Biology subjects

Orsi, A.

Publications and source records attributed to Orsi, A..

3 recordsLinked to original sources

bioRxiv2024

Biological modifications of the immune response to COVID-19 vaccine in patients treated with anti-CD20 agents and immune-checkpoint inhibitors

Investigating the impact of immune-modulating therapies on mRNA vaccine efficacy transcends the immediate context of the COVID-19 pandemic. This study focuses on the differential immune responses to the third dose of COVID-19 mRNA vaccine among healthy volunteers, cancer patients treated with immune-checkpoint inhibitors (ICIs), and those treated with the anti-CD20 antibody rituximab. Utilizing RNA sequencing, serology, and interferon-{gamma} release assessment, we charted the temporal dynamics of the immune response in such cohorts. Our findings indicate that ICIs maintain an immune profile similar to that of healthy individuals, whereas treatment with rituximab is associated with impairment of type I interferon response and the upregulation of transcripts pertaining to regulatory T cells, with a global dysfunction of both humoral and cellular immunity. This research deepens our understanding of the sophisticated interplay within the immune system in health and disease states, potentially informing therapeutic strategies across a spectrum of immunological conditions. Significance statementOur study examines how cancer treatments that modify the immune system affect transcriptional, serological, and cellular responses to a model for repeated antigenic stimulation in humans, represented by the SARS-CoV-2 booster vaccine. Specifically, we investigated patients treated with rituximab (RTX), which impairs antibody production, and immune checkpoint inhibitors (ICI), which can trigger autoimmune disorders. We discovered that RTX-treated patients not only exhibit a reduced antibody response but actually show a diminished interferon-mediated immune response, indicating a broader immune disruption than anticipated. Conversely, ICI-treated patients responded to the vaccine similarly to healthy individuals, suggesting that fears of adverse vaccine reactions in these patients may be unfounded. This research highlights important considerations for the clinical management of cancer patients receiving these treatments.

immunology↗

bioRxiv2023

Congress of multiple dimers is needed for cross-phosphorylation of IRE1α and its RNase activity

The unfolded protein response can switch from a pro-survival to a maladaptive, pro-apoptotic mode. During endoplasmic reticulum (ER) stress, IRE1 sensors dimerize, are phosphorylated and activate XBP1 splicing, increasing folding capacity in the ER protein factory. The steps that turn the IRE1 endonuclease activity against endogenous mRNAs during maladaptive ER stress are still unknown. Here we show that although necessary, IRE1 dimerization is not sufficient to trigger phosphorylation. Random and/or guided collisions amongst IRE1 dimers are needed to elicit cross-phosphorylation and endonuclease activities. Thus, reaching a critical concentration of IRE1 dimers in the ER membrane is a key event. Formation of stable IRE1 clusters is not necessary for RNase activity. However, clustering could modulate the potency of the response promoting interactions between dimers and decreasing the accessibility of phosphorylated IRE1 to phosphatases. The stepwise activation of IRE1 molecules and their low concentration at steady state prevent excessive responses, unleashing full-blown IRE1 activity only upon intense stress conditions.

cell biology↗

bioRxiv2017

The unfolded protein response turns from pro-survival to pro-death to cap the extent of endoplasmic reticulum expansion

Insufficient folding capacity of the endoplasmic reticulum (ER) activates the unfolded protein response (UPR) to restore homeostasis. Yet, how the UPR achieves and evaluates ER homeostatic readjustment is poorly understood. In a HeLa cell model we show that, upon a severe proteostatic insult that eclipses the ER chaperone BiP, the UPR transitions from acute full-gear activation to chronic submaximal activation, when BiP is in excess again. As such, the UPR-driven ER expansion is pro-survival, primarily via the UPR transducer ATF6. Simultaneous abrogation of ER-associated degradation (ERAD) leads to chronic full-gear UPR activation and further ER expansion, but the UPR transducers IRE1 and PERK turn pro-apoptotic. Pro-survival XBP1 mRNA processing by IRE1 is then trumped since unspliced XBP1 mRNA is depleted and IRE1s endonuclease activity is unleashed against other RNAs. Thus, the IRE1/XBP1 relay serves as a capacitor of ER expansion that heralds cell death if the expansion is deemed excessive.

cell biology↗