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Autoinflammation: Past, Present, and Future

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Textbook of Autoinflammation

Abstract

The concept of autoinflammation arose from the recognition of monogenic disorders with seemingly unprovoked inflammation without the high-titer autoantibodies or antigen-specific T cells seen in classic autoimmune diseases. During the first decade of the ‘autoinflammatory era’, a clear connection was established between autoinflammatory disease and the innate immune system, with targeted therapies providing a powerful affirmation of mechanistic hypotheses. Although the ‘inflammasomopathies’, which are associated with marked interleukin (IL)-1β production, were some of the earliest recognized autoinflammatory diseases, it soon became clear that autoinflammation can be caused by a variety of genetic lesions affecting a range of innate immune pathways, including nuclear factor kappa B (NF-κB) activation and type I interferon production. The advent of next-generation sequencing has resulted in the discovery of multiple new diseases, genes, and pathways, while genome-wide association studies (GWAS) have shed light on the pathogenesis of genetically complex autoinflammatory diseases, such as Behçet disease. During the next decade, the universe of autoinflammatory diseases will continue to expand, but it is likely that distinctions between clinical disease and normal variation will blur, and that treatments developed for autoinflammation will be applied to a much broader range of human illnesses.

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Abbreviations

CAPS:

Cryopyrin-associated periodic syndromes

CINCA:

Chronic infantile neurologic cutaneous and articular syndrome

CNO:

Chronic non-bacterial osteomyelitis

CRMO:

Chronic recurrent multifocal osteomyelitis

DIRA:

Deficiency of interleukin-1 receptor antagonist

FMF:

Familial Mediterranean fever

GWAS:

Genome-wide association studies

HIDS:

Hyperimmunoglobulinemia D with periodic fever syndrome

IL:

Interleukin

ISSAID:

International Society for Systemic Autoinflammatory Diseases

MKD:

Mevalonate kinase deficiency

MWS:

Muckle-Wells syndrome

NF-κB:

Nuclear factor kappa B

NLR:

Nucleotide-binding domain, leucine-rich repeat

NLRP3:

NLR family, pyrin domain containing 3

NOMID:

Neonatal-onset multisystem inflammatory disorder

PAAND:

Pyrin-associated autoinflammation with neutrophilic dermatosis

PAPA:

Pyogenic arthritis, pyoderma gangrenosum and acne

PFAPA:

Periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis

SAVI:

STING-associated vasculopathy with onset in infancy

SIFD :

Sideroblastic anemia with immunodeficiency, fevers, and developmental delay

STING:

Stimulator of interferon genes

TNF:

Tumor necrosis factor

TRAPS:

TNF receptor-associated periodic syndrome

References

  1. Silverstein AM. Autoimmunity versus horror autotoxicus: the struggle for recognition. Nat Immunol. 2001;2:279–81.

    Article  CAS  Google Scholar 

  2. 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.

    Article  Google Scholar 

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

    Article  Google Scholar 

  4. Park YH, Wood G, Kastner DL, Chae JJ. Pyrin inflammasome activation and RhoA signaling in the autoinflammatory disease FMF and HIDS. Nat Immunol. 2016;17:914–21.

    Article  CAS  Google Scholar 

  5. Manthiram K, Zhou Q, Aksentijevich I, Kastner DL. The monogenic autoinflammatory diseases define new pathways in human innate immunity and inflammation. Nat Immunol. 2017;18:832–42.

    Article  CAS  Google Scholar 

  6. McDermott MF, Aksenitijevich I, Galon J, et al. Germline mutations in the extracellular domains of the 55 kDA TNF receptor, TNFR1, define a family of dominantly inherited autoinflammatory syndromes. Cell. 1999;97:133–44.

    Article  CAS  Google Scholar 

  7. Galon J, Aksentijevich I, McDermott MF, O’Shea JJ, Kastner DL. TNFRSF1A mutations and autoinflammatory syndromes. Curr Opin Immunol. 2000;12:479–86.

