Immunology of Auto-inflammatory Syndromes

  • Grant S. SchulertEmail author


The body’s first line of defense is the innate immune system, an ancestrally ancient response distinct from the adaptive immune system. At the heart of innate immunity are host germline-encoded pattern recognition receptors, which sense conserved structural features present on pathogens or signs of tissue damage, and trigger production of inflammatory responses. In contrast, autoinflammation represents a disordered and inappropriate innate immune response, with excessive production of inflammatory cytokines in the absence of high-titer autoantibodies and antigen-specific T cells. This chapter reviews the innate immune system, with a particular focus on how defects in these immune sensors and their associated signaling pathways are linked to autoinflammation. Central to this is a large family of intracellular pattern recognition receptors including the nucleotide-binding oligomerization domain (NOD) proteins and the NOD-like receptors (NLRs), which serve as key mediators in both innate immunity and autoinflammation largely through ability to form inflammasomes. Indeed, many autoinflammatory disorders converge at the level of inflammasome activation. Inflammasomes and other sensors trigger rapid production of inflammatory cytokines, and defective regulation and attenuation of cytokine responses can also underlie autoinflammation. In addition, the type I interferon response represents a distinct innate immune pathway able to elicit a potent antiviral response but when dysregulated is increasingly recognized as an important cause of autoinflammation. The objective of this overview of innate immune responses is to provide a framework for understanding autoinflammation and inform clinical diagnosis and rationally directed therapies.


Innate immunity Inflammasome Nucleotide-oligomerization domain (NOD) protein NOD-like receptor Cytokine Cytokine storm syndrome Type I interferon 


