Table 7.
Autoinflammatory disorders.
| Disease | Genetic defect/presumed pathogenesis | Inheritance | Affected cells | Functional defects | Associated features | OMIM number |
|---|---|---|---|---|---|---|
| 1. Defects effecting the inflammasome | ||||||
| (a) Familial Mediterranean fever | Mutations of MEFV (lead to gain of pyrin function, resulting in inappropriate IL-1β release) | AR | Mature granulocytes, cytokine-activated monocytes | Decreased production of pyrin permits ASC-induced IL-1 processing and inflammation following subclinical serosal injury; macrophage apoptosis decreased | Recurrent fever, serositis, and inflammation responsive to colchicine. Predisposes to vasculitis and inflammatory bowel disease | 249100 |
| (b) Mevalonate kinase deficiency (hyper IgD syndrome) | Mutations of MVK (lead to a block in the mevalonate pathway). Interleukin-1beta mediates the inflammatory phenotype | AR | Affecting cholesterol synthesis; pathogenesis of disease is unclear | Periodic fever and leukocytosis with high IgD levels | 260920 | |
| (c) Muckle–Wells syndrome | Mutations of CIAS1 (also called PYPAF1 or NALP3) lead to constitutive activation of the NLRP3 inflammasome | AD | PMNs monocytes | Defect in cryopyrin, involved in leukocyte apoptosis and NF-κB signaling and IL-1 processing | Urticaria, SNHL, amyloidosis | 191900 |
| (d) Familial cold autoinflammatory syndrome | Mutations of CIAS1 (see above) Mutations of NLRP12 | AD | PMNs, monocytes | Same as above | Non-pruritic urticaria, arthritis, chills, fever, and leukocytosis after cold exposure | 120100 |
| 5. Neonatal onset multisystem inflammatory disease (NOMID) or chronic infantile neurologic cutaneous and articular syndrome (CINCA) | Mutations of CIAS1 (see above) | AD | PMNs, chondrocytes | Same as above | Neonatal onset rash, chronic meningitis, and arthropathy with fever and inflammation | 607115 |
| 2. Non inflammasome-related conditions | ||||||
| (a) TNF receptor-associated periodic syndrome (TRAPS) | Mutations of TNFRSF1 (resulting in increased TNF inflammatory signaling) | AD | PMNs, monocytes | Mutations of 55-kDa TNF receptor leading to intracellular receptor retention or diminished soluble cytokine receptor available to bind TNF | Recurrent fever, serositis, rash, and ocular or joint inflammation | 142680 |
| (b) Early-onset inflammatory bowel disease | Mutations in IL-10 (results in increase many proinflammatory cytokines) | AR | Monocyte/macrophage, activated T cells | IL-10 deficiency leads to increase of TNFγ and other proinflammatory cytokines | Early-onset enterocolitis enteric fistulas, perianal abscesses, chronic folliculitis | 124092 |
| (b) Early-onset inflammatory bowel disease | Mutations in IL-10RA (see above) | AR | Monocyte/macrophage, activated T cells | Mutation in IL-10 receptor alpha leads to increase of TNFγ and other proinflammatory cytokines | Early-onset enterocolitis enteric fistulas, perianal abscesses, chronic folliculitis | 146933 |
| (b) Early-onset inflammatory bowel disease | Mutations in IL-10RB (see above) | AR | Monocyte/macrophage, activated T cells | Mutation in IL-10 receptor beta leads to increase of TNFγ and other proinflammatory cytokines | Early-onset enterocolitis enteric fistulas, perianal abscesses, chronic folliculitis | 123889 |
| (c) Pyogenic sterile arthritis, pyoderma gangrenosum, acne (PAPA) syndrome | Mutations of PSTPIP1 (also called C2BP1) (affects both pyrin and protein tyrosine phosphatase to regulate innate and adaptive immune responses) | AD | Hematopoietic tissues, upregulated in activated T cells | Disordered actin reorganization leading to compromised physiologic signaling during inflammatory response | Destructive arthritis, inflammatory skin rash, myositis | 604416 |