    Article  CAS  Google Scholar 

  8. Medzhitov R, Janeway C Jr. Innate immunity. N Engl J Med. 2000;343:338–44.

    Article  CAS  Google Scholar 

  9. 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;364:1779–85.

    Article  CAS  Google Scholar 

  10. Goldbach-Mansky R, Dailey NJ, Canna SW, et al. Neonatal-onset multisystem inflammatory disease responsive to interleukin-1β inhibition. N Engl J Med. 2006;355:581–92.

    Article  CAS  Google Scholar 

  11. Lachmann HJ, Kone-Paut I, Kuemmerle-Deschner JB, et al. Use of canakinumab in the cryopyrin-associated periodic syndrome. N Engl J Med. 2009;360:2416–25.

    Article  CAS  Google Scholar 

  12. Hoffman HM, Mueller JL, Broide DH, Wandere AA, Koldner RD. Mutation of a new gene encoding a putative pyrin-like protein causes familial cold autoinflammatory syndrome and Muckle-Wells syndrome. Nat Genet. 2001;29:301–5.

    Article  CAS  Google Scholar 

  13. 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.

    Article  CAS  Google Scholar 

  14. 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;46:3340–8.

    Article  CAS  Google Scholar 

  15. Wang L, Manji GA, Grenier JM, et al. PYPAF7, a novel PYRIN-containing Apaf1-like protein that regulates activation of NF-kappa B and caspase-1-dependent cytokine processing. J Biol Chem. 2002;277:29874–80.

    Article  CAS  Google Scholar 

  16. Agostini L, Martinon F, Burns K, McDermott MF, Hawkins PN, Tschopp J. NALP3 forms an IL-1β-processing inflammasome with increased activity in Muckle-Wells autoinflammatory disorder. Immunity. 2004;20:319–25.

    Article  CAS  Google Scholar 

  17. Tschopp J, Martinon F, Burns K. NALPS: a novel protein family involved in inflammation. Nat Rev Mol Cell Biol. 2003;4:95–104.

    Article  CAS  Google Scholar 

  18. Aksentijevich I, Masters SL, Ferguson PJ, et al. An autoinflammatory disease with deficiency of the interleukin-1-receptor antagonist. N Engl J Med. 2009;360:2426–37.

    Article  CAS  Google Scholar 

  19. Reddy S, Jia S, Geoffrey R, et al. An autoinflammatory disease due to homozygous deletion of the IL1RN locus. N Engl J Med. 2009;360:2438–44.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  21. Shoham NG, Genola M, Mansfield E, 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;100:13501–6.

    Article  CAS  Google Scholar 

  22. Hugot JP, Chamaillard M, Zouali H, et al. Association of NOD2 leucine-rich repeat variants with susceptibility to Crohn’s disease. Nature. 2001;411:599–603.

    Article  CAS  Google Scholar 

  23. Miceli-Richard C, Lesage S, Rybojad M, et al. CARD15 mutations in Blau syndrome. Nat Genet. 2001;29:19–20.

    Article  CAS  Google Scholar 

  24. Jeru I, Duquesnoy P, Fernandes-Alnemri T, et al. Mutations in NALP12 cause hereditary periodic fever syndromes. Proc Natl Acad Sci U S A. 2008;105:1614–9.

    Article  CAS  Google Scholar 

  25. Houten SM, Kulis W, Duran M, et al. Mutations in MVK, encoding mevalonate kinase, cause hyperimmunoglobulinaemia D and periodic fever syndrome. Nat Genet. 1999;22:175–7.

    Article  CAS  Google Scholar 

  26. Drenth JPH, Cuisset L, Grateau G, et al. Mutations in the gene encoding mevalonate kinase cause hyper-IgD and periodic fever syndrome. Nat Genet. 1999;22:178–81.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  28. Martinon F, Pétrilli V, Mayor A, Tardivel A, Tschopp J. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature. 2006;440:237–41.