  1. 1.
    Netea MG, Balkwill F, Chonchol M, et al. A guiding map for inflammation. Nat Immunol. 2017;18:826–31. Scholar
  2. 2.
    Matzinger P. The danger model: a renewed sense of self. Science. 2002;296:301–5. Scholar
  3. 3.
    Pandey S, Kawai T, Akira S. Microbial sensing by Toll-like receptors and intracellular nucleic acid sensors. Cold Spring Harb Perspect Biol. 2014;7:a016246. Scholar
  4. 4.
    McDermott MF, Aksentijevich 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.CrossRefGoogle Scholar
  5. 5.
    Masters SL, Simon A, Aksentijevich I, et al. Horror autoinflammaticus: the molecular pathophysiology of autoinflammatory disease (*). Annu Rev Immunol. 2009;27:621–68. Scholar
  6. 6.
    Philpott DJ, Sorbara MT, Robertson SJ, et al. NOD proteins: regulators of inflammation in health and disease. Nat Rev Immunol. 2014;14:9–23. Scholar
  7. 7.
    Zhong Y, Kinio A, Saleh M. Functions of NOD-like receptors in human diseases. Front Immunol. 2013;4:333. Scholar
  8. 8.
    Kastner DL, O’Shea JJ. A fever gene comes in from the cold. Nat Genet. 2001;29:241–2. Scholar
  9. 9.
    Martinon F, Hofmann K, Tschopp J. The pyrin domain: a possible member of the death domain-fold family implicated in apoptosis and inflammation. Curr Biol. 2001;11:R118–20.CrossRefGoogle Scholar
  10. 10.
    Mariathasan S, Newton K, Monack DM, et al. Differential activation of the inflammasome by caspase-1 adaptors ASC and Ipaf. Nature. 2004;430:213–8. Scholar
  11. 11.
    Inohara N, Ogura Y, Fontalba A, et al. Host recognition of bacterial muramyl dipeptide mediated through NOD2. Implications for Crohn’s disease. J Biol Chem. 2003;278:5509–12. Scholar
  12. 12.
    Girardin SE, Boneca IG, Carneiro LAM, et al. Nod1 detects a unique muropeptide from gram-negative bacterial peptidoglycan. Science. 2003;300:1584–7. Scholar
  13. 13.
    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
  14. 14.
    French FMF Consortium, Bernot A, Clepet C, et al. A candidate gene for familial Mediterranean fever. Nat Genet. 1997;17:25–31. Scholar
  15. 15.
    Miceli-Richard C, Lesage S, Rybojad M, et al. CARD15 mutations in Blau syndrome. Nat Genet. 2001;29:19–20. Scholar
  16. 16.
    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. Scholar
  17. 17.
    Ogura Y, Bonen DK, Inohara N, et al. A frameshift mutation in NOD2 associated with susceptibility to Crohn’s disease. Nature. 2001;411:603–6. Scholar
  18. 18.
    Hoffman HM, Mueller JL, Broide DH, 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;29:301–5. Scholar
  19. 19.
    Mathur A, Hayward JA, Man SM. Molecular mechanisms of inflammasome signaling. J Leukoc Biol. 2017;:jlb.3MR0617-250R.
  20. 20.
    He Y, Zeng MY, Yang D, et al. NEK7 is an essential mediator of NLRP3 activation downstream of potassium efflux. Nature. 2016;530:354–7. Scholar
  21. 21.
    Shi H, Wang Y, Li X, et al. NLRP3 activation and mitosis are mutually exclusive events coordinated by NEK7, a new inflammasome component. Nat Immunol. 2016;17:250–8. Scholar
  22. 22.
    Franchi L, Muñoz-Planillo R, Núñez G. Sensing and reacting to microbes through the inflammasomes. Nat Immunol. 2012;13:325–32. Scholar
  23. 23.
    Kayagaki N, Stowe IB, Lee BL, et al. Caspase-11 cleaves gasdermin D for non-canonical inflammasome signalling. Nature. 2015;526:666–71. Scholar
  24. 24.
    He W, Wan H, Hu L, et al. Gasdermin D is an executor of pyroptosis and required for interleukin-1β secretion. Cell Res. 2015;25:1285–98. Scholar
  25. 25.
    Shi J, Zhao Y, Wang K, et al. Cleavage of GSDMD by inflammatory caspases determines pyroptotic cell death. Nature. 2015;526:660–5. Scholar
  26. 26.
    Manthiram K, Zhou Q, Aksentijevich I, et al. The monogenic autoinflammatory diseases define new pathways in human innate immunity and inflammation. Nat Immunol. 2017;18:832–42. Scholar
  27. 27.
    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. Scholar
  28. 28.
    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. Scholar
  29. 29.
    Schulert GS, Grom AA. Pathogenesis of macrophage activation syndrome and potential for cytokine- directed therapies. Annu Rev Med. 2015;66:145–59. Scholar
  30. 30.
    Maeda S, Hsu L-C, Liu H, et al. Nod2 mutation in Crohn’s disease potentiates NF-kappaB activity and IL-1beta processing. Science. 2005;307:734–8. Scholar
  31. 31.
