Skip to main content
SpringerLink
Log in

Pattern Recognition Receptors in Autoinflammation

  • Chapter
  • First Online:
Textbook of Autoinflammation

Abstract

The immune system is essential for maintenance of tissue homeostasis. This task requires that immune cells detect and respond to dyshomeostatic states (when homeostasis has broken down) that can occur during invasion of the host with pathogenic microbes, after sterile trauma of tissues or during metabolic derangements. Research in the field of innate immunity has uncovered many molecular mechanisms by which the immune system can prevent the spread of infection, restore damaged tissues and respond to altered metabolism. These pathways involve different classes of pattern recognition receptors, some of which can directly detect minimal motifs (patterns) that are common to multiple pathogens or types of damaged cells. Here, we summarize the general concepts that have been developed to explain how immune recognition of dyshomeostasis is achieved and discuss our current knowledge of the innate immune signaling receptors that are known to directly bind ligands.

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

Access this chapter

Log in via an institution
Chapter
USD 29.95
Price excludes VAT (USA)
  • Available as PDF
  • Read on any device
  • Instant download
  • Own it forever
eBook
USD 169.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Hardcover Book
USD 219.99
Price excludes VAT (USA)
  • Durable hardcover edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info

Tax calculation will be finalised at checkout

Purchases are for personal use only

Institutional subscriptions

Abbreviations

ADAR1:

Adenosine deaminase acting on RNA 1

AGS:

Aicardi-Goutières syndrome

AIM2:

Absent in melanoma 2

ASC:

Apoptosis related speck-like protein containing CARD

ATP:

Adenosine triphosphate

BS:

Blau syndrome

CARD:

Caspase activation and recruitment domain

CD:

Crohn’s disease

CDN:

Cyclic dinucleotides

cGAMP:

Cyclic GMP-AMP

cGAS:

cGAMP synthase

CLR:

C-type lectin receptor

CRISPR:

Clustered regularly interspaced short palindromic repeats

CTLD:

C-type lectin like domain

DAMP:

Damage associated molecular patterns

DAP:

Diaminopimelic acid

DC-SIGN:

Dendritic cell-specific intercellular adhesion molecule-3-grabbing non-integrin

dsDNA:

Double-stranded DNA

dsRNA:

Double-stranded RNA

EOS:

Early onset sarcoidosis

FcRγ:

Fc receptor gamma chain

GTP:

Guanosine triphosphate

HA:

Hyaluronic acid

HAMP:

Homeostasis-altering molecular processes

HIN:

Hematopoietic expression, interferon-inducible nature, and nuclear localization

HIV:

Human immunodeficiency virus

HMGB:

High mobility group box 1

HMW:

High molecular weight

HSE:

Herpes simplex encephalitis

HSP:

Heat shock protein

IBD:

Inflammatory bowel disease

IFN:

Interferon

IFNAR:

Interferon alpha/beta receptor 1

IKK:

IκB kinase

IL:

Interleukin

IRF3:

Interferon regulatory factor 3

ITAM:

Immunoreceptor tyrosine-based activation motif

ITIM:

Immunoreceptor tyrosine-based inhibition motif

IκB:

Inhibitor of NF-ĸB

JAK:

Janus kinase

KO:

Knock-out

LGP2:

Laboratory of genetics and physiology 2

LMW:

Low molecular weight

LOX-1:

Lectin-like oxidized LDL receptor 1

LPS:

Lipopolysaccharide

LRR:

Leucine-rich-repeat

MAL:

MyD88 adaptor like (= TIRAP)

MAPK:

Mitogen-activated protein kinase 1

MAVS:

Mitochondrial antiviral signaling

MCMV:

Mouse cytomegalovirus

MD2:

Myeloid differentiation factor 2

MDA5:

Melanoma differentiation-associated protein 5

MDP:

Muramyl dipeptide

MICL:

Myeloid inhibitory C-type lectin

Mincle:

Macrophage-inducible C-type lectin

miRNA:

Micro RNA

mRNA:

Messenger RNA

MSU:

Monosodium urate

MyD88:

Myeloid differentiation primary response gene 88

NBS:

Nucleotide binding site

NFAT:

Nuclear factor of activated T-cells

NF-ĸB:

Nuclear factor–ĸB

NK:

Natural killer

NLR:

NOD-like receptor

NLRP:

NOD-like receptor protein

NOD:

Nucleotide-binding oligomerization domain

oxPAPC:

Oxidized 1-palmitoyl-2-arachidonoyl-sn-glycero-3-phosphorylcholine

PAMP:

Pathogen-associated molecular patterns

PBMCs:

Peripheral blood mononuclear cells

pDCs:

Plasmacytoid dendritic cells

PID:

Primary immunodeficiency

POP:

PYD-only protein

PRR:

Pattern-recognition receptors

PYD:

Pyrin domain

RIG-I:

Retinoic acid-inducible gene 1

RIPK2:

Receptor-interacting serine/threonine kinase 2

RLR:

RIG-I-like receptor

RNA:

Ribonucleic acid

ROS:

Reactive oxygen species

SARM:

Sterile α- and armadillo motif containing protein

SAVI:

STING-associated vasculopathy with onset in infancy

SH2:

Src homology region 2

SHP:

SH2 domain-containing phosphatase

siRNA:

Small interfering RNA

SMS:

Singleton-Merten syndrome

SNP:

Single nucleotide polymorphism

ssRNA:

Single stranded RNA

STAT:

Signal transducer and activator of transcription

STING:

Stimulator of interferon genes

TBK1:

TANK-binding kinase 1

TFAM:

Mitochondrial transcription factor A

TIR:

Toll/IL-1 receptor

TIRAP:

TIR domain containing adaptor protein (= MAL)

TLR:

Toll-like receptor

TMEM173:

Transmembrane protein 173

TRAM:

TRIF-related adaptor molecule

TREX:

Three-prime repair exonuclease 1

TRIF:

TIR-domain containing adaptor protein inducing IFN-β (=TICAM1)

tRNA:

Transfer RNA

UNC93B1:

Unc-93 homologue B1

WES:

Whole exome sequencing

WT:

Wild type

References

  1. Janeway CA Jr. Approaching the asymptote? Evolution and revolution in immunology. Cold Spring Harb Symp Quant Biol. 1989;54(Pt 1):1–13.

    Article  CAS  PubMed  Google Scholar 

  2. Raetz CRH, Whitfield C. Lipopolysaccharide endotoxins. Annu Rev Biochem. 2002;71:635–700.

    Article  CAS  PubMed  Google Scholar 

  3. Trent MS, Stead CM, Tran AX, Hankins JV. Diversity of endotoxin and its impact on pathogenesis. J Endotoxin Res. 2006;12:205–23.

    Google Scholar 

  4. Backhed F, Normark S, Schweda EK, et al. Structural requirements for TLR4-mediated LPS signalling: a biological role for LPS modifications. Microbes Infect. 2003;5:1057–63.

    Article  PubMed  CAS  Google Scholar 

  5. Seong SY, Matzinger P. Hydrophobicity: an ancient damage-associated molecular pattern that initiates innate immune responses. Nat Rev Immunol. 2004;4:469–78.

    Article  CAS  PubMed  Google Scholar 

  6. Bianchi ME. DAMPs, PAMPs and alarmins: all we need to know about danger. J Leukoc Biol. 2007;81:1–5.

    Google Scholar 

  7. Wang H, Bloom O, Zhang M, et al. HMG-1 as a late mediator of endotoxin lethality in mice. Science. 1999;285:248–51.

    Article  CAS  PubMed  Google Scholar 

  8. Andersson U, Wang H, Palmblad K, et al. High mobility group 1 protein (HMG-1) stimulates proinflammatory cytokine synthesis in human monocytes. J Exp Med. 2000;192:565–70.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  9. Scaffidi P, Misteli T, Bianchi ME. Release of chromatin protein HMGB1 by necrotic cells triggers inflammation. Nature. 2002;418:191–5.

    Article  CAS  PubMed  Google Scholar 

  10. Shi Y, Evans JE, Rock KL. Molecular identification of a danger signal that alerts the immune system to dying cells. Nature. 2003;425:516–21.

    Article  CAS  PubMed  Google Scholar 

  11. Martinon F, Pétrilli V, Mayor A, et al. Gout-associated uric acid crystals activate the NALP3 inflammasome. Nature. 2006;440:237–41.

