Skip to main content
SpringerLink
Log in

Pathogenesis

  • Chapter
Familial Mediterranean Fever

Part of the book series: Rare Diseases of the Immune System ((RDIS,volume 3))

Abstract

Since its recognition as a distinct illness with a genetic basis, FMF has held a special fascination for students of human biology. The disease is remarkable not only for its sudden, dramatic inflammatory attacks and predilection for systemic amyloidosis, but for the sometimes extended periods of apparent quiescence that punctuate its clinical course. How could mutations in some hypothetical gene cause such profound suffering, but only on an intermittent, at times periodic, basis? It seemed that the answer would surely hold some fundamental insight into the regulation of human inflammation.

This is a preview of subscription content, log in via an institution to check access.

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 89.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 119.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 119.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

References

  1. Agostini L, Martinon F, et al. NALP3 forms an IL-1beta-processing inflammasome with increased activity in Muckle-Wells autoinflammatory disorder. Immunity. 2004;20(3):319–25.

    Article  CAS  PubMed  Google Scholar 

  2. Aksentijevich I, Nowak M, et al. De novo CIAS1 mutations, cytokine activation, and evidence for genetic heterogeneity in patients with neonatal-onset multisystem inflammatory disease (NOMID): a new member of the expanding family of pyrin-associated autoinflammatory diseases. Arthritis Rheum. 2002;46(12):3340–8.

    Article  CAS  PubMed  Google Scholar 

  3. Aldea A, Campistol JM, et al. A severe autosomal-dominant periodic inflammatory disorder with renal AA amyloidosis and colchicine resistance associated to the MEFV H478Y variant in a Spanish kindred: an unusual familial Mediterranean fever phenotype or another MEFV-associated periodic inflammatory disorder? Am J Med Genet A. 2004;124A(1):67–73.

    Article  PubMed  Google Scholar 

  4. Ayesh SK, Azar Y, et al. Purification and characterization of a C5a-inactivating enzyme from human peritoneal fluid. Blood. 1995;85(12):3503–9.

    CAS  PubMed  Google Scholar 

  5. Bae JY, Park HH. Crystal structure of NALP3 protein pyrin domain (PYD) and its implications in inflammasome assembly. J Biol Chem. 2011;286(45):39528–36.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  6. Balci-Peynircioglu B, Waite AL, et al. Pyrin, product of the MEFV locus, interacts with the proapoptotic protein, Siva. J Cell Physiol. 2008;216(3):595–602.

    Article  CAS  PubMed  Google Scholar 

  7. Belkhir R, Moulonguet-Doleris L, et al. Treatment of familial Mediterranean fever with anakinra. Ann Intern Med. 2007;146(11):825–6.

    Article  PubMed  Google Scholar 

  8. Bertin J, DiStefano PS. The PYRIN domain: a novel motif found in apoptosis and inflammation proteins. Cell Death Differ. 2000;7(12):1273–4.

    Article  CAS  PubMed  Google Scholar 

  9. Booth DR, Gillmore JD, et al. The genetic basis of autosomal dominant familial Mediterranean fever. Q J Med. 2000;93(4):217–21.

    Article  CAS  Google Scholar 

  10. Booty MG, Chae JJ, et al. Familial Mediterranean fever with a single MEFV mutation: where is the second hit? Arthritis Rheum. 2009;60(6):1851–61.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  11. Borden KL. RING fingers and B-boxes: zinc-binding protein-protein interaction domains. Biochem Cell Biol Biochimie et biologie cellulaire. 1998;76(2–3):351–8.

    Article  CAS  Google Scholar 

  12. Calligaris L, Marchetti F, et al. The efficacy of anakinra in an adolescent with colchicine-resistant familial Mediterranean fever. Eur J Pediatr. 2008;167(6):695–6.

    Article  PubMed Central  PubMed  Google Scholar 

  13. Centola M, Aksentijevich I, et al. The hereditary periodic fever syndromes: molecular analysis of a new family of inflammatory diseases. Hum Mol Genet. 1998;7(10):1581–8.

