Abstract
Recent progress in DNA sequencing technology has made it possible to identify specific genetic mutations in familial disorders. For example, autoinflammatory syndromes are caused by mutations in gene coding for immunoproteasomes. These diseases include Japanese autoinflammatory syndrome with lipodystrophy, Nakajo-Nishimura syndrome, joint contractures, muscular atrophy, microcytic anemia, panniculitis-associated lipodystrophy syndrome, and chronic atypical neutrophilic dermatosis with lipodystrophy and elevated temperature syndrome. Causal mutations of these syndromes are present in gene coding for subunits of the immunoproteasome. Importantly, a genetically modified mouse that lacks the catalytic subunit of immunoproteasomes does not always develop an autoinflammatory syndrome. Analysis of causal gene mutations, assessment of patients’ phenotypic changes, and appropriate animal models will be indispensable for clarifying the underlying mechanisms responsible for the development of autoinflammatory syndromes and establishing curative approaches.
Highlights
BackgroundInflammation is caused by a variety of factors including endogenous abnormalities, infection, and toxins and involved in immune-mediated disorders including autoimmune or autoinflammatory disorders
Proteasomes and immunoproteasomes The proteasome is a multi-subunit protease complex that degrades ubiquitinated proteins in the cytosol for rapid turnover [10, 11]
The standard proteasome is present in most eukaryotic cells, and the thymoproteasome is a specific proteasome found in the thymus [12]
Summary
Inflammation is caused by a variety of factors including endogenous abnormalities, infection, and toxins and involved in immune-mediated disorders including autoimmune or autoinflammatory disorders. Recent studies have uncovered other types of inflammatory pathologies termed “autoinflammation” that are induced by activation of innate immune cells without apparent infection or autoimmune responses. Autoinflammatory syndromes are hereditary diseases and mainly caused by a mutation of a single gene that codes for a component of NACHT, LRR, and PYD domaincontaining protein (NLRP) inflammasomes, cytosolic DNA danger sensing machinery, cytokine receptors, and immunoproteasomes [3,4,5]. The causal gene mutations are unclear and/or involve multiple mutations in some cases. We and the other groups have reported an autoinflammatory syndrome in which the gene for proteasome subunit beta-type 8 (PSMB8) has been altered [6,7,8,9].
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