimmune diseases due to Foxp3 mutations.
• Foxp3 required for development of T-regulatory cells- mutations causes failure to regulate T cell responses and autoreactive B cells.

X-linked inheritance.

Question 16

What clinical features are present in immune dysregulation polyendocrinopathy, enteropathy (IPEX)?

Answer 16

Diabetes, hypothyroidism, enteropathy. “Diarrhoea, diabetes and dermatitis”.

Question 17

What occurs in Autoimmune lymphoproliferative syndrome (ALPS)? What is the inheritance pattern?

Answer 17

Abnormality of lymphocyte apoptosis.

• Mutations in FAS pathway- disease is heterogenous depending on the mutation.
• Defect in apoptosis of lymphocytes leads to failure of tolerance and lymphocyte homeostasis.
• Autosomal dominant with incomplete penetrance.

Question 18

What clinical features are present in Autoimmune lymphoproliferative syndrome?

Answer 18

• High lymphocyte numbers with large spleen and lymph nodes.
• Autoimmune diseases- commonly auto-immune cytopenias.
• Lymphoma

Question 19

What are the following HLA associations:

• Ankylosing spondylitis and seronegative arthropathies (PAIR)
• Goodpasture syndrome
• Grave’s disease
• Systemic lupus erythematosis
• Type 1 diabtes
• Rheumatoid arthritis
• Pernicious anaemia
• Coeliac disease- “I ate too much gluten at Dairy Queen”

Answer 19

- AS: HLA B27
Psoriatic arthritis, AS, IBD associated arthritis, reactive arthritis.
- GS: HLA DR15/ DR2
- Graves: HLA DR3/ B8
- SLE: HLA DR2/ 3 
- T1DM: HLA DR3/ 4
- RA: HLA DR4- there are 4 walls in a Rheum
- PA: HLA DR5
- Coealic: HLA DQ2/ 8