Immuno: Autoinflammatory and Autoimmune diseases 1 Flashcards
What is the difference between autoinflammatory and autoimmune disease?
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
Which cells are mainly responsible for:
- Autoinflammatory diseases
- Autoimmune diseases
- Autoinflammatory diseases = macrophages and neutrophils (disease is usually localised)
- Autoimmune diseases = T and B cells
List examples of monogenic autoinflammatory diseases
Familial Mediterranean Fever
TRAPS
List examples of polygenic autoinflammatory diseases
Crohn’s
UC
Osteoarthritis
Giant cell arteritis
Takayasu’s
List examples of monogenic autoimmune diseases
APECED
IPEX
ALPS
List examples of polygenic autoimmune diseases
Rheumatoid arthritis
Myasthenia
Pernicious anaemia
Graves disease
List examples of mixed pattern diseases
Ankylosing spondylitis
Psoriatic arthritis
Behcet’s
Mutations in which pathways are implicated in monogenic autoinflammatory disease?
Innate immune cell function - abnormal signalling via key cytokine pathways involving TNF-alpha or IL-1
Which protein is upregulated in autoinflammatory diseases caused by gain-of-function mutation in NLRP3?
Cryopyrin (NALP3)
Name 3 diseases that are caused by mutation of NLRP3?
- Muckle Wells syndrome
- Familial cold autoinflammatory syndrome
- Chronic infantile neurological cutaneous articular syndrome
- 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)
Which gene mutation causes Familial Mediterranean Fever and which protein does this gene encode?
MEFV gene
Encodes pyrin-marenostrin which is ordinarily a negative regulator of the inflammatory pathway → mutation leads to increased inflammation
Describe how the inflammasome complex functions.
- The pathway is activated by toxins, pathogens and urate crystals
- These act via cyropyrin and ASC (apoptosis-associated speck-like protein) to activate procaspin 1
- Activation of procaspin 1 results in the production of NFkB, IL-1 and apoptosis
- Pyrin-maronestrin is a negative regulator of this pathway
Which mutations can lead to hyperactivity of the inflammasome complex?
- Loss of function of pryin-marenostrin
- Gain of functiion of cryopyrin
What is the inheritance pattern of Familial Mediterranean Fever?
Autosomal recessive
Which cells contain pyrin-maronestrin?
Neutrophils
Outline the clinical presentation of Familial Mediterranean Fever.
Periodic fevers lasting 2-4 days associated with:
- Abdominal pain (peritonitis)
- Chest pain (pleurisy, pericarditis)
- Arthritis
- Rash
What is a complication of Familial Mediterranean Fever?
AA amyloidosis (due to chronic elevation of serum amyloid A)
This can deposit in the kidneys causing nephrotic syndome and renal failure
Outline the treatment of Familial Mediterranean Fever.
- 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
What are three types of pathogenesis in monogenic autoimmune diseases?
- Abnormality in tolerance
- Abnormality in regulatory T cells
- Abnormality of lymphocyte apoptosis