Analyse du sécrétome des leucocytes de patients suspectés d'être atteints de syndromes auto-inflammatoires chroniques

Authors: Longchamps, Marie-Pier
Advisor: Pelletier, MartinTessier, Philippe
Abstract: Autoinflammatory syndromes (AIS) are inherited conditions characterized by recurrent inflammation and hypersecretion of cytokines byinnate immune cells. Diagnosis and treatments are challenging as detection of mutations rates is low, symptoms are reminiscent of other autoimmune diseases, especially Systemic Autoimmune Rheumatic Diseases (SARDs), and the cytokines abnormally secreted by each individual are unknown. Thus, patients can be misdiagnosed, leading to inappropriate treatment andsevere complications. We hypothesized that the secretion of cytokines by peripheral blood leukocytes of suspected AIS patients could guide the diagnosis and treatment to the most suitable biotherapy. Plasma, peripheral blood mononuclear cells (PBMCs) and polymorphonuclear neutrophils (PMNs) were isolated from healthy controls, SARD patients and suspected AIS patients. PBMCs and PMNs were stimulated with well-known immune activators and levels of cytokines were analyzed by multiplex assays. On the one hand, cytokine levels detected in the plasma were similar between healthy donors, SARD patients and suspected AIS patients. On the other hand, PBMCs and PMNsfrom AIS patients secreted more IL-1α, IL-18, IFNγand IL-12than cells from SARD patients or healthy controlsin response to NLRP1/3, NOD1/2, AIM2 and pyrin inflammasome activation. Detailed analysis of the cytokines secreted by PBMCs and PMNs from each suspected AIS patient showed thatsome suspected AIS patientssecreted excessive IL-1αor IL-1βin the absence of the antagonist IL-1RA, suggesting blockers of IL-1 could be used as biotherapeutic approach. Cellsfrom other suspected AIS patients secreted high levels of IFNγ, IL-12 and IL-18, pointing to the usefulness of treatments such as janus kinase inhibitors, the anti-IL-12/IL-23 antagonist and/or the novel anti-IL-18 in clinical development. This study demonstrates that analyses of cytokine secretion by blood leukocytes can provide an overview of the abnormal pro-inflammatory environment, in addition to being a potential indicator for biotherapy treatment options for patients with suspected AIS.
Document Type: Mémoire de maîtrise
Issue Date: 2019
Open Access Date: 28 March 2019
Grantor: Université Laval
Collection:Thèses et mémoires

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