Immuno 5: Autoinflammatory + AI diseases Flashcards
Difference between autoinflammatory and autoimune diseases?
AutoINflammatory – driven by components of the INnate immune system
Autoimmune – driven by components of the adaptive immune system
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
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 a gain-of-function mutation in NLRP3?
Cryopyrin (NALP3)
Name 3 diseases that are caused by this mutation (GoF of NLRP3 gene)
Inheritance of these conditions?
This leads to upregulated cryopyrin as seen in:
- Muckle Wells syndrome
- Familial cold autoinflammatory syndrome
- Chronic infantile neurological cutaneous articular syndrome
All of these are autosomal dominant
What are some other examples of monogenic autoinflammatory conditions?
TNF receptor associated periodic syndrome (TNF receptor mutation)
Hyper IgD with periodic fever syndrome (mevalonate kinase mutation)
Describe how the inflammasome complex functions
Inflammasome complex pathway:
+ The pathway is activated by toxins, pathogens and urate crystals
+ These act via cryopyrin and ASC (apoptosis-associated speck-like protein) to activate procaspin 1
+ Activation of procaspin 1 results in the production of NFκB, IL1 and apoptosis
- Pyrin-maronestrin is a negative regulator of this pathway
Pathophysiology of Familial mediterranean fever?
This is an AR autoinflammatory disease
LoF mutation in MEFV -> decreased pyrin-marenostrin (normally inhibits inflam pathway) -> upregulated inflammasome complex
Which cells contain pyrin-maronestrin?
Neutrophils
Clinical features of familial mediterranean fever? increased risk?
Fever and serositis periodically (48-96 hrs) decreases after serositis
Serositis symptoms: Abdominal pain (peritonitis) Chest pain (pleurisy, pericarditis) Arthritis Rash
Increased risk of AA amyloidosis - due to reguar and chronic inflam
Mx of familial mediterranean fever?
Colchicine (inhibits neutrophil function)
Anakinra (anti-IL-1R)
Etanercept (TNFa inhibitor)
Most common cause of fever that comes and goes w/ unknown origin?
Subacute endocarditis - FMF is alot rarer
What are the three main mechanisms of monogenic autoimmune diseases + what conditions involved?
Defect of central tolerance – APS-1/APECED
Defect of peripheral tolerance – IPEX
Defect of lymphocyte apoptosis – ALPS
What is the difference between central and peripheral tolerance
CENTRAL TOLERANCE – deletion of auto-reactive lymphocytes in sites of maturation (BM + Thymus)
PERIPHERAL TOLERANCE (outside BM + thymus)
- T cells cannot be activated without co-stimulation
- Action of regulatory T cells
- Sites of immune privilege – e.g. eyes, testes, CNS
What is APS-1 / APECED?
This is a Monogenic Autoimune disease
Autoimmune polyendocrine syndrome type I (APS-1) or
Autoimmune polyendocrinopathy ectodermal dystrophy syndrome (APECED) - OLD NAME
What pathophysiology of APS-1 / APECED ? what gene?
AIRE = Transcription factor responsible for 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
Which autoimmune conditions tend to occur in APS-1 / APECED? which are main ones?
Hypoparathyroidism (COMMON) Addison’s disease (COMMON) Hypothyroidism Diabetes mellitus Vitiligo
what infection most likely to occur + why in APS-1 / APECED
Candidiasis – anti-IL17 and anti-IL22 antibody formation leads to chronic yeast infections
What is IPEX?
This is a Monogenic Autoimune disease
Immune dysregulation, poylendocrinopathy, enteropathy, X-linked syndrome (IPEX)
What is the pathophysiology of IPEX?
FoxP3 – required for the development of Treg cells
A lack of Tregs leads to autoantibody formation (failure of peripheral tolerance)
Tregs = important for down regulating immune response
What signs are seen in a person w/ IPEX?
Foxp3 hence 3 Ds (+H)
Diarrhoea - enteropathy
Diabetes - T1DM
Dermatitis
Hypothyroidism
What is ALPS?
This is a Monogenic Autoimune disease
Autoimmune lymphoproliferative syndrome (ALPS) - most heterogenous
Which mutations cause ALPS?
Various mutations in the FAS pathway -> defects in apoptosis of lymphocytes
This leads to:
- Failure of lymphocyte tolerance (as autoreactive lymphocytes don’t die by apoptosis)
- Failure of lymphocyte homeostasis (you keep producing lymphocytes)
Clinical presentation of ALPS? high risk of?
Very high lymphocyte count – double-negative (CD4- CD8-) T cells
Splenomegaly and lymphadenopathy
Autoimmune diseases, especially cytopaenias (thrombo, haemolytic anaemia)
High risk of lymphoma
