Skip to main content

Advertisement

SpringerLink
Log in

Typ-I-Interferonopathien

Durch Typ-1-Interferone bedingte entzündliche Systemerkrankungen

Type I interferonopathies

Systemic inflammatory diseases triggered by type I interferons

  • Leitthema
  • Published:
Zeitschrift für Rheumatologie Aims and scope Submit manuscript

Zusammenfassung

Typ-I-Interferone dienen dem Organismus v. a. zur Abwehr von Viren. Die Induktion von Typ-I-Interferon wirkt stimulierend und modulierend sowohl auf das angeborene als auch das adaptive Immunsystem, was mit einer verminderten Toleranz gegenüber körpereigenen Strukturen einhergeht. Eine genetisch bedingte inadäquate Aktivierung des Typ-I-Interferon-Systems kann zu entzündlichen Systemerkrankungen führen, die unter dem Oberbegriff der Typ-I-Interferonopathien subsumiert werden. Das klinische Spektrum der Typ-I-Interferonopathien ist sehr breit und heterogen, wobei neurologische und kutane Manifestationen im Vordergrund stehen. Die klinischen Symptome entsprechen dabei oft Teilsymptomen multifaktorieller Autoimmunerkrankungen wie dem systemischen Lupus erythematodes oder systemischen Vaskulitiden. Einblicke in die molekulare Pathogenese der Typ-I-Interferonopathien bieten erste kausal orientierte Ansätze für therapeutische Interventionen.

Abstract

Type I interferons mediate immune defense against viral infections. The induction of type I interferons has stimulating and modulating effects on the innate and adaptive immune systems thereby reducing tolerance against self-antigens. Genetic defects that result in an inadequate activation of the type I interferon system can cause a group of inflammatory disorders, which are collectively referred to as type I interferonopathies. While the clinical spectrum of type I interferonopathies is broad and heterogeneous, neurological and cutaneous symptoms are the most frequent manifestations. Some clinical and genetic features of type I interferonopathies are shared by multifactorial diseases, such as systemic lupus erythematosus and systemic vasculitis. Advances in understanding the disease mechanisms underlying type I interferonopathies have pinpointed novel targets for therapeutic interventions.

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

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Abb. 1

Literatur

  1. Stetson DB, Medzhitov R (2006) Type I interferons in host defense. Immunity 25:373–381

    Article  CAS  PubMed  Google Scholar 

  2. Ronnblom LE, Alm GV, Oberg KE (1991) Autoimmunity after alpha-interferon therapy for malignant carcinoid tumors. Ann Intern Med 115:178–183

    Article  CAS  PubMed  Google Scholar 

  3. Vallin H, Blomberg S, Alm GV et al (1999) Patients with systemic lupus erythematosus (SLE) have a circulating inducer of interferon-alpha (IFN-alpha) production acting on leucocytes resembling immature dendritic cells. Clin Exp Immunol 115:196–202

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Baechler EC, Batliwalla FM, Karypis G et al (2003) Interferon-inducible gene expression signature in peripheral blood cells of patients with severe lupus. Proc Natl Acad Sci U S A 100:2610–2615

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Lande R, Gregorio J, Facchinetti V et al (2007) Plasmacytoid dendritic cells sense self-DNA coupled with antimicrobial peptide. Nature 449:564–569

    Article  CAS  PubMed  Google Scholar 

  6. Iwasaki A, Medzhitov R (2010) Regulation of adaptive immunity by the innate immune system. Science 327:291–295

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  7. Atianand MK, Fitzgerald KA (2013) Molecular basis of DNA recognition in the immune system. J Immunol 190:1911–1918

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Crow YJ (2011) Type I interferonopathies: a novel set of inborn errors of immunity. Ann N Y Acad Sci 1238:91–98

    Article  CAS  PubMed  Google Scholar 

  9. Aicardi J, Goutieres F (1984) A progressive familial encephalopathy in infancy with calcifications of the basal ganglia and chronic cerebrospinal fluid lymphocytosis. Ann Neurol 15:49–54

