Genetic Dissection of Autoinflammatory Syndrome

Abstract

Autoinflammatory syndromes are characterised by inflammatory responses without infection or autoimmune responses. As autoinflammatory syndromes cause both acute and chronic inflammation, the identification of the caus-ative genes for this syndrome would help to reveal the molecular mechanisms underlying chronic inflammation. Recent studies have revealed that mutations in the PSMB8 gene, which codes for an immunoproteasome component, cause an autoinflammatory disorder with lipodystrophy. The missense mutation in PSMB8 disturbs the assembly of immunoproteasomes, which decreases immunoproteasome functions. The decreased immunoproteasome function increases the level of proinflammatory cytokines, including interleukin-6. Furthermore, dysfunction of the immunoproteasome suppresses adipocyte differentiation, which might explain the progressive lipodystrophy that is a characteristic symptom of these patients. The identification of immunoproteasome dysfunction-related autoinflammatory disorders highlights immunoproteasomes as crucial intracellular complexes in the regulation of inflammatory responses. Furthermore, analysis of this syndrome will provide new insights into the key molecular networks related to chronic inflammation.