Zusammenfassung
Funktionsstörungen des Proteasoms können zu schweren Beeinträchtigungen des angeborenen Immunsystems führen. Diese neuen Interferonopathien mit autosomal-rezessivem Erbgang werden inzwischen als ein Erkrankungsspektrum angesehen und unter dem Oberbegriff der Proteasomen-assoziierten autoinflammatorischen Syndrome (PRAAS) zusammengefasst. In der Pathogenese werden eine Akkumulation von ubiquitinierten Proteinen und die Induktion von Typ-I-IFN-Genen angenommen. Zu den typischen klinischen Manifestationen gehören Lipodystrophie, Haut-, Gelenk- und Muskelbeteiligung mit einer bemerkenswerten Variabilität weiterer assoziierter Symptome. Dieser Beitrag gibt einen Überblick zu den aktuell bekannten molekularen Veränderungen sowie zu klinischen Gemeinsamkeiten und Unterschieden bei PRAAS. Weiterhin wird auf bisher eingesetzte immunsuppressive Therapieansätze eingegangen.
Abstract
Functional disorders of the proteasome can have a severe impact on the innate immune system. Characterized by an autosomal recessive mode of inheritance, this novel type of interferonopathy is considered to be a spectrum of diseases of proteasome-associated autoinflammatory syndromes (PRAAS). Accumulation of ubiquitinated proteins and the induction of type I interferon (IFN) genes seem to play a role in the pathogenesis. The typical clinical manifestations are lipodystrophy, skin, joint and muscle involvement accompanied by a remarkable variability of other associated symptoms. This article provides an overview on currently known molecular alterations as well as clinical similarities and differences of PRAAS. Furthermore, the reported effects of the immunosuppressive therapy approaches used so far are summarized.
Literatur
Hipp MS, Park SH, Hartl FU (2014) Proteostasis impairment in protein-misfolding and -aggregation diseases. Trends Cell Biol 24(9):506–514
Kriegenburg F, Poulsen EG, Koch A, Kruger E, Hartmann-Petersen R (2011) Redox control of the ubiquitin-proteasome system: from molecular mechanisms to functional significance. Antioxid Redox Signal 15(8):2265–2299
Feist E, Burmester GR, Kruger E (2016) The proteasome – victim or culprit in autoimmunity. Clin Immunol 172:83–89. doi:10.1016/j.clim.2016.07.018
Kruger E, Kloetzel PM (2012) Immunoproteasomes at the interface of innate and adaptive immune responses: two faces of one enzyme. Curr Opin Immunol 24(1):77–83
Chen ZJ (2005) Ubiquitin signalling in the NF-kappaB pathway. Nat Cell Biol 7(8):758–765
Seifert U, Bialy LP, Ebstein F et al (2010) Immunoproteasomes preserve protein homeostasis upon interferon-induced oxidative stress. Cell 142(4):613–624
Ebstein F, Voigt A, Lange N et al (2013) Immunoproteasomes are important for proteostasis in immune responses. Cell 152(5):935–937
Neubert K, Meister S, Moser K et al (2008) The proteasome inhibitor bortezomib depletes plasma cells and protects mice with lupus-like disease from nephritis. Nat Med 14(7):748–755
Agarwal AK, Xing C, DeMartino GN 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
Arima K, Kinoshita A, Mishima H 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 USA 108(36):14914–14919
Kitamura A, Maekawa Y, Uehara H et al (2011) A mutation in the immunoproteasome subunit PSMB8 causes autoinflammation and lipodystrophy in humans. J Clin Invest 121(10):4150–4160
Brehm A, Liu Y, Sheikh A et al (2015) Additive loss-of-function proteasome subunit mutations in CANDLE/PRAAS patients promote type I IFN production. J Clin Invest 125(11):4196–4211
McDermott A, Jacks J, Kessler M, Emanuel PD, Gao L (2015) Proteasome-associated autoinflammatory syndromes: advances in pathogeneses, clinical presentations, diagnosis, and management. Int J Dermatol 54(2):121–129
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(3):895–907
Kluk J, Rustin M, Brogan PA et al (2014) Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature syndrome: a report of a novel mutation and review of the literature. Br J Dermatol 170(1):215–217
Brehm A, Kruger E (2015) Dysfunction in protein clearance by the proteasome: impact on autoinflammatory diseases. Semin Immunopathol 37(4):323–333
Warnatsch A, Bergann T, Kruger E (2013) Oxidation matters: the ubiquitin proteasome system connects innate immune mechanisms with MHC class I antigen presentation. Mol Immunol 55(2):106–109
Kunimoto K, Kimura A, Uede K et al (2013) A new infant case of Nakajo-Nishimura syndrome with a genetic mutation in the immunoproteasome subunit: an overlapping entity with JMP and CANDLE syndrome related to PSMB8 mutations. Dermatology 227(1):26–30
Torrelo A, Patel S, Colmenero I et al (2010) Chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature (CANDLE) syndrome. J Am Acad Dermatol 62(3):489–495
Cavalcante MP, Brunelli JB, Miranda CC et al (2016) CANDLE syndrome: chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature-a rare case with a novel mutation. Eur J Pediatr 175(5):735–740
Kanazawa N (2012) Nakajo-Nishimura syndrome: an autoinflammatory disorder showing pernio-like rashes and progressive partial lipodystrophy. Allergol Int 61(2):197–206
Kanazawa N, Kunimoto K, Ishii N, Inamo Y, Furukawa F (2014) Is CANDLE the best nomenclature? Br J Dermatol 171(3):659–660
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Interessenkonflikt
E. Feist, A. Brehm, T. Kallinich und E. Krüger geben an, dass kein Interessenkonflikt besteht.
Dieser Beitrag beinhaltet keine von den Autoren durchgeführten Studien an Menschen oder Tieren.
Additional information
Redaktion
R.E. Schmidt, Hannover
G. Horneff, St. Augustin
Rights and permissions
About this article
Cite this article
Feist, E., Brehm, A., Kallinich, T. et al. Klinik und Genetik bei Proteasomen-assoziierten autoinflammatorischen Syndromen (PRAAS). Z Rheumatol 76, 328–334 (2017). https://doi.org/10.1007/s00393-017-0264-x
Published:
Issue Date:
DOI: https://doi.org/10.1007/s00393-017-0264-x