Patients with autoinflammatory diseases present with noninfectious fever flares and systemic and/or disease-specific organ inflammation. Their excessive proinflammatory cytokine and chemokine responses can be life threatening and lead to organ damage over time. Studying such patients has revealed genetic defects that have helped unravel key innate immune pathways, including excessive IL-1 signaling, constitutive NF-κB activation, and, more recently, chronic type I IFN signaling. Discoveries of monogenic defects that lead to activation of proinflammatory cytokines have inspired the use of anticytokine-directed treatment approaches that have been life changing for many patients and have led to the approval of IL-1-blocking agents for a number of autoinflammatory conditions. In this review, we describe the genetically characterized autoinflammatory diseases, we summarize our understanding of the molecular pathways that drive clinical phenotypes and that continue to inspire the search for novel treatment targets, and we provide a conceptual framework for classification.


Article metrics loading...

Loading full text...

Full text loading...


Literature Cited

  1. McDermott MF, Aksentijevich I, Galon J, McDermott EM, Ogunkolade BW. 1.  et al. 1999. Germline mutations in the extracellular domains of the 55 kDa TNF receptor, TNFR1, define a family of dominantly inherited autoinflammatory syndromes. Cell 97:133–44 [Google Scholar]
  2. Janeway CA Jr. 2.  1989. Approaching the asymptote? Evolution and revolution in immunology. Cold Spring Harb. Symp. Quant. Biol. 54:Part 11–13 [Google Scholar]
  3. Matzinger P. 3.  1994. Tolerance, danger, and the extended family. Annu. Rev. Immunol. 12:991–1045 [Google Scholar]
  4. Wen H, Miao EA, Ting JP. 4.  2013. Mechanisms of NOD-like receptor-associated inflammasome activation. Immunity 39:432–41 [Google Scholar]
  5. Wu J, Chen ZJ. 5.  2014. Innate immune sensing and signaling of cytosolic nucleic acids. Annu. Rev. Immunol. 32:461–88 [Google Scholar]
  6. Kawai T, Akira S. 6.  2011. Toll-like receptors and their crosstalk with other innate receptors in infection and immunity. Immunity 34:637–50 [Google Scholar]
  7. Medzhitov R, Preston-Hurlburt P, Janeway CA Jr. 7.  1997. A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature 388:394–97 [Google Scholar]
  8. 8. International FMF Consortium 1997. Ancient missense mutations in a new member of the RoRet gene family are likely to cause familial Mediterranean fever. Cell 90:797–807 [Google Scholar]
  9. 9. French FMF Consortium 1997. A candidate gene for familial Mediterranean fever. Nat. Genet. 17:25–31 [Google Scholar]
  10. Ting JP, Kastner DL, Hoffman HM. 10.  2006. CATERPILLERs, pyrin and hereditary immunological disorders. Nat. Rev. Immunol. 6:183–95 [Google Scholar]
  11. Hoffman HM, Mueller JL, Broide DH, Wanderer AA, Kolodner RD. 11.  2001. Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle-Wells syndrome. Nat. Genet. 29:301–5 [Google Scholar]
  12. Aksentijevich I, Nowak M, Mallah M, Chae JJ, Watford WT. 12.  et al. 2002. 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 Rheumatol. 46:3340–48 [Google Scholar]
  13. Feldmann J, Prieur AM, Quartier P, Berquin P, Certain S. 13.  et al. 2002. 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. 71:198–203 [Google Scholar]
  14. Miceli-Richard C, Lesage S, Rybojad M, Prieur AM, Manouvrier-Hanu S. 14.  et al. 2001. CARD15 mutations in Blau syndrome. Nat. Genet. 29:19–20 [Google Scholar]
  15. Wang L, Manji GA, Grenier JM, Al-Garawi A, Merriam S. 15.  et al. 2002. PYPAF7, a novel PYRIN-containing Apaf1-like protein that regulates activation of NF-κB and caspase-1-dependent cytokine processing. J. Biol. Chem. 277:29874–80 [Google Scholar]
  16. Martinon F, Burns K, Tschopp J. 16.  2002. The inflammasome: a molecular platform triggering activation of inflammatory caspases and processing of proIL-beta. Mol. Cell 10:417–26 [Google Scholar]
  17. Yoneyama M, Kikuchi M, Natsukawa T, Shinobu N, Imaizumi T. 17.  et al. 2004. The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses. Nat. Immunol. 5:730–37 [Google Scholar]
  18. Yoneyama M, Kikuchi M, Matsumoto K, Imaizumi T, Miyagishi M. 18.  et al. 2005. Shared and unique functions of the DExD/H-box helicases RIG-I, MDA5, and LGP2 in antiviral innate immunity. J. Immunol. 175:2851–58 [Google Scholar]
  19. Atianand MK, Fitzgerald KA. 19.  2013. Molecular basis of DNA recognition in the immune system. J. Immunol. 190:1911–18 [Google Scholar]
  20. Rice GI, del Toro Duany Y, Jenkinson EM, Forte GM, Anderson BH. 20.  et al. 2014. Gain-of-function mutations in IFIH1 cause a spectrum of human disease phenotypes associated with upregulated type I interferon signaling. Nat. Genet. 46:503–9 [Google Scholar]
  21. Liu Y, Jesus AA, Marrero B, Yang D, Ramsey SE. 21.  et al. 2014. Activated STING in a vascular and pulmonary syndrome. N. Engl. J. Med. 371:507–18 [Google Scholar]
  22. Medzhitov R. 22.  2008. Origin and physiological roles of inflammation. Nature 454:428–35 [Google Scholar]
  23. Lamkanfi M, Dixit VM. 23.  2014. Mechanisms and functions of inflammasomes. Cell 157:1013–22 [Google Scholar]
  24. Jesus AA, Goldbach-Mansky R. 24.  2014. IL-1 blockade in autoinflammatory syndromes. Annu. Rev. Med. 65:223–44 [Google Scholar]
  25. Aksentijevich I, Masters SL, Ferguson PJ, Dancey P, Frenkel J. 25.  et al. 2009. An autoinflammatory disease with deficiency of the interleukin-1-receptor antagonist. N. Engl. J. Med. 360:2426–37 [Google Scholar]
  26. Reddy S, Jia S, Geoffrey R, Lorier R, Suchi M. 26.  et al. 2009. An autoinflammatory disease due to homozygous deletion of the IL1RN locus. N. Engl. J. Med. 360:2438–44 [Google Scholar]
  27. Glocker EO, Kotlarz D, Klein C, Shah N, Grimbacher B. 27.  2011. IL-10 and IL-10 receptor defects in humans. Ann. N.Y. Acad. Sci. 1246:102–7 [Google Scholar]
  28. Eitel J, Suttorp N, Opitz. 28.  2011. Innate immune recognition and inflammasome activation in Listeria monocytogenes infection. Front. Microbiol 1:149 [Google Scholar]
  29. Dinarello CA. 29.  2009. Immunological and inflammatory functions of the interleukin-1 family. Annu. Rev. Immunol. 27:519–50 [Google Scholar]
  30. Sibley CH, Plass N, Snow J, Wiggs EA, Brewer CC. 30.  et al. 2012. Sustained response and prevention of damage progression in patients with neonatal-onset multisystem inflammatory disease treated with anakinra: a cohort study to determine three- and five-year outcomes. Arthritis Rheumatol. 64:2375–86 [Google Scholar]
  31. Mariathasan S, Newton K, Monack DM, Vucic D, French DM. 31.  et al. 2004. Differential activation of the inflammasome by caspase-1 adaptors ASC and Ipaf. Nature 430:213–18 [Google Scholar]
