Skip to main content
SpringerLink
Log in

Genetic Dissection of Autoinflammatory Syndrome

  • Chapter
  • First Online:
Chronic Inflammation

  • 1978 Accesses

Abstract

Autoinflammatory syndromes are characterised by inflammatory responses without infection or autoimmune responses. As autoinflammatory syndromes cause both acute and chronic inflammation, the identification of the causative genes for this syndrome would help to reveal the molecular mechanisms underlying chronic inflammation. Recent studies have revealed that mutations in the PSMB8 gene, which codes for an immunoproteasome component, cause an autoinflammatory disorder with lipodystrophy. The missense mutation in PSMB8 disturbs the assembly of immunoproteasomes, which decreases immunoproteasome functions. The decreased immunoproteasome function increases the level of proinflammatory cytokines, including interleukin-6. Furthermore, dysfunction of the immunoproteasome suppresses adipocyte differentiation, which might explain the progressive lipodystrophy that is a characteristic symptom of these patients. The identification of immunoproteasome dysfunction-related autoinflammatory disorders highlights immunoproteasomes as crucial intracellular complexes in the regulation of inflammatory responses. Furthermore, analysis of this syndrome will provide new insights into the key molecular networks related to chronic inflammation.

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 219.00
Price excludes VAT (USA)
  • Available as EPUB and PDF
  • Read on any device
  • Instant download
  • Own it forever
Softcover Book
USD 279.99
Price excludes VAT (USA)
  • Compact, lightweight edition
  • Dispatched in 3 to 5 business days
  • Free shipping worldwide - see info
Hardcover Book
USD 279.99
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

Similar content being viewed by others

References

  • Agarwal AK, Xing C, DeMartino GN, Mizrachi D, Hernandez MD, Sousa AB et al (2010) PSMB8 encoding the beta5i proteasome subunit is mutated in joint contractures, muscle atrophy, microcytic anemia, and panniculitis-induced lipodystrophy syndrome. Am J Hum Genet 87(6):866–872. doi:10.1016/j.ajhg.2010.10.031; PubMed PMID: 21129723, PubMed Central PMCID: PMC2997366, Epub 2010/12/07

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Akiyama K, Yokota K, Kagawa S, Shimbara N, Tamura T, Akioka H et al (1994) cDNA cloning and interferon gamma down-regulation of proteasomal subunits X and Y. Science 265(5176):1231–1234; Epub 1994/08/26

    Article  CAS  PubMed  Google Scholar 

  • Aksentijevich I, Kastner DL (2011) Genetics of monogenic autoinflammatory diseases: past successes, future challenges. Nat Rev Rheumatol 7(8):469–478. doi:10.1038/nrrheum.2011.94; Epub 2011/07/06

    Article  CAS  PubMed  Google Scholar 

  • Arima K, Kinoshita A, Mishima H, Kanazawa N, Kaneko T, Mizushima T et al (2011) 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 108(36):14914–14919. doi:10.1073/pnas.1106015108; PubMed PMID: 21852578, PubMed Central PMCID: PMC3169106, Epub 2011/08/20

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Basler M, Dajee M, Moll C, Groettrup M, Kirk CJ (2010) Prevention of experimental colitis by a selective inhibitor of the immunoproteasome. J Immunol 185(1):634–641. doi:10.4049/jimmunol.0903182; Epub 2010/06/08

    Article  CAS  PubMed  Google Scholar 

  • Canna SW, de Jesus AA, Gouni S, Brooks SR, Marrero B, Liu Y et al (2014) An activating NLRC4 inflammasome mutation causes autoinflammation with recurrent macrophage activation syndrome. Nat Genet 46(10):1140–1146. doi:10.1038/ng.3089; PubMed PMID: 25217959, PubMed Central PMCID: PMC4177369

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Chen W, Norbury CC, Cho Y, Yewdell JW, Bennink JR (2001) Immunoproteasomes shape immunodominance hierarchies of antiviral CD8(+) T cells at the levels of T cell repertoire and presentation of viral antigens. J Exp Med 193(11):1319–1326; PubMed PMID: 11390439, PubMed Central PMCID: PMC2193381, Epub 2001/06/08