    Article  CAS  PubMed  Google Scholar 

  12. Laurent TC, Laurent UB, Fraser JR. The structure and function of hyaluronan: an overview. Immunol Cell Biol. 1996;74:A1–7.

    Article  CAS  PubMed  Google Scholar 

  13. Elias JA, Krol RC, Freundlich B, Sampson PM. Regulation of human lung fibroblast glycosaminoglycan production by recombinant interferons, tumor necrosis factor, and lymphotoxin. J Clin Invest. 1988;81:325–33.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Sampson PM, Rochester CL, Freundlich B, Elias JA. Cytokine regulation of human lung fibroblast hyaluronan (hyaluronic acid) production. Evidence for cytokine-regulated hyaluronan (hyaluronic acid) degradation and human lung fibroblast-derived hyaluronidase. J Clin Invest. 1992;90:1492–503.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Scheibner KA, Lutz MA, Boodoo S, et al. Hyaluronan fragments act as an endogenous danger signal by engaging TLR2. J Immunol. 2006;177:1272–81.

    Article  CAS  PubMed  Google Scholar 

  16. Liston A, Masters SL. Homeostasis-altering molecular processes as mechanisms of inflammasome activation. Nat Rev Immunol. 2017;17:208–14.

    Article  CAS  PubMed  Google Scholar 

  17. Anderson KV, Bokla L, Nusslein-Volhard C. Establishment of dorsal-ventral polarity in the Drosophila embryo: the induction of polarity by the Toll gene product. Cell. 1985;42:791–8.

    Article  CAS  PubMed  Google Scholar 

  18. Lemaitre B, Nicolas E, Michaut L, et al. The dorsoventral regulatory gene cassette spatzle/Toll/cactus controls the potent antifungal response in Drosophila adults. Cell. 1996;86:973–83.

    Article  CAS  PubMed  Google Scholar 

  19. Michel T, Reichhart JM, Hoffmann JA, Royet J. Drosophila Toll is activated by Gram-positive bacteria through a circulating peptidoglycan recognition protein. Nature. 2001;414:756–9.

    Article  CAS  PubMed  Google Scholar 

  20. Medzhitov R, Preston-Hurlburt P, Janeway CA Jr. A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. Nature. 1997;388:394–7.

    Article  CAS  PubMed  Google Scholar 

  21. Bell JK, Mullen GE, Leifer CA, et al. Leucine-rich repeats and pathogen recognition in Toll-like receptors. Trends Immunol. 2003;24:528–33.

    Article  CAS  PubMed  Google Scholar 

  22. Botos I, Segal DM, Davies DR. The structural biology of Toll-like receptors. Structure. 2011;19:447–59.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Kang JY, Lee JO. Structural biology of the Toll-like receptor family. Annu Rev Biochem. 2011;80:917–41.

    Article  CAS  PubMed  Google Scholar 

  24. Gay NJ, Gangloff M. Structure and function of Toll receptors and their ligands. Annu Rev Biochem. 2007;76:141–65.

    Article  CAS  PubMed  Google Scholar 

  25. Weber AN, Moncrieffe MC, Gangloff M, et al. Ligand-receptor and receptor-receptor interactions act in concert to activate signaling in the Drosophila toll pathway. J Biol Chem. 2005;280:22793–9.

    Article  CAS  PubMed  Google Scholar 

  26. Gay NJ, Gangloff M, Weber AN. Toll-like receptors as molecular switches. Nat Rev Immunol. 2006;6:693–8.

    Article  CAS  PubMed  Google Scholar 

  27. Poltorak A, He X, Smirnova I, et al. Defective LPS signaling in C3H/HeJ and C57BL/10ScCr mice: mutations in Tlr4 gene. Science. 1998;282:2085–8.

    Article  CAS  PubMed  Google Scholar 

  28. Xu Y, Tao X, Shen B, et al. Structural basis for signal transduction by the Toll/interleukin-1 receptor domains. Nature. 2000;408:111–5.

    Article  CAS  PubMed  Google Scholar 

  29. Hultmark D. Macrophage differentiation marker MyD88 is a member of the Toll/IL-1 receptor family. Biochem Biophys Res Commun. 1994;199:144–6.

    Article  CAS  PubMed  Google Scholar 

  30. Hardiman G, Rock FL, Balasubramanian S, et al. Molecular characterization and modular analysis of human MyD88. Oncogene. 1996;13:2467–75.

    Google Scholar 

  31. Medzhitov R, Preston-Hurlburt P, Kopp E, et al. MyD88 is an adaptor protein in the hToll/IL-1 receptor family signaling pathways. Mol Cell. 1998;2:253–8.

    Article  CAS  PubMed  Google Scholar 

  32. Adachi O, Kawai T, Takeda K, et al. Targeted disruption of the MyD88 gene results in loss of IL-1- and IL-18-mediated function. Immunity. 1998;9:143–50.

    Article  CAS  PubMed  Google Scholar 

  33. Burns K, Martinon F, Esslinger C, et al. MyD88, an adapter protein involved in interleukin-1 signaling. J Biol Chem. 1998;273:12203–9.

    Article  CAS  PubMed  Google Scholar 

  34. Wesche H, Henzel WJ, Shillinglaw W, et al. MyD88: an adapter that recruits IRAK to the IL-1 receptor complex. Immunity. 1997;7:837–47.

    Article  CAS  PubMed  Google Scholar 

  35. Kawai T, Adachi O, Ogawa T, et al. Unresponsiveness of MyD88-deficient mice to endotoxin. Immunity. 1999;11:115–22.

    Article  CAS  PubMed  Google Scholar 

  36. von Bernuth H, Picard C, Jin Z, et al. Pyogenic bacterial infections in humans with MyD88 deficiency. Science. 2008;321:691–6.

    Google Scholar 

  37. Horng T, Barton GM, Medzhitov R. TIRAP: an adapter molecule in the Toll signaling pathway. Nat Immunol. 2001;2:835–41.

    Article  CAS  PubMed  Google Scholar 

  38. Horng T, Barton GM, Flavell RA, Medzhitov R. The adaptor molecule TIRAP provides signalling specificity for Toll-like receptors. Nature. 2002;420:329–33.

    Article  CAS  PubMed  Google Scholar 

  39. Yamamoto M, Sato S, Mori K, et al. Cutting edge: a novel Toll/IL-1 receptor domain-containing adapter that preferentially activates the IFN-beta promoter in the Toll-like receptor signaling. J Immunol. 2002;169:6668–72.

    Article  CAS  PubMed  Google Scholar 

  40. Oshiumi H, Matsumoto M, Funami K, et al. TICAM-1, an adaptor molecule that participates in Toll-like receptor 3-mediated interferon-beta induction. Nat Immunol. 2003;4:161–7.

    Article  CAS  PubMed  Google Scholar 

  41. Yamamoto M, Sato S, Hemmi H, et al. Role of adaptor TRIF in the MyD88-independent toll-like receptor signaling pathway. Science. 2003;301:640–3.

    Article  CAS  PubMed  Google Scholar 

  42. Sancho-Shimizu V, Perez de Diego R, Lorenzo L, et al. Herpes simplex encephalitis in children with autosomal recessive and dominant TRIF deficiency. J Clin Invest. 2011;121:4889–902.

    Google Scholar 

  43. Yamamoto M, Sato S, Hemmi H, et al. TRAM is specifically involved in the Toll-like receptor 4-mediated MyD88-independent signaling pathway. Nat Immunol. 2003;4:1144–50.

    Article  CAS  PubMed  Google Scholar 

  44. Fitzgerald KA, Rowe DC, Barnes BJ, et al. LPS-TLR4 signaling to IRF-3/7 and NF-kappaB involves the toll adapters TRAM and TRIF. J Exp Med. 2003;198:1043–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Kagan JC, Su T, Horng T, et al. TRAM couples endocytosis of Toll-like receptor 4 to the induction of interferon-beta. Nat Immunol. 2008;9:361–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  46. Carty M, Goodbody R, Schroder M, et al. The human adaptor SARM negatively regulates adaptor protein TRIF-dependent Toll-like receptor signaling. Nat Immunol. 2006;7:1074–81.

    Article  CAS  PubMed  Google Scholar 

  47. Pelka K, Bertheloot D, Reimer E, et al. The chaperone UNC93B1 regulates Toll-like receptor stability independently of endosomal TLR transport. Immunity. 2018;48:911–922.e7.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  48. Kim YM, Brinkmann MM, Paquet ME, Ploegh HL. UNC93B1 delivers nucleotide-sensing toll-like receptors to endolysosomes. Nature. 2008;452:234–8.