    Article  CAS  PubMed  Google Scholar 

  14. Centola M, Wood G, 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(10):3223–31.

    CAS  PubMed  Google Scholar 

  15. Chae JJ, Aksentijevich I, et al. Advances in the understanding of familial Mediterranean fever and possibilities for targeted therapy. Br J Haematol. 2009;146(5):467–78.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  16. Chae JJ, Cho YH, et al. Gain-of-function pyrin mutations induce NLRP3 protein-independent interleukin-1beta activation and severe autoinflammation in mice. Immunity. 2011;34(5):755–68.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  17. Chae JJ, Komarow HD, et al. Targeted disruption of pyrin, the FMF protein, causes heightened sensitivity to endotoxin and a defect in macrophage apoptosis. Mol Cell. 2003;11(3):591–604.

    Article  CAS  PubMed  Google Scholar 

  18. Chae JJ, Wood G, et al. The B30.2 domain of pyrin, the familial Mediterranean fever protein, interacts directly with caspase-1 to modulate IL-1beta production. Proc Natl Acad Sci U S A. 2006;103(26):9982–7.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  19. Chae JJ, Wood G, et al. The familial Mediterranean fever protein, pyrin, is cleaved by caspase-1 and activates NF-kappaB through its N-terminal fragment. Blood. 2008;112(5):1794–803.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  20. de Zoete MR, Flavell RA. Detecting “different”: pyrin senses modified GTPases. Cell Res. 2014;24:1286–7.

    Article  PubMed  Google Scholar 

  21. Diaz A, Hu C, et al. Lipopolysaccharide-induced expression of multiple alternatively spliced MEFV transcripts in human synovial fibroblasts: a prominent splice isoform lacks the C-terminal domain that is highly mutated in familial Mediterranean fever. Arthritis Rheum. 2004;50(11):3679–89.

    Article  CAS  PubMed  Google Scholar 

  22. Dinarello CA. Biologic basis for interleukin-1 in disease. Blood. 1996;87(6):2095–147.

    CAS  PubMed  Google Scholar 

  23. Dowds TA, Masumoto J, et al. Regulation of cryopyrin/pypaf1 signaling by pyrin, the familial Mediterranean fever gene product. Biochem Biophys Res Commun. 2003;302(3):575–80.

    Article  CAS  PubMed  Google Scholar 

  24. Dumas A, Amiable N, et al. The inflammasome pyrin contributes to pertussis toxin-induced IL-1beta synthesis, neutrophil intravascular crawling and autoimmune encephalomyelitis. PLoS Pathog. 2014;10(5):e1004150.

    Article  PubMed Central  PubMed  Google Scholar 

  25. Everett RD, Chelbi-Alix MK. PML and PML nuclear bodies: implications in antiviral defence. Biochimie. 2007;89(6–7):819–30.

    Article  CAS  PubMed  Google Scholar 

  26. Fairbrother WJ, Gordon NC, et al. The PYRIN domain: a member of the death domain-fold superfamily. Protein Sci. 2001;10(9):1911–8.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  27. Faustin B, Lartigue L, et al. Reconstituted NALP1 inflammasome reveals two-step mechanism of caspase-1 activation. Mol Cell. 2007;25(5):713–24.

    Article  CAS  PubMed  Google Scholar 

  28. French FMF Consortium. A candidate gene for familial Mediterranean fever. Nat Genet. 1997;17(1):25–31.

    Article  Google Scholar 

  29. Gavrilin MA, Abdelaziz DH, et al. Activation of the pyrin inflammasome by intracellular Burkholderia cenocepacia. J Immunol. 2012;188(7):3469–77.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  30. Gavrilin MA, Mitra S, et al. Pyrin critical to macrophage IL-1beta response to Francisella challenge. J Immunol. 2009;182(12):7982–9.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  31. Goldbach-Mansky R, Dailey NJ, et al. Neonatal-onset multisystem inflammatory disease responsive to interleukin-1beta inhibition. N Engl J Med. 2006;355(6):581–92.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  32. Grutter C, Briand C, et al. Structure of the PRYSPRY-domain: implications for autoinflammatory diseases. FEBS Lett. 2006;580(1):99–106.

