Ivanova, V. | Search bioRxiv

bioRxiv2024

Investigating the effects of protons versus x-rays on radiation-induced lymphopenia after brain irradiation

BackgroundConventional x-ray-based radiotherapy is a standard treatment for patients with brain tumors. However, is associated with systemic effects like lymphopenia that correlates with poor prognosis. Proton therapy has emerged as a new radiation strategy, given that the lower entry dose and absence of exit dose can be exploited to spare healthy brain tissues and reduce side-effects caused by systemic inflammation. We evaluated if brain irradiation with protons could spare circulating leukocytes along with other variables in rodent models. MethodsTumor-free C57BL/6 mice were irradiated with a total dose of 20Gy in 2.5Gy twice-daily sessions over four consecutive days with either x-rays or protons. Groups of mice were defined according to irradiation volume (whole-brain or hemisphere) and dose rate (1 or 2Gy/min). Blood was withdrawn at various time points and circulating lymphoid, with myeloid subpopulations analyzed using flow cytometry. Brain tissue histochemical analyses were performed late after irradiation. ResultsBlood sampling showed severe and acute radiation-induced lymphopenia after x-rays, with marked depletion of 50% CD4+ and CD8+, as well as B and NK cells. With protons, the decrease was 20% on average for whole-brain irradiations, suggesting a conservative effect on circulating lymphocytes. The data showed no effect in CD11b+ myeloid cells for both x-rays and protons. Histological analyses revealed a more intense expression level of CD68 and Iba1 immunostaining after x-ray irradiation. GFAP staining was well detected after both beams. ConclusionProton therapy for brain tumors differs from photon therapy in terms of its effects on circulating cells and tissues. Key pointsO_LIX-ray brain irradiation induced an acute severe lymphopenia, with a reduction of at least 50% lymphocytes. The whole-brain irradiation caused a more pronounced decrease in lymphocytes than hemisphere irradiation. Proton brain irradiation exhibited a conservative effect on circulating leukocytes. C_LIO_LIX-ray irradiation-induced lymphopenia is followed by a recovery of all lymphocyte subpopulations to control levels. However, this recovery is longer for CD3+ lymphocytes, and B and NK cells, depending on irradiation modalities. C_LIO_LILong-term brain tissue histochemical analyses demonstrated differences between the two beams, consisting of a macrophage/microglial activation seen mostly after x-rays while an astrocyte reaction was seen after brain exposure to the two beams. These differences may explain the disparities observed in leukocytes, thereby favoring a specific biological reaction between the brain and blood. C_LI Importance of the StudyOur study demonstrated that while whole-brain or hemispheric irradiation with x-rays resulted in lymphopenia, proton brain irradiation exhibited a conservative effect on circulating lymphocytes, which was paralleled by a less intense brain tissue reaction.

cell biology↗

bioRxiv2021

3C-seq-captured chromosome conformation of the hyperthermophilic archaeon Thermofilum adornatum

Three-dimensional structure of chromosomes displays diverse patterns across the tree of life, with compartments, interaction domains and loops being quite universally observed. The archaeal kingdom remains understudied to this extent so far, despite representing an interesting area from evolutionary and other perspectives. Here we describe the spatial chromosomal organization of a hyperthermophilic crenarchaeon Thermofilum adornatum strain 1910b based on high-throughput chromosome conformation capture (3C-seq) approach. The chromosome contact map showed a curved secondary diagonal almost orthogonal to the main one. No evidence of chromosome loops was present. We were able to identify boundaries of different strengths between chromosome interaction domains (CIDs) albeit moderate. The plaid-like patterns previously reported for Sulfolobus archaea were not observed. However, the calculation of A/B compartments divided the genome into 2 domains that were different by the density of predicted highly expressed genes and location of origins. Further comparison of these domains with whole-genome gene expression profiles will allow to test whether these domains represent expression-associated compartments. If so, it is possible that they represent primitive compartments evolutionarily older than the plaid patterns of Sulfolobus and higher eukaryotes. Further exploration of 3D chromatin in all branches of archaeal diversity will elucidate the evolution of the links between structural and functional organization in live organisms.

bioinformatics↗

bioRxiv2018

Type-I interferons inhibit interleukin-10 signaling and favor type 1 diabetes development in NOD mice

Destruction of insulin-producing {beta}-cells by autoreactive T lymphocytes leads to the development of type 1 diabetes. Type I interferons (TI-IFN) and interleukin-10 (IL-10) have been connected with the pathophysiology of this disease; however, their interplay in the modulation of diabetogenic T cells remains unknown. We have discovered that TI-IFN cause a selective inhibition of IL-10 signaling in effector and regulatory T cells, altering their responses. This correlates with diabetes development in NOD mice, where the inhibition is also spatially localized to T cells of pancreatic and mesenteric lymph nodes. IL-10 signaling inhibition is reversible and can be restored via blockade of TI-IFN/IFN-R interaction, paralleling with the resulting delay in diabetes onset and reduced severity. Overall, we propose a novel molecular link between TI-IFN and IL-10 signaling that helps better understand the complex dynamics of autoimmune diabetes development and reveals new strategies of intervention.\n\nAbbreviations

immunology↗