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. 2020 Aug 25;11:1840. doi: 10.3389/fimmu.2020.01840

Figure 2.

Figure 2

Inflammasomes and inflammasomopathies. GOF mutations in Inflammasome sensors (NLRP3, Pyrin, NLRC4, NLRP1) cause systemic autoinflammatory diseases. While GOF mutations in NLRP3, pyrin, and NLRP1 lead to predominantly IL-1b activation (A), GOF mutations in NLRC4 lead to IL-1b activation and very high IL-18 levels (B). (A) GOF mutations in NLRP3 cause the cryopyrin-associated autoinflammatory diseases (CAPS) (images depict conjunctivitis, MRI with leptomeningeal enhancement in NOMID patient with aseptic neutrophilic meningitis and neutrophilic urticarial rash) and secondary NLRP3 inflammasome activation by recessive LOF mutations in LPIN2 has been linked to the generation of a metabolic triggers/stress (Inline graphic) that cause Majeed syndrome (depicted is sterile osteomyelitis of the growth plates, the disease is not discussed in the text). Additive GOF mutations in pyrin cause familial Mediterranean fever (FMF) (depicted are abdominal adhesions that can develop in chronic sterile peritonitis and erysipelas-like erythema of the ankle in FMF) or Pyrin-Associated Autoinflammatory with Neutrophilic Dermatosis (PAAND) (depicted is cystic acne and pyoderma gangrenosum in a patient with neutrophilic dermatitis), and secondary pyrin inflammasome activation is caused by LOF mutations in MVK that cause Mevalonate kinase deficiency (MKD) (depicted is lymphadenitis and a papular rash). GOF mutations in NLRP1 cause NLRP1-Associated Autoinflammation with Arthritis and Dyskeratosis (NAIAD) (depicted is follicular dyskeratosis, hyperkeratosis of the soles and lesions on left hand). (B) GOF mutations in NLRC4 cause the NLRC4-Associated Autoinflammatory Disorders (NLRC4-AID) associated with often ultra-high serum IL-18 expression which predisposes to the development of MAS [images depict the rash from a patient with NLRC4-associated macrophage activation syndrome (MAS)]. Other high IL-18 states include CDC42 mediated autoinflammatory disease (depicted are mild facial dysmorphisms including frontal bossing and nasal bridge depression); IL-18 PAP-MAS (a subset of SOJIA-ILD), an autoinflammatory disease without known genetic defect (depicted are a chest CT scan with interstitial lung disease and clubbing of the fingernails). For the 2 latter diseases, increased NLRC4 inflammasome activation as cause of the high IL-18 has not been demonstrated. (A,B) Inflammatory markers during MAS and CAPS flares differ. Flare episodes in patients with CAPS (C) differ from flare episodes in patients with high IL-18 levels (shown in a patient with NLRC4-AID in D). ESR and CRP are similarly elevated in both diseases, in MAS other features include elevated ferritin and LDH, and cytopenias (leukopenia, thrombocytopenia); while in CAPS, ferritin and LDH increase little if at all and patients develop leukocytosis and thrombocytosis. (The shaded area shows longitudinal laboratory markers collected during a 2-week period during a disease flare). CAPS, Cryopyrin-Associated Periodic Syndrome; CDC42, Cell Division Control protein 42 homolog; FMF, Familial Mediterranean Fever; IL18-BP, IL-18 binding protein; IL-1Ra, IL-1 receptor antagonist; MKD or HIDS, Mevalonate Kinase Deficiency or Hyper-IgD Syndrome; NAIAD, NLRP1 Associated Autoinflammation with Arthritis and Dyskeratosis; NLRC4-AID, NLRC4-Associated Autoinflammatory Disorders; NOMID, Neonatal-Onset Multisystem Inflammatory Disease; PAAND, Pyrin-Associated Autoinflammatory with Neutrophilic Dermatosis; PAP-MAS, Pulmonary Alveolar Proteinosis-Macrophage Activation Syndrome; PRR, Pattern recognition receptor.