    Article  PubMed  Google Scholar 

  33. Hashkes PJ, Spalding SJ, et al. Rilonacept for colchicine-resistant or -intolerant familial Mediterranean fever: a randomized trial. Ann Intern Med. 2012;157(8):533–41.

    Article  PubMed  Google Scholar 

  34. Hawkins PN, Lachmann HJ, et al. Interleukin-1-receptor antagonist in the Muckle-Wells syndrome. N Engl J Med. 2003;348(25):2583–4.

    Article  PubMed  Google Scholar 

  35. Henry J, Mather IH, et al. B30.2-like domain proteins: update and new insights into a rapidly expanding family of proteins. Mol Biol Evol. 1998;15(12):1696–705.

    Article  CAS  PubMed  Google Scholar 

  36. Hesker PR, Nguyen M, et al. Genetic loss of murine pyrin, the Familial Mediterranean Fever protein, increases interleukin-1beta levels. PLoS One. 2012;7(11):e51105.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  37. Hoffman HM, Mueller JL, et al. Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle-Wells syndrome. Nat Genet. 2001;29(3):301–5.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  38. Hoffman HM, Rosengren S, et al. Prevention of cold-associated acute inflammation in familial cold autoinflammatory syndrome by interleukin-1 receptor antagonist. Lancet. 2004;364(9447):1779–85.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  39. 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(4):797–807.

    Article  Google Scholar 

  40. Javanbakht H, Yuan W, et al. Characterization of TRIM5alpha trimerization and its contribution to human immunodeficiency virus capsid binding. Virology. 2006;353(1):234–46.

    Article  CAS  PubMed  Google Scholar 

  41. Jeru I, Papin S, et al. Interaction of pyrin with 14.3.3 in an isoform-specific and phosphorylation-dependent manner regulates its translocation to the nucleus. Arthritis Rheum. 2005;52(6):1848–57.

    Article  CAS  PubMed  Google Scholar 

  42. Keller M, Ruegg A, et al. Active caspase-1 is a regulator of unconventional protein secretion. Cell. 2008;132(5):818–31.

    Article  CAS  PubMed  Google Scholar 

  43. Kersse K, Verspurten J, et al. The death-fold superfamily of homotypic interaction motifs. Trends Biochem Sci. 2011;36(10):541–52.

    Article  CAS  PubMed  Google Scholar 

  44. Kuijk LM, Govers AM, et al. Effective treatment of a colchicine-resistant familial Mediterranean fever patient with anakinra. Ann Rheum Dis. 2007;66(11):1545–6.

    Article  PubMed Central  PubMed  Google Scholar 

  45. Lachmann HJ, Sengul B, et al. Clinical and subclinical inflammation in patients with familial Mediterranean fever and in heterozygous carriers of MEFV mutations. Rheumatology (Oxford). 2006;45(6):746–50.

    Article  CAS  Google Scholar 

  46. Lee GS, Subramanian N, et al. The calcium-sensing receptor regulates the NLRP3 inflammasome through Ca2+ and cAMP. Nature. 2012;492(7427):123–7.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  47. Liepinsh E, Barbals R, et al. The death-domain fold of the ASC PYRIN domain, presenting a basis for PYRIN/PYRIN recognition. J Mol Biol. 2003;332(5):1155–63.

    Article  CAS  PubMed  Google Scholar 

  48. Mansfield E, Chae JJ, et al. The familial Mediterranean fever protein, pyrin, associates with microtubules and colocalizes with actin filaments. Blood. 2001;98(3):851–9.

