autoinflammatory diseases part II Flashcards
What mutations are seen in familial Mediterranean fever (FMF)? What kind of inheritance?
mutations in MEFV encoding Pyrin. Autosomal recessive.
What are the symptoms seen every 2 weeks for around 48-72 hours in FMF?
fever, abdominal pain, pleural (chest) pain, arthritis in knees pelvis and hips, peritonitic pain.
Risk of AA amyloidosis.
What immunological indications are there for FMF?
neutrophilia and high acute phase proteins in absence of infection.
What domain of the pyrin are the infections clustered within?
Has a PYD domain but they are clustered within the B32 domain.
Two most common and most severe FMF mutations?
M694V
and V726A.
Are all mutations in MEFV pathogenic? what ones can be likely AD?
not all clearly pathogenic, but variants with deletions can be AD.
What about carriers might explain selection pressure for these ancient FMF variants?
GOF mutations that give higher basal and peak levels of acute phase proteins- improved innate host responses.
Calprotectin Acute phase protein constitutively upregulated in neutrophils and macrophages.
What other molecules does pyrin associate with to form an inflammasome?
Associates with ASC and caspase I to from an inflammasomes and IL-1B.
What maintains the inhibition of pyrin inflammasome.
Phosphorylation of the pyrin inhibitor 14,3,3.
Phosphorylation of 14,3,3 controlled by kinases that are dependent on Rho GTPase phosphorylation.
How can entero bacteria toxins modify and inhibit pyrin inflammasome?
by dephosphorylating Rho GTPases leading to no phosphorylation of 14,3,3.
As well as protecting from bacterial diarrhoea what other disease could pyrin gof variants be protective against?
against plague toxin YopE inhibition of pyrin inflammasome.
What drug is used to inhibit pyrin in FMF and what mechanisms of action are suggested?
prophylactic colchicine, may inhibit NF-KB upregulation of pryin
activates Rho GTPases
cleaves pyrin for nuclear translocation.
What can FMF patients use if resistant to colchicine?
anti IL-1B agents: canikinumab, anakinra.
What are two other syndromes (rare) that cause inflammao-pathies?
PAPI (PSTPIPI mutation due to Il-18)
NLRC4 inflammaosomes - IL1 and IL-18 overpoduction in children with eneterocolitis.
What are four different effects of IL-1B?
On brain, affecting the thermoregulatory centre inducing fever.
increases bone resorpition
Induces hepatic acute-phase protein production and IL-6
Induces production and activation of immune cells.
