Table 1.
Molecular basis of selected monogenic autoinflammatory diseases
| Disease | Gene | Protein | Proposed mechanism | References |
| Hereditary periodic fever syndromes | ||||
| Familial Mediterranean fever (FMF) | MEFV | Pyrin | Pyrin senses modifications of Rho GTPases induced by bacterial toxins. In FMF, increased IL-1β production plays a major role in mediating inflammation | [1,2,9▪▪,10] |
| TNF receptor-associated periodic syndrome (TRAPS) | TNFRSF1A | p55 TNF receptor | Protein misfolding causes retention of mutant TNFR1 in the endoplasmic reticulum, increased mitogen-activated protein (MAP) kinase activation,increased mitochondrial reactive oxygen species (ROS) production, and increased proinflammatory cytokine production | [3,11] |
| Hyper IgD syndrome (HIDS) | MVK | Mevalonate kinase enzyme | Mutations decrease geranylgeranylation of RhoA GTPase, leading to increased Rac1 activity and increased IL-1β production | [12,R13,14▪,15▪] |
| Cryopyrinopathies | ||||
| Familial cold autoinflammatory syndome (FCAS); Muckle▪Wells syndrome (MWS); neonatal-onset multisystem inflammatory disease (NOMID)/chronic infantile neurologic cutaneous and articular syndrome (CINCA) | NLRP3 | Cryopyrin | Mutations cause constitutive activation of the NLRP3 inflammasome, leading to excessive IL-1β production; mutant NLRP3 has diminished binding affinity for the inhibitory effects of cAMP | [4–6,16] |
| Other inflammasomopathies | ||||
| Deficiency of IL-1 receptor antagonist (DIRA) | IL1RN | IL-1 receptor antagonist | Impaired inhibition of the IL-1β signaling pathway | [17,18] |
| Deficiency of IL-36 receptor antagonist (DITRA) | IL36RN | IL-36 receptor antagonist | Impaired inhibition of the IL-36 signaling pathway | [19,20] |
| Pyogenic arthritis, pyoderma gangrenosum, and acne syndrome (PAPA) | PSTPIP1 | PSTPIP1/CD2BP1 | Increased binding of PSTPIP1 to pyrin, increased production of IL-1β | [21–23] |
| NF-κB disorders | ||||
| Blau syndrome | NOD2 | NOD2 (CARD15) | Constitutive activation of NF-κB pathways | [24,25] |
| Early-onset enterocolitis | IL10RA, IL10RB, IL10 | IL-10R1, IL-10R2, IL-10 | Impaired signaling through the anti-inflammatory IL-10 pathway | [26,27] |
| Familial psoriasis (PSORS2) | CARD14 | CARD14 | Activation of NF-κB and upregulation of psoriasis-related genes in keratinocytes | [28] |
| Interferonopathies | ||||
| Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) | PSMB8 | PSMB8 | Impaired proteasome catalytic activity or assembly, impaired removal of damaged proteins. Increased production of proinflammatory cytokines, interferon-signaling signature on gene-expression profiling | [29–32,33▪] |
| STING-associated vasculopathy with onset in infancy (SAVI) | TMEM173 | STING | Constitutive activation of STING and the interferon-β pathway | [34▪▪] |
| Other | ||||
| Deficiency of adenosine deaminase 2 (DADA2) | CECR1 | ADA2 | Impaired endothelial development and M2 macrophage differentiation | [35▪▪36▪▪] |
| PLCγ2-associated antibody deficiency and immune dysregulation (PLAID) | PLCG2 | PLCγ2 | Constitutive activation of PLCγ2 | [37] |
| Autoinflammation and PLCγ2-associated antibody deficiency and immune dysregulation (APLAID) | PLCG2 | PLCγ2 | Decreased threshold for triggering PLCγ2, without constitutive activation | [38] |
| HOIL-1 deficiency | RBCK1 | RBCK1 | Increased production of inflammatory cytokines by monocytes in response to IL-1β stimulation | [39▪▪,40▪▪] |