Current Allergy and Asthma Reports

, Volume 7, Issue 5, pp 323–330

Hereditary immunologic disorders caused by pyrin and cryopyrin



A new family of hereditary immunologic disorders known as the autoinflammatory diseases involves dysregulation of the innate immune system. Elucidation of the genetic basis of these disorders has resulted in improved understanding of the disease pathophysiology of systemic and tissue inflammation, and has also revealed novel nonpathologic innate immune mechanisms. These advances have also resulted in direct improvement in diagnosis and therapy for autoinflammatory disorders such as the cryopyrinopathies and familial Mediterranean fever and have implications for more common inflammatory diseases.


Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References and Recommended Reading

  1. 1.
    Austen KF: Inborn and acquired abnormalities of the complement system of man. Johns Hopkins Med J 1971, 128:57–74.PubMedGoogle Scholar
  2. 2.
    Curnutte JT, Babior BM: Chronic granulomatous disease. Adv Hum Genet 1987, 16:229–297.PubMedGoogle Scholar
  3. 3.
    Conley ME: Primary immunodeficiencies: a flurry of new genes. Immunol Today 1995, 16:313–315.PubMedCrossRefGoogle Scholar
  4. 4.
    Bonilla FA, Geha RS: 2. Update on primary immunodeficiency diseases. J Allergy Clin Immunol 2006, 117:S435–441.PubMedCrossRefGoogle Scholar
  5. 5.
    Brydges S, Kastner DL: The systemic autoinflammatory diseases: inborn errors of the innate immune system. Curr Top Microbiol Immunol 2006, 305:127–160.PubMedCrossRefGoogle Scholar
  6. 6.
    French FMF Consortium: A candidate gene for familial Mediterranean fever. The French FMF Consortium. Nat Genet 1997, 17:25–31.CrossRefGoogle Scholar
  7. 7.
    International FMF Consortium: Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever. The International FMF Consortium. Cell 1997, 90:797–807.CrossRefGoogle Scholar
  8. 8.
    Hoffman HM, Mueller JL, Broide DH, et al.: Mutation of a new gene encoding a putative pyrin-like protein cause familial cold autoinflammatory syndrome and Muckle-Wells syndrome. Nat Genet 2001, 29:301–305.PubMedCrossRefGoogle Scholar
  9. 9.
    Beutler B: The Toll-like receptors: analysis by forward genetic methods. Immunogenetics 2005, 57:385–392.PubMedCrossRefGoogle Scholar
  10. 10.
    Medzhitov R, Preston-Hurlburt P, Janeway CA Jr: A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature 1997, 388:394–397.PubMedCrossRefGoogle Scholar
  11. 11.
    Harton JA, Linhoff MW, Zhang J, Ting JP: Cutting edge: CATERPILLER: a large family of mammalian genes containing CARD, pyrin, nucleotide-binding, and leucine-rich repeat domains. J Immunol 2002, 169:4088–4093.PubMedGoogle Scholar
  12. 12.
    Inohara N, Nunez G: NODs: intracellular proteins involved in inflammation and apoptosis. Nat Rev Immunol 2003, 3:371–382.PubMedCrossRefGoogle Scholar
  13. 13.
    Tschopp J, Martinon F, Burns K: NALPs: a novel protein family involved in inflammation. Nat Rev Mol Cell Biol 2003, 4:95–104.PubMedCrossRefGoogle Scholar
  14. 14.
    Bertin J, DiStefano PS: The PYRIN domain: a novel motif found in apoptosis and inflammation proteins. Cell Death Differ 2000, 7:1273–1274.PubMedCrossRefGoogle Scholar
  15. 15.
    Ting JP, Kastner DL, Hoffman HM: CATERPILLERs, pyrin and hereditary immunological disorders. Nat Rev Immunol 2006, 6:183–195.PubMedCrossRefGoogle Scholar
  16. 16.
    Ausubel FM: Are innate immune signaling pathways in plants and animals conserved? Nat Immunol 2005, 6:973–979.PubMedCrossRefGoogle Scholar
  17. 17.
    Belkhadir Y, Subramaniam R, Dangl JL: Plant disease resistance protein signaling: NBS-LRR proteins and their partners. Curr Opin Plant Biol 2004, 7:391–399.PubMedCrossRefGoogle Scholar
  18. 18.