  32. Robbins GR, Wen H, Ting JP. 32.  2014. Inflammasomes and metabolic disorders: old genes in modern diseases. Mol. Cell 54:297–308 [Google Scholar]
  33. Bergsbaken T, Fink SL, Cookson BT. 33.  2009. Pyroptosis: host cell death and inflammation. Nat. Rev. Microbiol. 7:99–109 [Google Scholar]
  34. Miao EA, Leaf IA, Treuting PM, Mao DP, Dors M. 34.  et al. 2010. Caspase-1-induced pyroptosis is an innate immune effector mechanism against intracellular bacteria. Nat. Immunol. 11:1136–42 [Google Scholar]
  35. Hacham M, Argov S, White RM, Segal S, Apte RN. 35.  2000. Distinct patterns of IL-1 alpha and IL-1 beta organ distribution—a possible basis for organ mechanisms of innate immunity. Adv. Exp. Med. Biol. 479:185–202 [Google Scholar]
  36. Pothlichet J, Meunier I, Davis BK, Ting JP, Skamene E. 36.  et al. 2013. Type I IFN triggers RIG-I/TLR3/NLRP3-dependent inflammasome activation in influenza A virus infected cells. PLOS Pathog. 9:e1003256 [Google Scholar]
  37. Gross O, Yazdi AS, Thomas CJ, Masin M, Heinz LX. 37.  et al. 2012. Inflammasome activators induce interleukin-1α secretion via distinct pathways with differential requirement for the protease function of caspase-1. Immunity 36:388–400 [Google Scholar]
  38. Deleted in proof
  39. 39. Int. Soc. Syst. Autoinflamm. Dis 2014. Infevers Online Database for Autoinflammatory Mutations, Montpellier, Fr., updated Oct. 29, accessed Jan. 20, 2015. http://fmf.igh.cnrs.fr/ISSAID/infevers/
  40. Tanaka N, Izawa K, Saito MK, Sakuma M, Oshima K. 40.  et al. 2011. High incidence of NLRP3 somatic mosaicism in patients with chronic infantile neurologic, cutaneous, articular syndrome: results of an international multicenter collaborative study. Arthritis Rheumatol. 63:3625–32 [Google Scholar]
  41. Arostegui JI, Aldea A, Modesto C, Rua MJ, Arguelles F. 41.  et al. 2004. Clinical and genetic heterogeneity among Spanish patients with recurrent autoinflammatory syndromes associated with the CIAS1/PYPAF1/NALP3 gene. Arthritis Rheumatol. 50:4045–50 [Google Scholar]
  42. Hill SC, Namde M, Dwyer A, Poznanski A, Canna S, Goldbach-Mansky R. 42.  2007. Arthropathy of neonatal onset multisystem inflammatory disease (NOMID/CINCA). Pediatr. Radiol. 37:145–52 [Google Scholar]
  43. Agostini L, Martinon F, Burns K, McDermott MF, Hawkins PN, Tschopp J. 43.  2004. NALP3 forms an IL-1β-processing inflammasome with increased activity in Muckle-Wells autoinflammatory disorder. Immunity 20:319–25 [Google Scholar]
  44. Haneklaus M, O'Neill LA, Coll RC. 44.  2013. Modulatory mechanisms controlling the NLRP3 inflammasome in inflammation: recent developments. Curr. Opin. Immunol. 25:40–45 [Google Scholar]
  45. Lee GS, Subramanian N, Kim AI, Aksentijevich I, Goldbach-Mansky R. 45.  et al. 2012. The calcium-sensing receptor regulates the NLRP3 inflammasome through Ca2+ and cAMP. Nature 492:123–27 [Google Scholar]
  46. Gattorno M, Tassi S, Carta S, Delfino L, Ferlito F. 46.  et al. 2007. Pattern of interleukin-1β secretion in response to lipopolysaccharide and ATP before and after interleukin-1 blockade in patients with CIAS1 mutations. Arthritis Rheumatol. 56:3138–48 [Google Scholar]
  47. Baroja-Mazo A, Martin-Sanchez F, Gomez AI, Martinez CM, Amores-Iniesta J. 47.  et al. 2014. The NLRP3 inflammasome is released as a particulate danger signal that amplifies the inflammatory response. Nat. Immunol. 15:738–48 [Google Scholar]
  48. Heller H, Sohar E, Pras M. 48.  1961. Ethnic distribution and amyloidosis in familial Mediterranean fever (FMF). Pathol. Microbiol. 24:718–23 [Google Scholar]
  49. Stoffels M, Szperl A, Simon A, Netea MG, Plantinga TS. 49.  et al. 2013. MEFV mutations affecting pyrin amino acid 577 cause autosomal dominant autoinflammatory disease. Ann. Rheum. Dis. 73:455–61 [Google Scholar]
  50. Ben-Chetrit E, Levy M. 50.  1998. Familial Mediterranean fever. Lancet 351:659–64 [Google Scholar]
  51. Chae JJ, Aksentijevich I, Kastner DL. 51.  2009. Advances in the understanding of familial Mediterranean fever and possibilities for targeted therapy. Br. J. Haematol. 146:467–78 [Google Scholar]
  52. Gedalia A, Zamir S. 52.  1993. Neurologic manifestations in familial Mediterranean fever. Pediatr. Neurol. 9:301–2 [Google Scholar]
  53. Zemer D, Pras M, Sohar E, Modan M, Cabili S, Gafni J. 53.  1986. Colchicine in the prevention and treatment of the amyloidosis of familial Mediterranean fever. N. Engl. J. Med. 314:1001–5 [Google Scholar]
  54. Hashkes PJ, Spalding SJ, Giannini EH, Huang B, Johnson A. 54.  et al. 2012. Rilonacept for colchicine-resistant or -intolerant familial Mediterranean fever: a randomized trial. Ann. Intern. Med. 157:533–41 [Google Scholar]
  55. Woo JS, Imm JH, Min CK, Kim KJ, Cha SS, Oh BH. 55.  2006. Structural and functional insights into the B30.2/SPRY domain. EMBO J. 25:1353–63 [Google Scholar]
  56. Uchil PD, Quinlan BD, Chan WT, Luna JM, Mothes W. 56.  2008. TRIM E3 ligases interfere with early and late stages of the retroviral life cycle. PLOS Pathog. 4:e16 [Google Scholar]
  57. Tsuchida T, Zou J, Saitoh T, Kumar H, Abe T. 57.  et al. 2010. The ubiquitin ligase TRIM56 regulates innate immune responses to intracellular double-stranded DNA. Immunity 33:765–76 [Google Scholar]
  58. Richards N, Schaner P, Diaz A, Stuckey J, Shelden E. 58.  et al. 2001. Interaction between pyrin and the apoptotic speck protein (ASC) modulates ASC-induced apoptosis. J. Biol. Chem. 276:39320–29 [Google Scholar]
  59. Omenetti A, Carta S, Delfino L, Martini A, Gattorno M, Rubartelli A. 59.  2014. Increased NLRP3-dependent interleukin 1β secretion in patients with familial Mediterranean fever: correlation with MEFV genotype. Ann. Rheum. Dis. 73:462–69 [Google Scholar]
  60. Chae JJ, Komarow HD, Cheng J, Wood G, Raben N. 60.  et al. 2003. Targeted disruption of pyrin, the FMF protein, causes heightened sensitivity to endotoxin and a defect in macrophage apoptosis. Mol. Cell 11:591–604 [Google Scholar]
  61. Jank T, Giesemann T, Aktories K. 61.  2007. Rho-glucosylating Clostridium difficile toxins A and B: new insights into structure and function. Glycobiology 17:15R–22R [Google Scholar]
  62. Xu H, Yang J, Gao W, Li L, Li P. 62.  et al. 2014. Innate immune sensing of bacterial modifications of Rho GTPases by the pyrin inflammasome. Nature 513:237–41 [Google Scholar]
  63. Mansfield E, Chae JJ, Komarow HD, Brotz TM, Frucht DM. 63.  et al. 2001. The familial Mediterranean fever protein, pyrin, associates with microtubules and colocalizes with actin filaments. Blood 98:851–59 [Google Scholar]
  64. Waite AL, Schaner P, Hu C, Richards N, Balci-Peynircioglu B. 64.  et al. 2009. Pyrin and ASC co-localize to cellular sites that are rich in polymerizing actin. Exp. Biol. Med. 234:40–52 [Google Scholar]