    Kobayashi KS, Chamaillard M, Ogura Y, et al. Nod2-dependent regulation of innate and adaptive immunity in the intestinal tract. Science. 2005;307:731–4. Scholar
  32. 32.
    Yao Q. Nucleotide-binding oligomerization domain containing 2: structure, function, and diseases. Semin Arthritis Rheum. 2013;43:125–30. Scholar
  33. 33.
    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. Scholar
  34. 34.
    Park YH, Wood G, Kastner DL, et al. Pyrin inflammasome activation and RhoA signaling in the autoinflammatory diseases FMF and HIDS. Nat Immunol. 2016;17:914–21. Scholar
  35. 35.
    Jamilloux Y, Lefeuvre L, Magnotti F, et al. Familial Mediterranean fever mutations are hypermorphic mutations that specifically decrease the activation threshold of the Pyrin inflammasome. Rheumatology (Oxford). Published Online First: 12 October 2017. Scholar
  36. 36.
    Favier LA, Schulert GS. Mevalonate kinase deficiency: current perspectives. Appl Clin Genet. 2016;9:101–10. Scholar
  37. 37.
    van der Burgh R, Ter Haar NM, Boes ML, et al. Mevalonate kinase deficiency, a metabolic autoinflammatory disease. Clin Immunol. 2013;147:197–206. Scholar
  38. 38.
    Akula MK, Shi M, Jiang Z, et al. Control of the innate immune response by the mevalonate pathway. Nat Immunol. 2016;17:922–9. Scholar
  39. 39.
    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.CrossRefGoogle Scholar
  40. 40.
    Holzinger D, Fassl SK, de Jager W, et al. Single amino acid charge switch defines clinically distinct proline-serine-threonine phosphatase-interacting protein 1 (PSTPIP1)-associated inflammatory diseases. J Allergy Clin Immunol. 2015;136:1337–45. Scholar
  41. 41.
    Yu J-W, Fernandes-Alnemri T, Datta P, et al. Pyrin activates the ASC pyroptosome in response to engagement by autoinflammatory PSTPIP1 mutants. Mol Cell. 2007;28:214–27. Scholar
  42. 42.
    Waite AL, Schaner P, Hu C, et al. Pyrin and ASC co-localize to cellular sites that are rich in polymerizing actin. Exp Biol Med (Maywood). 2009;234:40–52. Scholar
  43. 43.
    Kim ML, Chae JJ, Park YH, et al. Aberrant actin depolymerization triggers the pyrin inflammasome and autoinflammatory disease that is dependent on IL-18, not IL-1β. J Exp Med. 2015;212:927–38. Scholar
  44. 44.
    Standing ASI, 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. Scholar
  45. 45.
    Gadina M, Gazaniga N, Vian L, et al. Small molecules to the rescue: inhibition of cytokine signaling in immune-mediated diseases. J Autoimmun. Published Online First: 1 July 2017. Scholar
  46. 46.
    Goldbach-Mansky R, Kastner DL. Autoinflammation: the prominent role of IL-1 in monogenic autoinflammatory diseases and implications for common illnesses. J Allergy Clin Immunol. 2009;124:1141–9. Scholar
  47. 47.
    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. Scholar
  48. 48.
    Shouval DS, Biswas A, Kang YH, et al. Interleukin 1β mediates intestinal inflammation in mice and patients with interleukin 10 receptor deficiency. Gastroenterology. 2016;151:1100–4. Scholar
  49. 49.
    Kotlarz D, Beier R, Murugan D, et al. Loss of interleukin-10 signaling and infantile inflammatory bowel disease: implications for diagnosis and therapy. Gastroenterology. 2012;143:347–55. Scholar
  50. 50.
    Glocker E-O, Kotlarz D, Boztug K, et al. Inflammatory bowel disease and mutations affecting the interleukin-10 receptor. N Engl J Med. 2009;361:2033–45. Scholar
  51. 51.
    Williamson LM, Hull D, Mehta R, et al. Familial Hibernian fever. Q J Med. 1982;51:469–80.Google Scholar
  52. 52.
    Gattorno M, Obici L, Cattalini M, et al. Canakinumab treatment for patients with active recurrent or chronic TNF receptor-associated periodic syndrome (TRAPS): an open-label, phase II study. Ann Rheum Dis. 2017;76:173–8. Scholar
  53. 53.
    Cantarini L, Lucherini OM, Muscari I, et al. Tumour necrosis factor receptor-associated periodic syndrome (TRAPS): state of the art and future perspectives. Autoimmun Rev. 2012;12:38–43. Scholar
  54. 54.
    Aganna E, Hammond L, Hawkins PN, et al. Heterogeneity among patients with tumor necrosis factor receptor-associated periodic syndrome phenotypes. Arthritis Rheum. 2003;48:2632–44. Scholar
  55. 55.
    Aksentijevich I, Galon J, Soares M, et al. The tumor-necrosis-factor receptor-associated periodic syndrome: new mutations in TNFRSF1A, ancestral origins, genotype-phenotype studies, and evidence for further genetic heterogeneity of periodic fevers. Am J Hum Genet. 2001;69:301–14. Scholar
