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Current Rheumatology Reports
Erschienen in: Current Rheumatology Reports 7/2018

01.07.2018 | Pediatric Rheumatology (S Ozen, Section Editor)

An Update on Autoinflammatory Diseases: Relopathies

verfasst von: Annemarie Steiner, Cassandra R. Harapas, Seth L. Masters, Sophia Davidson

Erschienen in: Current Rheumatology Reports | Ausgabe 7/2018

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Abstract

Purpose of Review

The nuclear factor κB (NF-κB) pathway is tightly regulated through multiple posttranslational mechanisms including ubiquitination. Mutations in these regulatory pathways can cause disease and are the focus of this review.

Recent Findings

The linear ubiquitin chain assembly complex (LUBAC) is a trimer made up of HOIL-1L, SHARPIN, and the catalytic subunit HOIP. Loss of function mutations in HOIL-1L and HOIP result in largely overlapping phenotypes, characterized by multi-organ autoinflammation, immunodeficiency, and amylopectinosis. Interestingly, patient fibroblasts exhibited diminished IL-1β- and TNF-induced NF-κB activation, yet monocytes were hyper-responsive to IL-1β, hinting at cell type or target specific roles of LUBAC-mediated ubiquitination. Ubiquitin-driven signaling is counterbalanced by deubiquitinase enzymes (DUBs), such as OTULIN and A20. Hypomorphic mutations in OTULIN result in elevated NF-κB signaling causing an autoinflammatory syndrome. Similarly, patients with high-penetrance heterozygous mutations in the gene encoding A20 (haploinsufficiency of A20 (HA20)) display excessive ubiquitination and increased activity of NF-κB and of NLRP3 inflammasome activation. HA20 patients present with Behçet-like characteristics or an autoimmune lymphoproliferative syndrome (ALPS)-like phenotype, indicating diverse protein functions.

Summary

This review summarizes recent discoveries in the field of NF-kB-related autoinflammatory diseases (relopathies) within the past 3 years and points to several questions that still remain unanswered.
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Metadaten
Titel
An Update on Autoinflammatory Diseases: Relopathies
verfasst von
Annemarie Steiner
Cassandra R. Harapas
Seth L. Masters
Sophia Davidson
Publikationsdatum
01.07.2018
Verlag
Springer US
Erschienen in
Current Rheumatology Reports / Ausgabe 7/2018
Print ISSN: 1523-3774
Elektronische ISSN: 1534-6307
DOI
https://doi.org/10.1007/s11926-018-0749-x

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