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Ciechanover A (2005) Proteolysis: from the lysosome to ubiquitin and the proteasome. Nat Rev Mol Cell Biol 6(1):79–87. doi:10.1038/nrm1552; Epub 2005/02/03

    Article  CAS  PubMed  Google Scholar 

  • Fehling HJ, Swat W, Laplace C, Kuhn R, Rajewsky K, Muller U et al (1994) MHC class I expression in mice lacking the proteasome subunit LMP-7. Science 265(5176):1234–1237; Epub 1994/08/26

    Article  CAS  PubMed  Google Scholar 

  • Finley D (2009) Recognition and processing of ubiquitin-protein conjugates by the proteasome. Annu Rev Biochem 78:477–513. doi:10.1146/annurev.biochem.78.081507.101607; Epub 2009/06/06

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Franchi L, Eigenbrod T, Munoz-Planillo R, Nunez G (2009) The inflammasome: a caspase-1-activation platform that regulates immune responses and disease pathogenesis. Nat Immunol 10(3):241–247. doi:10.1038/ni.1703; PubMed PMID: 19221555, PubMed Central PMCID: PMC2820724, Epub 2009/02/18

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Garg A, Hernandez MD, Sousa AB, Subramanyam L, de Martinez VL, dos Santos HG et al (2010) An autosomal recessive syndrome of joint contractures, muscular atrophy, microcytic anemia, and panniculitis-associated lipodystrophy. J Clin Endocrinol Metab 95(9):E58–E63. doi:10.1210/jc.2010-0488; PubMed PMID: 20534754, PubMed Central PMCID: PMC2936059, Epub 2010/06/11

    Article  PubMed  PubMed Central  Google Scholar 

  • Goldbach-Mansky R, Shroff SD, Wilson M, Snyder C, Plehn S, Barham B et al (2008) A pilot study to evaluate the safety and efficacy of the long-acting interleukin-1 inhibitor rilonacept (interleukin-1 Trap) in patients with familial cold autoinflammatory syndrome. Arthritis Rheum 58(8):2432–2442. doi:10.1002/art.23620; PubMed PMID: 18668591, PubMed Central PMCID: PMC2875198, Epub 2008/08/01

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Gordon S, Trinchieri G (2009) Innate resistance and inflammation. Curr Opin Immunol 21(1):1–2. doi:10.1016/j.coi.2009.02.001; Epub 2009/02/19

    Article  CAS  PubMed  Google Scholar 

  • Greenwald RJ, Freeman GJ, Sharpe AH (2005) The B7 family revisited. Annu Rev Immunol 23:515–548. doi:10.1146/annurev.immunol.23.021704.115611; Epub 2005/03/18

    Article  PubMed  Google Scholar 

  • Gregor MF, Hotamisligil GS (2011) Inflammatory mechanisms in obesity. Annu Rev Immunol 29:415–445. doi:10.1146/annurev-immunol-031210-101322; Epub 2011/01/12

    Article  CAS  PubMed  Google Scholar 

  • Hendil KB, Khan S, Tanaka K (1998) Simultaneous binding of PA28 and PA700 activators to 20 S proteasomes. Biochem J 332(Pt 3):749–754; PubMed PMID: 9620878, PubMed Central PMCID: PMC1219536, Epub 1998/06/11

    Article  PubMed  PubMed Central  Google Scholar 

  • Kasagi S, Kawano S, Nakazawa T, Sugino H, Koshiba M, Ichinose K et al (2008) A case of periodic-fever-syndrome-like disorder with lipodystrophy, myositis, and autoimmune abnormalities. Mod Rheumatol 18(2):203–207. doi:10.1007/s10165-008-0033-4; Epub 2008/03/15

    Article  PubMed  Google Scholar 

  • Keir ME, Butte MJ, Freeman GJ, Sharpe AH (2008) PD-1 and its ligands in tolerance and immunity. Annu Rev Immunol 26:677–704. doi:10.1146/annurev.immunol.26.021607.090331; Epub 2008/01/05