  56. 56.
    Lobito AA, Kimberley FC, Muppidi JR, et al. Abnormal disulfide-linked oligomerization results in ER retention and altered signaling by TNFR1 mutants in TNFR1-associated periodic fever syndrome (TRAPS). Blood. 2006;108:1320–7. Scholar
  57. 57.
    Simon A, Park H, Maddipati R, et al. Concerted action of wild-type and mutant TNF receptors enhances inflammation in TNF receptor 1-associated periodic fever syndrome. Proc Natl Acad Sci U S A. 2010;107:9801–6. Scholar
  58. 58.
    Bulua AC, Simon A, Maddipati R, et al. Mitochondrial reactive oxygen species promote production of proinflammatory cytokines and are elevated in TNFR1-associated periodic syndrome (TRAPS). J Exp Med. 2011;208:519–33. Scholar
  59. 59.
    Behrens EM, Koretzky GA. Review: cytokine storm syndrome: looking toward the precision medicine era. Arthritis Rheumatol. 2017;69:1135–43. Scholar
  60. 60.
    Rigante D, Emmi G, Fastiggi M, et al. Macrophage activation syndrome in the course of monogenic autoinflammatory disorders. Clin Rheumatol. 2015;34:1333. Scholar
  61. 61.
    Schulert GS, Canna SW. Convergent pathways of the hyperferritinemic syndromes. Int Immunol. 2018;30:195–203. Scholar
  62. 62.
    Bracaglia C, de Graaf K, Pires Marafon D, et al. Elevated circulating levels of interferon-γ and interferon-γ-induced chemokines characterise patients with macrophage activation syndrome complicating systemic juvenile idiopathic arthritis. Ann Rheum Dis. 2017;76:166–72. Scholar
  63. 63.
    Shimizu M, Nakagishi Y, Yachie A. Distinct subsets of patients with systemic juvenile idiopathic arthritis based on their cytokine profiles. Cytokine. 2013;61:345–8. Scholar
  64. 64.
    Put K, Avau A, Brisse E, et al. Cytokines in systemic juvenile idiopathic arthritis and haemophagocytic lymphohistiocytosis: tipping the balance between interleukin-18 and interferon-γ. Rheumatology (Oxford). 2015;54:1507–17. Scholar
  65. 65.
    Canna SW, Girard C, Malle L, et al. Life-threatening NLRC4-associated hyperinflammation successfully treated with IL-18 inhibition. J Allergy Clin Immunol. 2017;139:1698–701. Scholar
  66. 66.
    Durand M, Troyanov Y, Laflamme P, et al. Macrophage activation syndrome treated with anakinra. J Rheumatol. 2010;37:879–80. Scholar
  67. 67.
    Kelly A, Ramanan AV. A case of macrophage activation syndrome successfully treated with anakinra. Nat Clin Pract Rheumatol. 2008;4:615–20. Scholar
  68. 68.
    Kahn PJ, Cron RQ. Higher-dose Anakinra is effective in a case of medically refractory macrophage activation syndrome. J Rheumatol. 2013;40:743–4. Scholar
  69. 69.
    Prencipe G, Caiello I, Pascarella A, et al. Neutralization of IFN-γ reverts clinical and laboratory features in a mouse model of macrophage activation syndrome. J Allergy Clin Immunol. 2017. Published Online First: 12 August 2017. Scholar
  70. 70.
    Fuertes MB, Woo S-R, Burnett B, et al. Type I interferon response and innate immune sensing of cancer. Trends Immunol. 2013;34:67–73. Scholar
  71. 71.
    Darnell JE, Kerr IM, Stark GR. Jak-STAT pathways and transcriptional activation in response to IFNs and other extracellular signaling proteins. Science. 1994;264:1415–21.CrossRefGoogle Scholar
  72. 72.
    Lee CK, Rao DT, Gertner R, et al. Distinct requirements for IFNs and STAT1 in NK cell function. J Immunol. 2000;165:3571–7.CrossRefGoogle Scholar
  73. 73.
    Nguyen KB, Salazar-Mather TP, Dalod MY, et al. Coordinated and distinct roles for IFN-alpha beta, IL-12, and IL-15 regulation of NK cell responses to viral infection. J Immunol. 2002;169:4279–87.CrossRefGoogle Scholar
  74. 74.
    Montoya M, Schiavoni G, Mattei F, et al. Type I interferons produced by dendritic cells promote their phenotypic and functional activation. Blood. 2002;99:3263–71.CrossRefGoogle Scholar
  75. 75.
    Spadaro F, Lapenta C, Donati S, et al. IFN-α enhances cross-presentation in human dendritic cells by modulating antigen survival, endocytic routing, and processing. Blood. 2012;119:1407–17. Scholar
  76. 76.
    Fink K, Lang KS, Manjarrez-Orduno N, et al. Early type I interferon-mediated signals on B cells specifically enhance antiviral humoral responses. Eur J Immunol. 2006;36:2094–105. Scholar
  77. 77.
    Kolumam GA, Thomas S, Thompson LJ, et al. Type I interferons act directly on CD8 T cells to allow clonal expansion and memory formation in response to viral infection. J Exp Med. 2005;202:637–50. Scholar