    Article  CAS  PubMed  Google Scholar 

  49. Brinkmann MM, Spooner E, Hoebe K, et al. The interaction between the ER membrane protein UNC93B and TLR3, 7, and 9 is crucial for TLR signaling. J Cell Biol. 2007;177:265–75.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Casrouge A, Zhang SY, Eidenschenk C, et al. Herpes simplex virus encephalitis in human UNC-93B deficiency. Science. 2006;314:308–12.

    Article  CAS  PubMed  Google Scholar 

  51. Ozinsky A, Underhill DM, Fontenot JD, et al. The repertoire for pattern recognition of pathogens by the innate immune system is defined by cooperation between toll-like receptors. Proc Natl Acad Sci U S A. 2000;97:13766–71.

    Article  CAS  Google Scholar 

  52. Vignal C, Guerardel Y, Kremer L, et al. Lipomannans, but not lipoarabinomannans, purified from Mycobacterium chelonae and Mycobacterium kansasii induce TNF-alpha and IL-8 secretion by a CD14-toll-like receptor 2-dependent mechanism. J Immunol. 2003;171:2014–23.

    Article  CAS  PubMed  Google Scholar 

  53. Quesniaux VJ, Nicolle DM, Torres D, et al. Toll-like receptor 2 (TLR2)-dependent-positive and TLR2-independent-negative regulation of proinflammatory cytokines by mycobacterial lipomannans. J Immunol. 2004;172:4425–34.

    Article  CAS  PubMed  Google Scholar 

  54. Elass E, Aubry L, Masson M, et al. Mycobacterial lipomannan induces matrix metalloproteinase-9 expression in human macrophagic cells through a Toll-like receptor 1 (TLR1)/TLR2- and CD14-dependent mechanism. Infect Immun. 2005;73:7064–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Schwandner R, Dziarski R, Wesche H, et al. Peptidoglycan- and lipoteichoic acid-induced cell activation is mediated by toll-like receptor 2. J Biol Chem. 1999;274:17406–9.

    Article  CAS  PubMed  Google Scholar 

  56. Takeuchi O, Kawai T, Muhlradt PF, et al. Discrimination of bacterial lipoproteins by Toll-like receptor 6. Int Immunol. 2001;13:933–40.

    Article  CAS  PubMed  Google Scholar 

  57. Schenk M, Belisle JT, Modlin RL. TLR2 looks at lipoproteins. Immunity. 2009;31:847–9.

    Article  CAS  PubMed  Google Scholar 

  58. Kang TJ, Chae GT. Detection of Toll-like receptor 2 (TLR2) mutation in the lepromatous leprosy patients. FEMS Immunol Med Microbiol. 2001;31:53–8.

    Article  CAS  Google Scholar 

  59. Malhotra D, Relhan V, Reddy BS, Bamezai R. TLR2 Arg677Trp polymorphism in leprosy: revisited. Hum Genet. 2005;116:413–5.

    Article  CAS  PubMed  Google Scholar 

  60. Ogus AC, Yoldas B, Ozdemir T, et al. The Arg753GLn polymorphism of the human toll-like receptor 2 gene in tuberculosis disease. Eur Respir J. 2004;23:219–23.

    Article  CAS  PubMed  Google Scholar 

  61. Ben-Ali M, Barbouche MR, Bousnina S, et al. Toll-like receptor 2 Arg677Trp polymorphism is associated with susceptibility to tuberculosis in Tunisian patients. Clin Diagn Lab Immunol. 2004;11:625–6.

    Article  CAS  Google Scholar 

  62. Chuang T, Ulevitch RJ. Identification of hTLR10: a novel human Toll-like receptor preferentially expressed in immune cells. Biochim Biophys Acta. 2001;1518:157–61.

    Article  CAS  Google Scholar 

  63. Hasan U, Chaffois C, Gaillard C, et al. Human TLR10 is a functional receptor, expressed by B cells and plasmacytoid dendritic cells, which activates gene transcription through MyD88. J Immunol. 2005;174:2942–50.

    Article  CAS  PubMed  Google Scholar 

  64. Vogel SN, Wax JS, Perera PY, et al. Construction of a BALB/c congenic mouse, C.C3H-Lpsd, that expresses the Lpsd allele: analysis of chromosome 4 markers surrounding the Lps gene. Infect Immun. 1994;62:4454–9.

    Google Scholar 

  65. Watson J, Riblet R. Genetic control of responses to bacterial lipopolysaccharides in mice. I. Evidence for a single gene that influences mitogenic and immunogenic respones to lipopolysaccharides. J Exp Med. 1974;140:1147–61.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Coutinho A, Meo T. Genetic basis for unresponsiveness to lipopolysaccharide in C57BL/10Cr mice. Immunogenetics. 1978;7:17–24.

    Article  CAS  PubMed  Google Scholar 

  67. Qureshi ST, Lariviere L, Leveque G, et al. Endotoxin-tolerant mice have mutations in Toll-like receptor 4 (Tlr4). J Exp Med. 1999;189:615–25.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Kirschning CJ, Wesche H, Merrill Ayres T, Rothe M. Human toll-like receptor 2 confers responsiveness to bacterial lipopolysaccharide. J Exp Med. 1998;188:2091–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Shimazu R, Akashi S, Ogata H, et al. MD-2, a molecule that confers lipopolysaccharide responsiveness on Toll-like receptor 4. J Exp Med. 1999;189:1777–82.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  70. Wright SD. Toll, a new piece in the puzzle of innate immunity. J Exp Med. 1999;189:605–9.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  71. da Silva Correia J, Ulevitch RJ. MD-2 and TLR4 N-linked glycosylations are important for a functional lipopolysaccharide receptor. J Biol Chem. 2002;277:1845–54.

    Google Scholar 

  72. Visintin A, Mazzoni A, Spitzer JA, Segal DM. Secreted MD-2 is a large polymeric protein that efficiently confers lipopolysaccharide sensitivity to Toll-like receptor 4. Proc Natl Acad Sci U S A. 2001;98:12156–61.

    Article  CAS  Google Scholar 

  73. Nagai Y, Akashi S, Nagafuku M, et al. Essential role of MD-2 in LPS responsiveness and TLR4 distribution. Nat Immunol. 2002;3:667–72.

    Article  CAS  PubMed  Google Scholar 

  74. Lek M, Karczewski KJ, Minikel EV, et al. Analysis of protein-coding genetic variation in 60,706 humans. Nature. 2016;536:285–91.

    Google Scholar 

  75. Arbour NC, Lorenz E, Schutte BC, et al. TLR4 mutations are associated with endotoxin hyporesponsiveness in humans. Nat Genet. 2000;25:187–91.

    Article  CAS  PubMed  Google Scholar 

  76. Sebastiani G, Leveque G, Lariviere L, et al. Cloning and characterization of the murine toll-like receptor 5 (Tlr5) gene: sequence and mRNA expression studies in Salmonella-susceptible MOLF/Ei mice. Genomics. 2000;64:230–40.

    Article  CAS  PubMed  Google Scholar 

  77. Sebastiani G, Olien L, Gauthier S, et al. Mapping of genetic modulators of natural resistance to infection with Salmonella typhimurium in wild-derived mice. Genomics. 1998;47:180–6.

    Article  CAS  PubMed  Google Scholar 

  78. Hayashi F, Smith KD, Ozinsky A, et al. The innate immune response to bacterial flagellin is mediated by Toll-like receptor 5. Nature. 2001;410:1099–103.

    Google Scholar 

  79. Andersen-Nissen E, Smith KD, Bonneau R, et al. A conserved surface on Toll-like receptor 5 recognizes bacterial flagellin. J Exp Med. 2007;204:393–403.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Smith KD, Andersen-Nissen E, Hayashi F, et al. Toll-like receptor 5 recognizes a conserved site on flagellin required for protofilament formation and bacterial motility. Nat Immunol. 2003;4:1247–53.

    Article  CAS  PubMed  Google Scholar 

  81. Vijay-Kumar M, Aitken JD, Carvalho FA, et al. Metabolic syndrome and altered gut microbiota in mice lacking Toll-like receptor 5. Science. 2010;328:228–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  82. Muzio M, Bosisio D, Polentarutti N, et al. Differential expression and regulation of toll-like receptors (TLR) in human leukocytes: selective expression of TLR3 in dendritic cells. J Immunol. 2000;164:5998–6004.

