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. 2017 Mar;29(2):187-194.
doi: 10.1097/BOR.0000000000000362.

Lessons From Characterization and Treatment of the Autoinflammatory Syndromes

Free PMC article

Lessons From Characterization and Treatment of the Autoinflammatory Syndromes

Ivona Aksentijevich et al. Curr Opin Rheumatol. .
Free PMC article


Purpose of review: The list of genes associated with systemic inflammatory diseases has been steadily growing because of the explosion of new genomic technologies. Significant advances in the past year have deepened our understanding of the molecular mechanisms linked to inflammation and elucidated insights on the efficacy of specific therapies for these and related conditions. We review the molecular pathogenesis of four recently characterized monogenic autoinflammatory diseases: haploinsufficiency of A20, otulipenia, a severe form of pyrin-associated disease, and a monogenic form of systemic juvenile idiopathic arthritis.

Recent findings: The scope of autoinflammation has been broadened to include defects in deubiquitination and cellular redox homeostasis. At the clinical level, we discuss the biological rationale for treatment with cytokine inhibitors and colchicine in respective conditions and the use of interleukin-1 antagonism for diagnostic and therapeutic purposes in the management of undifferentiated autoinflammatory disorders.

Summary: Gene discoveries coupled with studies of molecular function provide knowledge into the biology of inflammatory responses and form the basis for genomically informed therapies. Diseases of dysregulated ubiquitination constitute a novel category of human inflammatory disorders.

Conflict of interest statement

Conflict of Interest: None of the authors had any conflict of interest


Figure 1
Figure 1. Proposed mechanisms of pathogenesis in Haploinsufficiency of A20 (HA20) and otulipenia
The canonical NF-κB pathway is regulated both by K63 (Lys63)-linked and linear (Met1)-linked ubiquitin chains. RIPK1 is the central adaptor for assembly of the TNFR1 receptor-signaling complex and is a predominant target for ubiquitination by K63 and linear ubiquitin chains. Polyubiquitylated RIPK1 mediates recruitment of IKK complex that is also target for ubiquitination. The activated IKK complex phosphorylates inhibitor of κB (IκB) and targets IκB for ubiquitin–proteasome system (UPS)-mediated degradation. A20 and OTULIN negatively regulate NF-κB signaling, by cleaving K63 and linear UB chains from target molecules, RIPK1 and IKK. Decreased expression of mutant A20 or OTULIN proteins will lead to activation of the NF-κB pathway and increased expression of proinflammatory transcripts in immune cells. The NLRP3 inflammasome is also negatively regulated by A20 [12,13]. TNF receptor 1 (TNFR1); TNFR1-associated death domain protein (TRADD); the death domain-containing protein kinase receptor-interacting protein1 (RIPK1); NACHT, LRR and PYD domains-containing protein 3 (NLRP3).
Figure 2
Figure 2. Proposed mechanisms of pyrin inflammasome inhibition and pyrin activation in PAAND and FMF diseases
Top panel: The pyrin inflammasome is suppressed following phosphorylation by RhoA effector kinases PKN1/PKN2 and binding to 14-3-3. Middle panel: PAAND-associated p.S242R mutation disrupts the pyrin phosphorylation site, which results in decreased phosphorylation of pyrin, decreased binding to 14-3-3 proteins, and subsequent activation of the pyrin inflammasome. Bottom panel: FMF-associated mutations inhibit the interaction of pyrin with PKN1/PKN2 and thus cause decreased phosphorylation of pyrin. It is unclear whether the B30.2 domain of pyrin can interact with the protein domain encoded by exon 2. A loop is drawn for the purpose of this figure. Figure adopted from the reference 38. Protein Kinase N1 (PKN1); Protein Kinase N2 (PKN2).

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