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Doyon-Laliberte, K.

Publications and source records attributed to Doyon-Laliberte, K..

2 recordsLinked to original sources
bioRxiv2022

Subclinical Atherosclerosis is Associated with Discrepancies in BAFF and APRIL Levels and Altered Breg Potential of Precursor-like Marginal Zone B-Cells in HIV Treated Individuals

Chronic inflammation persists in people living with HIV (PLHIV) despite antiretrovial therapy (ART), and is involved in their premature development of cardiovascular diseases (CVD) such as atherosclerosis. We have previously reported that an excess of "B-cell activating factor" (BAFF), an important molecule for the selection and activation of first line Marginal Zone (MZ) B-cell populations, is associated with deregulations of precursor-like MZ (MZp), whose potent B-cell regulatory (Breg) capacities are altered in PLHIV, early on and despite 1-2 years of ART. Based on these observations, and growing evidence that MZ populations are involved in atherosclerosis control, we designed a cross sectional study to explore the associations between BAFF and its analogue "A proliferation-inducing ligand" (APRIL) with subclinical CVD in long time treated individuals of the Canadian HIV and Aging Cohort Study (CHACS) imaging sub-study group. We also characterized the Breg profile of MZp from the blood of these individuals. Results were correlated with the total volume of atherosclerotic plaques (TPV) and with CVD risk factors and biomarkers. TPV was measured using cardiac computerised tomography angiography, and presence of CVD was defined as TPV > 0. We report that blood levels of BAFF are elevated and correlate positively with CVD and its risk factors in PLHIV from the CHACS, in contrast to APRIL levels, which correlate negatively with these factors. Expression levels of Breg markers such as NR4A3, CD39, CD73 and CD83 are significantly lower in PLHIV when compared to those of HIV-uninfected controls. In vitro experiments show that APRIL upregulates the expression of Breg markers by blood MZp from HIV-uninfected individuals, while this modulation is dampened by the addition of recombinant BAFF. Altogether, our observations suggest that strategies viewed to modulate levels of BAFF and/or APRIL could eventually represent a potential treatment target for CVD in PLHIV.

immunology↗
bioRxiv2022

Excess BAFF Alters NR4As Expression Levels and Breg Function of Human Precursor-like Marginal Zone B-cells in the Context of HIV-1 infection

We have shown that excess B-cell activating factor (BAFF) in the blood of HIV-infected individuals, is concomitant with increased frequencies of precursor-like marginal zone (MZp) B-cells, early on and despite successful antiretroviral therapy (ART). We have recently reported that in HIV-uninfected individuals, MZp possess a strong B-cell regulatory (Breg) potential. As such, MZp B-cells highly express IL-10, the orphan nuclear receptors (NR)4A1, NR4A2, NR4A3, the regulatory molecule CD83, as well as ectonucleotidases CD39 and CD73, all of which are associated with regulation of inflammation. Moreover, the Breg function of MZp B-cells involves CD83 signals. Herein, in order to address the impact of HIV infection and excessive BAFF environment on MZp B-cells and their regulatory capacities, we have performed transcriptomic analyses by RNA-seq of sorted MZp B-cells from the blood of HIV-infected progressors. The Breg profile and function of blood MZp B-cells from HIV-infected progressors were assessed by flow-cytometry and light microscopy high content screening (HCS) analyses, respectively. In addition, the effects of excess BAFF on the Breg profile of MZp B-cells from HIV-uninfected controls were investigated in vitro. We report significant downregulation of NR4A1, NR4A2, NR4A3 and CD83 gene transcripts in blood MZp B-cells from HIV-infected progressors when compared to HIV-uninfected controls. NR4A1, NR4A3 and CD83 protein expression levels and Breg function were also downregulated in blood MZp B-cells from HIV-infected progressors and not restored by ART. Moreover, we observe decreased expression levels of NR4A1, NR4A3, CD83 and IL-10 by blood and tonsillar MZp B-cells from HIV-uninfected individuals following treatment with excess BAFF, which significantly diminished their regulatory function. These findings suggest that excess BAFF contributes to the alteration of the Breg potential of MZp B-cells, which could lead to a loss of "immune surveillance", during HIV infection and possibly in other situations where BAFF is found in excess. Author SummaryThe precursor-like marginal zone (MZp) B-cell population, we previously described in human blood and tonsils, presents with an important regulatory "Breg" potential, depicted by elevated nuclear receptor (NR)4As expression levels, similarly to Tregs, and to our knowledge currently underexplored in human Breg studies. Herein, we present the impact that a chronic inflammatory context such as HIV-infection, and its excessive B-cell activating factor (BAFF) environment, may exert on the Breg capacities of MZp, both ex vivo and in vitro, significantly affecting their NR4As expression levels and Breg function. These findings are of growing significance, especially with the recently described importance of MZ B-cell NR4A1 expression in atherosclerosis immune surveillance. The finding that immune surveillance may be altered in circumstances of chronic inflammation and excessive BAFF, is of pivotal interest, as treated HIV-infected individuals often prematurely develop co-morbidities associated with aging such as cardiovascular diseases (CVD). Moreover, excess BAFF has been reported in several inflammatory autoimmune contexts where CVD is the leading cause of death.

immunology↗