    da Silva Correia J, Miranda Y, Leonard N, Ulevitch R: SGT1 is essential for Nod1 activation. Proc Natl Acad Sci U S A 2007.Google Scholar
  19. 19.
    Martinon F, Tschopp J: NLRs join TLRs as innate sensors of pathogens. Trends Immunol 2005, 26:447–454.PubMedCrossRefGoogle Scholar
  20. 20.
    Ting JP, Trowsdale J: Genetic control of MHC class II expression. Cell 2002, 109(Suppl):S21–33.PubMedCrossRefGoogle Scholar
  21. 21.
    Swanberg M, Lidman O, Padyukov L, et al.: MHC2TA is associated with differential MHC molecule expression and susceptibility to rheumatoid arthritis, multiple sclerosis and myocardial infarction. Nat Genet 2005, 37:486–494.PubMedCrossRefGoogle Scholar
  22. 22.
    Rosenstiel P, Till A, Schreiber S: NOD-like receptors and human diseases. Microbes and Infection 2007, In press.Google Scholar
  23. 23.
    Jin Y, Mailloux CM, Gowan K, et al.: NALP1 in vitiligo-associated multiple autoimmune disease. N Engl J Med 2007, 356, 1216–1225.PubMedCrossRefGoogle Scholar
  24. 24.
    Hoffman HM, Gregory SG, Mueller JL, et al.: Fine structure mapping of CIAS1: identification of an ancestral haplotype and a common FCAS mutation, L353P. Hum Genet 2003, 112:209–216.PubMedGoogle Scholar
  25. 25.
    Hoffman HM, Wanderer AA, Broide DH: Familial cold autoinflammatory syndrome: phenotype and genotype of an autosomal dominant periodic fever. J Allergy Clin Immunol 2001, 108:615–620.PubMedCrossRefGoogle Scholar
  26. 26.
    Muckle TJ: The ‘Muckle-Wells’ syndrome. Br J Dermatol 1979, 100:87–92.PubMedCrossRefGoogle Scholar
  27. 27.
    Prieur AM, Griscelli C, Lampert F, et al.: A chronic, infantile, neurological, cutaneous and articular (CINCA) syndrome. A specific entity analysed in 30 patients. Scand J Rheumatol Suppl 1987, 66:57–68.PubMedGoogle Scholar
  28. 28.
    Hawkins PN, Lachmann HJ, Aganna E, McDermott MF: Spectrum of clinical features in Muckle-Wells syndrome and response to anakinra. Arthritis Rheum 2004, 50:607–612.PubMedCrossRefGoogle Scholar
  29. 29.
    Aksentijevich I, Nowak M, Mallah 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, 46:3340–3348.PubMedCrossRefGoogle Scholar
  30. 30.
    Hentgen V, Despert V, Lepretre AC, et al.: Intrafamilial variable phenotypic expression of a CIAS1 mutation: from Muckle-Wells to chronic infantile neurological cutaneous and articular syndrome. J Rheumatol 2005, 32:747–751.PubMedGoogle Scholar
  31. 31.
    Feldmann J, Prieur AM, Quartier P, et al.: Chronic infantile neurological cutaneous and articular syndrome is caused by mutations in CIAS1, a gene highly expressed in polymorphonuclear cells and chondrocytes. Am J Hum Genet 2002, 71:198–203.PubMedCrossRefGoogle Scholar
  32. 32.
    Aksentijevich I, D Putnam C, Remmers EF, et al.: The clinical continuum of cryopyrinopathies: Novel CIAS1 mutations in North American patients and a new cryopyrin model. Arthritis Rheum 2007, 56:1273–1285.PubMedCrossRefGoogle Scholar
  33. 33.
    Anderson JP, Mueller JL, Rosengren S, et al.: Structural, expression, and evolutionary analysis of mouse CIAS1. Gene 2004, 338:25–34.PubMedCrossRefGoogle Scholar
  34. 34.
    Manji GA, Wang L, Geddes BJ, et al.: PYPAF1: A PYRIN-containing Apaf1-like protein that assembles with ASC and regulates activation of NF-kB. J Biol Chem 2002, 277:11570–11575.PubMedCrossRefGoogle Scholar
  35. 35.
    Kummer JA, Broekhuizen R, Everett H, et al.: Inflammasome components NALP 1 and 3 show distinct but separate expression profiles in human tissues suggesting a site-specific role in the inflammatory response. J Histochem Cytochem 2007, 55:443–452.PubMedCrossRefGoogle Scholar
  36. 36.
    Rosengren S, Hoffman HM, Bugbee W, Boyle DL: Expression and regulation of cryopyrin and related proteins in rheumatoid arthritis synovium. Ann Rheum Dis. 2005, 64:708–714.PubMedCrossRefGoogle Scholar
  37. 37.