    Article  CAS  PubMed  Google Scholar 

  83. Alexopoulou L, Holt AC, Medzhitov R, Flavell RA. Recognition of double-stranded RNA and activation of NF-kappaB by Toll-like receptor 3. Nature. 2001;413:732–8.

    Article  CAS  PubMed  Google Scholar 

  84. Leonard JN, Ghirlando R, Askins J, et al. The TLR3 signaling complex forms by cooperative receptor dimerization. Proc Natl Acad Sci U S A. 2008;105:258–63.

    Article  CAS  Google Scholar 

  85. Liu L, Botos I, Wang Y, et al. Structural basis of toll-like receptor 3 signaling with double-stranded RNA. Science. 2008;320:379–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Zhang SY, Jouanguy E, Ugolini S, et al. TLR3 deficiency in patients with herpes simplex encephalitis. Science. 2007;317:1522–7.

    Google Scholar 

  87. Hemmi H, Takeuchi O, Kawai T, et al. A Toll-like receptor recognizes bacterial DNA. Nature. 2000;408:740–5.

    Article  CAS  PubMed  Google Scholar 

  88. Krieg AM. The role of CpG motifs in innate immunity. Curr Opin Immunol. 2000;12:35–43.

    Article  CAS  PubMed  Google Scholar 

  89. Bauer S, Kirschning CJ, Hacker H, et al. Human TLR9 confers responsiveness to bacterial DNA via species-specific CpG motif recognition. Proc Natl Acad Sci U S A. 2001;98:9237–42.

    Article  CAS  Google Scholar 

  90. Ohto U, Shibata T, Tanji H, et al. Structural basis of CpG and inhibitory DNA recognition by Toll-like receptor 9. Nature. 2015;520:702–5.

    Article  CAS  PubMed  Google Scholar 

  91. Hemmi H, Kaisho T, Takeuchi O, et al. Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway. Nat Immunol. 2002;3:196–200.

    Article  CAS  PubMed  Google Scholar 

  92. Lee J, Chuang TH, Redecke V, et al. Molecular basis for the immunostimulatory activity of guanine nucleoside analogs: activation of Toll-like receptor 7. Proc Natl Acad Sci U S A. 2003;100:6646–51.

    Article  CAS  Google Scholar 

  93. Diebold SS, Kaisho T, Hemmi H, et al. Innate antiviral responses by means of TLR7-mediated recognition of single-stranded RNA. Science. 2004;303:1529–31.

    Article  CAS  PubMed  Google Scholar 

  94. Jurk M, Heil F, Vollmer J, et al. Human TLR7 or TLR8 independently confer responsiveness to the antiviral compound R-848. Nat Immunol. 2002;3:499.

    Article  CAS  PubMed  Google Scholar 

  95. Heil F, Hemmi H, Hochrein H, et al. Species-specific recognition of single-stranded RNA via toll-like receptor 7 and 8. Science. 2004;303:1526–9.

    Article  CAS  PubMed  Google Scholar 

  96. Zhang S, Hu Z, Tanji H, et al. Small-molecule inhibition of TLR8 through stabilization of its resting state. Nat Chem Biol. 2018;14:58–64.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  97. Kubli-Garfias C, Vázquez-Ramírez R, Trejo-Muñoz C, Berber A. Insights on the mechanism of action of immunostimulants in relation to their pharmacological potency. The effects of imidazoquinolines on TLR8. PLoS One. 2017;12:e0178846.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  98. Zhang Z, Ohto U, Shibata T, et al. Structural analysis reveals that Toll-like receptor 7 is a dual receptor for guanosine and single-stranded RNA. Immunity. 2016;45:737–48.

    Article  CAS  PubMed  Google Scholar 

  99. Tanji H, Ohto U, Shibata T, et al. Structural reorganization of the Toll-like receptor 8 dimer induced by agonistic ligands. Science. 2013;339:1426–9.

    Article  CAS  PubMed  Google Scholar 

  100. Ting JP-Y, Lovering RC, Alnemri ES, et al. The NLR gene family: a standard nomenclature. Immunity. 2008;28:285–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  101. Bertin J, Nir WJ, Fischer CM, et al. Human CARD4 protein is a novel CED-4/Apaf-1 cell death family member that activates NF-kappaB. J Biol Chem. 1999;274:12955–8.

    Google Scholar 

  102. Inohara N, Koseki T, del Peso L, et al. Nod1, an Apaf-1-like activator of caspase-9 and nuclear factor-kappaB. J Biol Chem. 1999;274:14560–7.

    Google Scholar 

  103. McCarthy JV, Ni J, Dixit VM. RIP2 is a novel NF-kappaB-activating and cell death-inducing kinase. J Biol Chem. 1998;273:16968–75.

    Google Scholar 

  104. Inohara N, Koseki T, Lin J, et al. An induced proximity model for NF-kappa B activation in the Nod1/RICK and RIP signaling pathways. J Biol Chem. 2000;275:27823–31.

    Google Scholar 

  105. Inohara N, Ogura Y, Chen FF, et al. Human Nod1 confers responsiveness to bacterial lipopolysaccharides. J Biol Chem. 2001;276:2551–4.

    Article  PubMed  Google Scholar 

  106. Chamaillard M, Hashimoto M, Horie Y, et al. An essential role for NOD1 in host recognition of bacterial peptidoglycan containing diaminopimelic acid. Nat Immunol. 2003;4:702–7.

    Article  CAS  PubMed  Google Scholar 

  107. Girardin SE, Boneca IG, Carneiro LA, et al. Nod1 detects a unique muropeptide from gram-negative bacterial peptidoglycan. Science. 2003;300:1584–7.

    Article  CAS  PubMed  Google Scholar 

  108. Keestra AM, Winter MG, Auburger JJ, et al. Manipulation of small Rho GTPases is a pathogen-induced process detected by NOD1. Nature. 2013;496:233–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Ogura Y, Inohara N, Benito A, et al. Nod2, a Nod1/Apaf-1 family member that is restricted to monocytes and activates NF-kappaB. J Biol Chem. 2001;276:4812–8.

    Google Scholar 

  110. 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  PubMed  Google Scholar 

  111. 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.

    Article  CAS  PubMed  Google Scholar 

  112. Girardin SE, Boneca IG, Viala J, et al. Nod2 is a general sensor of peptidoglycan through muramyl dipeptide (MDP) detection. J Biol Chem. 2003;278:8869–72.

    Article  CAS  PubMed  Google Scholar 

  113. Cooney R, Baker J, Brain O, et al. NOD2 stimulation induces autophagy in dendritic cells influencing bacterial handling and antigen presentation. Nat Med. 2010;16:90–7.

    Article  PubMed  CAS  Google Scholar 

  114. Blau EB. Familial granulomatous arthritis, iritis, and rash. J Pediatr. 1985;107:689–93.

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  116. Tromp G, Kuivaniemi H, Raphael S, et al. Genetic linkage of familial granulomatous inflammatory arthritis, skin rash, and uveitis to chromosome 16. Am J Hum Genet. 1996;59:1097–107.

    Google Scholar 

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

    Article  PubMed  CAS  Google Scholar 

  118. Reikine S, Nguyen JB, Modis Y. Pattern recognition and signaling mechanisms of RIG-I and MDA5. Front Immunol. 2014;5:342.

    Google Scholar 

  119. Childs KS, Randall RE, Goodbourn S. LGP2 plays a critical role in sensitizing mda-5 to activation by double-stranded RNA. PLoS One. 2013;8:e64202.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Rothenfusser S, Goutagny N, DiPerna G, et al. The RNA helicase Lgp2 inhibits TLR-independent sensing of viral replication by retinoic acid-inducible gene-I. J Immunol. 2005;175:5260–8.

    Article  CAS  PubMed  Google Scholar 

  121. Yoneyama M, Kikuchi M, Matsumoto K, et al. Shared and unique functions of the DExD/H-box helicases RIG-I, MDA5, and LGP2 in antiviral innate immunity. J Immunol. 2005;175:2851–8.

    Article  CAS  PubMed  Google Scholar 

  122. Hornung V, Ellegast J, Kim S, et al. 5′-triphosphate RNA is the ligand for RIG-I. Science. 2006;314:994–7.

    Article  PubMed  Google Scholar 

  123. Pichlmair A, Schulz O, Tan CP, et al. RIG-I-mediated antiviral responses to single-stranded RNA bearing 5′-phosphates. Science. 2006;314:997–1001.

