• Le 17 novembre 2020
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  • 11h via zoom

« Cellular and molecular mechanisms of self-DNA immunogenicity in systemic autoimmunity »

Unité de Recherche CNRS 5164 Immunoconcept, Université de Bordeaux.
Invité par le Pr Régis Josien​


Antibodies to self-DNA drive autoimmunity in systemic lupus erythematous (SLE). The break of tolerance to self-DNA in SLE patients is commonly associated with defect in pathways involved in the clearance of dying cells and particularly of their nucleic acids. We have previously characterised the role of the deoxyribonuclease DNASE1L3 in this process. Indeed, DNASE1L3 deficient mice rapidly develop anti-DNA and anti-chromatin autoantibodies and all the major hallmarks of SLE. DNASE1L3 specifically degrades nucleosmal DNA and DNA associated to microparticles released by dying cells. Accordingly, DNASE1L3 deficient individuals and mice accumulate DNA in nucleosome and microparticle associated forms. Such DNA activates in MYD88 dependant manner the production of anti-DNA antibodies by B cells and contribute to SLE pathogenesis (Sisirak et al, Cell, 2016). The talk that I will present will mostly focus on the cellular and molecular mechanisms that are involved in SLE pathogenesis driven by DNASE1L3 deficiency. We have recently shown that the production of anti-DNA autoantibodies in DNASE1L3 deficient mice does not require CD40L-mediated T cell help and a germinal center reaction. The production of anti-DNA antibodies rather relies on short-lived plasmablasts that are activated in extra-follicular regions. Plasmacytoid dendritic cells (pDCs) play an essential role in the activation of these auto-reactive short lived plasmablasts, most likely through their ability to produce type I interferons (IFN-I). Interestingly, the production of anti-DNA antibodies in DNASE1L3 deficient mice was dependent of both TLR7 and TLR9 which are the main endosomal nucleic acids sensors. Indeed single KO of both TLR7 and TLR9 did not affected SLE pathogenesis in DNASE1L3 KO mice while their double deficiency totally prevented it, indicating redundancy in their function (Soni et al, Immunity, 2020). Finally during my talk we will explore how DNASE1L3 function my be modulated in sporadic SLE patients without any genetic defects in DNASE1L3 and discuss its potential role in other pathological contexts.