    Article  CAS  PubMed  Google Scholar 

  • Kincaid EZ, Che JW, York I, Escobar H, Reyes-Vargas E, Delgado JC et al (2012) Mice completely lacking immunoproteasomes show major changes in antigen presentation. Nat Immunol 13(2):129–135. doi:10.1038/ni.2203; PubMed PMID: 22197977, PubMed Central PMCID: PMC3262888, Epub 2011/12/27

    Article  CAS  Google Scholar 

  • Kitamura A, Maekawa Y, Uehara H, Izumi K, Kawachi I, Nishizawa M et al (2011) A mutation in the immunoproteasome subunit PSMB8 causes autoinflammation and lipodystrophy in humans. J Clin Invest 121(10):4150–4160. doi:10.1172/JCI58414; PubMed PMID: 21881205, PubMed Central PMCID: PMC3195477, Epub 2011/09/02

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kitamura A, Sasaki Y, Abe T, Kano H, Yasutomo K (2014) An inherited mutation in NLRC4 causes autoinflammation in human and mice. J Exp Med 211(12):2385–2396. doi:10.1084/jem.20141091; PubMed PMID: 25385754, PubMed Central PMCID: PMC4235634

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Kitano Y, Matsunaga E, Morimoto T, Okada N, Sano S (1985) A syndrome with nodular erythema, elongated and thickened fingers, and emaciation. Arch Dermatol 121(8):1053–1056; Epub 1985/08/01

    Article  CAS  PubMed  Google Scholar 

  • Muchamuel T, Basler M, Aujay MA, Suzuki E, Kalim KW, Lauer C et al (2009) A selective inhibitor of the immunoproteasome subunit LMP7 blocks cytokine production and attenuates progression of experimental arthritis. Nat Med 15(7):781–787. doi:10.1038/nm.1978; Epub 2009/06/16

    Article  CAS  PubMed  Google Scholar 

  • Murata S, Yashiroda H, Tanaka K (2009) Molecular mechanisms of proteasome assembly. Nat Rev Mol Cell Biol 10(2):104–115. doi:10.1038/nrm2630; Epub 2009/01/24

    Article  CAS  PubMed  Google Scholar 

  • Ortiz-Lazareno PC, Hernandez-Flores G, Dominguez-Rodriguez JR, Lerma-Diaz JM, Jave-Suarez LF, Aguilar-Lemarroy A et al (2008) MG132 proteasome inhibitor modulates proinflammatory cytokines production and expression of their receptors in U937 cells: involvement of nuclear factor-kappaB and activator protein-1. Immunology 124(4):534–541. doi:10.1111/j.1365-2567.2008.02806.x; PubMed PMID: 18298552, PubMed Central PMCID: PMC2492945, Epub 2008/02/27

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Preckel T, Fung-Leung WP, Cai Z, Vitiello A, Salter-Cid L, Winqvist O et al (1999) Impaired immunoproteasome assembly and immune responses in PA28−/− mice. Science 286(5447):2162–2165; Epub 1999/12/11

    Article  CAS  PubMed  Google Scholar 

  • Romberg N, Al Moussawi K, Nelson-Williams C, Stiegler AL, Loring E, Choi M et al (2014) Mutation of NLRC4 causes a syndrome of enterocolitis and autoinflammation. Nat Genet 46(10):1135–1139. doi:10.1038/ng.3066; PubMed PMID: 25217960, PubMed Central PMCID: PMC4177367

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Schmidt N, Gonzalez E, Visekruna A, Kuhl AA, Loddenkemper C, Mollenkopf H et al (2010) Targeting the proteasome: partial inhibition of the proteasome by bortezomib or deletion of the immunosubunit LMP7 attenuates experimental colitis. Gut 59(7):896–906. doi:10.1136/gut.2009.203554; Epub 2010/06/29

    Article  CAS  PubMed  Google Scholar 

  • Seifert U, Bialy LP, Ebstein F, Bech-Otschir D, Voigt A, Schroter F et al (2010) Immunoproteasomes preserve protein homeostasis upon interferon-induced oxidative stress. Cell 142(4):613–624. doi:10.1016/j.cell.2010.07.036; Epub 2010/08/21