  65. Cronstein BN, Molad Y, Reibman J, Balakhane E, Levin RI, Weissmann G. 65.  1995. Colchicine alters the quantitative and qualitative display of selectins on endothelial cells and neutrophils. J. Clin. Investig. 96:994–1002 [Google Scholar]
  66. Liao G, Nagasaki T, Gundersen GG. 66.  1995. Low concentrations of nocodazole interfere with fibroblast locomotion without significantly affecting microtubule level: implications for the role of dynamic microtubules in cell locomotion. J. Cell Sci. 108:Part 113473–83 [Google Scholar]
  67. Canna SW, de Jesus AA, Gouni S, Brooks SR, Marrero B. 67.  et al. 2014. An activating NLRC4 inflammasome mutation causes autoinflammation with recurrent macrophage activation syndrome. Nat. Genet. 46:1140–46 [Google Scholar]
  68. Romberg N, Al Moussawi K, Nelson-Williams C, Stiegler AL, Loring E. 68.  et al. 2014. Mutation of NLRC4 causes a syndrome of enterocolitis and autoinflammation. Nat. Genet. 46:1135–49 [Google Scholar]
  69. Strowig T, Henao-Mejia J, Elinav E, Flavell R. 69.  2012. Inflammasomes in health and disease. Nature 481:278–86 [Google Scholar]
  70. Kitamura A, Sasaki Y, Abe T, Kano H, Yasutomo K. 70.  2014. An inherited mutation in NLRC4 causes autoinflammation in human and mice. J. Exp. Med. 211:2385–96 [Google Scholar]
  71. Houten SM, Kuis W, Duran M, de Koning TJ, van Royen-Kerkhof A. 71.  et al. 1999. Mutations in MVK, encoding mevalonate kinase, cause hyperimmunoglobulinaemia D and periodic fever syndrome. Nat. Genet. 22:175–77 [Google Scholar]
  72. Frenkel J, Houten SM, Waterham HR, Wanders RJ, Rijkers GT. 72.  et al. 2000. Mevalonate kinase deficiency and Dutch type periodic fever. Clin. Exp. Rheumatol. 18:525–32 [Google Scholar]
  73. Cuisset L, Drenth JP, Simon A, Vincent MF, van der Velde Visser S. 73.  et al. 2001. Molecular analysis of MVK mutations and enzymatic activity in hyper-IgD and periodic fever syndrome. Eur. J. Hum. Genet. 9:260–66 [Google Scholar]
  74. Rigante D, Ansuini V, Bertoni B, Pugliese AL, Avallone L. 74.  et al. 2006. Treatment with anakinra in the hyperimmunoglobulinemia D/periodic fever syndrome. Rheumatol. Int. 27:97–100 [Google Scholar]
  75. Galeotti C, Meinzer U, Quartier P, Rossi-Semerano L, Bader-Meunier B. 75.  et al. 2012. Efficacy of interleukin-1-targeting drugs in mevalonate kinase deficiency. Rheumatology 51:1855–59 [Google Scholar]
  76. Takada K, Aksentijevich I, Mahadevan V, Dean JA, Kelley RI, Kastner DL. 76.  2003. Favorable preliminary experience with etanercept in two patients with the hyperimmunoglobulinemia D and periodic fever syndrome. Arthritis Rheumatol. 48:2645–51 [Google Scholar]
  77. Drenth JP, Cuisset L, Grateau G, Vasseur C, van de Velde-Visser SD. 77.  et al. 1999. Mutations in the gene encoding mevalonate kinase cause hyper-IgD and periodic fever syndrome. Nat. Genet. 22:178–81 [Google Scholar]
  78. Lutz RJ, McLain TM, Sinensky M. 78.  1992. Feedback inhibition of polyisoprenyl pyrophosphate synthesis from mevalonate in vitro: implications for protein prenylation. J. Biol. Chem. 267:7983–86 [Google Scholar]
  79. Mandey SH, Kuijk LM, Frenkel J, Waterham HR. 79.  2006. A role for geranylgeranylation in interleukin-1β secretion. Arthritis Rheumatol. 54:3690–95 [Google Scholar]
  80. Kuijk LM, Beekman JM, Koster J, Waterham HR, Frenkel J, Coffer PJ. 80.  2008. HMG-CoA reductase inhibition induces IL-1β release through Rac1/PI3K/PKB-dependent caspase-1 activation. Blood 112:3563–73 [Google Scholar]
  81. van der Burgh R, Pervolaraki K, Turkenburg M, Waterham HR, Frenkel J, Boes M. 81.  2014. Unprenylated RhoA contributes to IL-1β hypersecretion in mevalonate kinase deficiency model through stimulation of Rac1 activity. J. Biol. Chem. 289:27757–65 [Google Scholar]
  82. Hull KM, Drewe E, Aksentijevich I, Singh HK, Wong K. 82.  et al. 2002. The TNF receptor-associated periodic syndrome (TRAPS): emerging concepts of an autoinflammatory disorder. Medicine 81:349–68 [Google Scholar]
  83. Gattorno M, Pelagatti MA, Meini A, Obici L, Barcellona R. 83.  et al. 2008. Persistent efficacy of anakinra in patients with tumor necrosis factor receptor-associated periodic syndrome. Arthritis Rheumatol. 58:1516–20 [Google Scholar]
  84. Sacre K, Brihaye B, Lidove O, Papo T, Pocidalo MA. 84.  et al. 2008. Dramatic improvement following interleukin 1β blockade in tumor necrosis factor receptor-1-associated syndrome (TRAPS) resistant to anti-TNF-α therapy. J. Rheumatol. 35:357–58 [Google Scholar]
  85. Bulua AC, Mogul DB, Aksentijevich I, Singh H, He DY. 85.  et al. 2012. Efficacy of etanercept in the tumor necrosis factor receptor-associated periodic syndrome: a prospective, open-label, dose-escalation study. Arthritis Rheumatol. 64:908–13 [Google Scholar]
  86. Nedjai B, Hitman GA, Yousaf N, Chernajovsky Y, Stjernberg-Salmela S. 86.  et al. 2008. Abnormal tumor necrosis factor receptor I cell surface expression and NF-κB activation in tumor necrosis factor receptor-associated periodic syndrome. Arthritis Rheumatol. 58:273–83 [Google Scholar]
  87. Banner DW, D'Arcy A, Janes W, Gentz R, Schoenfeld HJ. 87.  et al. 1993. Crystal structure of the soluble human 55 kd TNF receptor-human TNFβ complex: implications for TNF receptor activation. Cell 73:431–45 [Google Scholar]
  88. Lobito AA, Kimberley FC, Muppidi JR, Komarow H, Jackson AJ. 88.  et al. 2006. Abnormal disulfide-linked oligomerization results in ER retention and altered signaling by TNFR1 mutants in TNFR1-associated periodic fever syndrome (TRAPS). Blood 108:1320–27 [Google Scholar]
  89. Simon A, Park H, Maddipati R, Lobito AA, Bulua AC. 89.  et al. 2010. Concerted action of wild-type and mutant TNF receptors enhances inflammation in TNF receptor 1-associated periodic fever syndrome. PNAS 107:9801–6 [Google Scholar]
  90. Bulua AC, Simon A, Maddipati R, Pelletier M, Park H. 90.  et al. 2011. Mitochondrial reactive oxygen species promote production of proinflammatory cytokines and are elevated in TNFR1-associated periodic syndrome (TRAPS). J. Exp. Med. 208:519–33 [Google Scholar]
  91. Rebelo SL, Bainbridge SE, Amel-Kashipaz MR, Radford PM, Powell RJ. 91.  et al. 2006. Modeling of tumor necrosis factor receptor superfamily 1A mutants associated with tumor necrosis factor receptor-associated periodic syndrome indicates misfolding consistent with abnormal function. Arthritis Rheumatol. 54:2674–87 [Google Scholar]
  92. Stojanov S, Dejaco C, Lohse P, Huss K, Duftner C. 92.  et al. 2008. Clinical and functional characterisation of a novel TNFRSF1A c.605T>A/V173D cleavage site mutation associated with tumour necrosis factor receptor-associated periodic fever syndrome (TRAPS), cardiovascular complications and excellent response to etanercept treatment. Ann. Rheum. Dis. 67:1292–98 [Google Scholar]
