CE15 - Immunologie, Infectiologie et Inflammation

Deciphering tolerance breakdown in Immune ThrombocytoPenia (BREAK-TOL) – BREAK-ITP

Submission summary

The aim of this proposal is to explore the mechanisms and fundamental step(s) of tolerance breakdown in the spleen of immune thrombocytopenia (ITP) patients, taking advantage of the unique access to autoreactive splenic germinal centers from these patients as well as of rare cohorts of ITP patients with known genetic insufficiency in genes implicated in controlling B and T cell tolerance. To first unravel the complexity of cellular and molecular mechanisms leading to tolerance breakdown, we will combine single cell approaches recently developed in our group to characterize the tolerance checkpoints and affinity selection threshold governing the maturation of major splenic B cell subsets in healthy individuals and ITP patients and analyze, in parallel, the contribution of anti-GPIIbIIIa-reactive T cells. Similar studies will further be performed in two cohorts of rare patients with known genetic deficiencies leading to ITP and likely encompassing both ends of the spectra regarding the respective pathogenic role of T and B cell in driving ITP. In ITP patients with heterozygous haplo-insufficient mutations of CTLA-4 and SOCS1, and suspected T cells intrinsic tolerance breakdown, we will aim at identifying a second hit in T or B cells, mandatory to trigger auto-immunity. Alternatively, we will characterize the origin, molecular imprint, and repertoire of auto-reactive B cell clones in spleen of patients with autoimmune lymphoproliferative syndrome (ALPS), carrying mutations of FAS in B and T cells. Whether a “FAS mutated” signature is the sole driver of B cell tolerance breakdown will be at the center of this analysis. Overall, this project aims to provide new insights into the molecular and cellular events driving autoreactive B-cells clones toward pathogenicity in ITP with the goal of better understanding the precise underlying causes and best cellular targets.

Project coordinator

Monsieur Matthieu Mahévas (Institut National de la Santé et de la Recherche Médicale)

The author of this summary is the project coordinator, who is responsible for the content of this summary. The ANR declines any responsibility as for its contents.

Partner

IMAGINE INSTITUT DES MALADIES GÉNÉTIQUES (IHU)
INSERM - UMR 1151 Institut National de la Santé et de la Recherche Médicale

Help of the ANR 572,518 euros
Beginning and duration of the scientific project: March 2023 - 36 Months

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