    Article  CAS  PubMed  Google Scholar 

  124. Jiang F, Ramanathan A, Miller MT, et al. Structural basis of RNA recognition and activation by innate immune receptor RIG-I. Nature. 2011;479:423–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Kowalinski E, Lunardi T, McCarthy AA, et al. Structural basis for the activation of innate immune pattern-recognition receptor RIG-I by viral RNA. Cell. 2011;147:423–35.

    Article  CAS  PubMed  Google Scholar 

  126. Luo D, Ding SC, Vela A, et al. Structural insights into RNA recognition by RIG-I. Cell. 2011;147:409–22.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Wu B, Peisley A, Richards C, et al. Structural basis for dsRNA recognition, filament formation, and antiviral signal activation by MDA5. Cell. 2013;152:276–89.

    Article  CAS  PubMed  Google Scholar 

  128. 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.

    Article  CAS  PubMed  Google Scholar 

  129. Berke IC, Modis Y. MDA5 cooperatively forms dimers and ATP-sensitive filaments upon binding double-stranded RNA. EMBO J. 2012;31:1714–26.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Peisley A, Jo MH, Lin C, et al. Kinetic mechanism for viral dsRNA length discrimination by MDA5 filaments. Proc Natl Acad Sci U S A. 2012;109:E3340–9.

    Article  CAS  Google Scholar 

  131. Berke IC, Yu X, Modis Y, Egelman EH. MDA5 assembles into a polar helical filament on dsRNA. Proc Natl Acad Sci U S A. 2012;109:18437–41.

    Article  CAS  Google Scholar 

  132. Peisley A, Lin C, Wu B, et al. Cooperative assembly and dynamic disassembly of MDA5 filaments for viral dsRNA recognition. Proc Natl Acad Sci U S A. 2011;108:21010–5.

    Article  CAS  Google Scholar 

  133. Zeng W, Sun L, Jiang X, et al. Reconstitution of the RIG-I pathway reveals a signaling role of unanchored polyubiquitin chains in innate immunity. Cell. 2010;141:315–30.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Jiang X, Kinch LN, Brautigam CA, et al. Ubiquitin-induced oligomerization of the RNA sensors RIG-I and MDA5 activates antiviral innate immune response. Immunity. 2012;36:959–73.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Kawai T, Takahashi K, Sato S, et al. IPS-1, an adaptor triggering RIG-I- and Mda5-mediated type I interferon induction. Nat Immunol. 2005;6:981–8.

    Article  CAS  PubMed  Google Scholar 

  136. Meylan E, Curran J, Hofmann K, et al. Cardif is an adaptor protein in the RIG-I antiviral pathway and is targeted by hepatitis C virus. Nature. 2005;437:1167–72.

    Article  CAS  PubMed  Google Scholar 

  137. Seth RB, Sun L, Ea C-K, Chen ZJ. Identification and characterization of MAVS, a mitochondrial antiviral signaling protein that activates NF-kappaB and IRF 3. Cell. 2005;122:669–82.

    Article  CAS  PubMed  Google Scholar 

  138. Xu L-G, Wang Y-Y, Han K-J, et al. VISA is an adapter protein required for virus-triggered IFN-beta signaling. Mol Cell. 2005;19:727–40.

    Google Scholar 

  139. Dixit E, Boulant S, Zhang Y, et al. Peroxisomes are signaling platforms for antiviral innate immunity. Cell. 2010;141:668–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  140. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Xu H, He X, Zheng H, et al. Structural basis for the prion-like MAVS filaments in antiviral innate immunity. Elife. 2014;3:e01489.

    Google Scholar 

  142. Yoneyama M, Kikuchi M, Natsukawa T, et al. The RNA helicase RIG-I has an essential function in double-stranded RNA-induced innate antiviral responses. Nat Immunol. 2004;5:730–7.

    Article  CAS  PubMed  Google Scholar 

  143. Lässig C, Hopfner K-P. Discrimination of cytosolic self and non-self RNA by RIG-I-like receptors. J Biol Chem. 2017;292:9000–9.

    Article  PubMed  PubMed Central  Google Scholar 

  144. Marques JT, Devosse T, Wang D, et al. A structural basis for discriminating between self and nonself double-stranded RNAs in mammalian cells. Nat Biotechnol. 2006;24:559–65.

    Article  CAS  PubMed  Google Scholar 

  145. Liddicoat BJ, Piskol R, Chalk AM, et al. RNA editing by ADAR1 prevents MDA5 sensing of endogenous dsRNA as nonself. Science. 2015;349:1115–20.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  146. Chung H, Calis JJA, Wu X, et al. Human ADAR1 prevents endogenous RNA from triggering translational shutdown. Cell. 2018;172:811–824.e14.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  147. Ahmad S, Mu X, Yang F, et al. Breaching self-tolerance to Alu duplex RNA underlies MDA5-mediated inflammation. Cell. 2018;172:797–810.e13.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  148. Bruns AM, Leser GP, Lamb RA, Horvath CM. The innate immune sensor LGP2 activates antiviral signaling by regulating MDA5-RNA interaction and filament assembly. Mol Cell. 2014;55:771–81.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Anchisi S, Guerra J, Garcin D. RIG-I ATPase activity and discrimination of self-RNA versus non-self-RNA. MBio. 2015;6:e02349.

    Google Scholar 

  150. Lässig C, Matheisl S, Sparrer KM, et al. ATP hydrolysis by the viral RNA sensor RIG-I prevents unintentional recognition of self-RNA. Elife. 2015;4:e10859.

    Google Scholar 

  151. Yao H, Dittmann M, Peisley A, et al. ATP-dependent effector-like functions of RIG-I-like receptors. Mol Cell. 2015;58:541–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  152. Kretschmer S, Lee-Kirsch MA. Type I interferon-mediated autoinflammation and autoimmunity. Curr Opin Immunol. 2017;49:96–102.

    Article  CAS  PubMed  Google Scholar 

  153. Rice GI, del Toro Duany Y, Jenkinson EM, et al. Gain-of-function mutations in IFIH1 cause a spectrum of human disease phenotypes associated with upregulated type I interferon signaling. Nat Genet. 2014;46:503–9.

    Google Scholar 

  154. Rice GI, Kasher PR, Forte GMA, et al. Mutations in ADAR1 cause Aicardi-Goutières syndrome associated with a type I interferon signature. Nat Genet. 2012;44:1243–8.

    Google Scholar 

  155. Jang M-A, Kim EK, Now H, et al. Mutations in DDX58, which encodes RIG-I, cause atypical Singleton-Merten syndrome. Am J Hum Genet. 2015;96:266–74.

    Article  CAS  PubMed  Google Scholar 

  156. Rutsch F, MacDougall M, Lu C, et al. A specific IFIH1 gain-of-function mutation causes Singleton-Merten syndrome. Am J Hum Genet. 2015;96:275–82.

    Article  CAS  PubMed  Google Scholar 

  157. Brown GD, Willment JA, Whitehead L. C-type lectins in immunity and homeostasis. Nat Rev Immunol. 2018;18:374–89.

    Article  CAS  PubMed  Google Scholar 

  158. Ivetic A. Signals regulating L-selectin-dependent leucocyte adhesion and transmigration. Int J Biochem Cell Biol. 2013;45:550–5.

    Article  CAS  Google Scholar 

  159. Cibrián D, Sánchez-Madrid F. CD69: from activation marker to metabolic gatekeeper. Eur J Immunol. 2017;47:946–53.

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  160. Ali MF, Driscoll CB, Walters PR, et al. β-glucan-activated human B lymphocytes participate in innate immune responses by releasing proinflammatory cytokines and stimulating neutrophil chemotaxis. J Immunol. 2015;195:5318–26.

    Article  CAS  PubMed  Google Scholar 

  161. Drummond RA, Gaffen SL, Hise AG, Brown GD. Innate defense against fungal pathogens. Cold Spring Harb Perspect Med. 2015;5:a019620.

    Article  PubMed  CAS  Google Scholar 

  162. Geijtenbeek TBH, Gringhuis SI. C-type lectin receptors in the control of T helper cell differentiation. Nat Rev Immunol. 2016;16:433–48.

    Article  CAS  PubMed  Google Scholar 

  163. Rogers NC, Slack EC, Edwards AD, et al. Syk-dependent cytokine induction by dectin-1 reveals a novel pattern recognition pathway for C type lectins. Immunity. 2005;22:507–17.