  93. Ferguson PJ, Chen S, Tayeh MK, Ochoa L, Leal SM. 93.  et al. 2005. Homozygous mutations in LPIN2 are responsible for the syndrome of chronic recurrent multifocal osteomyelitis and congenital dyserythropoietic anaemia (Majeed syndrome). J. Med. Genet. 42:551–57 [Google Scholar]
  94. Majeed HA, Kalaawi M, Mohanty D, Teebi AS, Tunjekar MF. 94.  et al. 1989. Congenital dyserythropoietic anemia and chronic recurrent multifocal osteomyelitis in three related children and the association with Sweet syndrome in two siblings. J. Pediatr. 115:730–34 [Google Scholar]
  95. Herlin T, Fiirgaard B, Bjerre M, Kerndrup G, Hasle H. 95.  et al. 2012. Efficacy of anti-IL-1 treatment in Majeed syndrome. Ann. Rheum. Dis. 72:410–13 [Google Scholar]
  96. Donkor J, Zhang P, Wong S, O'Loughlin L, Dewald J. 96.  et al. 2009. A conserved serine residue is required for the phosphatidate phosphatase activity but not the transcriptional coactivator functions of lipin-1 and lipin-2. J. Biol. Chem. 284:29968–78 [Google Scholar]
  97. Fakas S, Qiu Y, Dixon JL, Han GS, Ruggles KV. 97.  et al. 2011. Phosphatidate phosphatase activity plays key role in protection against fatty acid-induced toxicity in yeast. J. Biol. Chem. 286:29074–85 [Google Scholar]
  98. Valdearcos M, Esquinas E, Meana C, Pena L, Gil-de-Gomez L. 98.  et al. 2012. Lipin-2 reduces proinflammatory signaling induced by saturated fatty acids in macrophages. J. Biol. Chem. 287:10894–904 [Google Scholar]
  99. Jesus AA, Osman M, Silva CA, Kim PW, Pham TH. 99.  et al. 2011. A novel mutation of IL1RN in the deficiency of interleukin-1 receptor antagonist syndrome: description of two unrelated cases from Brazil. Arthritis Rheumatol. 63:4007–17 [Google Scholar]
  100. Crow YJ. 100.  2011. Type I interferonopathies: a novel set of inborn errors of immunity. Ann. N.Y. Acad. Sci. 1238:91–98 [Google Scholar]
  101. Bennett L, Palucka AK, Arce E, Cantrell V, Borvak J. 101.  et al. 2003. Interferon and granulopoiesis signatures in systemic lupus erythematosus blood. J. Exp. Med. 197:711–23 [Google Scholar]
  102. Hall JC, Rosen A. 102.  2010. Type I interferons: crucial participants in disease amplification in autoimmunity. Nat. Rev. Rheumatol. 6:40–49 [Google Scholar]
  103. Eli Lilly. 103.  2014. Compassionate use protocol for the treatment of autoinflammatory syndromes Study record NCT01724580. US Natl. Inst. Health, Bethesda, MD, updated July. https://clinicaltrials.gov/ct2/show/NCT01724580
  104. Seth RB, Sun L, Ea CK, Chen ZJ. 104.  2005. Identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NF-κB and IRF 3. Cell 122:669–82 [Google Scholar]
  105. Ivashkiv LB, Donlin LT. 105.  2014. Regulation of type I interferon responses. Nat. Rev. Immunol. 14:36–49 [Google Scholar]
  106. Sun L, Wu J, Du F, Chen X, Chen ZJ. 106.  2013. Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway. Science 339:786–91 [Google Scholar]
  107. Wu J, Sun L, Chen X, Du F, Shi H. 107.  et al. 2013. Cyclic GMP-AMP is an endogenous second messenger in innate immune signaling by cytosolic DNA. Science 339:826–30 [Google Scholar]
  108. Ouyang S, Song X, Wang Y, Ru H, Shaw N. 108.  et al. 2012. Structural analysis of the STING adaptor protein reveals a hydrophobic dimer interface and mode of cyclic di-GMP binding. Immunity 36:1073–86 [Google Scholar]
  109. Zhang X, Shi H, Wu J, Zhang X, Sun L. 109.  et al. 2013. Cyclic GMP-AMP containing mixed phosphodiester linkages is an endogenous high-affinity ligand for STING. Mol. Cell 51:226–35 [Google Scholar]
  110. Al-Herz W, Bousfiha A, Casanova JL, Chatila T, Conley ME. 110.  et al. 2014. Primary immunodeficiency diseases: an update on the classification from the International Union of Immunological Societies Expert Committee for Primary Immunodeficiency. Front. Immunol. 5:162 [Google Scholar]
  111. Ramantani G, Kohlhase J, Hertzberg C, Innes AM, Engel K. 111.  et al. 2010. Expanding the phenotypic spectrum of lupus erythematosus in Aicardi-Goutieres syndrome. Arthritis Rheumatol. 62:1469–77 [Google Scholar]
  112. Crow YJ, Vanderver A, Orcesi S, Kuijpers TW, Rice GI. 112.  2014. Therapies in Aicardi-Goutieres syndrome. Clin. Exp. Immunol. 175:1–8 [Google Scholar]
  113. Crow YJ. 113.  2013. Aicardi-Goutieres syndrome. Handb. Clin. Neurol. 113:1629–35 [Google Scholar]
  114. Stetson DB, Ko JS, Heidmann T, Medzhitov R. 114.  2008. Trex1 prevents cell-intrinsic initiation of autoimmunity. Cell 134:587–98 [Google Scholar]
  115. Gall A, Treuting P, Elkon KB, Loo YM, Gale M Jr. 115.  et al. 2012. Autoimmunity initiates in nonhematopoietic cells and progresses via lymphocytes in an interferon-dependent autoimmune disease. Immunity 36:120–31 [Google Scholar]
  116. Ablasser A, Hemmerling I, Schmid-Burgk JL, Behrendt R, Roers A, Hornung V. 116.  2014. TREX1 deficiency triggers cell-autonomous immunity in a cGAS-dependent manner. J. Immunol. 192:5993–97 [Google Scholar]
  117. Agranat L, Raitskin O, Sperling J, Sperling R. 117.  2008. The editing enzyme ADAR1 and the mRNA surveillance protein hUpf1 interact in the cell nucleus. PNAS 105:5028–33 [Google Scholar]
  118. Volkman HE, Stetson DB. 118.  2014. The enemy within: endogenous retroelements and autoimmune disease. Nat. Immunol. 15:415–22 [Google Scholar]
  119. Yang YG, Lindahl T, Barnes DE. 119.  2007. Trex1 exonuclease degrades ssDNA to prevent chronic checkpoint activation and autoimmune disease. Cell 131:873–86 [Google Scholar]
  120. Kind B, Muster B, Staroske W, Herce HD, Sachse R. 120.  et al. 2014. Altered spatio-temporal dynamics of RNase H2 complex assembly at replication and repair sites in Aicardi-Goutières syndrome. Hum. Mol. Genet. 23:5950–60 [Google Scholar]
  121. Kitamura A, Maekawa Y, Uehara H, Izumi K, Kawachi I. 121.  et al. 2011. A mutation in the immunoproteasome subunit PSMB8 causes autoinflammation and lipodystrophy in humans. J. Clin. Investig. 121:4150–60 [Google Scholar]
  122. Arima K, Kinoshita A, Mishima H, Kanazawa N, Kaneko T. 122.  et al. 2011. Proteasome assembly defect due to a proteasome subunit beta type 8 (PSMB8) mutation causes the autoinflammatory disorder, Nakajo-Nishimura syndrome. PNAS 108:14914–19 [Google Scholar]
  123. Liu Y, Ramot Y, Torrelo A, Paller A, Si N. 123.  et al. 2012. Mutations in proteasome subunit β type 8 cause chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature with evidence of genetic and phenotypic heterogeneity. Arthritis Rheumatol. 64:895–907 [Google Scholar]
  124. Agarwal A, Xing C, DeMartino G, Mizrachi D, Hernandez MD. 124.  et al. 2010. PSMB8 encoding the β5i proteasome subunit is mutated in joint contractures, muscle atrophy, microcytic anemia, and panniculitis-induced lipodystrophy syndrome. Am. J. Hum. Genet. 87:866–72 [Google Scholar]
  125. Baumeister W, Walz J, Zühl F, Seemüller E. 125.  1998. The proteasome: paradigm of a self-compartmentalizing protease. Cell 92:367–80 [Google Scholar]
