Study of mast cell involvment in autoinflammatory diseases. – INFLAMAST

Autoinflammatory diseases (AIDs) are rare genetic diseases beginning in childhood and characterized by recurrent episodes of fever with inflammation in the blood, arthromyalgia, gastrointestinal tract features, skin lesions and neuropsychological disorders. AIDs are linked to innate immunity abnormalities, especially inflammasome activation. Innate immunity cells concerned are mostly monocytes, macrophages and neutrophils. Some clinical symptoms impacting the daily quality of life of patients remain unexplained including allergic reactions, diarrhea, digestive bloating, anxiety, and asthenia. Mast cells belong to innate immunity. My previous works have shown the involvement of mast cells in these symptoms in mast cell mediated diseases, especially mastocytosis which is associated to KIT mutations leading to mast cells autoactivation and proliferation. The aim of this work is to investigate the clinical, biological and physiopathological roles of mast cells in AIDs, and eventually find out new genetic mutations in genes expressed in mast cells. The project will take place in my new laboratory which is specialized in autoinflammation. We will first focus on familial Mediterranean fever which is the most frequent AIDs and then extend our work to other AIDs, especially unclassified AIDs (UAIDs) with allergic features and rare monogenic AIDs with urticaria. Firstly, we will study the prevalence of mast cells activation symptoms in patients with FMF and UCAIDs using a standardized clinical score; we will also measure mast cells mediators in blood and urine by biochemistry measurements. Secondly, we will Study in mast cells the role of inflammasomes activation involved in AIDs, especially pyrin, NLRP3 and NLRC4. Our preliminary data on 50 adult patients with FMF show that patients with FMF they display significantly more mast cell activation symptoms, including anxiety, asthenia, pruritus, dermographism, chronic abdominal pain and bloating, than healthy age matched controls (p<0.0001). Twenty eight FMF patients displayed elevated mast cell mediators (56%) compared to normal rates. Altogether, when we combined the clinical score and biological results, 48% of FMF patients (n=24/50) had positive criteria for mast cell activation syndrome.Thirdly, we suspected a role of MC in the chronic digestive symptoms of FMF, and among the 15 patients with mast cell staining on digestive biopsies, all of them displayed mast cell infiltration (attested by more than 5 mast cells per field) especially in duodenum. We have access to many patients thru the national reference center for familial Mediterranean fever and other AIDs, where the coordinator of the project is working. We have very well established collaborations with specialists on mast cells in Paris, France and the host laboratory is specialized in genetic and molecular aspects of AIDs. The feasibility of the project is thus excellent. This novel approach aims to find new players and new pathways in the pathophysiology of AIDs as well as therapeutic targets directed against mast cells in order to improve the quality of life of patients.