    Article  CAS  PubMed  Google Scholar 

  164. Underhill DM, Rossnagle E, Lowell CA, Simmons RM. Dectin-1 activates Syk tyrosine kinase in a dynamic subset of macrophages for reactive oxygen production. Blood. 2005;106:2543–50.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Sancho D, Reis e Sousa C. Signaling by myeloid C-type lectin receptors in immunity and homeostasis. Annu Rev Immunol. 2012;30:491–529.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. LeibundGut-Landmann S, Gross O, Robinson MJ, et al. Syk- and CARD9-dependent coupling of innate immunity to the induction of T helper cells that produce interleukin 17. Nat Immunol. 2007;8:630–8.

    Article  CAS  PubMed  Google Scholar 

  167. Slack EC, Robinson MJ, Hernanz-Falcón P, et al. Syk-dependent ERK activation regulates IL-2 and IL-10 production by DC stimulated with zymosan. Eur J Immunol. 2007;37:1600–12.

    Article  CAS  PubMed  Google Scholar 

  168. Goodridge HS, Simmons RM, Underhill DM. Dectin-1 stimulation by Candida albicans yeast or zymosan triggers NFAT activation in macrophages and dendritic cells. J Immunol. 2007;178:3107–15.

    Article  CAS  PubMed  Google Scholar 

  169. Gringhuis SI, den Dunnen J, Litjens M, et al. Dectin-1 directs T helper cell differentiation by controlling noncanonical NF-kappaB activation through Raf-1 and Syk. Nat Immunol. 2009;10:203–13.

    Article  CAS  PubMed  Google Scholar 

  170. Yamasaki S, Ishikawa E, Sakuma M, et al. Mincle is an ITAM-coupled activating receptor that senses damaged cells. Nat Immunol. 2008;9:1179–88.

    Article  CAS  PubMed  Google Scholar 

  171. Redelinghuys P, Brown GD. Inhibitory C-type lectin receptors in myeloid cells. Immunol Lett. 2011;136:1–12.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  172. Drummond RA, Lionakis MS. Mechanistic insights into the role of C-type lectin receptor/CARD9 signaling in human antifungal immunity. Front Cell Infect Microbiol. 2016;6:39.

    Google Scholar 

  173. Iliev ID, Funari VA, Taylor KD, et al. Interactions between commensal fungi and the C-type lectin receptor dectin-1 influence colitis. Science. 2012;336:1314–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  174. Tang C, Kamiya T, Liu Y, et al. Inhibition of Dectin-1 signaling ameliorates colitis by inducing Lactobacillus-mediated regulatory T cell expansion in the intestine. Cell Host Microbe. 2015;18:183–97.

    Article  CAS  Google Scholar 

  175. Hornung V, Ablasser A, Charrel-Dennis M, et al. AIM2 recognizes cytosolic dsDNA and forms a caspase-1-activating inflammasome with ASC. Nature. 2009;458:514–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  176. Fernandes-Alnemri T, Yu J-W, Datta P, et al. AIM2 activates the inflammasome and cell death in response to cytoplasmic DNA. Nature. 2009;458:509–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Bürckstümmer T, Baumann C, Blüml S, et al. An orthogonal proteomic-genomic screen identifies AIM2 as a cytoplasmic DNA sensor for the inflammasome. Nat Immunol. 2009;10:266–72.

    Article  PubMed  CAS  Google Scholar 

  178. Roberts TL, Idris A, Dunn JA, et al. HIN-200 proteins regulate caspase activation in response to foreign cytoplasmic DNA. Science. 2009;323:1057–60.

    Article  CAS  PubMed  Google Scholar 

  179. Man SM, Karki R, Kanneganti T-D. AIM2 inflammasome in infection, cancer, and autoimmunity: role in DNA sensing, inflammation, and innate immunity. Eur J Immunol. 2016;46:269–80.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  180. Jin T, Perry A, Jiang J, et al. Structures of the HIN domain:DNA complexes reveal ligand binding and activation mechanisms of the AIM2 inflammasome and IFI16 receptor. Immunity. 2012;36:561–71.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Jin T, Perry A, Smith P, et al. Structure of the absent in melanoma 2 (AIM2) pyrin domain provides insights into the mechanisms of AIM2 autoinhibition and inflammasome assembly. J Biol Chem. 2013;288:13225–35.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. Lu A, Kabaleeswaran V, Fu T, et al. Crystal structure of the F27G AIM2 PYD mutant and similarities of its self-association to DED/DED interactions. J Mol Biol. 2014;426:1420–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  183. Hou X, Niu X. The NMR solution structure of AIM2 PYD domain from Mus musculus reveals a distinct α2–α3 helix conformation from its human homologues. Biochem Biophys Res Commun. 2015;461:396–400.

    Article  CAS  PubMed  Google Scholar 

  184. Stacey KJ, Ross IL, Hume DA. Electroporation and DNA-dependent cell death in murine macrophages. Immunol Cell Biol. 1993;71:75–85.

    Article  CAS  PubMed  Google Scholar 

  185. Muruve DA, Pétrilli V, Zaiss AK, et al. The inflammasome recognizes cytosolic microbial and host DNA and triggers an innate immune response. Nature. 2008;452:103–7.

    Article  CAS  PubMed  Google Scholar 

  186. Cai X, Chiu Y-H, Chen ZJ. The cGAS-cGAMP-STING pathway of cytosolic DNA sensing and signaling. Mol Cell. 2014;54:289–96.

    Article  CAS  PubMed  Google Scholar 

  187. Cridland JA, Curley EZ, Wykes MN, et al. The mammalian PYHIN gene family: phylogeny, evolution and expression. BMC Evol Biol. 2012;12:140.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  188. Samanta H, Pravtcheva DD, Ruddle FH, Lengyel P. Chromosomal location of mouse gene 202 which is induced by interferons and specifies a 56.5 kD protein. J Interf Res. 1984;4:295–300.

    Article  CAS  PubMed  Google Scholar 

  189. Kingsmore SF, Snoddy J, Choubey D, et al. Physical mapping of a family of interferon-activated genes, serum amyloid P-component, and alpha-spectrin on mouse chromosome 1. Immunogenetics. 1989;30:169–74.

    Article  CAS  PubMed  Google Scholar 

  190. Landolfo S, Gariglio M, Gribaudo G, Lembo D. The Ifi 200 genes: an emerging family of IFN-inducible genes. Biochimie. 1998;80:721–8.

    Article  CAS  PubMed  Google Scholar 

  191. Lugrin J, Martinon F. The AIM2 inflammasome: sensor of pathogens and cellular perturbations. Immunol Rev. 2018;281:99–114.

    Article  CAS  Google Scholar 

  192. Hara H, Tsuchiya K, Kawamura I, et al. Phosphorylation of the adaptor ASC acts as a molecular switch that controls the formation of speck-like aggregates and inflammasome activity. Nat Immunol. 2013;14:1247–55.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Rodgers MA, Bowman JW, Fujita H, et al. The linear ubiquitin assembly complex (LUBAC) is essential for NLRP3 inflammasome activation. J Exp Med. 2014;211:1333–47.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  194. Shi C-S, Shenderov K, Huang N-N, et al. Activation of autophagy by inflammatory signals limits IL-1β production by targeting ubiquitinated inflammasomes for destruction. Nat Immunol. 2012;13:255–63.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  195. de Almeida L, Khare S, Misharin AV, et al. The PYRIN domain-only protein POP1 inhibits inflammasome assembly and ameliorates inflammatory disease. Immunity. 2015;43:264–76.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  196. Khare S, Ratsimandresy RA, de Almeida L, et al. The PYRIN domain-only protein POP3 inhibits ALR inflammasomes and regulates responses to infection with DNA viruses. Nat Immunol. 2014;15:343–53.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  197. Man SM, Zhu Q, Zhu L, et al. Critical role for the DNA sensor AIM2 in stem cell proliferation and cancer. Cell. 2015;162:45–58.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  198. Wilson JE, Petrucelli AS, Chen L, et al. Inflammasome-independent role of AIM2 in suppressing colon tumorigenesis via DNA-PK and Akt. Nat Med. 2015;21:906–13.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Dihlmann S, Tao S, Echterdiek F, et al. Lack of Absent in Melanoma 2 (AIM2) expression in tumor cells is closely associated with poor survival in colorectal cancer patients. Int J Cancer. 2014;135:2387–96.