  126. Stohwasser R, Kuckelkorn U, Kraft R, Kostka S, Kloetzel PM. 126.  1996. 20S proteasome from LMP7 knock out mice reveals altered proteolytic activities and cleavage site preferences. FEBS Lett. 383:109–13 [Google Scholar]
  127. Chen BP, Wolfgang CD, Hai T. 127.  1996. Analysis of ATF3, a transcription factor induced by physiological stresses and modulated by gadd153/Chop10. Mol. Cell. Biol. 16:1157–68 [Google Scholar]
  128. Eckard SC, Rice GI, Fabre A, Badens C, Gray EE. 128.  et al. 2014. The SKIV2L RNA exosome limits activation of the RIG-I-like receptors. Nat. Immunol. 15:839–45 [Google Scholar]
  129. Lausch E, Janecke A, Bros M, Trojandt S, Alanay Y. 129.  et al. 2011. Genetic deficiency of tartrate-resistant acid phosphatase associated with skeletal dysplasia, cerebral calcifications and autoimmunity. Nat. Genet. 43:132–37 [Google Scholar]
  130. Briggs TA, Rice GI, Daly S, Urquhart J, Gornall H, Bader-Meunier B. 130.  et al. 2011. Tartrate-resistant acid phosphatase deficiency causes a bone dysplasia with autoimmunity and a type I interferon expression signature. Nat. Genet. 43:127–31 [Google Scholar]
  131. Jiang C, Lin X. 131.  2012. Regulation of NF-κB by the CARD proteins. Immunol. Rev. 246:141–53 [Google Scholar]
  132. Kanazawa N, Okafuji I, Kambe N, Nishikomori R, Nakata-Hizume M. 132.  et al. 2005. Early-onset sarcoidosis and CARD15 mutations with constitutive nuclear factor-κB activation: common genetic etiology with Blau syndrome. Blood 105:1195–97 [Google Scholar]
  133. Rose CD, Arostegui JI, Martin TM, Espada G, Scalzi L. 133.  et al. 2009. NOD2-associated pediatric granulomatous arthritis, an expanding phenotype: study of an international registry and a national cohort in Spain. Arthritis Rheumatol. 60:1797–803 [Google Scholar]
  134. Rose CD, Wouters CH, Meiorin S, Doyle TM, Davey MP. 134.  et al. 2006. Pediatric granulomatous arthritis: an international registry. Arthritis Rheumatol. 54:3337–44 [Google Scholar]
  135. Arostegui JI, Arnal C, Merino R, Modesto C, Antonia Carballo M. 135.  et al. 2007. NOD2 gene-associated pediatric granulomatous arthritis: clinical diversity, novel and recurrent mutations, and evidence of clinical improvement with interleukin-1 blockade in a Spanish cohort. Arthritis Rheumatol. 56:3805–13 [Google Scholar]
  136. Becker ML, Rose CD. 136.  2005. Blau syndrome and related genetic disorders causing childhood arthritis. Curr. Rheumatol. Rep. 7:427–33 [Google Scholar]
  137. Rose CD, Martin TM, Wouters CH. 137.  2011. Blau syndrome revisited. Curr. Opin. Rheumatol. 23:411–18 [Google Scholar]
  138. Chen G, Shaw MH, Kim YG, Nunez G. 138.  2009. NOD-like receptors: role in innate immunity and inflammatory disease. Annu. Rev. Pathol. 4:365–98 [Google Scholar]
  139. Zurek B, Proell M, Wagner RN, Schwarzenbacher R, Kufer TA. 139.  2012. Mutational analysis of human NOD1 and NOD2 NACHT domains reveals different modes of activation. Innate Immun. 18:100–11 [Google Scholar]
  140. Kobayashi K, Inohara N, Hernandez LD, Galan JE, Nunez G. 140.  et al. 2002. RICK/Rip2/CARDIAK mediates signalling for receptors of the innate and adaptive immune systems. Nature 416:194–99 [Google Scholar]
  141. Magalhaes JG, Lee J, Geddes K, Rubino S, Philpott DJ, Girardin SE. 141.  2011. Essential role of Rip2 in the modulation of innate and adaptive immunity triggered by Nod1 and Nod2 ligands. Eur. J. Immunol. 41:1445–55 [Google Scholar]
  142. Ogura Y, Inohara N, Benito A, Chen FF, Yamaoka S, Nunez G. 142.  2001. Nod2, a Nod1/Apaf-1 family member that is restricted to monocytes and activates NF-κaB. J. Biol. Chem. 276:4812–18 [Google Scholar]
  143. Jordan CT, Cao L, Roberson ED, Pierson KC, Yang CF. 143.  et al. 2012. PSORS2 is due to mutations in CARD14. Am. J. Hum. Genet. 90:784–95 [Google Scholar]
  144. Fuchs-Telem D, Sarig O, van Steensel MA, Isakov O, Israeli S. 144.  et al. 2012. Familial pityriasis rubra pilaris is caused by mutations in CARD14. Am. J. Hum. Genet. 91:163–70 [Google Scholar]
  145. Jordan CT, Cao L, Roberson ED, Duan S, Helms CA. 145.  et al. 2012. Rare and common variants in CARD14, encoding an epidermal regulator of NF-κB, in psoriasis. Am. J. Hum. Genet. 90:796–808 [Google Scholar]
  146. Vasher M, Smithberger E, Lien MH, Fenske NA. 146.  2010. Familial pityriasis rubra pilaris: report of a family and therapeutic response to etanercept. J. Drugs Dermatol. 9:844–50 [Google Scholar]
  147. Ohyagi H, Onai N, Sato T, Yotsumoto S, Liu J. 147.  et al. 2013. Monocyte-derived dendritic cells perform hemophagocytosis to fine-tune excessive immune responses. Immunity 39:584–98 [Google Scholar]
  148. Canna SW, Costa-Reis P, Bernal WE, Chu N, Sullivan KE. 148.  et al. 2014. Brief report: alternative activation of laser-captured murine hemophagocytes. Arthritis Rheumatol. 66:1666–71 [Google Scholar]
  149. Castillo L, Carci llo J. 149.  2009. Secondary hemophagocytic lymphohistiocytosis and severe sepsis/systemic inflammatory response syndrome/multiorgan dysfunction syndrome/macrophage activation syndrome share common intermediate phenotypes on a spectrum of inflammation. Pediatr. Crit. Care Med. 10:387–92 [Google Scholar]
  150. Bleesing J, Prada A, Siegel DM, Villanueva J, Olson J. 150.  et al. 2007. The diagnostic significance of soluble CD163 and soluble interleukin-2 receptor alpha-chain in macrophage activation syndrome and untreated new-onset systemic juvenile idiopathic arthritis. Arthritis Rheumatol. 56:965–71 [Google Scholar]
  151. Van Gorp H, Delputte PL, Nauwynck HJ. 151.  2010. Scavenger receptor CD163, a Jack-of-all-trades and potential target for cell-directed therapy. Mol. Immunol. 47:1650–60 [Google Scholar]
  152. Henter JI, Horne A, Arico M, Egeler RM, Filipovich AH. 152.  et al. 2007. HLH-2004: diagnostic and therapeutic guidelines for hemophagocytic lymphohistiocytosis. Pediatr. Blood Cancer 48:124–31 [Google Scholar]
  153. Lin TF, Ferlic-Stark LL, Allen CE, Kozinetz CA, McClain KL. 153.  2011. Rate of decline of ferritin in patients with hemophagocytic lymphohistiocytosis as a prognostic variable for mortality. Pediatr. Blood Cancer 56:154–55 [Google Scholar]
  154. Fardet L, Coppo P, Kettaneh A, Dehoux M, Cabane J, Lambotte O. 154.  2008. Low glycosylated ferritin, a good marker for the diagnosis of hemophagocytic syndrome. Arthritis Rheumatol. 58:1521–27 [Google Scholar]
  155. Wada T, Kanegane H, Ohta K, Katoh F, Imamura T. 155.  et al. 2014. Sustained elevation of serum interleukin-18 and its association with hemophagocytic lymphohistiocytosis in XIAP deficiency. Cytokine 65:74–78 [Google Scholar]
  156. Shimizu M, Nakagishi Y, Yachie A. 156.  2013. Distinct subsets of patients with systemic juvenile idiopathic arthritis based on their cytokine profiles. Cytokine 61:345–48 [Google Scholar]
