The monogenic autoinflammatory diseases define new pathways in human innate immunity and inflammation - Nature Immunology

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• FCAS

• Monogenic periodic fever syndromes

• heralded a deeper understanding of inflammasomes

• ow they mediate release of the proinflammatory cytokine IL-1β.

• nucleation of ASC, an adaptor protein with a PYRIN domain

• domain (CARD)

• NLRC4 and NLRP1, which contain CARDs, directly activate caspase-1

• Caspase-1 in turn cleaves the cytokine precursors pro-IL-1β and pro-IL-18 into their active forms, IL-1β and IL-18

• Caspase-1 also cleaves gasdermin D,

• cleavage product forms pores in the cell membrane

• FMF is caused by mutations in MEFV

• encodes the protein pyrin

• recurrent episodes of fever with inflammation of serosal membranes in the abdomen, heart and lungs;

• deposition of a cleavage fragment of serum amyloid A protein in various organs, particularly the kidneys

• t doubt on the loss-of-function hypothesis

• asymptomatic carriers of MEFV mutations have elevated acute-phase reactants

• no null mutations in MEFV have been identified in people with FMF

• neither Mefv−/− mice

• nor crosses between knock-in mice and Mefv−/− mice have an overt inflammatory phenotype,

• homozygous knock-in mice expressing FMF-associated mutations display a severe inflammatory phenotype similar to that of people with FMF