FMF, MEFV, IFNg, Jak, and STAT
FMF, MEFV, IFNg, Jak, and STAT
abstract & commentary
Synopsis: Febrile episodes in familial Mediterranean fever may occur as the result of uninhibited triggering of the inflammatory response as a consequence of mutations in a gene encoding an IFNg-induced inhibitory molecule.
Source: Centola M, et al. The gene for familial Mediterranean fever, MEFV, is expressed in early leukocyte development and is regulated in response to inflammatory mediators. Blood 2000;95:3223-3231.
The discovery in the last decade of a series of mutations within a gene on the short arm of chromosome 16p in patients with familial Mediterranean fever (FMF) was a major advance in our understanding of this often perplexing disease.1-4 The gene, MEFV, encodes a 781 amino acid protein called pyrin by the Israeli discoverers and marenostrin ("our sea," from Latin) by the French. The disease is an ancient one; mutations associated with FMF have been reportedly traced to a son of Shem (and, thus, a grandson of Noah).2,5
Initial studies found evidence of expression of the gene only in polymorphonuclear cells. The most frequently cited hypothesis was that the normal gene product was involved in downregulation of neutrophil chemotaxis and that this negative feedback was lost in the presence of an altered gene product. The work reviewed here, however, points to a different pathogenetic mechanism.
Centola and colleagues found that MEFV message was detected not only in peripheral blood neutrophils of patients with FMF, but also in eosinophils and, variably, in monocytes. In examining cultured CD34 hematopoietic stem cells in vitro, they found that MEFV messenger RNA was first detectable at the myelocyte stage, at the time of lineage commitment.
Further studies demonstrated that MEFV expression was induced by exposure of monocytes to the proinflammatory cytokines, IFNg, IFNa, or TNF, as well as to LPS, while IL4, IL10, and TGFb each inhibited expression. IFNg, as well as the combination of colchicine and IFNa upregulated MEFV expression; induction by IFN-gamma occurred rapidly and was resistant to cycloheximide. These and additional findings indicated that MEFV is an IFNg immediate early gene that is involved in down-regulation of the IFNg-induced inflammatory response. These data lead the investigators to propose the hypothesis that "MEFV mediates a Th-1-responsive negative-feedback loop during proinflammatory activation of myeloid cells and that the pathophysiologic features of FMF result from defects in this inhibitory activity."
Comment by stan deresinski, md, facp
FMF has long been identified as a disease transmitted genetically in an autosomally recessive fashion. The episodes of febrile illness with serositis, as well as other manifestations such as arthritis and erysipelas, usually begin in childhood and, in some, culminate in the development of type AA amyloidosis and renal failure. The frequency of febrile episodes, their manifestations and severity, are highly variable among ethnic groups. Episodes may be triggered by a wide variety of inflammatory and non-inflammatory stimuli.
This study by Centola and colleagues provides us with an improved understanding of the pathogenesis of FMF as well as into IFNg function. The normal product of the affected gene appears to be expressed shortly after interaction of IFNg with its receptor. Receptors for IFNg are expressed on all types of human cells with the exception of mature erythrocytes. The IFNg receptor (IFNgR), a member of the class II cytokine receptor complex, consists of two distinct chains. IFNg R1, the ligand-binding unit, and IFNg R2, whose intracellular domain is necessary for signaling, undergo oligomerization upon binding of IFNg. Binding of IFNg to its receptor initiates signal transduction, which involves a series of events with activation of Jak1 and Jak2 receptor-associated protein tyrosine kinases, phosphorylation of Tyr440 of the IFNg R1 intracellular domain, and phosphorylation and activation of STAT1a, the latent transcription factor. These events lead to transcription of regulatory genes called interferon-stimulated response elements that function as binding sites for transcription factors, including interferon consensus sequence-binding protein.6
| Table 1-Tel Hashomer Criteria for the Clinical Diagnosis of FMF10 |
| Major Criteria |
| • recurrent febrile episodes accompanied by peritonitis, synovitis, or pleuritis |
| • type AA amyloidosis without other predisposing disease |
| • response to colchicine maintenance |
| Minor Criteria |
| • recurrent febrile episodes |
| • erysipelas-like erythema |
| • FMF in a first-degree relative |
| Definite diagnosis: Two major or one major and two minor criteria |
| Probable diagnosis: One major and one minor criteria |
The function of the normal MEFV gene product appears to be analagous to a molecule called Jab/SOCS-I, a member of a family of proteins implicated in regulation of signal transduction by a number of cytokines.7 The product of this gene, which is inducible by IFNg, inhibits signal transduction by the Janus kinase (Jak) system, thus effecting a negative feedback loop on the IFNg-induced response.