  157. Ichida H, Kawaguchi Y, Sugiura T, Takagi K, Katsumata Y. 157.  et al. 2014. Clinical manifestations of adult-onset Still's disease presenting with erosive arthritis: association with low levels of ferritin and IL-18. Arthritis Care Res. 66:642–46 [Google Scholar]
  158. Villanueva J, Lee S, Giannini EH, Graham TB, Passo MH. 158.  et al. 2005. Natural killer cell dysfunction is a distinguishing feature of systemic onset juvenile rheumatoid arthritis and macrophage activation syndrome. Arthritis Res. Ther. 7:R30–37 [Google Scholar]
  159. de Jager W, Vastert SJ, Beekman JM, Wulffraat NM, Kuis W. 159.  et al. 2009. Defective phosphorylation of interleukin-18 receptor β causes impaired natural killer cell function in systemic-onset juvenile idiopathic arthritis. Arthritis Rheumatol. 60:2782–93 [Google Scholar]
  160. Iannello A, Samarani S, Debbeche O, Ahmad R, Boulassel MR. 160.  et al. 2009. Potential role of interleukin-18 in the immunopathogenesis of AIDS: involvement in fratricidal killing of NK cells. J. Virol. 83:5999–6010 [Google Scholar]
  161. Nedvetzki S, Sowinski S, Eagle RA, Harris J, Vely F. 161.  et al. 2007. Reciprocal regulation of human natural killer cells and macrophages associated with distinct immune synapses. Blood 109:3776–85 [Google Scholar]
  162. Gattorno M, Piccini A, Lasiglie D, Tassi S, Brisca G. 162.  et al. 2008. The pattern of response to anti-interleukin-1 treatment distinguishes two subsets of patients with systemic-onset juvenile idiopathic arthritis. Arthritis Rheumatol. 58:1505–15 [Google Scholar]
  163. Bruck N, Suttorp M, Kabus M, Heubner G, Gahr M, Pessler F. 163.  2011. Rapid and sustained remission of systemic juvenile idiopathic arthritis-associated macrophage activation syndrome through treatment with anakinra and corticosteroids. J. Clin. Rheumatol. 17:23–27 [Google Scholar]
  164. Rigaud S, Fondaneche MC, Lambert N, Pasquier B, Mateo V. 164.  et al. 2006. XIAP deficiency in humans causes an X-linked lymphoproliferative syndrome. Nature 444:110–14 [Google Scholar]
  165. Marsh RA, Madden L, Kitchen BJ, Mody R, McClimon B. 165.  et al. 2010. XIAP deficiency: a unique primary immunodeficiency best classified as X-linked familial hemophagocytic lymphohistiocytosis and not as X-linked lymphoproliferative disease. Blood 116:1079–82 [Google Scholar]
  166. Aguilar C, Lenoir C, Lambert N, Begue B, Brousse N. 166.  et al. 2014. Characterization of Crohn disease in X-linked inhibitor of apoptosis-deficient male patients and female symptomatic carriers. J. Allergy Clin. Immunol. 134:1131–41.e9 [Google Scholar]
  167. Speckmann C, Lehmberg K, Albert MH, Damgaard RB, Fritsch M. 167.  et al. 2013. X-linked inhibitor of apoptosis (XIAP) deficiency: the spectrum of presenting manifestations beyond hemophagocytic lymphohistiocytosis. Clin. Immunol. 149:133–41 [Google Scholar]
  168. Stepp SE, Dufourcq-Lagelouse R, Le Deist F, Bhawan S, Certain S. 168.  et al. 1999. Perforin gene defects in familial hemophagocytic lymphohistiocytosis. Science 286:1957–59 [Google Scholar]
  169. Pachlopnik Schmid J, Cote M, Menager MM, Burgess A, Nehme N. 169.  et al. 2010. Inherited defects in lymphocyte cytotoxic activity. Immunol. Rev. 235:10–23 [Google Scholar]
  170. Jessen B, Kogl T, Sepulveda FE, de Saint Basile G, Aichele P, Ehl S. 170.  2013. Graded defects in cytotoxicity determine severity of hemophagocytic lymphohistiocytosis in humans and mice. Front. Immunol. 4:448 [Google Scholar]
  171. Horne A, Trottestam H, Arico M, Egeler RM, Filipovich AH. 171.  et al. 2008. Frequency and spectrum of central nervous system involvement in 193 children with haemophagocytic lymphohistiocytosis. Br. J. Haematol. 140:327–35 [Google Scholar]
  172. Imashuku S. 172.  2002. Clinical features and treatment strategies of Epstein-Barr virus-associated hemophagocytic lymphohistiocytosis. Crit. Rev. Oncol. Hematol. 44:259–72 [Google Scholar]
  173. Demirkol D, Yildizdas D, Bayrakci B, Karapinar B, Kendirli T. 173.  et al. 2012. Hyperferritinemia in the critically ill child with secondary hemophagocytic lymphohistiocytosis/sepsis/multiple organ dysfunction syndrome/macrophage activation syndrome: What is the treatment?. Crit. Care 16:R52 [Google Scholar]
  174. Terrell CE, Jordan MB. 174.  2013. Perforin deficiency impairs a critical immunoregulatory loop involving murine CD8+ T cells and dendritic cells. Blood 121:5184–91 [Google Scholar]
  175. Krebs P, Crozat K, Popkin D, Oldstone MB, Beutler B. 175.  2011. Disruption of MyD88 signaling suppresses hemophagocytic lymphohistiocytosis in mice. Blood 117:6582–88 [Google Scholar]
  176. Sepulveda FE, Maschalidi S, Vosshenrich CA, Garrigue A, Kurowska M. 176.  et al. 2015. A novel immunoregulatory role for NK cell cytotoxicity in protection from HLH-like immunopathology in mice. Blood 1251427–34
  177. Zoller EE, Lykens JE, Terrell CE, Aliberti J, Filipovich AH. 177.  et al. 2011. Hemophagocytosis causes a consumptive anemia of inflammation. J. Exp. Med. 208:1203–14 [Google Scholar]
  178. Osugi Y, Hara J, Tagawa S, Takai K, Hosoi G. 178.  et al. 1997. Cytokine production regulating Th1 and Th2 cytokines in hemophagocytic lymphohistiocytosis. Blood 89:4100–3 [Google Scholar]
  179. Vastert SJ, van Wijk R, D'Urbano LE, de Vooght KM, de Jager W. 179.  et al. 2010. Mutations in the perforin gene can be linked to macrophage activation syndrome in patients with systemic onset juvenile idiopathic arthritis. Rheumatology 49:441–49 [Google Scholar]
  180. Zhang K, Biroschak J, Glass DN, Thompson SD, Finkel T. 180.  et al. 2008. Macrophage activation syndrome in patients with systemic juvenile idiopathic arthritis is associated with MUNC13-4 polymorphisms. Arthritis Rheumatol. 58:2892–96 [Google Scholar]
  181. Jordan MB, Hildeman D, Kappler J, Marrack P. 181.  2004. An animal model of hemophagocytic lymphohistiocytosis (HLH): CD8+ T cells and interferon gamma are essential for the disorder. Blood 104:735–43 [Google Scholar]
  182. Pachlopnik Schmid J, Ho CH, Chretien F, Lefebvre JM, Pivert G. 182.  et al. 2009. Neutralization of IFNγ defeats haemophagocytosis in LCMV-infected perforin- and Rab27a-deficient mice. EMBO Mol. Med. 1:112–24 [Google Scholar]
  183. Behrens EM, Canna SW, Slade K, Rao S, Kreiger PA. 183.  et al. 2011. Repeated TLR9 stimulation results in macrophage activation syndrome-like disease in mice. J. Clin. Investig. 121:2264–77 [Google Scholar]
  184. Sumegi J, Barnes MG, Nestheide SV, Molleran-Lee S, Villanueva J. 184.  et al. 2011. Gene expression profiling of peripheral blood mononuclear cells from children with active hemophagocytic lymphohistiocytosis. Blood 117:e151–60 [Google Scholar]
  185. Sikora KA, Fall N, Thornton S, Grom AA. 185.  2012. The limited role of interferon-gamma in systemic juvenile idiopathic arthritis cannot be explained by cellular hyporesponsiveness. Arthritis Rheumatol. 64:3799–808 [Google Scholar]
