Outcome of SARS-CoV-2 infection is linked to MAIT cell activation and cytotoxicity.

Immune system dysfunction is paramount in coronavirus disease 2019 (COVID-19) severity and fatality rate. Mucosal-associated invariant T (MAIT) cells are innate-like T cells involved in mucosal immunity and protection against viral infections. Here, we studied the immune cell landscape, with emphasis on MAIT cells, in cohorts totaling 208 patients with various stages of disease. MAIT cell frequency is strongly reduced in blood. They display a strong activated and cytotoxic phenotype that is more pronounced in lungs. Blood MAIT cell alterations positively correlate with the activation of other innate cells, proinflammatory cytokines, notably interleukin (IL)-18, and with the severity and mortality of severe acute respiratory syndrome coronavirus 2 infection. We also identified a monocyte/macrophage interferon (IFN)-α-IL-18 cytokine shift and the ability of infected macrophages to induce the cytotoxicity of MAIT cells in an MR1-dependent manner. Together, our results suggest that altered MAIT cell functions due to IFN-α-IL-18 imbalance contribute to disease severity, and their therapeutic manipulation may prevent deleterious inflammation in COVID-19 aggravation.

MAIT cell alterations in adults with recent-onset and long-term type 1 diabetes.

AIMS/HYPOTHESIS: Mucosal-associated invariant T (MAIT) cells are innate-like T lymphocytes expressing an αß T cell antigen receptor that recognises the MHC-related 1 molecule. MAIT cells are altered in children at risk for and with type 1 diabetes, and mouse model studies have shown MAIT cell involvement in type 1 diabetes development. Since several studies support heterogeneity in type 1 diabetes physiopathology according to the age of individuals, we investigated whether MAIT cells were altered in adults with type 1 diabetes. METHODS: MAIT cell frequency, phenotype and function were analysed by flow cytometry, using fresh peripheral blood from 21 adults with recent-onset type 1 diabetes (2-14 days after disease onset) and 47 adults with long-term disease (>2 years after diagnosis) compared with 55 healthy blood donors. We also separately analysed 17 women with long-term type 1 diabetes and an associated autoimmune disease, compared with 30 healthy women and 27 women with long-term type 1 diabetes. RESULTS: MAIT cells from adults with recent-onset type 1 diabetes, compared with healthy adult donors, harboured a strongly activated phenotype indicated by an elevated CD25+ MAIT cell frequency. In adults with long-term type 1 diabetes, MAIT cells displayed an activated and exhausted phenotype characterised by high CD25 and programmed cell death 1 (PD1) expression and a decreased production of proinflammatory cytokines, IL-2, IFN-γ and TNF-α. Even though MAIT cells from these patients showed upregulated IL-17 and IL-4 production, the polyfunctionality of MAIT cells was decreased (median 4.8 vs 13.14% of MAIT cells, p < 0.001) and the frequency of MAIT cells producing none of the effector molecules analysed increased (median 34.40 vs 19.30% of MAIT cells, p < 0.01). Several MAIT cell variables correlated with HbA1c level and more particularly in patients with recent-onset type 1 diabetes. In women with long-term type 1 diabetes, MAIT cell alterations were more pronounced in those with an associated autoimmune disease than in those without another autoimmune disease. In women with long-term type 1 diabetes and an associated autoimmune disease, there was an increase in CD69 expression and a decrease in the survival B-cell lymphoma 2 (BCL-2) (p < 0.05) and CD127 (IL-7R) (p < 0.01) marker expression compared with women without a concomitant autoimmune disorder. Concerning effector molecules, TNF-α and granzyme B production by MAIT cells was decreased. CONCLUSIONS/INTERPRETATION: Alterations in MAIT cell frequency, phenotype and function were more pronounced in adults with long-term type 1 diabetes compared with adults with recent-onset type 1 diabetes. There were several correlations between MAIT cell variables and clinical characteristics. Moreover, the presence of another autoimmune disease in women with long-term type 1 diabetes further exacerbated MAIT cell alterations. Our results suggest that MAIT cell alterations in adults with type 1 diabetes could be associated with two aspects of the disease: impaired glucose homeostasis; and autoimmunity.

Deficiency and altered phenotype of mucosal-associated invariant T cells in systemic sclerosis.

Objective: Systemic sclerosis is an autoimmune disease characterized by fibrosis of the skin and internal organs including the lung. Mucosal-associated invariant T cells are innate-like T lymphocytes able to produce various cytokines and cytotoxic mediators such as granzyme B. A large body of evidence supports a role of mucosal-associated invariant T cells in autoimmune disease but more recent reports suggest also a potential role in fibrotic conditions. Therefore, we herein addressed the question as whether mucosal-associated invariant T cells may have an altered profile in systemic sclerosis. Methods: Mucosal-associated invariant T cell frequency was analyzed by flow cytometry, using fresh peripheral blood from 74 consecutive systemic sclerosis patients who were compared to 44 healthy donors. In addition, in-depth mucosal-associated invariant T cell phenotype and function were analyzed in unselected 29 women with systemic sclerosis who were compared to 23 healthy women donors. Results: Proportion of circulating mucosal-associated invariant T cells was significantly reduced by 68% in systemic sclerosis compared to healthy donors (0.78% in systemic sclerosis vs 2.5%, p < 0.0001). Within systemic sclerosis subsets, mucosal-associated invariant T cells were reduced in patients with interstitial lung disease (systemic sclerosis-interstitial lung disease) (0.56% vs 0.96% in patients without interstitial lung disease, p = 0.04). Moreover, in systemic sclerosis patients, mucosal-associated invariant T cells displayed an activated phenotype indicated by markedly increased CD69+ mucosal-associated invariant T cell frequency (20% mucosal-associated invariant T cell CD69+ compared to 9.4% in healthy donors, p = 0.0014). Interestingly, mucosal-associated invariant T cells from systemic sclerosis-interstitial lung disease patients had a more pronounced altered phenotype compared to systemic sclerosis without interstitial lung disease with a correlation between mucosal-associated invariant T cells expressing CCR6+ and mucosal-associated invariant T cell frequency (r = 0.8, p = 0.006). Conclusion: Circulating mucosal-associated invariant T cells were reduced and exhibited an activated phenotype in systemic sclerosis patients. This peripheral mucosal-associated invariant T cell deficiency may be related to enhanced apoptosis and/or homing in inflamed tissue, particularly in systemic sclerosis-interstitial lung disease patients.