  78. 78.
    Shrivastav M, Niewold TB. Nucleic acid sensors and type I interferon production in systemic lupus erythematosus. Front Immunol. 2013;4:319. Scholar
  79. 79.
    Jensen KE, Neal AL, Owens RE, et al. Interferon responses of Chick embryo fibroblasts to nucleic acids and related compounds. Nature. 1963;200:433–4.CrossRefGoogle Scholar
  80. 80.
    Ishikawa H, Ma Z, Barber GN. STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity. Nature. 2009;461:788–92. Scholar
  81. 81.
    Ishikawa H, Barber GN. STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling. Nature. 2008;455:674–8. Scholar
  82. 82.
    Burdette DL, Monroe KM, Sotelo-Troha K, et al. STING is a direct innate immune sensor of cyclic di-GMP. Nature. 2011;478:515–8. Scholar
  83. 83.
    Wu J, Sun L, Chen X, et al. Cyclic GMP-AMP is an endogenous second messenger in innate immune signaling by cytosolic DNA. Science. 2013;339:826–30. Scholar
  84. 84.
    Sun L, Wu J, Du F, et al. Cyclic GMP-AMP synthase is a cytosolic DNA sensor that activates the type I interferon pathway. Science. 2013;339:786–91. Scholar
  85. 85.
    Liu Y, Jesus AA, Marrero B, et al. Activated STING in a vascular and pulmonary syndrome. N Engl J Med. 2014;371:507–18. Scholar
  86. 86.
    König N, Fiehn C, Wolf C, et al. Familial chilblain lupus due to a gain-of-function mutation in STING. Ann Rheum Dis. 2017;76:468–72. Scholar
  87. 87.
    Melki I, Rose Y, Uggenti C, et al. Disease-associated mutations identify a novel region in human STING necessary for the control of type I interferon signaling. J Allergy Clin Immunol. 2017;140:543–552.e5 Published Online First: 3 January 2017. Scholar
  88. 88.
    Moghaddas F, Masters SL. Monogenic autoinflammatory diseases: Cytokinopathies. Cytokine. 2015;74:237–46. Scholar
  89. 89.
    Crow YJ. Type I interferonopathies: a novel set of inborn errors of immunity. Ann N Y Acad Sci. 2011;1238:91–8. Scholar
  90. 90.
    Kato H, Takeuchi O, Sato S, et al. Differential roles of MDA5 and RIG-I helicases in the recognition of RNA viruses. Nature. 2006;441:101–5. Scholar
  91. 91.
    Hornung V, Ellegast J, Kim S, et al. 5′-Triphosphate RNA is the ligand for RIG-I. Science. 2006;314:994–7. Scholar
  92. 92.
    Kawai T, Akira S. Innate immune recognition of viral infection. Nat Immunol. 2006;7:131–7. Scholar
  93. 93.
    Loo Y-M, Gale M. Immune signaling by RIG-I-like receptors. Immunity. 2011;34:680–92. Scholar
  94. 94.
    Hou F, Sun L, Zheng H, et al. MAVS forms functional prion-like aggregates to activate and propagate antiviral innate immune response. Cell. 2011;146:448–61. Scholar
  95. 95.
    Rice GI, Bond J, Asipu A, et al. Mutations involved in Aicardi-Goutières syndrome implicate SAMHD1 as regulator of the innate immune response. Nat Genet. 2009;41:829–32. Scholar
  96. 96.
    Grieves JL, Fye JM, Harvey S, et al. Exonuclease TREX1 degrades double-stranded DNA to prevent spontaneous lupus-like inflammatory disease. Proc Natl Acad Sci U S A. 2015;112:5117–22. Scholar
  97. 97.
    Crow YJ, Hayward BE, Parmar R, et al. Mutations in the gene encoding the 3′-5’ DNA exonuclease TREX1 cause Aicardi-Goutières syndrome at the AGS1 locus. Nat Genet. 2006;38:917–20. Scholar
  98. 98.
    Crow YJ, Leitch A, Hayward BE, et al. Mutations in genes encoding ribonuclease H2 subunits cause Aicardi-Goutières syndrome and mimic congenital viral brain infection. Nat Genet. 2006;38:910–6. Scholar
  99. 99.
    Volpi S, Picco P, Caorsi R, et al. Type I interferonopathies in pediatric rheumatology. Pediatr Rheumatol. 2016;14:35. Scholar
  100. 100.
    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. Scholar
  101. 101.
    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. Scholar
  102. 102.
    Brehm A, Liu Y, Sheikh A, et al. Additive loss-of-function proteasome subunit mutations in CANDLE/PRAAS patients promote type I IFN production. J Clin Invest. 2015;125:4196–211. Scholar
  103. 103.
    de Jesus AA, Canna SW, Liu Y, et al. Molecular mechanisms in genetically defined autoinflammatory diseases: disorders of amplified danger signaling. Annu Rev Immunol. 2015;33:823–74. Scholar

Copyright information

© Springer Nature Switzerland AG 2019

Authors and Affiliations

  1. 1.Division of RheumatologyCincinnati Children’s Hospital Medical CenterCincinnatiUSA
  2. 2.Department of PediatricsUniversity of CincinnatiCincinnatiUSA

Personalised recommendations