Research fields

Auto-inflammatory diseases
Non-exhaustive classification
Pathophysiology
Clinical features & Diagnosis

            The concept of auto-inflammatory diseases was introduced in 1999 and encompasses a group of inflammatory syndromes characterized by dysfunction of the innate immune system (without high titer auto-antibodies or auto-reactive T-cells) in opposition to auto-immune diseases that relate to a deficit of acquired immunity

Non-exhaustive classification (Schema)

1. Monogenic auto-inflammatory diseases

            Ten genes identified between 1997 and 2009 ( see the list of mutations on Infevers) are responsible for auto-inflammatory entities, that can be divided into four principal groups:

• Hereditary recurrent fevers : FMF (Familial Mediterranean fever), TRAPS (TNF Receptor Associated Periodic Syndrome), MKD (Mevalonate kinase deficiency), CAPS (Cryopyrin Associated Periodic Syndrome) and NAPS12 (NLRP12 associated periodic syndrome
• Pyogenic diseases: PAPA (Pyogenic sterile Arthritis, Pyoderma), DIRA syndrome and Majeed syndrome
• Granulomatous diseases: Blau syndrome
• Hereditary reproductive wastage: RHMs (recurrent hydatidiform moles)

2. Multifactorial auto-inflammatory diseases

            For example, Behçet and Crohn diseases

3. Diseases with a probable genetic component 

            JIA (Juvenile idiopathic arthritis), Still disease and PFAPA (Periodic Fever Aphtous Stomatis Pharyngitis Adenitis)

Pathophysiology

            Immune system comprises two complex and narrowly connected cellular process: non specific innate immunity and specific acquired immunity. When a danger signal is detected by our organism, the cells of the innate immunity system are activated and an inflammatory response is triggered. The danger signal can be either endogenous such as toxic compounds, defective nucleic acids or exogenous such as pathogens (bacteria, virus).
            Inflammation is a physiological reaction of the organism to an aggression. It is characterized by the occurrence of fever, pain, erythema and swelling caused by the effect of soluble molecules on the local blood vessels. These vessels dilate and become permeable to the circulating leucocytes which reach the site of infection or inflammation. Neutrophiles and monocytes/macrophages are the main leucocytes involved in innate immunity. These cells migrate by chemotaxis towards the inflammatory site and secrete pro-inflammatory mediators such as the cytokine IL-1b, that amplify the immune response.

            Most of the currently known proteins involved in hereditary auto-inflammatory diseases are related to the death domain fold (DDF) superfamily involved in inflammation and apoptosis. These molecules mediate regulation of NFkB activation, cell apoptosis and IL1b secretion through cross-regulated and sometimes common signalling pathways. Although mutations in these proteins induce increased and/or prolonged secretion of IL-1b, the potent pro-inflammatory and pyogenic cytokine, the molecular mechanisms implicated are still being studied.

Clinical features & Diagnosis

Clinical features(Consutations)

These diseases include a broad number of unexplained periodic fevers. The main symptoms are recurrent attacks of fever of unknown origin, abdominal pain, arthritis and cutaneous signs, which sometimes overlap, obscuring the diagnosis. Indeed, all HRFs are associated with biological acute inflammation during febrile crises. Blood tests show leukocytosis, monocytosis, a variable degree of hypochromic anemia, and elevated acute-phase reactants(C-reactive protein, SAA protein). Search for distinguishing signs such as periorbital oedema in TRAPS, and use of specific functional tests where available, are of valuable help.
          The prognosis of the diseases is different from one affection to another. Renal amyloidosis is the most serious complication in untreated patients and makes these syndromes potentially fatal disease. Therefore it is critical to make an accurate diagnosis and distinguish one entity from other. The treatment also varies and must be targeted on the deficiency pathway to be effective: for example anti-TNF (Ethanercept) in TRAPS or anti-IL1 (Anakinra) in CAPS (Cryopyrin Associated Periodic Syndrome).

Diagnosis (also...)

Molecular screening of the causative genes has dramatically improved patient quality of life, by providing early and accurate diagnosis, allowing subsequent appropriate treatment. Some patients, however, remain hard to manage due to absence of clear genetic confirmation or low penetrance of several variants and/or lack of effective treatment.
            Moreover, an emerging hypothesis is that some mutations segregating with specific monogenic disorders, would act as susceptibility factors in multifactorial diseases (Behçet, Crohn) or auto-immune (Vasculitis, disseminated sclerosis, Lupus, Erythema,.Rhumatoid arthritis). Screening of the general population for recessive genes showed a very high rate of healthy carriers ranging from 1 to 30% suggesting a selective advantage conferred by these mutations. The currently recognized patients would thus represent only the top of the iceberg.