Immuno: Autoinflammatory and Autoimmune diseases Pt.1

Question 1

What is the difference between autoinflammatory and autoimmune disease?

Answer 1

Autoinflammatory = driven by components of the innate immune system

Not characterised by autoantibodies and HLA associations are usually less strong

Autoimmune = driven by components of the adaptive immune system

Autoantibodies are found and HLA associations are common

(Breaking of tolerance - aberrant T and B cell response ni 1 and 2 lymphoid organs)

Note: mixed pattern diseases involve mutations affecting the innate and adaptive immune system → HLA associations may be present but autoantibodies are NOT usually a feature

Question 2

Which cells are mainly responsible for:

1. Autoinflammatory diseases
2. Autoimmune diseases

Answer 2

1. Autoinflammatory diseases = macrophages and neutrophils (disease is usually localised)
2. Autoimmune diseases = T and B cells

Question 3

List examples of monogenic autoinflammatory diseases

Answer 3

Familial Mediterranean Fever

TRAPS

Question 4

List examples of polygenic autoinflammatory diseases

Answer 4

Crohn’s

UC

Osteoarthritis

Giant cell arteritis

Takayasu’s

Question 5

List examples of monogenic autoimmune diseases

Answer 5

APECED

IPEX

ALPS

Question 6

List examples of polygenic autoimmune diseases

Answer 6

Rheumatoid arthritis

Myasthenia

Pernicious anaemia

Graves disease

Question 7

List examples of mixed pattern diseases

Answer 7

Ankylosing spondylitis

Psoriatic arthritis

Behcet’s

Question 8

Mutations in which pathways are implicated in monogenic autoinflammatory disease?

Answer 8

Innate immune cell function - abnormal signalling via key cytokine pathways involving TNF-alpha or IL-1

Question 9

Which protein is upregulated in autoinflammatory diseases caused by gain-of-function mutation in NLRP3?

Answer 9

Cryopyrin (aka NLRP3)

Question 10

Name 3 diseases that are caused by mutation of NLRP3?

Answer 10

• Muckle Wells syndrome
• Familial cold autoinflammatory syndrome
• Chronic infantile neurological cutaneous articular syndrome/Neonatal Onset Multisystem inflammatory disorder (NOMID)
• These are all autosomal dominant

NOTE: other examples of monogenic autoinflammatory conditions: TNF receptor associated periodic syndrome (TNF receptor mutation), Hyper IgD with periodic fever syndrome (mevalonate kinase mutation)

Question 11

Which gene mutation causes Familial Mediterranean Fever and which protein does this gene encode?

Answer 11

MEFV gene

Encodes pyrin-marenostrin which is ordinarily a negative regulator of the inflammatory pathway → mutation leads to increased inflammation

Question 12

Describe how the inflammasome complex functions.

Answer 12

1. The pathway is activated by toxins, pathogens and urate crystals
2. These act via cyropyrin and ASC (apoptosis-associated speck-like protein) to activate procaspin 1
3. Activation of procaspin 1 results in the production of NFkB, IL-1 and apoptosis
4. Pyrin-marenostrin is a negative regulator of this pathway

Question 13

Which mutations can lead to hyperactivity of the inflammasome complex?

Answer 13

• Loss of function of pyrin-marenostrin
• Gain of function of cryopyrin

Question 14

What is the inheritance pattern of Familial Mediterranean Fever?

Answer 14

Autosomal recessive

Question 15

Which cells contain pyrin-maronostrin?

Answer 15

Neutrophils

Question 16

Outline the clinical presentation of Familial Mediterranean Fever.

Answer 16

Periodic fevers lasting 2-4 days associated with:

• Abdominal pain (peritonitis)
• Chest pain (pleurisy, pericarditis)
• Arthritis
• Rash

Question 17

What is a complication of Familial Mediterranean Fever?

Answer 17

AA amyloidosis
(due to chronic elevation of serum amyloid A)

This can deposit in the kidneys causing nephrotic syndome and renal failure

Question 18

Outline the treatment of Familial Mediterranean Fever.

Answer 18

• Colchicine 500µg BD (binds to tubulin and disrupts neutrophil migration and chemokine secretion)
• 2nd line: blocking cytokines
  
  • Anakinra - IL-1 receptor blocker
  • Etanercept - TNF-alpha blocker

Question 19

What are three types of pathogenesis in monogenic autoimmune diseases?

Answer 19

• Abnormality in tolerance
• Abnormality in regulatory T cells
• Abnormality of lymphocyte apoptosis

Question 20

What does APECED stand for?

Answer 20

Autoimmune polyendocrinopathy candidiasis ectodermal dystrophy

NOTE: it is autosomal recessive

Question 21

What mutation causes APECED? What is the role of this gene?

Answer 21

AIRE - this is a transcription factor that is responsible for the expression of self-antigens in the thymus and promotes apoptosis of self-reactive T cells. Defects in AIRE leads to a failure of central tolerance and the release of auto-reactive T cells.

Question 22

Which autoimmune conditions tend to occur in APECED?

Answer 22

• Hypoparathyroidism (COMMON)
• Addison’s disease (COMMON)
• Hypothyroidism
• Diabetes mellitus
• Vitiligo

Question 23

Why are patients with APECED prone to Candida infection?

Answer 23

They produce antibodies against IL-17 and IL-22

Question 24

What does IPEX stand for?

Answer 24

Immune dysregulation polyendocrinopathy enteropathy X-linked syndrome

Question 25

What mutation causes IPEX? What is the role of this gene?

Answer 25

FoxP3 - required for the development of Treg cells

A lack of Tregs leads to autoantibody formation