    Article  CAS  PubMed  Google Scholar 

  200. Baum R, Sharma S, Carpenter S, et al. Cutting edge: AIM2 and endosomal TLRs differentially regulate arthritis and autoantibody production in DNase II-deficient mice. J Immunol. 2015;194:873–7.

    Article  PubMed  CAS  Google Scholar 

  201. Jakobs C, Perner S, Hornung V. AIM2 drives joint inflammation in a self-DNA triggered model of chronic polyarthritis. PLoS One. 2015;10:e0131702.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  202. Dombrowski Y, Peric M, Koglin S, et al. Cytosolic DNA triggers inflammasome activation in keratinocytes in psoriatic lesions. Sci Transl Med. 2011;3:82ra38.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  203. Ishikawa H, Barber GN. STING is an endoplasmic reticulum adaptor that facilitates innate immune signalling. Nature. 2008;455:674–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Sun W, Li Y, Chen L, et al. ERIS, an endoplasmic reticulum IFN stimulator, activates innate immune signaling through dimerization. Proc Natl Acad Sci U S A. 2009;106:8653–8.

    Article  CAS  Google Scholar 

  205. Ishikawa H, Ma Z, Barber GN. STING regulates intracellular DNA-mediated, type I interferon-dependent innate immunity. Nature. 2009;461:788–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. 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.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  207. 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.

    Article  PubMed  CAS  Google Scholar 

  208. 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.

    Article  PubMed  CAS  Google Scholar 

  209. Diner EJ, Burdette DL, Wilson SC, et al. The innate immune DNA sensor cGAS produces a noncanonical cyclic dinucleotide that activates human STING. Cell Rep. 2013;3:1355–61.

    Article  CAS  PubMed  Google Scholar 

  210. Ablasser A, Schmid-Burgk JL, Hemmerling I, et al. Cell intrinsic immunity spreads to bystander cells via the intercellular transfer of cGAMP. Nature. 2013;503:530–4.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  211. Civril F, Deimling T, de Oliveira Mann CC, et al. Structural mechanism of cytosolic DNA sensing by cGAS. Nature. 2013;498:332–7.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  212. Li X, Shu C, Yi G, et al. Cyclic GMP-AMP synthase is activated by double-stranded DNA-induced oligomerization. Immunity. 2013;39:1019–31.

    Article  CAS  PubMed  Google Scholar 

  213. Andreeva L, Hiller B, Kostrewa D, et al. cGAS senses long and HMGB/TFAM-bound U-turn DNA by forming protein-DNA ladders. Nature. 2017;549:394–8.

    Article  CAS  PubMed  Google Scholar 

  214. Li X-D, Wu J, Gao D, et al. Pivotal roles of cGAS-cGAMP signaling in antiviral defense and immune adjuvant effects. Science. 2013;341:1390–4.

    Article  CAS  PubMed  Google Scholar 

  215. Lio C-WJ, McDonald B, Takahashi M, et al. cGAS-STING signaling regulates initial innate control of cytomegalovirus infection. J Virol. 2016;90:7789–97.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. Paijo J, Döring M, Spanier J, et al. cGAS senses human cytomegalovirus and induces type I interferon responses in human monocyte-derived cells. PLoS Pathog. 2016;12:e1005546.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  217. Gao D, Wu J, Wu Y-T, et al. Cyclic GMP-AMP synthase is an innate immune sensor of HIV and other retroviruses. Science. 2013;341:903–6.

    Article  CAS  PubMed  Google Scholar 

  218. Lahaye X, Satoh T, Gentili M, et al. The capsids of HIV-1 and HIV-2 determine immune detection of the viral cDNA by the innate sensor cGAS in dendritic cells. Immunity. 2013;39:1132–42.

    Article  CAS  PubMed  Google Scholar 

  219. Berg RK, Rahbek SH, Kofod-Olsen E, et al. T cells detect intracellular DNA but fail to induce type I IFN responses: implications for restriction of HIV replication. PLoS One. 2014;9:e84513.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  220. Schoggins JW, MacDuff DA, Imanaka N, et al. Pan-viral specificity of IFN-induced genes reveals new roles for cGAS in innate immunity. Nature. 2014;505:691–5.

    Article  PubMed  PubMed Central  CAS  Google Scholar 

  221. Hansen K, Prabakaran T, Laustsen A, et al. Listeria monocytogenes induces IFNβ expression through an IFI16-, cGAS- and STING-dependent pathway. EMBO J. 2014;33:1654–66.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  222. Andrade WA, Agarwal S, Mo S, et al. Type I interferon induction by Neisseria gonorrhoeae: dual requirement of cyclic GMP-AMP synthase and Toll-like receptor 4. Cell Rep. 2016;15:2438–48.

    Article  CAS  PubMed  Google Scholar 

  223. Collins AC, Cai H, Li T, et al. Cyclic GMP-AMP synthase is an innate immune DNA sensor for Mycobacterium tuberculosis. Cell Host Microbe. 2015;17:820–8.

    Article  CAS  Google Scholar 

  224. Watson RO, Bell SL, MacDuff DA, et al. The cytosolic sensor cGAS detects Mycobacterium tuberculosis DNA to induce type I interferons and activate autophagy. Cell Host Microbe. 2015;17:811–9.

    Article  CAS  Google Scholar 

  225. Wassermann R, Gulen MF, Sala C, et al. Mycobacterium tuberculosis differentially activates cGAS- and inflammasome-dependent intracellular immune responses through ESX-1. Cell Host Microbe. 2015;17:799–810.

    Article  CAS  Google Scholar 

  226. Zhang Y, Yeruva L, Marinov A, et al. The DNA sensor, cyclic GMP-AMP synthase, is essential for induction of IFN-β during Chlamydia trachomatis infection. J Immunol. 2014;193:2394–404.

    Article  CAS  PubMed  Google Scholar 

  227. 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.

    Article  CAS  PubMed  Google Scholar 

  228. Lee-Kirsch MA, Chowdhury D, Harvey S, et al. A mutation in TREX1 that impairs susceptibility to granzyme A-mediated cell death underlies familial chilblain lupus. J Mol Med (Berl). 2007;85:531–7.

    Article  CAS  PubMed  Google Scholar 

  229. Lee-Kirsch MA, Gong M, Chowdhury D, et al. Mutations in the gene encoding the 3′-5′ DNA exonuclease TREX1 are associated with systemic lupus erythematosus. Nat Genet. 2007;39:1065–7.

    Article  CAS  PubMed  Google Scholar 

  230. Richards A, van den Maagdenberg AMJM, Jen JC, et al. C-terminal truncations in human 3′-5′ DNA exonuclease TREX1 cause autosomal dominant retinal vasculopathy with cerebral leukodystrophy. Nat Genet. 2007;39:1068–70.

    Article  CAS  PubMed  Google Scholar 

  231. 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.

    Article  CAS  Google Scholar 

  232. Günther C, Berndt N, Wolf C, Lee-Kirsch MA. Familial chilblain lupus due to a novel mutation in the exonuclease III domain of 3′ repair exonuclease 1 (TREX1). JAMA Dermatol. 2015;151:426–31.

    Article  PubMed  Google Scholar 

  233. Mazur DJ, Perrino FW. Identification and expression of the TREX1 and TREX2 cDNA sequences encoding mammalian 3′-->5′ exonucleases. J Biol Chem. 1999;274:19655–60.

    Article  CAS  PubMed  Google Scholar 

  234. Yang Y-G, Lindahl T, Barnes DE. Trex1 exonuclease degrades ssDNA to prevent chronic checkpoint activation and autoimmune disease. Cell. 2007;131:873–86.

    Article  CAS  PubMed  Google Scholar 

  235. Stetson DB, Ko JS, Heidmann T, Medzhitov R. Trex1 prevents cell-intrinsic initiation of autoimmunity. Cell. 2008;134:587–98.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  236. Gall A, Treuting P, Elkon KB, et al. Autoimmunity initiates in nonhematopoietic cells and progresses via lymphocytes in an interferon-dependent autoimmune disease. Immunity. 2012;36:120–31.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  237. Ablasser A, Hemmerling I, Schmid-Burgk JL, et al. TREX1 deficiency triggers cell-autonomous immunity in a cGAS-dependent manner. J Immunol. 2014;192:5993–7.