    Article  CAS  Google Scholar 

  29. Kanazawa N, Okafuji I, Kambe N, et al. Early-onset sarcoidosis and CARD15 mutations with constitutive nuclear factor-κB activation: common genetic etiology with Blau syndrome. Blood. 2005;105:1195–7.

    Article  CAS  Google Scholar 

  30. Masters SL, Simon A, Aksentijevich I, Kastner DL. Horror Autoinflammaticus: the molecular pathophysiology of autoinflammatory disease. Annu Rev Immunol. 2009;27:621–68.

    Article  CAS  Google Scholar 

  31. Szentivanyi A, Friedman H. The immunologic revolution: facts and witnesses. Boca Raton: CRC Press; 1993. p. 107.

    Google Scholar 

  32. Romberg N, Al Moussawi K, Nelson-Williams C, et al. Mutation of NLRC4 causes a syndrome of enterocolitis and autoinflammation. Nat Genet. 2014;46:1135–9.

    Article  CAS  Google Scholar 

  33. Canna SW, de Jesus AA, Gouni S, et al. An activating NLRC4 inflammasome mutation causes autoinflammation with recurrent macrophage activation syndrome. Nat Genet. 2014;46:1140–6.

    Article  CAS  Google Scholar 

  34. Zhong FL, Mamai O, Sborgi L, et al. Germline NLRP1 mutations cause skin inflammatory and cancer susceptibility syndromes via inflammasome activation. Cell. 2016;167:187–202.

    Article  CAS  Google Scholar 

  35. Grandemange S, Sanchez E, Louis-Plence P, et al. A new autoinflammatory and autoimmune syndrome associated with NLRP1 mutations: NAIAD (NLRP1-assocaited autoinflammation with arthritis and dyskeratosis). Ann Rheum Dis. 2017;76:1191–8.

    Article  CAS  Google Scholar 

  36. Liu Y, Jesus AA, Marrero B, et al. Activated STING in a vascular and pulmonary syndrome. N Engl J Med. 2014;371:507–18.

    Article  CAS  Google Scholar 

  37. Masters SL, Lagou V, Jéru I, et al. Familial autoinflammation with neutrophilic dermatosis reveals a regulatory mechanism of pyrin activation. Sci Transl Med. 2016;8:332ra45.

    Article  Google Scholar 

  38. Standing AS, Malinova D, Hong Y, et al. Autoinflammatory periodic fever, immunodeficiency, and thrombocytopenia (PFIT) caused by mutation in actin-regulatory gene WDR1. J Exp Med. 2017;214:59–71.

    Article  CAS  Google Scholar 

  39. Zhou Q, Yang D, Ombrello AK, et al. Early-onset stroke and vasculopathy associated with mutations in ADA2. N Engl J Med. 2014;370:911–20.

    Article  CAS  Google Scholar 

  40. Navon Elkan P, Pierce SB, Segel R, et al. Mutant adenosine deaminase 2 in a polyarteritis nodosa vasculopathy. N Engl J Med. 2014;370:921–31.

    Article  Google Scholar 

  41. Agarwal AK, Xing C, DeMartino GN, et al. PSMB8 encoding the β5i proteasome subunit is mutated in joint contractures, muscle atrophy, microcytic anemia, and panniculitis-induced lipodystrophy syndrome. Am J Hum Genet. 2010;87:866–72.

    Article  CAS  Google Scholar 

  42. Arima K, Kinoshita A, Mishima H, et al. Proteasome assembly defect due to a proteasome subunit beta type 8 (PSMB8) mutation causes the autoinflammatory disorder, Nakajo-Nishimura syndrome. Proc Natl Acad Sci U S A. 2011;108:14914–9.

    Article  CAS  Google Scholar 

  43. Kitamura A, Maekawa Y, Uehara H, et al. A mutation in the immunoproteasome subunit PSMB8 causes autoinflammation and lipodystrophy in humans. J Clin Invest. 2011;121:4150–60.

