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hereditary autoinflammatory diseases

Tuesday 14 June 2005

Definition: Autoinflammatory diseases are defined as recurrent "unprovoked" inflammatory events which do not produce high-titer autoantibodies or antigen-specific T cells.

The autoinflammatory disorders are a new and expanding classification of inflammatory diseases characterized by recurrent episodes of systemic inflammation in the absence of pathogens, autoantibodies or antigen specific T cells.

These disorders are caused by primary dysfunction of the innate immune system, without evidence of adaptive immune dysregulation.

Innate immune abnormalities include aberrant responses to pathogen associated molecular patterns (PAMPs) like lipopolysaccharide and peptidoglycan, prominent neutrophilia in blood and tissues, and dysregulation of inflammatory cytokines (IL-1beta, TNF-alpha) or their receptors.

The hereditary autoinflammatory diseases arise from mutations of genes regulating the innate immune system. These rare disorders are well characterized, both clinically and in terms of their molecular pathogenesis.

The recurrent attacks of febrile polyserositis of Familial Mediterranean Fever (FMF) are due to defective pyrin, a protein that down-regulates inflammation.

The Hyperimmunoglobulinemia D Syndrome (HIDS), which mimics FMF, results from a genetically conferred deficiency of mevalonate kinase.

TRAPS (TNF Receptor Associated Periodic Syndrome), formerly known as Familial Hibernian Fever, is caused by a defective membrane receptor for TNF.

Three other hereditary disorders which overlap in their clinical expression - Familial Cold Autoinflammatory Syndrome, the Muckle Wells syndrome, and Neonatal Onset Multisystem Inflamatory Disease (NOMID) - are a consequence of gain-of-function mutations of the gene encoding cryopyrin, the scaffolding protein of the inflammasome.

The PAPA syndrome (Pyogenic Arthritis, Pyoderma gangrenosum, Acne) results from mutations of a gene that increases the binding of its product (PSPSTPIP1) to pyrin, thereby blunting the inhibitory effect of pyrin on inflammasome activation.


- Familial Mediterranean fever (FMF)
- mevalonate kinase deficiency (MKD)
- hyperimmunoglobulinemia D with periodic fever syndrome (HIDS)
- tumor necrosis factor receptor-associated periodic syndrome (TRAPS)
- cryopyrin-associated periodic syndrome (CAPS)
- Pyogenic sterile Arthritis, Pyoderma gangrenosum and Acne syndrome, (PAPA syndrome)
- chronic recurrent multifocal osteomyelitis (CRMO)
- familial juvenile systemic granulomatosis (Blau syndrome)
- Muckle-Wells syndrome (MWS)
- familial cold autoinflammatory syndrome (FCAS)
- chronic infantile neurologic cutaneous articular (CINCA) syndrome or neonatal-onset multisystem inflammatory disease (NOMID)
- pyogenic sterile arthritis
- pyoderma gangrenosum
- acne (PAPA)
- Crohn disease
- Behçet disease

Open References

- The autoinflammatory diseases. Federici S, Caorsi R, Gattorno M. Swiss Med Wkly. 2012 Jun 19;142:0. PMID: 22714396 (Free)


- Galeazzi M, Gasbarrini G, Ghirardello A, Grandemange S, Hoffman HM, Manna R, Podswiadek M, Punzi L, Sebastiani GD, Touitou I, Doria A. Autoinflammatory syndromes. Clin Exp Rheumatol. 2006 Jan-Feb;24(1 Suppl 40):S79-85. PMID: 16466630

- Tunca M, Ozdogan H. Molecular and genetic characteristics of hereditary autoinflammatory diseases. Curr Drug Targets Inflamm Allergy. 2005 Feb;4(1):77-80. PMID: 15720239

- Touitou I, Notarnicola C, Grandemange S. Identifying mutations in autoinflammatory diseases: towards novel genetic tests and therapies? Am J Pharmacogenomics. 2004;4(2):109-18. PMID: 15059033

- McDermott MF, Aksentijevich I. The autoinflammatory syndromes. Curr Opin Allergy Clin Immunol. 2002 Dec;2(6):511-6. PMID: 14752334

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