autoinflammatory diseases I Flashcards
What are the three main inherited autoinflammatory diseases (SAIDs)?
CAPS (mutations in NLRP3)
FMF (HLH)
TRAPS (TNF receptor-associated periodic syndrome)
What is the acquired SAID?
AOSDs
what is the genetic cause and 2 symptoms of Blau syndrome?
Mutation in NOD2, leading to autoinflammation characterised by uveitis and granulomatous arthritis.
What are four symptoms of autoinflammatory diseases?
Obvious immunological indicators.
Fever, rash (also often not seen on dark skin), serositis (inflammation of linings), joint pain and arthritis.
High levels of inflammation and acute-phase proteins.
when do monogenic autoinflammatory diseases normally have onset? When might this not be the case?
Onset is normally during early infancy.
May have genuine late onset if due to acquired mutations and somatic mosaicism.
What must you rule out when making auto-inflammatory diagnosis?
Other causes of infection or immunodeficiency (mostly child), connective tissue disorders and malignancy.
Are monogenic diseases of autoinflammation X linked, AD, AR?
Normally autosomal dominant (why you can get late onset due to somatic mosaicism).
What are the two main inflammasomo-pathies?
CAPS and FMF (familial Mediterranean fever)
What are the three manifestations of CAPS, the gene affected and their order of severity?
All are autosomal dominant (apart from sporadic NOMID/CINCA) GOF hypomorphic mutations in NLRP3
mild: familial cold uticaria
moderate: Muckle Wells syndrome
severe: NOMID/CINCA
symptoms of familial cold urticaria and muckle wells syndrome?
familial cold urticaria: cold-induced urticaria/rash, arthralgia (joint pain) and conjunctivitis.
Muckle-Wells syndrome: urticarial rash, deafness and AA amyloidosis and renal failure.
Symptoms of NOMID/CINCA?
joint destruction, meningitis and CNS damage-deafness and blindness, retardation.
What cells express NLRP3?
myeloid cells (DCs, monocytes macrophages and neutrophils).
What receptor-ligand signalling and cytokines can upregulate NLRP3 transcription?
LPS (TLR4), CpG (TLR9) and TNF-a.
What chaperone proteins can maintain NLRP3 in an autorepressive state?
SGT1 and HSP90 bind to LRR to maintain autorepressive state.
What happens upon NLRP3 activation?
relief of repression, and NLRP3 polymerisatoin, binding of ASC adaptor (PYD-PYD domain interactions) which recruits CARD with capsase 1 to CARD domain.
Caspase 1 cleaves IL-1B and IL18.
What is 1 effect of IL-1B autocrine signalling?
Upregulation of all genes in IL-1B pathway.
What foreign and self signals activate NLRP3?
bacteria, fungi and viruses.
DAMPS, uric acid crystals (GOUT), alum crystals. Amyloid B (Alzheimer's) and cholesterol crystals from type 2 diabetes.
What is required to prime NLRP3 inflammasome for activation?
TLR4-MyD88 deubiquitination of NLRP3 and NFKB mediated upregulated of NLRP3.
Can IL-1 be detected directly in blood?
nope, works in autocrine fashion
has to be detected through myeloid cell stimulation with LPS.
Three drugs that can inhibit IL-1B production and are effective for CAPS?
Vertex, a reversible inhibitor of caspase 1 (but also inhibits IL-6 and IL-18)
anakinra: a recombinant IL1Breceptor antagonist
canakinumab: monoclonal against IL-1B/