There is evidence that (albeit not duplicated in all studies) the severity of disease correlates with the presence of specific mutations. Thus, E148Q appears to be associated with a milder disease phenotype, while M694V has been associated with more severe manifestations, including an increased risk of amyloidosis.8,9 However, environmental factors also play a role in disease expression; the number of attacks in Armenians living in Yerevan is significantly greater than among Armenians, with similar genotype distribution, living in the United States.9
At least 17 distinct missense mutations have been uncovered to date and mutations have been uncovered in the majority, but by no means all patients with FMF.10 Thus, while genetic analysis can be used to confirm the diagnosis, clinical criteria, such as the Tel Hashomer criteria, remain important (see Table 1). Furthermore, there are a number of other genetically determined periodic fevers that may resemble FMF (see Table 2). Additional diagnoses, such as Still’s disease, may have to be considered in some patients.
| Table 2-Inherited Periodic Fever Syndromes | |||
| Syndrome | Inheritance | Clinical Manifestations | Locus of Mutation |
| Familial Mediterranean Fever | Autosomal recessive11 | Fever, peritonitis, synovitis, erysipelas-like lesions, amyloidosis | Short arm of chromosome 16p, esp. 10, but also exons 2,3,5 |
| Hyperimmunoglobulinemia D & Periodic Fever Syndrome12,13 | Autosomal recessive | Lymphadenopathy, fever, abdominal pain, diarrhea, arthritis, vomiting, headache | Chromosome 12q24 between D12S330 and D12S79: candidate gene encodes mevalonate kinase |
| Benign Autosomal Dominant | Autosomal dominant | Fever, abdominal pain | 19 cM region on distal |
| Familial Periodic Fever14 | chromosome 12p13 | ||
| Familial Hibernian Fever; | Autosomal dominant | Fever, abdominal pain, myalgia, | Chromosome 12p13 |
| TNF Receptor Associated | dermatitis, conjunctivitis, | ||
| Py Syndrome (TRAPS)15,16 | periorbital edema | ||
| Familial Cold Urticaria17 | Autosomal dominant | Fever, arthralgias, | Chromosome 1q44 |
| conjunctivitis, urticaria | |||
| Muckle-Wells Syndrome18 | Autosomal dominant | Fever, abdominal pain, | Chromosome 1q44 |
| arthritis, urticaria, progressive | |||
| nerve deafness amyloidosis | |||
| *Autosomal dominant inheritance has also been reported | |||
References
1. Pras E, et al. Mapping of a gene causing familial Mediterranean fever. N Engl J Med 1992;326:1509-1513.
2. The International FMF Consortium. Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever. Cell 1997;90:797-807.
3. The French FMF Consortium. A candidate gene for familial Mediterranean fever. Nat Genet 1997;17:25-31.
4. Deresinski SC. Familial Mediterranean Fever in the genes: Blame Noah’s offspring. Infect Dis Alert 1998;17:141-142.
5. The Bible. Genesis 9:19; 10:221-22; 11:10-11.
6. Giese NA, et al. Interferon (IFN) consensus sequence-binding protein, a transcription factor of the IFN regulatory factor family, regulates immune responses in vivo through control of interleukin-12 expression. J Exp Med 1997;186:1535-1546.
7. Sakamoto H, et al. The janus kinase inhibitor, Jab/SOCS-1, is an interferon-gamma inducible gene and determines the sensitivity to interferons. Leuk Lymphoma 2000;38:49-58.
8. Stoffman N, et al. Higher than expected carrier rates for familial Mediterranean fever in various Jewish ethnic groups. Eur J Hum Genet 2000;8:307-310.
9. Mimouni A, et al. Familial Mediterranean fever: Effects of genotype and ethnicity on inflammatory attacks and amyloidosis. Pediatrics 2000;105:E70.
10. Grateau G, et al. Clinical versus genetic diagnosis of familial Mediterranean fever. Q J Med 2000;93:223-229.
11. Booth DR, et al. The genetic basis of autosomal dominant familial Mediterranean fever. Q J Med 2000; 93:217-221.
12. Drenth JP, et al. Hyperimmunoglobulinemia D and periodic fever syndrome. The clinical spectrum in a series of 50 patients. International Hyper-IgD Study Group. Medicine 1994;73:133-144.
13. Centola M, et al. The hereditary periodic fever syndromes: Molecular analysis of a new family of inflammatory diseases. Hum Mol Genet 1998;7:1581-1588.
14. Mulley J, et al. Gene localization for an autosomal dominant familial periodic fever to 12p13. Am J Hum Genet 1998;62:884-889.
15. McDermott MF, et al. Linkage of familial Hibernian fever to chromosome 12p13. Am J Hum Genet 1998; 62(6):1446-1451.
16. Drenth JP, et al. Mutations in the gene encoding mevalonate kinase cause hyper-IgD and periodic fever syndrome. International Hyper-IgD Study Group. Nat Genet 1999;22:178-181.
17. Hoffman HM, et al. Identification of a locus on chromosome 1q44 for familial cold urticaria. Am J Hum Genet 2000;66:1693-1698.
18. Cuisset L, et al. Genetic linkage of the muckle-wells syndrome to chromosome 1q44. Am J Hum Genet 1999;65:1054-1059.
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