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Klinische Symptome und Pathogenese der Typ-1-Interferonopathien

Clinical symptoms and pathogenesis of type I interferonopathies

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Zusammenfassung

Die Typ-1-Interferonopathien stellen eine Gruppe genetisch bedingter seltener Erkrankungen dar, die durch eine Fehlfunktion des angeborenen Immunsystems hervorgerufen werden. Gemeinsames Kennzeichen ist eine Dysregulation der antiviralen Typ-1-Interferon(IFN)-Achse, die zu einer konstitutiven Typ-1-IFN-Aktivierung führt. Als systemisch-entzündliche Erkrankungen ist das klinische Spektrum der Typ-1-Interferonopathien sehr breit und sowohl durch Autoinflammation als auch durch Autoimmunität gekennzeichnet. Hierbei stehen neurologische und kutane Manifestationen im Vordergrund. Pathogenetisch liegen den Typ-1-Interferonopathien Störungen im Metabolismus und in der immunologischen Erkennung von intrazellulären Nukleinsäuren zugrunde. Unser derzeitiges Verständnis der molekularen Pathogenese der Typ-1-Interferonopathien weist darauf hin, dass eine immunmodulatorische Intervention, die der inadäquaten Typ-1-IFN-Aktvierung entgegenwirkt, therapeutisch wirksam sein könnte.

Abstract

Type 1 interferonopathies represent a group of genetically determined rare diseases caused by defects of the innate immune system. Central to all type 1 interferonopathies is a dysregulation of the antiviral type 1 interferon (IFN) axis, which results in constitutive overproduction of type 1 IFN. All type 1 interferonopathies present as systemic inflammatory disorders characterized by autoinflammation and autoimmunity. Although the clinical spectrum is highly variable and broad, neurological and cutaneous manifestations represent the most salient findings. Chronic type 1 IFN activation is due to defects in pathways affecting the metabolism or the immune recognition of intracellular nucleic acids. The current understanding of the molecular mechanisms underlying type 1 interferonopathies indicates that an immunomodulatory intervention targeting the type 1 IFN axis might be of therapeutic value.

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Abbreviations

ADAR:

„adenosine deaminase, RNA-specific“

AGS:

Aicardi-Goutières-Syndrom

CANDLE:

„chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature“

cGAMP:

„cyclic GMP-AMP“

cGAS:

„cyclic GMP-AMP synthase“

dNTP:

Desoxynukleosidtriphosphat

dsRNA:

doppelsträngige RNA

ESPED:

Erhebungseinheit für seltene pädiatrische Erkrankungen in Deutschland

IFIH1:

„interferon induced with helicase C domain 1“

IFN:

Interferon

IFNAR:

„interferon-alpha receptor“

IFNB:

Interferon-β-Gen

IRF:

„interferon regulatory factor“

ISG15:

„interferon-stimulated protein 15“

JAK:

Januskinase

MAVS:

„mitochondrial antiviral signaling protein“

MDA5:

„melanoma differentiation-associated gene 5“

MHC:

„major histocompatibility complex“

NF-κB:

„nuclear factor ‚kappa-light-chain-enhancer‘ of activated B-cells“

RIG-I:

„retinoic acid-inducible gene 1“

RNASEH2:

„ribonuclease H2“

RVCL:

„retinal vasculopathy with cerebral leukodystrophy“

SAMHD1:

„SAM domain and HD domain-containing protein 1“

SAVI:

„STING-associated vasculopathy, infantile-onset“

SLE:

systemischer Lupus erythematodes

SPENCD:

Spondyloenchondrodysplasie

ssDNA:

einzelsträngige DNA

STAT:

„signal transducers and activators of transcription“

STING:

„stimulator of interferon genes“

TLR:

„toll-like receptor“

TMEM173:

„transmembrane protein 173“

TRAP:

tartratresistente saure Phosphatase 5

TREX1:

“3‘ repair exonuclease 1“

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Einhaltung ethischer Richtlinien

Interessenkonflikt. M. Diesterheft, M. Schuster, A. Rösen-Wolff, R. Berner, V. Tüngler, M. Lee-Kirsch geben an, dass kein Interessenkonflikt besteht.

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Authors and Affiliations

  1. Klinik und Poliklinik für Kinder- und Jugendmedizin, Universitätsklinikum und Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Fetscherstr. 74, 01307, Dresden, Deutschland

    M. Diesterheft, M. Schuster, A. Rösen-Wolff, R. Berner, V. Tüngler &  M. Lee-Kirsch

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  1. M. Diesterheft
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  2. M. Schuster
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Correspondence to M. Lee-Kirsch.

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Diesterheft, M., Schuster, M., Rösen-Wolff, A. et al. Klinische Symptome und Pathogenese der Typ-1-Interferonopathien. Monatsschr Kinderheilkd 163, 1260–1268 (2015). https://doi.org/10.1007/s00112-015-3478-5

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