CR - CNRS
Origins and pathogenesis of Autoimmune and Inflammatory disorders
About Vanja Sisirak
I am a junior research scientist (PhD) starting his own group funded by the IDEX junior chair program of the University of Bordeaux. The research that we are developing aims at studying the role of DNA digesting enzymes in the regulation of anti-tumor immune responses as well as in the establishment of systemic autoimmune syndromes such as Systemic Lupus Erythematosus and Systemic Sclerosis.
My research / PhD / Post-doc / projects
I started my research career during my PhD in Lyon, France by studying how tumors escape the immune system. Particularly we were interested in understanding how human breast tumor microenvironment inhibit the function of a population of dendritic cells called plasmacytoid dendritic cells (pDC) and thus favor the escape of tumors to the immune system. We found that soluble factors produced by the tumor environment inhibit pDCs main ability to produce type I Interferons, an inflammatory cytokine involved in anti-viral immunity as well as in the initiation of anti-tumor immune responses. Such impaired pDCs within breast tumors were instead promoting the proliferation of suppressive T cells called regulatory T cells preventing thus anti-tumor immunity. These results paved the way to new therapeutic strategies aiming at restoring pDCs ability to produce type I Interferons in order to boost anti-tumor immune responses.
After completing my PhD I joined Columbia University and New York University to work with Dr. Reizis on pDCs functions in animals models in vivo. We particularly have shown using a genetic mouse model lacking functional pDCs, that pDCs play a deleterious role in an autoimmune syndrome called systemic lupus erythematosus (SLE). Indeed, absence of pDCs in two independent animal models of SLE ameliorated most of SLE cardinal features, including autoantibody production and kidney pathology. Two other independent groups further validated these results and established pDCs as an interesting therapeutic target to ameliorate the outcome of SLE patients. During my postdoctoral experience we were also interested in the origins of SLE pathology. We were particularly intrigued in the role of a DNA digesting enzyme Dnase1L3, which deficiency in humans was associated with early and aggressive form of SLE. We reproduced such results in Dnase1L3 deficient animals and identified the mechanisms leading to SLE in those animals. Particularly we have observed that the deficiency in Dnase1L3 causes the accumulation of DNA systemically in humans as well as in mice. Such DNA mostly accumulate in in microparticles released by dying cells rendering them highly immunogenic and activating the production of DNA specific autoantibodies by B cells causing SLE development.
The goals of our new research team at the University of Bordeaux as a member of the Immuno ConcEpT group is to combine both my expertise acquired during my career. Particularly, more and more evidence indicate that the recognition of DNA-derived from dying tumor cells is at the crux of anti-tumor immune responses. Such DNA activate the production of inflammatory cytokines such as type I Interferons by dendritic cells, that is required for the initiation of anti-tumor T cell responses. However most of the tumors are not rejected by the immune system, thus we speculate that Dnases, and especially Dnase1L3 may regulate the level of available DNA and may thus participate in tumor immune escape. We will test this hypothesis using Dnase1L3 deficient mice injected with syngeneic tumors as well as in a spontaneous breast tumor model, that is more precisely mimicking the human disease. In addition in collaboration with local clinical partners we will study the role of Dnase1L3 in the development of systemic sclerosis, a disease that was recently shown to be exacerbated by microparticles released by dying cells and that is strongly associated with genetic polymorphisms in Dnase1L3 locus. Thus our laboratory will tackle questions related to tumor-immunity and auto-immunity with the ultimate goal to apply finding from autoimmune syndromes to restore autoimmune like anti-tumor immune responses and vice-versa.
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