    Article  CAS  PubMed  Google Scholar 

  • Stojanov S, Lapidus S, Chitkara P, Feder H, Salazar JC, Fleisher TA et al (2011) Periodic fever, aphthous stomatitis, pharyngitis, and adenitis (PFAPA) is a disorder of innate immunity and Th1 activation responsive to IL-1 blockade. Proc Natl Acad Sci U S A 108(17):7148–7153. doi:10.1073/pnas.1103681108; PubMed PMID: 21478439, PubMed Central PMCID: PMC3084055, Epub 2011/04/12

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Takeuchi O, Akira S (2010) Pattern recognition receptors and inflammation. Cell 140(6):805–820. doi:10.1016/j.cell.2010.01.022; Epub 2010/03/23

    Article  CAS  PubMed  Google Scholar 

  • Tanaka K, Ichihara A (1988) Involvement of proteasomes (multicatalytic proteinase) in ATP-dependent proteolysis in rat reticulocyte extracts. FEBS Lett 236(1):159–162; Epub 1988/08/15

    Article  CAS  PubMed  Google Scholar 

  • Van den Eynde BJ, Morel S (2001) Differential processing of class-I-restricted epitopes by the standard proteasome and the immunoproteasome. Curr Opin Immunol 13(2):147–153; Epub 2001/03/03

    Article  PubMed  Google Scholar 

  • van Deventer S, Neefjes J (2010) The immunoproteasome cleans up after inflammation. Cell 142(4):517–518. doi:10.1016/j.cell.2010.08.002; Epub 2010/08/21

    Article  PubMed  Google Scholar 

  • Vasuri F, Capizzi E, Bellavista E, Mishto M, Santoro A, Fiorentino M et al (2010) Studies on immunoproteasome in human liver. Part I: absence in fetuses, presence in normal subjects, and increased levels in chronic active hepatitis and cirrhosis. Biochem Biophys Res Commun 397(2):301–306. doi:10.1016/j.bbrc.2010.05.104; Epub 2010/06/01

    Article  CAS  PubMed  Google Scholar 

  • Veldhoen M, Hocking RJ, Flavell RA, Stockinger B (2006) Signals mediated by transforming growth factor-beta initiate autoimmune encephalomyelitis, but chronic inflammation is needed to sustain disease. Nat Immunol 7(11):1151–1156. doi:10.1038/ni1391; Epub 2006/09/26

    Article  CAS  PubMed  Google Scholar 

  • Wang XC, Jobin C, Allen JB, Roberts WL, Jaffe GJ (1999) Suppression of NF-kappaB-dependent proinflammatory gene expression in human RPE cells by a proteasome inhibitor. Invest Ophthalmol Vis Sci 40(2):477–486; Epub 1999/02/09

    CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Department of Immunology and Parasitology, Graduate School of Medicine, Tokushima University, Tokushima, Japan

    Koji Yasutomo

  2. AMED-CREST, Tokushima, Japan

    Koji Yasutomo

Authors
  1. Koji Yasutomo
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Koji Yasutomo .

Editor information

Editors and Affiliations

  1. Interdisciplinary Program for Biomedical Sciences Institute for Academic Initiatives, Osaka University, Suita, Japan

    Masayuki Miyasaka

  2. Department of Immunobiology and Pharmacological Genetics Graduate School of Medicine and Pharmaceutical Sciences, University of Toyama, Toyama, Japan

    Kiyoshi Takatsu

Rights and permissions

Reprints and permissions

Copyright information

© 2016 Springer Japan

About this chapter

Cite this chapter

Yasutomo, K. (2016). Genetic Dissection of Autoinflammatory Syndrome. In: Miyasaka, M., Takatsu, K. (eds) Chronic Inflammation. Springer, Tokyo. https://doi.org/10.1007/978-4-431-56068-5_5

Download citation

Publish with us

Policies and ethics

Search

Navigation