    Martinon F, Burns K, Tschopp J: The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol Cell 2002, 10:417–426.PubMedCrossRefGoogle Scholar
  38. 38.
    Grahames CB, Michel AD, Chessell IP, Humphrey PP: Pharmacological characterization of ATP-and LPS-induced IL-1beta release in human monocytes. Br J Pharmacol 1999, 127:1915–1921.PubMedCrossRefGoogle Scholar
  39. 39.
    Mariathasan S, Monack DM: Inflammasome adaptors and sensors: intracellular regulators of infection and inflammation. Nat Rev Immunol 2007, 7:31–40.PubMedCrossRefGoogle Scholar
  40. 40.
    Martinon F, Agostini L, Meylan E, Tschopp J: Identification of bacterial muramyl dipeptide as activator of the NALP3/cryopyrin inflammasome. Curr Biol 2004, 14:1929–1934.PubMedCrossRefGoogle Scholar
  41. 41.
    Pan Q, Mathison J, Fearns C, et al.: MDP-induced interleukin-1{beta} processing requires Nod2 and CIAS1/NALP3. J Leukoc Biol 2007, Epub ahead of print.Google Scholar
  42. 42.
    Agostini L, Martinon F, Burns K, et al.: NALP3 forms an IL-1beta-processing inflammasome with increased activity in Muckle-Wells autoinflammatory disorder. Immunity 2004, 20:319–325.PubMedCrossRefGoogle Scholar
  43. 43.
    Stack JH, Beaumont K, Larsen PD, et al.: ICE/caspase-1 inhibitor VX-765 blocks the hypersensitive response to an inflammatory stimulus in monocytes from FCAS patients. J Immunol 2005, 175:2630–2634.PubMedGoogle Scholar
  44. 44.
    Dowds TA, Masumoto J, Chen FF, et al.: Regulation of cryopyrin/Pypaf1 signaling by pyrin, the familial Mediterranean fever gene product. Biochem Biophys Res Commun 2003, 302:575–580.PubMedCrossRefGoogle Scholar
  45. 45.
    Fujisawa A, Kambe N, Saito M, et al.: Disease-associated mutations in CIAS1 induce cathepsin B-dependent rapid cell death of human THP-1 monocytic cells. Blood 2006.Google Scholar
  46. 46.
    Goldbach-Mansky R, Dailey NJ, Canna SW, et al.: Neonatal-onset multisystem inflammatory disease responsive to interleukin-1beta inhibition. N Engl J Med 2006, 355:581–592.PubMedCrossRefGoogle Scholar
  47. 47.
    Hawkins PN, Lachmann HJ, McDermott MF: Interleukin-1-receptor antagonist in the Muckle-Wells syndrome. N Engl J Med 2003, 348:2583–2584.PubMedCrossRefGoogle Scholar
  48. 48.
    Hoffman HM, Rosengren S, Boyle DL, et al.: Prevention of cold-associated acute inflammation in familial cold autoinflammatory syndrome by interleukin-1 receptor antagonist. Lancet 2004, 364:1779–1785.PubMedCrossRefGoogle Scholar
  49. 49.
    Kastner DL: Familial Mediterranean fever: the genetics of inflammation. Hosp Pract (Off Ed) 1998, 33:131–134, 139–140, 143–136 passim.Google Scholar
  50. 50.
    Samuels J, Ozen S: Familial Mediterranean fever and the other autoinflammatory syndromes: evaluation of the patient with recurrent fever. Curr Opin Rheumatol 2006, 18:108–117.PubMedCrossRefGoogle Scholar
  51. 51.
    Stojanov S, Kastner DL: Familial autoinflammatory diseases: genetics, pathogenesis and treatment. Curr Opin Rheumatol 2005, 17:586–599.PubMedCrossRefGoogle Scholar
  52. 52.
    Schaner P, Richards N, Wadhwa A, et al.: Episodic evolution of pyrin in primates: human mutations recapitulate ancestral amino acid states. Nat Genet 2001, 27:318–321.PubMedCrossRefGoogle Scholar
  53. 53.
    Chae JJ, Wood G, Masters SL, 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, 103:9982–9987.PubMedCrossRefGoogle Scholar
  54. 54.
    Papin S, Cuenin S, Agostini L, 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.Google Scholar
  55. 55.
    Niel E, Scherrmann JM: Colchicine today. Joint Bone Spine 2006, 73:672–678.PubMedCrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2007

Authors and Affiliations

  1. 1.Division of Rheumatology, Allergy, and ImmunologyUniversity of California at San Diego Medical SchoolLa JollaUSA

Personalised recommendations