  186. Fall N, Barnes M, Thornton S, Luyrink L, Olson J. 186.  et al. 2007. Gene expression profiling of peripheral blood from patients with untreated new-onset systemic juvenile idiopathic arthritis reveals molecular heterogeneity that may predict macrophage activation syndrome. Arthritis Rheumatol. 56:3793–804 [Google Scholar]
  187. Strippoli R, Carvello F, Scianaro R, De Pasquale L, Vivarelli M. 187.  et al. 2012. Amplification of the response to Toll-like receptor ligands by prolonged exposure to interleukin-6 in mice: implication for the pathogenesis of macrophage activation syndrome. Arthritis Rheumatol. 64:1680–88 [Google Scholar]
  188. Wise CA, Gillum JD, Seidman CE, Lindor NM, Veile R. 188.  et al. 2002. Mutations in CD2BP1 disrupt binding to PTP PEST and are responsible for PAPA syndrome, an autoinflammatory disorder. Hum. Mol. Genet. 11:961–69 [Google Scholar]
  189. Demidowich AP, Freeman AF, Kuhns DB, Aksentijevich I, Gallin JI. 189.  et al. 2012. Brief report: genotype, phenotype, and clinical course in five patients with PAPA syndrome (pyogenic sterile arthritis, pyoderma gangrenosum, and acne). Arthritis Rheumatol. 64:2022–27 [Google Scholar]
  190. Wu Y, Spencer SD, Lasky LA. 190.  1998. Tyrosine phosphorylation regulates the SH3-mediated binding of the Wiskott-Aldrich syndrome protein to PSTPIP, a cytoskeletal-associated protein. J. Biol. Chem. 273:5765–70 [Google Scholar]
  191. Shoham NG, Centola M, Mansfield E, Hull KM, Wood G. 191.  et al. 2003. Pyrin binds the PSTPIP1/CD2BP1 protein, defining familial Mediterranean fever and PAPA syndrome as disorders in the same pathway. PNAS 100:13501–6 [Google Scholar]
  192. Starnes TW, Bennin DA, Bing X, Eickhoff JC, Grahf DC. 192.  et al. 2014. The F-BAR protein PSTPIP1 controls extracellular matrix degradation and filopodia formation in macrophages. Blood 123:2703–14 [Google Scholar]
  193. Yu JW, Fernandes-Alnemri T, Datta P, Wu J, Juliana C. 193.  et al. 2007. Pyrin activates the ASC pyroptosome in response to engagement by autoinflammatory PSTPIP1 mutants. Mol. Cell 28:214–27 [Google Scholar]
  194. Wang D, Hoing S, Patterson HC, Ahmad UM, Rathinam VA. 194.  et al. 2013. Inflammation in mice ectopically expressing human Pyogenic Arthritis, Pyoderma Gangrenosum, and Acne (PAPA) Syndrome-associated PSTPIP1 A230T mutant proteins. J. Biol. Chem. 288:4594–601 [Google Scholar]
  195. Zhou Q, Yang D, Ombrello AK, Zavialov AV, Toro C. 195.  et al. 2014. Early-onset stroke and vasculopathy associated with mutations in ADA2. N. Engl. J. Med. 370:911–20 [Google Scholar]
  196. Elkan P, Pierce SB, Segel R, Walsh T, Barash J. 196.  Navon et al. 2014. Mutant adenosine deaminase 2 in a polyarteritis nodosa vasculopathy. N. Engl. J. Med. 370:921–31 [Google Scholar]
  197. Wiseman DH, May A, Jolles S, Connor P, Powell C. 197.  et al. 2013. A novel syndrome of congenital sideroblastic anemia, B-cell immunodeficiency, periodic fevers, and developmental delay (SIFD). Blood 122:112–23 [Google Scholar]
  198. Chakraborty PK, Schmitz-Abe K, Kennedy EK, Mamady H, Naas T. 198.  et al. 2014. Mutations in TRNT1 cause congenital sideroblastic anemia with immunodeficiency, fevers, and developmental delay (SIFD). Blood 124:2867–71 [Google Scholar]
  199. Marrakchi S, Guigue P, Renshaw BR, Puel A, Pei XY. 199.  et al. 2011. Interleukin-36–receptor antagonist deficiency and generalized pustular psoriasis. N. Engl. J. Med. 365:620–28 [Google Scholar]
  200. Onoufriadis A, Simpson MA, Pink AE, Di Meglio P, Smith CH. 200.  et al. 2011. Mutations in IL36RN/IL1F5 are associated with the severe episodic inflammatory skin disease known as generalized pustular psoriasis. Am. J. Hum. Genet. 89:432–37 [Google Scholar]
  201. Blumberg H, Dinh H, Trueblood ES, Pretorius J, Kugler D. 201.  et al. 2007. Opposing activities of two novel members of the IL-1 ligand family regulate skin inflammation. J. Exp. Med. 204:2603–14 [Google Scholar]
  202. Engelhardt KR, Shah N, Faizura-Yeop I, Kocacik Uygun DF, Frede N. 202.  et al. 2013. Clinical outcome in IL-10– and IL-10 receptor–deficient patients with or without hematopoietic stem cell transplantation. J. Allergy Clin. Immunol. 131:825–30 [Google Scholar]
  203. Kotlarz D, Beier R, Murugan D, Diestelhorst J, Jensen O. 203.  et al. 2012. Loss of interleukin-10 signaling and infantile inflammatory bowel disease: implications for diagnosis and therapy. Gastroenterology 143:347–55 [Google Scholar]
  204. Mosser DM, Zhang X. 204.  2008. Interleukin-10: new perspectives on an old cytokine. Immunol. Rev. 226:205–18 [Google Scholar]
  205. Glocker EO, Kotlarz D, Boztug K, Gertz EM, Schaffer AA. 205.  et al. 2009. Inflammatory bowel disease and mutations affecting the interleukin-10 receptor. N. Engl. J. Med. 361:2033–45 [Google Scholar]
  206. Kuhn R, Lohler J, Rennick D, Rajewsky K, Muller W. 206.  1993. Interleukin-10-deficient mice develop chronic enterocolitis. Cell 75:263–74 [Google Scholar]
  207. Begue B, Verdier J, Rieux-Laucat F, Goulet O, Morali A. 207.  et al. 2011. Defective IL10 signaling defining a subgroup of patients with inflammatory bowel disease. Am. J. Gastroenterol. 106:1544–55 [Google Scholar]
  208. Glocker EO, Frede N, Perro M, Sebire N, Elawad M. 208.  et al. 2010. Infant colitis—it's in the genes. Lancet 376:1272 [Google Scholar]
  209. Roers A, Siewe L, Strittmatter E, Deckert M, Schluter D. 209.  et al. 2004. T cell–specific inactivation of the interleukin 10 gene in mice results in enhanced T cell responses but normal innate responses to lipopolysaccharide or skin irritation. J. Exp. Med. 200:1289–97 [Google Scholar]
  210. Zigmond E, Bernshtein B, Friedlander G, Walker CR, Yona S. 210.  et al. 2014. Macrophage-restricted interleukin-10 receptor deficiency, but not IL-10 deficiency, causes severe spontaneous colitis. Immunity 40:720–33 [Google Scholar]
  211. Zhou Q, Lee GS, Brady J, Datta S, Katan M. 211.  et al. 2012. A hypermorphic missense mutation in PLCG2, encoding phospholipase Cγ2, causes a dominantly inherited autoinflammatory disease with immunodeficiency. Am. J. Hum. Genet. 91:713–20 [Google Scholar]
  212. Hibbs ML, Harder KW, Armes J, Kountouri N, Quilici C. 212.  et al. 2002. Sustained activation of Lyn tyrosine kinase in vivo leads to autoimmunity. J. Exp. Med. 196:1593–604 [Google Scholar]
  213. Ueki Y, Tiziani V, Santanna C, Fukai N, Maulik C, Garfinkle J. 213.  et al. 2001. Mutations in the gene encoding c-Abl-binding protein SH3BP2 cause cherubism. Nat. Genet 28:125–26 [Google Scholar]
  214. Reichenberger EJ, Levine MA, Olsen BR, Papadaki ME, Lietman SA. 214.  2012. The role of SH3BP2 in the pathophysiology of cherubism. Orphanet J. Rare Dis. 7:Suppl. 1S5 [Google Scholar]