    Article  CAS  Google Scholar 

  44. Liu Y, Ramot Y, Torrelo A, et al. 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 Rheum. 2012;64:895–907.

    Article  CAS  Google Scholar 

  45. Zhou Q, Wang H, Schwartz DM, et al. Loss-of-function mutations in TNFAIP3 leading to A20 haploinsufficiency cause an early-onset autoinflammatory disease. Nat Genet. 2016;48:67–73.

    Article  CAS  Google Scholar 

  46. Zhou Q, Yu X, Demirkaya E, et al. Biallelic hypomorphic mutations in a linear deubiquitinase define otulipenia, an early-onset autoinflammatory disease. Proc Natl Acad Sci U S A. 2016;113:10127–32.

    Article  CAS  Google Scholar 

  47. Boisson B, Laplantine E, Prando C, et al. Immunodeficiency, autoinflammation and amylopectinosis in humans with inherited HOIL-1 and LUBAC deficiency. Nat Immunol. 2012;13:1178–86.

    Article  CAS  Google Scholar 

  48. Boisson B, Laplantine E, Dobbs K, et al. Human HOIP and LUBAC deficiency underlies autoinflammation, immunodeficiency, amylopectinosis, and lymphangiectasia. J Exp Med. 2015;212:939–51.

    Article  CAS  Google Scholar 

  49. Zhou Q, Lee G-S, Brady J, et al. A hypermorphic missense mutation in PLCG2, encoding phospholipase Cy2, causes a dominantly inherited autoinflammatory disease with immunodeficiency. Am J Hum Genet. 2012;91:713–20.

    Article  CAS  Google Scholar 

  50. Boyden SE, Desai A, Cruse G, et al. Vibratory urticaria associated with a missense variant in ADGRE2. N Engl J Med. 2016;374:656–63.

    Article  CAS  Google Scholar 

  51. Wakil SM, Monies DM, Aboulhoda M, et al. Association of a mutation in LACC1 with a monogenic form of systemic juvenile idiopathic arthritis. Arthritis Rheumatol. 2015;67:288–95.

    Article  CAS  Google Scholar 

  52. Giannelou A, Wang H, Zhou Q, et al. Aberrant tRNA processing causes an autoinflammatory syndrome responsive to TNF inhibitors. Ann Rheum Dis. 2018;77:612–9.

    Article  CAS  Google Scholar 

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

    Article  CAS  Google Scholar 

  54. Shi J, Zhao Y, Wang K, et al. Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. Nature. 2015;526:660–5.

    Article  CAS  Google Scholar 

  55. Kayagaki N, Stowe IB, Lee BL, et al. Caspase-11 cleaves gasdermin D for non-canonical inflammasome signaling. Nature. 2015;526:666–71.

    Article  CAS  Google Scholar 

  56. Liu X, Zhang Z, Ruan J, et al. Inflammasome-activated gasdermin D causes pyroptosis by forming membrane pores. Nature. 2016;535:153–8.

    Article  CAS  Google Scholar 

  57. Brehm A, Liu Y, Sheikh A, et al. Additive loss-of-function proteasome subunit mutation in CANDLE/PRAAS patients promote type I IFN production. J Clin Invest. 2015;125:4196–211.

    Article  Google Scholar 

  58. Sanchez GAM, Reinhardt A, Ramsey S, et al. JAK 1/2 inhibition with baricitinib in the treatment of autoinflammatory interferonopathies. J Clin Invest. 2018;128:3041–52.

    Article  Google Scholar 

  59. Tanaka N, Izawa K, Saito MK, et al. High incidence of NLRP3 somatic mosaicism in patients with chronic infantile neurologic, cutaneous, articular syndrome: results of an International Multicenter Collaborative Study. Arthritis Rheum. 2011;63:3625–32.

    Article  CAS  Google Scholar 

  60. Zhou Q, Aksentijevich I, Wood GM, et al. Cryopyrin-associated periodic syndrome caused by a myeloid-restricted somatic NLRP3 mutation. Arthritis Rheumatol. 2015;67:2482–6.