    Article  CAS  PubMed  Google Scholar 

  49. Marek-Yagel D, Berkun Y, et al. Clinical disease among patients heterozygous for familial Mediterranean fever. Arthritis Rheum. 2009;60(6):1862–6.

    Article  CAS  PubMed  Google Scholar 

  50. Mariathasan S, Newton K, et al. Differential activation of the inflammasome by caspase-1 adaptors ASC and Ipaf. Nature. 2004;430(6996):213–8.

    Article  CAS  PubMed  Google Scholar 

  51. Martinon F, Burns K, et al. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol Cell. 2002;10(2):417–26.

    Article  CAS  PubMed  Google Scholar 

  52. Martinon F, Hofmann K, et al. The pyrin domain: a possible member of the death domain-fold family implicated in apoptosis and inflammation. Curr Biol. 2001;11(4):R118–20.

    Article  CAS  PubMed  Google Scholar 

  53. Masters SL, Simon A, et al. Horror autoinflammaticus: the molecular pathophysiology of autoinflammatory disease (*). Annu Rev Immunol. 2009;27:621–68.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  54. Masumoto J, Dowds TA, et al. ASC is an activating adaptor for NF-kappa B and caspase-8-dependent apoptosis. Biochem Biophys Res Commun. 2003;303(1):69–73.

    Article  CAS  PubMed  Google Scholar 

  55. Masumoto J, Taniguchi S, et al. ASC, a novel 22-kDa protein, aggregates during apoptosis of human promyelocytic leukemia HL-60 cells. J Biol Chem. 1999;274(48):33835–8.

    Article  CAS  PubMed  Google Scholar 

  56. Omenetti A, Carta S, et al. Increased NLRP3-dependent interleukin 1beta secretion in patients with familial Mediterranean fever: correlation with MEFV genotype. Ann Rheum Dis. 2014;73(2):462–9.

    Article  CAS  PubMed  Google Scholar 

  57. Papin S, Cuenin S, et al. The SPRY domain of Pyrin, mutated in familial Mediterranean fever patients, interacts with inflammasome components and inhibits proIL-1beta processing. Cell Death Differ. 2007;14(8):1457–66.

    Article  CAS  PubMed  Google Scholar 

  58. Papin S, Duquesnoy P, et al. Alternative splicing at the MEFV locus involved in familial Mediterranean fever regulates translocation of the marenostrin/pyrin protein to the nucleus. Hum Mol Genet. 2000;9(20):3001–9.

    Article  CAS  PubMed  Google Scholar 

  59. Pawlowski K, Pio F, et al. PAAD – a new protein domain associated with apoptosis, cancer and autoimmune diseases. Trends Biochem Sci. 2001;26(2):85–7.

    Article  CAS  PubMed  Google Scholar 

  60. Reddy BA, Etkin LD, et al. A novel zinc finger coiled-coil domain in a family of nuclear proteins. Trends Biochem Sci. 1992;17(9):344–5.

    Article  CAS  PubMed  Google Scholar 

  61. Reymond A, Meroni G, et al. The tripartite motif family identifies cell compartments. EMBO J. 2001;20(9):2140–51.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  62. Richards N, Schaner P, et al. Interaction between pyrin and the apoptotic speck protein (ASC) modulates ASC-induced apoptosis. J Biol Chem. 2001;276(42):39320–9.

    Article  CAS  PubMed  Google Scholar 

  63. Roldan R, Ruiz AM, et al. Anakinra: new therapeutic approach in children with Familial Mediterranean Fever resistant to colchicine. Joint Bone Spine. 2008;75(4):504–5.

    Article  PubMed  Google Scholar 

  64. Schroder K, Tschopp J. The inflammasomes. Cell. 2010;140(6):821–32.

    Article  CAS  PubMed  Google Scholar 

  65. Seshadri S, Duncan MD, et al. Pyrin levels in human monocytes and monocyte-derived macrophages regulate IL-1beta processing and release. J Immunol. 2007;179(2):1274–81.