    Article  CAS  PubMed  Google Scholar 

  10. Lee-Kirsch MA, Wolf C, Gunther C (2013) Aicardi-Goutieres syndrome: a model disease for systemic autoimmunity. Clin Exp Immunol 175:17–24

    Article  PubMed Central  Google Scholar 

  11. Ramantani G, Kohlhase J, Hertzberg C et al (2010) Expanding the phenotypic spectrum of lupus erythematosus in Aicardi-Goutieres syndrome. Arthritis Rheum 62:1469–1477

    Article  CAS  PubMed  Google Scholar 

  12. Crow YJ, Manel N (2015) Aicardi-Goutieres syndrome and the type I interferonopathies. Nat Rev Immunol 15:429–440

    Article  CAS  PubMed  Google Scholar 

  13. Yang YG, Lindahl T, Barnes DE (2007) Trex1 exonuclease degrades ssDNA to prevent chronic checkpoint activation and autoimmune disease. Cell 131:873–886

    Article  CAS  PubMed  Google Scholar 

  14. Lee-Kirsch MA, Chowdhury D, Harvey S et al (2007) A mutation in TREX1 that impairs susceptibility to granzyme A-mediated cell death underlies familial chilblain lupus. J Mol Med 85:531–537

    Article  CAS  PubMed  Google Scholar 

  15. Stetson DB, Ko JS, Heidmann T et al (2008) Trex1 prevents cell-intrinsic initiation of autoimmunity. Cell 134:587–598

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  16. Ablasser A, Hemmerling I, Schmid-Burgk JL et al (2014) TREX1 deficiency triggers cell-autonomous immunity in a cGaS-dependent manner. J Immunol 192:5993–5997

    Article  CAS  PubMed  Google Scholar 

  17. Reijns MA, Rabe B, Rigby RE et al (2012) Enzymatic removal of ribonucleotides from DNA is essential for mammalian genome integrity and development. Cell 149:1008–1022

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  18. Gunther C, Berndt N, Wolf C et al (2015) Familial chilblain lupus due to a novel mutation in the exonuclease III domain of 3’ repair exonuclease 1 (TREX1). JAMA Dermatol 151:426–431

    Article  PubMed  Google Scholar 

  19. Lee-Kirsch MA, Gong M, Schulz H et al (2006) Familial chilblain lupus, a monogenic form of cutaneous lupus erythematosus, maps to chromosome 3p. Am J Hum Genet 79:731–737

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  20. Gunther C, Hillebrand M, Brunk J et al (2013) Systemic involvement in TREX1-associated familial chilblain lupus. J Am Acad Dermatol 69:e179–e181

    Article  PubMed  Google Scholar 

  21. Richards A, van den Maagdenberg AM, Jen JC et al (2007) C-terminal truncations in human 3’-5’ DNA exonuclease TREX1 cause autosomal dominant retinal vasculopathy with cerebral leukodystrophy. Nat Genet 39:1068–1070

    Article  CAS  PubMed  Google Scholar 

  22. Schuh E, Ertl-Wagner B, Lohse P et al (2015) Multiple sclerosis-like lesions and type I interferon signature in a patient with RVCL. Neurol Neuroimmunol Neuroinflamm 2:e55

    Article  PubMed  PubMed Central  Google Scholar 

  23. Lee-Kirsch MA, Gong M, Chowdhury D et al (2007) Mutations in the gene encoding the 3’-5’ DNA exonuclease TREX1 are associated with systemic lupus erythematosus. Nat Genet 39:1065–1067

    Article  CAS  PubMed  Google Scholar 

  24. Gunther C, Kind B, Reijns MA et al (2015) Defective removal of ribonucleotides from DNA promotes systemic autoimmunity. J Clin Invest 125:413–424

    Article  PubMed  PubMed Central  Google Scholar 

  25. Cunninghame Graham DS, Morris DL, Bhangale TR et al (2011) Association of NCF2, IKZF1, IRF8, IFIH1, and TYK2 with systemic lupus erythematosus. PLoS Genet 7:e1002341