    Article  CAS  Google Scholar 

  61. de Koning HD, van Gijn ME, Stoffels M, et al. Myeloid lineage-restricted somatic mosaicism of NLRP3 mutations in patients with variant Schnitzler syndrome. J Allergy Clin Immunol. 2015;135:561–4.

    Article  Google Scholar 

  62. Remmers EF, Cosan F, Kirino Y, et al. Genome-wide association study identifies variants in the MHC class I, IL10, and IL23R-IL12RB2 regions associated with Behçet’s disease. Nat Genet. 2010;42:698–702.

    Article  CAS  Google Scholar 

  63. Kirino Y, Bertsias G, Ishigatsubo Y, et al. Genome-wide association analysis identifies new susceptibility loci for Behçet’s disease and epistasis between HLA-B*51 and ERAP1. Nat Genet. 2013;45:202–7.

    Article  CAS  Google Scholar 

  64. Kirino Y, Zhou Q, Ishigatsubo Y, et al. Targeted resequencing implicates the familial Mediterranean fever gene MEFV and the toll-like receptor 4 gene TLR4 in Behçet’s disease. Proc Natl Acad Sci U S A. 2013;110:8134–9.

    Article  CAS  Google Scholar 

  65. Ombrello MJ, Kirino Y, de Bakker PIW, Gül A, Kastner DL, Remmers EF. Behçet disease-associated MHC class I residues implicate antigen binding and regulation of cell-mediated cytotoxicity. Proc Natl Acad Sci U S A. 2014;111:8867–72.

    Article  CAS  Google Scholar 

  66. Takeuchi M, Mizuki N, Megure A, et al. Dense genotyping of immune-related loci implicates host responses to microbial exposure in Behçet’s disease susceptibility. Nat Genet. 2017;49:438–43.

    Article  CAS  Google Scholar 

  67. Sathirapongsasuti F. GWAS of canker sores implicates Th-1 pathway and shared genetic architecture with immune-mediated disease. 23andMe, Inc. ASHG’17. https://research.23andme.com/wp-content/uploads/2018/03/Fah_Canker_Sores_ASHG17.pdf

  68. Ridker PM, Everett BM, Thuren T, et al. Antiinflammatory therapy with canakinumab for atherosclerotic disease. N Engl J Med. 2017;377:1119–31.

    Article  CAS  Google Scholar 

  69. Ridker PM, MacFadyen JJ, Thuren T, et al. Effect of interleukin-1β inhibition with canakinumab on incident lung cancer in patients with atherosclerosis: exploratory results from a randomized, double-blind, placebo-controlled trial. Lancet. 2017;390:1833–42.

    Google Scholar 

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Authors and Affiliations

  1. National Human Genome Research Institute (NHGRI), National Institutes of Health (NIH), Bethesda, MD, USA

    Daniel L. Kastner

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  1. Daniel L. Kastner
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Correspondence to Daniel L. Kastner .

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Editors and Affiliations

  1. Pediatric Rheumatology Unit, Shaare Zedek Medical Center and Hebrew University, Jerusalem, Israel

    Philip J. Hashkes

  2. Department Paediatrics, Division of Rheumatology, The Hospital for Sick Children and University of Toronto, Toronto, ON, Canada

    Ronald M. Laxer

  3. Department of Internal Medicine, Radboudumc Expertisecenter for Immunodeficiency and Autoinflammation, Radboud University Medical Center, Nijmegen, The Netherlands

    Anna Simon

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Kastner, D.L. (2019). Autoinflammation: Past, Present, and Future. In: Hashkes, P., Laxer, R., Simon, A. (eds) Textbook of Autoinflammation. Springer, Cham. https://doi.org/10.1007/978-3-319-98605-0_1

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  • DOI: https://doi.org/10.1007/978-3-319-98605-0_1

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