Autoinflammatory diseases unit
French National referral centre
Biology-Pathology research pole – University Hospital of Montpellier


   

 
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Autoinflammatory diseases
  • Definition
  • Physiopathology
  • Modes of transmission

 

Definition


A selection of publications
  • Disorders of innate immunity:
    The term autoinflammatory diseases (AIDs) was first proposed in 1999 and groups together the inflammatory syndromes characterized by an absence of raised levels of auto-antibodies and of activated lymphocytes.
  • Continuum with autoimmune diseases:
    The immune system draws upon two complex and closely connected processes: nonspecific natural innate immunity and specific acquired immunity.

Physiopathology


The danger signals
  • Step 1: Detection of danger signals
    Immediately after a danger signal appears in our organism, specialized cells and proteins of the innate immune system are activated and induce an immune response.

Innate immunity, first line of defence, is related to the recognition by host cells of molecular motifs peculiar to danger signals thanks to their specific receptors: toll-like receptors (TLR) that identify extracellular signals, and NOD-like receptors (NLR) that identify intracellular signals. Among the danger signals can be distinguished those that are:

  • Endogenous or DAMPS (Damage associated molecular patterns): microcrystals, cellular debris (ATP…)
  • Exogenous or PAMPS (Pathogen associated molecular patterns): pathogens (bacterial surface, nucleic acids of virus, etc.)

The inflammatory reaction
  • Step 2: Induction of inflammation
    The inflammatory reaction is a physiological mechanism induced by an aggression which brings into play mediators such as the highly pyrogenic cytokine interleukin 1.
  • Inflammation is a physiological reaction of the organism to an aggression and is characterized by the appearance of fever, pain redness and swelling provoked by the effect of soluble molecules on local blood vessels.
  • The blood vessels dilate and become permeable to circulating leukocytes which enter the site of infection. Neutrophils and monocytes/macrophages are the main leukocytes to intervene in innate immunity.
  • The cells migrate chemotactically towards the site of inflammation and there secrete pro-inflammatory mediators such as cytokine IL-1β which amplify the immune response.

Protéines défectueuses
  • Step 3: Appearance of symptoms
    In AIDs, the proteins regulating this reaction are mutated and the inflammatory reaction is excessive. Clinical signs such as fever and serous effusions will appear.
  • Most of the proteins altered in autoinflammatory diseases are related to the death domain-fold superfamily of proteins implicated in inflammation and apoptosis.
  • These proteins participate with other proteins towards the activation of the transcription factor NF-κB, apoptosis and the secretion of the cytokine IL-1β by cross-regulation and sometimes common signalling pathways.
  • Activation of Nod-like receptors (NLR) leads to the recruitment of a multiprotein complex called an inflammasome which induces the maturation of the pro-interleukin-1β into mature IL-1β.
  • While we know that mutations in these proteins induce an exaggerated inflammatory response consecutive to excessive or deregulated activation of the diverse signalling cascades involved, the exact molecular mechanisms are still under investigation.

 

 

Modes of transmission

Monogenic AIDs

  • These are rare hereditary diseases and the only ones eligible for genetic testing
  • The first gene identified was the one responsible for familial Mediterranean fever (FMF) in 1997.
    French FMF consortium | International FMF consortium
  • Since then the list has continued to grow year on year

 

Multifactorial AIDs

  • Crohn’s disease
  • Behçet's disease
  • Gout
  • Systemic juvenile idiopathic arthritis (JIA)
  • Ankylosing spondylitis...

 

AIDs of unknown origin

  • Schnitzler syndrome
  • Marshall syndrome or PFAPA: periodic fever, aphthous stomatitis, pharyngitis, cervical adenitis
 
Réalisé par Florian Milhavet   |   Mentions légales   |   Contact & Plan d'accès