Environmental and individual determinants of burrow-site microhabitat selection, occupancy, and fidelity in eastern chipmunks living in a pulsed-resource ecosystem.

Background: Habitat selection has major consequences on individual fitness, particularly selection for breeding sites such as nests or burrows. Theory predicts that animals will first use optimal habitats or rearrange their distribution by moving to higher-quality habitats whenever possible, for instance when another resident disperses or dies, or when environmental changes occur. External constraints, such as predation risk or resource abundance, and interindividual differences in age, sex and body condition can lead to variation in animals' perception of habitat quality. Following habitat use by individuals over their lifetime is thus essential to understand the causes of variation in habitat selection within a population. Methods: We used burrow occupancy data collected over eight years to assess burrow-site selection in a population of wild eastern chipmunks (Tamias striatus) relying on pulsed resources. We first compared characteristics of burrow microhabitats with those of equivalent unused plots. We then investigated the factors influencing the frequency of burrow occupation over time, and the individual and environmental causes of annual burrow fidelity decisions. Results: Our results indicate that chipmunks select microhabitats with a greater number of woody debris and greater slopes. Microhabitats of burrows with higher occupancy rates had a lower shrub stratum, were less horizontally opened and their occupants' sex-ratio was skewed towards males. Burrow fidelity was higher in non-mast years and positively related to the occupant's age, microhabitat canopy cover and density of large red maples. Conclusion: The quality of a burrow microhabitat appears to be determined in part by characteristics that favour predation avoidance, but consideration of occupancy and fidelity patterns over several years also highlighted the importance of including individual and contextual factors in habitat selection studies.

Interactions between antidepressants, sleep aids and selected breast cancer therapy.

Depression and insomnia are very significant pathologies in cancer patients as they contribute to the patient's overall cure and quality of life. Moreover, untreated depression and ongoing insomnia are associated with decreased immune responses and lower survival rates. With all disease states and especially with cancer, close attention to drug-drug interactions and the potential impact on the efficacy of therapy is paramount. One area of particular interest due to the lack of well-done clinical trials is drug-drug interaction(s) between antidepressants and cancer treatment. Pharmacokinetics of a certain drug allows for prediction of certain drug interactions based on chemical properties of the agents involved. If the agents depend on their metabolites for activity, active drug level will be decreased through this enzyme inhibition. In this paper, we looked at the cytochrome-P450 drug interactions between antidepressants and sleep aids with Selective Estrogen Receptor Modulators (SERM). Newer SERM metabolisms are less influenced by interactions with medications used to treat depression. However, tamoxifen metabolism could be severely altered by several antidepressants. This has direct consequences as patients on tamoxifen and antidepressant can have double the risk of relapse to cancer in two years. We discussed those interactions and made recommendations for clinical use.

[Validity of cardiovascular prescriptions to the guidelines in the elderly according to the STOPP and START method]. / Adéquation des prescriptions cardiovasculaires aux guides de bonnes pratiques chez le sujet âgé selon les outils « STOPP and START ¼

Cardiovascular diseases are the first cause of death in elderly patients. So it seems important to estimate the adequacy of the medical prescriptions to the guidelines in this population and for these diseases. A retrospective analysis was performed in nine hospitals on 736 patients aged 65 years old and over hospitalized in the acute care geriatric unit. Cardiovascular prescribing were analyzed for each patient according to STOPP and START. The population (n=736) has a mean age of 86.7 years and belongs in 45.0% of the cases to the group of dependence GIR3-4. According to STOPP, two inappropriate prescriptions are noticed: calcium channel blockers with chronic constipation concerning 9% of the included population and aspirin at dose > 150 mg/day representing 8.4% of this population. According to START, angiotensin converting enzyme inhibitor are under-prescribed in elderly patients with heart failure (140 patients = 19.0% of the population) and following acute myocardial infarction (116 patients = 15.8%). Anticoagulation in patients with atrial fibrillation is also under-prescribed: 82 patients are concerned (11.0% of the population). The prescription of ACE inhibitor is influenced by renal insufficency in patients with heart failure. The anticoagulation in atrial fibrillation is age and dependence-related. This analysis demonstrates an inadequacy between the clinical practice and guidelines for two major cardiovascular diseases: the heart failure and the atrial fibrillation. The importance of the inadequacy was suspected of opportunities for improvement, in particular in the presence of their risk factors: very elderly patients, loss of autonomy and renal insufficiency.