    Article  CAS  PubMed  Google Scholar 

  238. Rodero MP, Tesser A, Bartok E, et al. Type I interferon-mediated autoinflammation due to DNase II deficiency. Nat Commun. 2017;8:2176.

    Google Scholar 

  239. Evans CJ, Aguilera RJ. DNase II: genes, enzymes and function. Gene. 2003;322:1–15.

    Article  CAS  PubMed  Google Scholar 

  240. Kawane K, Fukuyama H, Kondoh G, et al. Requirement of DNase II for definitive erythropoiesis in the mouse fetal liver. Science. 2001;292:1546–9.

    Article  CAS  PubMed  Google Scholar 

  241. Yoshida H, Okabe Y, Kawane K, et al. Lethal anemia caused by interferon-beta produced in mouse embryos carrying undigested DNA. Nat Immunol. 2005;6:49–56.

    Google Scholar 

  242. Kawane K, Ohtani M, Miwa K, et al. Chronic polyarthritis caused by mammalian DNA that escapes from degradation in macrophages. Nature. 2006;443:998–1002.

    Article  CAS  PubMed  Google Scholar 

  243. Kawane K, Tanaka H, Kitahara Y, et al. Cytokine-dependent but acquired immunity-independent arthritis caused by DNA escaped from degradation. Proc Natl Acad Sci U S A. 2010;107:19432–7.

    Article  CAS  Google Scholar 

  244. Ahn J, Gutman D, Saijo S, Barber GN. STING manifests self DNA-dependent inflammatory disease. Proc Natl Acad Sci U S A. 2012;109:19386–91.

    Article  CAS  Google Scholar 

  245. Gao D, Li T, Li X-D, et al. Activation of cyclic GMP-AMP synthase by self-DNA causes autoimmune diseases. Proc Natl Acad Sci. 2015;112:E5699–705.

    Article  CAS  Google Scholar 

  246. Baum R, Sharma S, Organ JM, et al. STING contributes to abnormal bone formation induced by deficiency of DNase II in mice. Arthritis Rheumatol. 2017;69:460–71.

    Article  CAS  Google Scholar 

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

    Google Scholar 

  248. Jeremiah N, Neven B, Gentili M, et al. Inherited STING-activating mutation underlies a familial inflammatory syndrome with lupus-like manifestations. J Clin Invest. 2014;124:5516–20.

    Article  PubMed  PubMed Central  Google Scholar 

  249. Kim H, Brooks KM, Tang CC, et al. Pharmacokinetics, pharmacodynamics, and proposed dosing of the oral JAK1 and JAK2 inhibitor baricitinib in pediatric and young adult CANDLE and SAVI patients. Clin Pharmacol Ther. 2018;104(2):364–73.

    Article  CAS  Google Scholar 

  250. 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.

    Article  PubMed  CAS  Google Scholar 

  251. Cerboni S, Jeremiah N, Gentili M, et al. Intrinsic antiproliferative activity of the innate sensor STING in T lymphocytes. J Exp Med. 2017;214:1769–85.

    Google Scholar 

  252. Warner JD, Irizarry-Caro RA, Bennion BG, et al. STING-associated vasculopathy develops independently of IRF3 in mice. J Exp Med. 2017;214:3279–92.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  253. Okabe Y, Kawane K, Nagata S. IFN regulatory factor (IRF) 3/7-dependent and -independent gene induction by mammalian DNA that escapes degradation. Eur J Immunol. 2008;38:3150–8.

    Article  CAS  PubMed  Google Scholar 

  254. Kayagaki N, Warming S, Lamkanfi M, et al. Non-canonical inflammasome activation targets caspase-11. Nature. 2011;479:117–21.

    Article  CAS  PubMed  Google Scholar 

  255. Shi J, Zhao Y, Wang Y, et al. Inflammatory caspases are innate immune receptors for intracellular LPS. Nature. 2014;514:187–92.

    Article  CAS  PubMed  Google Scholar 

  256. Broz P, Ruby T, Belhocine K, et al. Caspase-11 increases susceptibility to Salmonella infection in the absence of caspase-1. Nature. 2012;490:288–91.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  257. Case CL, Kohler LJ, Lima JB, et al. Caspase-11 stimulates rapid flagellin-independent pyroptosis in response to Legionella pneumophila. Proc Natl Acad Sci U S A. 2013;110:1851–6.

    Article  CAS  Google Scholar 

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

    Google Scholar 

  259. Rühl S, Broz P. Caspase-11 activates a canonical NLRP3 inflammasome by promoting K+ efflux. Eur J Immunol. 2015;45:2927–36.

    Article  PubMed  CAS  Google Scholar 

  260. Schmid-Burgk JL, Gaidt MM, Schmidt T, et al. Caspase-4 mediates non-canonical activation of the NLRP3 inflammasome in human myeloid cells. Eur J Immunol. 2015;45:2911–7.

    Article  CAS  PubMed  Google Scholar 

  261. Kayagaki N, Wong MT, Stowe IB, et al. Noncanonical inflammasome activation by intracellular LPS independent of TLR4. Science. 2013;341:1246–9.

    Article  CAS  PubMed  Google Scholar 

  262. Aachoui Y, Leaf IA, Hagar JA, et al. Caspase-11 protects against bacteria that escape the vacuole. Science. 2013;339:975–8.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  263. Vanaja SK, Russo AJ, Behl B, et al. Bacterial outer membrane vesicles mediate cytosolic localization of LPS and caspase-11 activation. Cell. 2016;165:1106–19.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  264. Berliner JA, Subbanagounder G, Leitinger N, et al. Evidence for a role of phospholipid oxidation products in atherogenesis. Trends Cardiovasc Med. 2001;11:142–7.

    Article  CAS  PubMed  Google Scholar 

  265. Leitinger N. Oxidized phospholipids as modulators of inflammation in atherosclerosis. Curr Opin Lipidol. 2003;14:421–30.

    Article  CAS  PubMed  Google Scholar 

  266. Berliner JA, Watson AD. A role for oxidized phospholipids in atherosclerosis. N Engl J Med. 2005;353:9–11.

    Article  CAS  PubMed  Google Scholar 

  267. Chu LH, Indramohan M, Ratsimandresy RA, et al. The oxidized phospholipid oxPAPC protects from septic shock by targeting the non-canonical inflammasome in macrophages. Nat Commun. 2018;9:996.

    Google Scholar 

  268. Zanoni I, Tan Y, Di Gioia M, et al. An endogenous caspase-11 ligand elicits interleukin-1 release from living dendritic cells. Science. 2016;352:1232–6.

    Google Scholar 

  269. O’Neill LA, Golenbock D, Bowie AG. The history of Toll-like receptors—redefining innate immunity. Nat Rev Immunol. 2013;13:453–60.

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Author notes

  1. Victor Saavedra and Fiona Moghaddas contributed equally to this work.

Authors and Affiliations

  1. Institute of Innate Immunity, University Hospital Bonn, Bonn, Germany

    Victor Saavedra & Eicke Latz

  2. Inflammation Division, The Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia

    Fiona Moghaddas & Seth L. Masters

  3. Department of Medical Biology, The University of Melbourne, Parkville, VIC, Australia

    Fiona Moghaddas & Seth L. Masters

  4. Department of Medicine, University of Massachusetts Medical School, Worcester, MA, USA

    Eicke Latz

  5. German Center for Neurodegenerative Diseases, Bonn, Germany

    Eicke Latz

Authors
  1. Victor Saavedra
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Fiona Moghaddas
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Eicke Latz
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Seth L. Masters
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Eicke Latz or Seth L. Masters .

Editor information

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

Rights and permissions

Reprints and permissions

Copyright information

© 2019 Springer Nature Switzerland AG

About this chapter

Check for updates. Verify currency and authenticity via CrossMark

Cite this chapter

Saavedra, V., Moghaddas, F., Latz, E., Masters, S.L. (2019). Pattern Recognition Receptors in Autoinflammation. In: Hashkes, P., Laxer, R., Simon, A. (eds) Textbook of Autoinflammation. Springer, Cham. https://doi.org/10.1007/978-3-319-98605-0_4

Download citation

  • DOI: https://doi.org/10.1007/978-3-319-98605-0_4

  • Published:

  • Publisher Name: Springer, Cham

  • Print ISBN: 978-3-319-98604-3

  • Online ISBN: 978-3-319-98605-0

  • eBook Packages: MedicineMedicine (R0)

Publish with us

Policies and ethics

Search

Navigation