  215. Ueki Y, Lin CY, Senoo M, Ebihara T, Agata N, Onji M. 215.  et al. 2007. Increased myeloid cell responses to M-CSF and RANKL cause bone loss and inflammation in SH3BP2 “cherubism” mice. Cell 128:71–83 [Google Scholar]
  216. Hero M, Suomalainen A, Hagström J, Stoor P, Kontio R, Alapulli H. 216.  et al. 2013. Anti-tumor necrosis factor treatment in cherubism—clinical, radiological and histological findings in two children. Bone 52:347–53 [Google Scholar]
  217. Kadlub N, Vazquez MP, Galmiche L, L'Herminé AC, Dainese L, Ulinski T. 217.  et al. 2014. The calcineurin inhibitor tacrolimus as a new therapy in severe cherubism. J. Bone Miner. Res. In press
  218. Setta-Kaffetzi N, Simpson MA, Navarini AA, Patel VM, Lu HC. 218.  et al. 2014. AP1S3 mutations are associated with pustular psoriasis and impaired Toll-like receptor 3 trafficking. Am. J. Hum. Genet. 94:790–97 [Google Scholar]
  219. Blaydon DC, Biancheri P, Di WL, Plagnol V, Cabral RM. 219.  et al. 2011. Inflammatory skin and bowel disease linked to ADAM17 deletion. N. Engl. J. Med. 365:1502–8 doi: 10.1056/NEJMoa1100721 [Google Scholar]
  220. Jéru I, Duquesnoy P, Fernandes-Alnemri T, Cochet E, Yu JW. 220.  et al. 2008. Mutations in NALP12 cause hereditary periodic fever syndromes. PNAS 105:1614–19 [Google Scholar]
  221. Borghini S, Tassi S, Chiesa S, Caroli F, Carta S. 221.  et al. 2011. Clinical presentation and pathogenesis of cold-induced autoinflammatory disease in a family with recurrence of an NLRP12 mutation. Arthritis Rheumatol. 63:830–39 [Google Scholar]
  222. Jéru I, Le Borgne G, Cochet E, Hayrapetyan H, Duquesnoy P. 222.  et al. 2011. Identification and functional consequences of a recurrent NLRP12 missense mutation in periodic fever syndromes. Arthritis Rheumatol. 63:1459–64 [Google Scholar]
  223. Jéru I, Cochet E, Duquesnoy P, Hentgen V, Copin B. 223.  et al. 2014. Brief Report: involvement of TNFRSF11A molecular defects in autoinflammatory disorders. Arthritis Rheumatol. 66:2621–27 [Google Scholar]
  224. Molho-Pessach V, Ramot Y, Camille F, Doviner V, Babay S. 224.  et al. 2014. H syndrome: the first 79 patients. J. Am. Acad. Dermatol. 70:80–88 [Google Scholar]
  225. Melki I, Lambot K, Jonard L, Couloigner V, Quartier P. 225.  et al. 2013. Mutation in the SLC29A3 gene: a new cause of a monogenic, autoinflammatory condition. Pediatrics 131:e1308–13 [Google Scholar]
  226. Cheng LE, Kanwar B, Tcheurekdjian H, Grenert JP, Muskat M. 226.  et al. 2009. Persistent systemic inflammation and atypical enterocolitis in patients with NEMO syndrome. Clin. Immunol. 132:124–31 [Google Scholar]
  227. Boisson B, Laplantine E, Prando C, Giliani S, Israelsson E. 227.  et al. 2012. Immunodeficiency, autoinflammation and amylopectinosis in humans with inherited HOIL-1 and LUBAC deficiency. Nat. Immunol. 13:1178–86 [Google Scholar]
  228. Kanneganti TD, Lamkanfi M, Nunez G. 228.  2007. Intracellular NOD-like receptors in host defense and disease. Immunity 27:549–59 [Google Scholar]
  229. Seok J, Warren HS, Cuenca AG, Mindrinos MN, Baker HV. 229.  et al. 2013. Genomic responses in mouse models poorly mimic human inflammatory diseases. PNAS 110:3507–12 [Google Scholar]
  230. Brydges SD, Mueller JL, McGeough MD, Pena CA, Misaghi A. 230.  et al. 2009. Inflammasome-mediated disease animal models reveal roles for innate but not adaptive immunity. Immunity 30:875–87 [Google Scholar]
  231. Brydges SD, Broderick L, McGeough MD, Pena CA, Mueller JL, Hoffman HM. 231.  2013. Divergence of IL-1, IL-18, and cell death in NLRP3 inflammasomopathies. J. Clin. Investig. 123:4695–705 [Google Scholar]
  232. Meng G, Zhang F, Fuss I, Kitani A, Strober W. 232.  2009. A mutation in the Nlrp3 gene causing inflammasome hyperactivation potentiates Th17 cell-dominant immune responses. Immunity 30:860–74 [Google Scholar]
  233. Chae JJ, Cho YH, Lee GS, Cheng J, Liu PP. 233.  et al. 2011. Gain-of-function pyrin mutations induce NLRP3 protein-independent interleukin-1β activation and severe autoinflammation in mice. Immunity 34:755–68 [Google Scholar]
  234. Hager EJ, Tse HM, Piganelli JD, Gupta M, Baetscher M. 234.  et al. 2007. Deletion of a single mevalonate kinase (Mvk) allele yields a murine model of hyper-IgD syndrome. J. Inherit. Metab. Dis. 30:888–95 [Google Scholar]
  235. Komarow HD, Chae JJ, Raben N, Wood G, Kastner DL. 235.  2004. Mice with mutations of TNFRSF1A may reveal insights into pathogenesis of TRAPS, a dominantly inherited autoinflammatory disease. J. Allergy Clin. Immunol. 113:2 Suppl.S205 [Google Scholar]
  236. Horai R, Saijo S, Tanioka H, Nakae S, Sudo K. 236.  et al. 2000. Development of chronic inflammatory arthropathy resembling rheumatoid arthritis in interleukin 1 receptor antagonist-deficient mice. J. Exp. Med. 191:313–20 [Google Scholar]
  237. Nicklin MJ, Hughes DE, Barton JL, Ure JM, Duff GW. 237.  2000. Arterial inflammation in mice lacking the interleukin 1 receptor antagonist gene. J. Exp. Med. 191:303–12 [Google Scholar]
  238. Fehling HJ, Swat W, Laplace C, Kühn R, Rajewsky K. 238.  et al. 1994. MHC class I expression in mice lacking the proteasome subunit LMP-7. Science 265:1234–37 [Google Scholar]
  239. Czar MJ, Kersh EN, Mijares LA, Lanier G, Lewis J. 239.  et al. 2001. Altered lymphocyte responses and cytokine production in mice deficient in the X-linked lymphoproliferative disease gene SH2D1A/DSHP/SAP. PNAS 98:7449–54 [Google Scholar]
  240. Wu C, Nguyen KB, Pien GC, Wang N, Gullo C. 240.  et al. 2001. SAP controls T cell responses to virus and terminal differentiation of TH2 cells. Nat. Immunol. 2:410–14 [Google Scholar]
  241. Yin L, Al-Alem U, Liang J, Tong WM, Li C. 241.  et al. 2003. Mice deficient in the X-linked lymphoproliferative disease gene sap exhibit increased susceptibility to murine gammaherpesvirus-68 and hypo-gammaglobulinemia. J. Med. Virol. 71:446–55 [Google Scholar]
  242. Harlin H, Reffey SB, Duckett CS, Lindsten T, Thompson CB. 242.  2001. Characterization of XIAP-deficient mice. Mol. Cell. Biol. 21:103604–8 [Google Scholar]
  243. Olayioye MA, Kaufmann H, Pakusch M, Vaux DL, Lindeman GJ. 243.  et al. 2005. XIAP-deficiency leads to delayed lobuloalveolar development in the mammary gland. Cell Death Differ. 12:87–90 [Google Scholar]
  244. Harder KW, Parsons LM, Armes J, Evans N, Kountouri N. 244.  et al. 2001. Gain- and loss-of-function Lyn mutant mice define a critical inhibitory role for Lyn in the myeloid lineage. Immunity 15:603–15 [Google Scholar]
  245. Hibbs ML, Harder KW, Armes J, Kountouri N, Quilici C. 245.  et al. 2002. Sustained activation of Lyn tyrosine kinase in vivo leads to autoimmunity. J. Exp. Med. 196:1593–604 [Google Scholar]

Data & Media loading...

  • Article Type: Review Article
This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error