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Van EL, De SL, Pombal D et al (2015) Brief report: IFIH1 mutation causes systemic lupus erythematosus with selective IgA deficiency. Arthritis Rheumatol 67:1592–1597

    Article  Google Scholar 

  27. Julia A, Tortosa R, Hernanz JM et al (2012) Risk variants for psoriasis vulgaris in a large case-control collection and association with clinical subphenotypes. Hum Mol Genet 21:4549–4557

    Article  CAS  PubMed  Google Scholar 

  28. Rutsch F, MacDougall M, Lu C et al (2015) A specific IFIH1 gain-of-function mutation causes Singleton-Merten syndrome. Am J Hum Genet 96:275–282

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Jang MA, Kim EK, Now H et al (2015) Mutations in DDX58, which encodes RIG-I, cause atypical Singleton-Merten syndrome. Am J Hum Genet 96:266–274

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Liu Y, Jesus AA, Marrero B et al (2014) Activated STING in a vascular and pulmonary syndrome. N Engl J Med 371:507–518

    Article  PubMed  PubMed Central  Google Scholar 

  31. Liu Y, Jesus AA, Marrero B et al (2014) Activated STING in a vascular and pulmonary syndrome. N Engl J Med 371:507–518

    Article  PubMed  PubMed Central  Google Scholar 

  32. Jeremiah N, Neven B, Gentili M et al (2014) Inherited STING-activating mutation underlies a familial inflammatory syndrome with lupus-like manifestations. J Clin Invest 124:5516–5520

    Article  PubMed  PubMed Central  Google Scholar 

  33. Lausch E, Janecke A, Bros M et al (2011) Genetic deficiency of tartrate-resistant acid phosphatase associated with skeletal dysplasia, cerebral calcifications and autoimmunity. Nat Genet 43:132–137

    Article  CAS  PubMed  Google Scholar 

  34. Briggs TA, Rice GI, Daly S et al (2011) Tartrate-resistant acid phosphatase deficiency causes a bone dysplasia with autoimmunity and a type I interferon expression signature. Nat Genet 43:127–131

    Article  CAS  PubMed  Google Scholar 

  35. Zhang X, Bogunovic D, Payelle-Brogard B et al (2015) Human intracellular ISG15 prevents interferon-alpha/beta over-amplification and auto-inflammation. Nature 517:89–93

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  36. Liu Y, Ramot Y, Torrelo A et al (2012) Mutations in proteasome subunit beta type 8 cause chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature with evidence of genetic and phenotypic heterogeneity. Arthritis Rheum 64:895–907

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Yan N, Regalado-Magdos AD, Stiggelbout B et al (2010) The cytosolic exonuclease TREX1 inhibits the innate immune response to human immunodeficiency virus type 1. Nat Immunol 11:1005–1013

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Gunther C (2015) Genetics of lupus erythematosus. Hautarzt 66:121–128

    Article  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Klinik für Dermatologie, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Fetscherstr. 74, 01307, Dresden, Deutschland

    C. Günther & F. Schmidt

  2. Klinik für Kinder- und Jugendmedizin, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Deutschland

    N. König & M. A. Lee-Kirsch

Authors
  1. C. Günther
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. F. Schmidt
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. N. König
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. M. A. Lee-Kirsch
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to C. Günther.

Ethics declarations

Interessenkonflikt

C. Günther, F. Schmidt, N. König und M.A. Lee-Kirsch geben an, dass kein Interessenkonflikt besteht.

Dieser Beitrag beinhaltet keine Studien an Menschen oder Tieren.

Additional information

Redaktion

B. Manger, Erlangen

B. Swoboda, Erlangen

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Günther, C., Schmidt, F., König, N. et al. Typ-I-Interferonopathien. Z Rheumatol 75, 134–140 (2016). https://doi.org/10.1007/s00393-015-0027-5

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s00393-015-0027-5

Schlüsselwörter

Keywords

Search

Navigation