    Article  CAS  PubMed  Google Scholar 

  66. Shoham NG, Centola M, et al. Pyrin binds the PSTPIP1/CD2BP1 protein, defining familial Mediterranean fever and PAPA syndrome as disorders in the same pathway. Proc Natl Acad Sci U S A. 2003;100(23):13501–6.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  67. Shumway SD, Maki M, et al. The PEST domain of IkappaBalpha is necessary and sufficient for in vitro degradation by mu-calpain. J Biol Chem. 1999;274(43):30874–81.

    Article  CAS  PubMed  Google Scholar 

  68. Sohar E, Gafni J, et al. Familial Mediterranean fever. A survey of 470 cases and review of the literature. Am J Med. 1967;43(2):227–53.

    Article  CAS  PubMed  Google Scholar 

  69. Staub E, Dahl E, et al. The DAPIN family: a novel domain links apoptotic and interferon response proteins. Trends Biochem Sci. 2001;26(2):83–5.

    Article  CAS  PubMed  Google Scholar 

  70. Stehlik C, Fiorentino L, et al. The PAAD/PYRIN-family protein ASC is a dual regulator of a conserved step in nuclear factor kappaB activation pathways. J Exp Med. 2002;196(12):1605–15.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  71. Touitou I. The spectrum of Familial Mediterranean Fever (FMF) mutations. Eur J Hum Genet. 2001;9(7):473–83.

    Article  CAS  PubMed  Google Scholar 

  72. Tschopp J, Schroder K. “NLRP3 inflammasome activation: the convergence of multiple signalling pathways on ROS production?” Nature reviews. Immunology. 2010;10(3):210–5.

    CAS  PubMed  Google Scholar 

  73. Wen H, Miao EA, et al. Mechanisms of NOD-like receptor-associated inflammasome activation. Immunity. 2013;39(3):432–41.

    Article  CAS  PubMed  Google Scholar 

  74. Wise CA, Gillum JD, et al. Mutations in CD2BP1 disrupt binding to PTP PEST and are responsible for PAPA syndrome, an autoinflammatory disorder. Hum Mol Genet. 2002;11(8):961–9.

    Article  CAS  PubMed  Google Scholar 

  75. Xu H, Yang J, et al. Innate immune sensing of bacterial modifications of Rho GTPases by the pyrin inflammasome. Nature. 2014;513(7517):237–41.

    Article  CAS  PubMed  Google Scholar 

  76. Yu JW, Fernandes-Alnemri T, et al. Pyrin activates the ASC pyroptosome in response to engagement by autoinflammatory PSTPIP1 mutants. Mol Cell. 2007;28(2):214–27.

    Article  PubMed Central  CAS  PubMed  Google Scholar 

  77. Yu JW, Wu J, et al. Cryopyrin and pyrin activate caspase-1, but not NF-kappaB, via ASC oligomerization. Cell Death Differ. 2006;13(2):236–49.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. National Human Genome Research Institute, National Institutes of Health, Bethesda, USA

    Jae Jin Chae & Daniel L. Kastner

Authors
  1. Jae Jin Chae
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Daniel L. Kastner
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Jae Jin Chae .

Editor information

Editors and Affiliations

  1. II Paediatric Unit-Rheumatology, G. Gaslini Institute, Genova, Genova, Italy

    Marco Gattorno

Rights and permissions

Reprints and permissions

Copyright information

© 2015 Springer International Publishing Switzerland

About this chapter

Cite this chapter

Chae, J.J., Kastner, D.L. (2015). Pathogenesis. In: Gattorno, M. (eds) Familial Mediterranean Fever. Rare Diseases of the Immune System, vol 3. Springer, Cham. https://doi.org/10.1007/978-3-319-14615-7_2

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-14615-7_2

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-14614-0

  • Online ISBN: 978-3-319-14615-7

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation