Biology subjects

Bongiovanni, L.

Publications and source records attributed to Bongiovanni, L..

3 recordsLinked to original sources

bioRxiv2021

Follicular helper T cell signature of replicative exhaustion, apoptosis and senescence in common variable immunodeficiency

BackgroundCommon variable immunodeficiency (CVID) is the most frequent primary antibody deficiency. A significant number of CVID patients are affected by various manifestations of immune dysregulation such as autoimmunity. Follicular T cells cells are thought to support the development of CVID by providing inappropriate signals to B cells during the germinal center (GC) response. ObjectivesWe determined the possible role of follicular helper (Tfh) and follicular regulatory T (Tfr) cells in patients with CVID by phenotypic, molecular, and functional studies. MethodsWe analyzed the frequency, phenotype, transcriptome, and function of circulating Tfh cells in the peripheral blood of 27 CVID patients (11 pediatric and 16 adult) displaying autoimmunity as additional phenotype and compared them to 106 (39 pediatric and 67 adult) age-matched healthy controls. We applied Whole Exome Sequencing (WES) and Sanger sequencing to identify mutations that could account for the development of CVID and associate with Tfh alterations. ResultsA group of CVID patients (n=9) showed super-physiological frequency of Tfh1 cells and a prominent expression of PD-1 and ICOS, as well as a Tfh RNA signature consistent with highly active, but exhausted and apoptotic cells. Plasmatic CXCL13 levels were elevated in these patients and positively correlated with Tfh1 cell frequency, PD-1 levels, and an elevated frequency of CD21loCD38lo autoreactive B cells. Monoallelic variants in RTEL1, a telomere length- and DNA repair-related gene, were ideintified in four patients belonging to this group. Lymphocytes with highly shortened telomeres, and a Tfh signature enriched in genes involved in telomere elongation and response to DNA damage were seen. Histopathological analysis of the spleen in one patient showed reduced amount and size of the GC that, unexpectedly, contained an increased number of Tfh cells. ConclusionThese data point toward a novel pathogenetic mechanism in a group of patients with CVID, whereby alterations in DNA repair and telomere elongation might be involved in GC B cells, and acquisition of a Th1, highly activated but exhausted and apoptotic phenotype by Tfh cells.

immunology↗

bioRxiv2020

PIDDosome-induced p53-activation for ploidy restriction facilitates hepatocarcinogenesis

Polyploidization frequently precedes tumorigenesis but also occurs during normal development in several tissues. Hepatocyte ploidy is controlled by the PIDDosome during development and regeneration. The PIDDosome multi-protein complex is activated by supernumerary centrosomes to induce p53 and restrict proliferation of polyploid cells, otherwise prone for chromosomal instability. PIDDosome-deficiency in the liver results in drastically increased polyploidy. To investigate PIDDosome-induced p53-activation in the pathogenesis of liver cancer, we chemically induced hepatocellular carcinoma (HCC) in mice. Strikingly, PIDDosome-deficiency reduced tumor number and burden, despite the inability to activate p53 in polyploid cells. Liver tumors arise primarily from cells with low ploidy, indicating an intrinsic pro-tumorigenic effect of PIDDosome-mediated ploidy restriction. These data suggest that hyperpolyploidization caused by PIDDosome-deficiency protects from HCC. Moreover, high tumor cell density, as a surrogate marker of low ploidy, predicts of survival of HCC patients receiving liver transplantation. Together, we show that the PIDDosome is a potential therapeutic target to manipulate hepatocyte polyploidization for HCC prevention and tumor cell density serves as a novel prognostic marker for recurrence free survival in HCC patients.

cancer biology↗

bioRxiv2019

OTULIN prevents liver inflammation and hepatocellular carcinoma by inhibiting FADD- and RIPK1 kinase-mediated hepatocyte apoptosis

Inflammatory signaling pathways are tightly regulated to avoid chronic inflammation and the development of inflammatory pathologies. OTULIN is a deubiquitinating enzyme that specifically cleaves linear ubiquitin chains generated by the linear ubiquitin chain assembly complex (LUBAC), and OTULIN deficiency causes OTULIN-related autoinflammatory syndrome (ORAS) in humans. OTULIN was shown to negatively control NF-{kappa}B signaling in response to various stimuli, but also to protect cells from tumor necrosis factor (TNF)-induced apoptosis. To investigate the importance of OTULIN in liver homeostasis and pathology, we developed a novel mouse line specifically lacking OTULIN in liver parenchymal cells. These mice spontaneously develop a severe liver disease, characterized by liver inflammation, hepatocyte apoptosis and compensatory hepatocyte proliferation, leading to steatohepatitis, fibrosis and hepatocellular carcinoma (HCC). Genetic ablation of Fas-associated death domain (FADD) completely rescues the severe liver pathology, and knock-in expression of kinase inactive receptor-interacting protein kinase 1 (RIPK1) significantly protects from developing liver disease, demonstrating that death receptor-mediated apoptosis of OTULIN-deficient hepatocytes triggers disease pathogenesis in this model. Finally, we demonstrate that type I interferons contribute to disease pathogenesis in hepatocyte-specific OTULIN deficient mice. Together, our study reveals the critical importance of OTULIN in protecting hepatocytes from death, and thereby avoid development of chronic liver inflammation and HCC in mice.

cancer biology↗