Autoinflammatory syndromes and cellular responses to stress: pathophysiology, diagnosis and new treatment perspectives

Best Pract Res Clin Rheumatol. 2012 Aug;26(4):505-33. doi: 10.1016/j.berh.2012.07.009.


The term 'autoinflammatory disease' was first proposed in 1999 to encompass some of the distinct clinicopathologic features of a group of monogenic conditions, characterised by recurrent episodes of inflammation, without high-titre autoantibodies or antigen-specific T cells. It was subsequently observed that several of these conditions were caused by mutations in proteins involved in the innate immune response, including, among others, components of the NLRP3 inflammasome, cytokine receptors (tumour necrosis factor receptor 1 (TNFR1)) and receptor antagonists (interleukin 1 receptor antagonist (IL-1RA)). More recently, additional mechanisms linking innate immune-mediated inflammation with a variety of cellular processes, including protein misfolding, oxidative stress and mitochondrial dysfunction, have been recognised to play a role in the pathogenesis of some monogenic autoinflammatory conditions, and also in more common diseases such as type 2 diabetes (T2D), previously perceived as a metabolic disorder, but reclassified as a chronic inflammatory condition. NLRP3 inflammasome activation is induced by islet amyloid polypeptides (IAPPs) in T2D and this condition may, in future, be more commonly treated with targeted anti-cytokine therapies. Caspase 1 activation and release of IL-1β/IL-1 family members is central to the pathogenesis of many autoinflammatory syndromes, as evidenced by the effectiveness of anti-IL-1 biologics in treating these disorders. However, many patients continue to experience symptoms of chronic inflammation, and it will be necessary to translate discoveries on the immunopathology of these conditions into more effective therapies. For example, in tumour necrosis factor receptor-associated periodic fever syndrome (TRAPS), the pathogenesis may vary with each mutation and therefore future approaches to treatment of individual patients will require a more tailored approach based on genetic and functional studies.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Carrier Proteins / immunology
  • Carrier Proteins / metabolism
  • Cytokines / immunology
  • Familial Mediterranean Fever / genetics
  • Hereditary Autoinflammatory Diseases* / diagnosis
  • Hereditary Autoinflammatory Diseases* / genetics
  • Hereditary Autoinflammatory Diseases* / immunology
  • Hereditary Autoinflammatory Diseases* / physiopathology
  • Hereditary Autoinflammatory Diseases* / therapy
  • Humans
  • Immunity, Innate
  • Inflammasomes / immunology
  • Inflammasomes / metabolism
  • Mutation
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • Syndrome


  • Carrier Proteins
  • Cytokines
  • Inflammasomes
  • NLR Family, Pyrin Domain-Containing 3 Protein
  • NLRP3 protein, human