Table 7.
Autoinflammatory disorders.
| Disease | Affected cells | Functional defects | Associated Features | Inheritance | Genetic defect/presumed pathogenesis | OMIM number |
|---|---|---|---|---|---|---|
| 1. Defects effecting the inflammasome | ||||||
| (a) Familial Mediterranean fever | 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 | AR | Mutations of MEFV | 249100 |
| (b) Hyper IgD syndrome | Mevalonate kinase deficiency affecting cholesterol synthesis; pathogenesis of disease unclear | Periodic fever and leukocytosis with high IgD levels | AR | Mutations of MVK | 260920 | |
| (c) Muckle–Wells syndrome | PMNs monocytes | Defect in cryopyrin, involved in leukocyte apoptosis and NFkB signaling and IL-1 processing | Urticaria, SNHL, amyloidosis | AD | Mutations of CIAS1(also called PYPAF1 or NALP3) | 191900 |
| (d) Familial cold autoinflammatory syndrome | PMNs, monocytes | same as above | Non-pruritic urticaria, arthritis, chills, fever, and leukocytosis after cold exposure | AD | Mutations of CIAS1 Mutations of NLRP12 | 120100 |
| (e) Neonatal onset multisystem inflammatory disease (NOMID) or chronic infantile neurologic cutaneous and articular syndrome (CINCA) | PMNs, chondrocytes | same as above | Neonatal onset rash, chronic meningitis, and arthropathy with fever and inflammation | AD | Mutations of CIAS1 | 607115 |
| 2. Non-inflammasome-related conditions | ||||||
| (a) TNF receptor-associated periodic syndrome (TRAPS) | PMNs, monocytes | Mutations of 55-kD 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 | AD | Mutations of TNFRSF1A | 142680 |
| (b) Early onset inflammatory bowel disease | Monocyte/macrophage, activated T cells | Mutation in IL-10 or IL-10 receptor leads to increase of TNFγ and other proinflammatory cytokines | Early onset enterocolitis enteric fistulas, perianal abscesses, chronic folliculitis | AR | Mutations in IL10, IL10RA, or IL10RB | 146933 |
| (c) Pyogenic sterile arthritis, pyoderma gangrenosum, acne (PAPA) syndrome | Hematopoietic tissues, upregulated in activated T cells | Disordered actin reorganization leading to compromised physiologic signaling during inflammatory response | Destructive arthritis, inflammatory skin rash, myositis | AD | Mutations of PSTPIP1 (also called C2BP1) | 604416 |
| (d) Blau syndrome | 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 | AD | Mutations of NOD2 (also called CARD15) | 186580 |
| (e) Chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anemia (Majeed syndrome)* | Neutrophils, bone marrow cells | Undefined | Chronic recurrent multifocal osteomyelitis, transfusion-dependent anemia, cutaneous inflammatory disorders | AR | Mutations of LPIN2 | 609628 |
| (f) DIRA (Deficiency of the interleukin 1 receptor antagonist)* | PMNs, monocytes | Mutations in the IL1 receptor antagonist allows unopposed action of interleukin 1 | Neonatal onset of sterile multifocal osteomyelitis, periostitis, and pustulosis | AR | Mutations of IL1RN | 612852 |
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.
*Ten 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-1 beta 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.