| (d) Blau syndrome | Mutations of NOD2 (also called CARD15) (involved in various inflammatory processes) | AD | Monocytes | Mutations in nucleotide binding site of CARD15, possibly disrupting interactions with lipopolysaccharides and NF-κB signaling | Uveitis, granulomatous synovitis, camptodactyly, rash, and cranial neuropathies, 30% develop Crohn’s disease | 186580 |
| 10. Chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anemia (Majeed syndrome)a | Mutations of LPIN2 (increased expression of the proinflammatory genes) | AR | Neutrophils, bone marrow cells | Undefined | Chronic recurrent multifocal osteomyelitis, transfusion-dependent anemia, cutaneous inflammatory disorders | 609628 |
| 11. DIRA (deficiency of the interleukin 1 receptor antagonist)a | Mutations of IL-1RN (see functional defect) | AR | PMNs, monocytes | Mutations in the IL-1 receptor antagonist allow unopposed action of Interleukin 1 | Neonatal onset of sterile multifocal osteomyelitis, periostitis, and pustulosis | 612852 |
| 12. DITRA – deficiency of IL-36 receptor antagonist | Mutation in IL-36RN (see functional defect) | AR | Keratinocyte leukocytes | Mutations in IL-36RN leads to increase IL-8 production | Pustular psoriasis | 614204 |
| 13. SLC29A3 mutation | Mutation in SLC29A3 (?) | AR | Leukocyte, bone cells | Macrophage activation? | Hyperpigmentation hypertrichosis | 602782 |
| 14. CAMPS (CARD14 mediated psoriasis) | Mutation in CARD14 (see functional defect) | AD | Mainly in keratinocyte | Mutations in CARD14 activate the NF-κB pathway and production of IL-8 | Psoriasis | 173200 |
| 15. Cherubism | Mutation in SH3BP2 (see functional defect) | AD | Stroma cells, bone cells | Hyperactivated macrophage and increased NF-κB | Bone degeneration in jaws | 11840 |
| 16. CANDLE (chronic atypical neutrophilic dermatitis with lipodystrophy) | Mutation in PSMB8 (see functional defect) | AD | Keratinocyte, B cell adipose cells | Mutations cause increase IL-6 production | Dystrophy, panniculitis | 256040 |
| 17. HOIL1 deficiency | Mutation in HOIL1 (see functional defect) | AR | PMNs, fibroblast | Mutation in HOIL1 leads to IL-1β dysfunction | Immunodeficiency autoinflammation amylopectinosis | 610924 |
| 18. PLAID (PLCγ2 associated antibody deficiency and immune dysregulation) | Mutation in PLCG2 (see functional defect) | AD | B cells, NK, mast cells | Mutations cause activation of IL-1 pathways | Cold urticaria hypogammaglobulinemia | 614878 |
AR, autosomal recessive inheritance; AD, autosomal dominant inheritance; PMN, polymorphonuclear cells; ASC, apoptosis-associated speck-like protein with a caspase recruitment domain; CARD, caspase recruitment domain; CD2BP1, CD2 binding protein 1; PSTPIP1, proline/serine/threonine phosphatase-interacting protein 1; SNHL, sensorineural hearing loss; CIAS1, cold-induced autoinflammatory syndrome 1.
aTen or fewer unrelated cases reported in the literature.
Autoinflammatory diseases are clinical disorders marked by abnormally increased inflammation, mediated predominantly by the cells and molecules of the innate immune system, with a significant host predisposition. While the genetic defect of one of the most common autoinflammatory conditions, PFAPA, is not known, recent studies suggest that it is associated with activation of IL-1 pathway and response to IL-1beta antagonists.
Muckle–Wells syndrome, familial cold autoinflammatory syndrome and neonatal onset multisystem inflammatory disease (NOMID), which is also called chronic infantile neurologic cutaneous and articular syndrome (CINCA) are caused by similar mutations in CIAS1 mutations. The disease phenotype in any individual appears to depend on modifying effects of other genes and environmental factors.