Showing papers by "Luisa Imberti published in 2023"
TL;DR: In this paper , a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 un vaccinated SARS-CoV-2-infected individuals without pneumonia was performed.
Abstract: We previously reported that impaired type I IFN activity, due to inborn errors of TLR3- and TLR7-dependent type I interferon (IFN) immunity or to autoantibodies against type I IFN, account for 15-20% of cases of life-threatening COVID-19 in unvaccinated patients. Therefore, the determinants of life-threatening COVID-19 remain to be identified in ~ 80% of cases.We report here a genome-wide rare variant burden association analysis in 3269 unvaccinated patients with life-threatening COVID-19, and 1373 unvaccinated SARS-CoV-2-infected individuals without pneumonia. Among the 928 patients tested for autoantibodies against type I IFN, a quarter (234) were positive and were excluded.No gene reached genome-wide significance. Under a recessive model, the most significant gene with at-risk variants was TLR7, with an OR of 27.68 (95%CI 1.5-528.7, P = 1.1 × 10-4) for biochemically loss-of-function (bLOF) variants. We replicated the enrichment in rare predicted LOF (pLOF) variants at 13 influenza susceptibility loci involved in TLR3-dependent type I IFN immunity (OR = 3.70[95%CI 1.3-8.2], P = 2.1 × 10-4). This enrichment was further strengthened by (1) adding the recently reported TYK2 and TLR7 COVID-19 loci, particularly under a recessive model (OR = 19.65[95%CI 2.1-2635.4], P = 3.4 × 10-3), and (2) considering as pLOF branchpoint variants with potentially strong impacts on splicing among the 15 loci (OR = 4.40[9%CI 2.3-8.4], P = 7.7 × 10-8). Finally, the patients with pLOF/bLOF variants at these 15 loci were significantly younger (mean age [SD] = 43.3 [20.3] years) than the other patients (56.0 [17.3] years; P = 1.68 × 10-5).Rare variants of TLR3- and TLR7-dependent type I IFN immunity genes can underlie life-threatening COVID-19, particularly with recessive inheritance, in patients under 60 years old.
10 citations
TL;DR: A tomato food supplement enriched with olive polyphenols, containing cis-lycopene concentrations far exceeding those present in industry-produced tomato commodities, has been shown to be superior to its single-nutrient counterparts in decreasing the incidence of age-related prostate diseases as mentioned in this paper .
Abstract: It is well-established that the beneficial properties of single phytonutrients can be better attained when they are taken with the complex of the molecules present in their natural milieu. Tomato, the fruit providing the most comprehensive complex of prostate-health-preserving micronutrients, has been shown to be superior to its single-nutrient counterparts in decreasing the incidence of age-related prostate diseases. Herein, we describe a novel tomato food supplement enriched with olive polyphenols, containing cis-lycopene concentrations far exceeding those present in industry-produced tomato commodities. The supplement, endowed with antioxidant activity comparable to that of N-acetylcysteine, significantly reduced, in experimental animals, the blood levels of prostate-cancer-promoting cytokines. In prospective, randomized, double-blinded, placebo-controlled studies performed on patients affected by benign prostatic hyperplasia, its uptake significantly improved urinary symptoms and quality of life. Therefore, this supplement can complement and, in some cases, be an alternative to current benign prostatic hyperplasia management. Furthermore, the product suppressed carcinogenesis in the TRAMP mouse model of human prostate cancer and interfered with prostate cancer molecular signaling. Thus, it may offer a step forward in exploring the potential of tomato consumption to delay or prevent the onset of age-related prostate diseases in high-risk individuals.
TL;DR: In this article , the authors reported a comprehensive typing of immune infiltrating cells in CRCpMMR and tested the expression and interferonγ-modulation of PD-L1/CD274.
Abstract: Simple Summary Consensus Molecular Subtypes have recently been proposed based on molecular and immune landscape of colorectal carcinoma (CRC). Only mismatch repair deficient and hyper-mutated CRC (CRCdMMR) can obtain clinical benefits from immune checkpoint blockades; on the other hand, mismatch repair proficient CRCs (CRCpMMR) have very limited therapeutic options. This study establishes that CRCpMMR displays an immunosuppressive microenvironment containing abundant tumor-associated macrophages (TAMs) and neutrophils, with a reduction in double negative T lymphocytes and B cells and increased exhausted tumor-infiltrating lymphocytes. Poor immunogenicity in CRCpMMR is further supported by interferon gamma (IFN-γ) unresponsiveness of both tumor cells and TAMs. Abstract Colorectal carcinoma (CRC) represents a lethal disease with heterogeneous outcomes. Only patients with mismatch repair (MMR) deficient CRC showing microsatellite instability and hyper-mutated tumors can obtain clinical benefits from current immune checkpoint blockades; on the other hand, immune- or target-based therapeutic strategies are very limited for subjects with mismatch repair proficient CRC (CRCpMMR). Here, we report a comprehensive typing of immune infiltrating cells in CRCpMMR. We also tested the expression and interferon-γ-modulation of PD-L1/CD274. Relevant findings were subsequently validated by immunohistochemistry on fixed materials. CRCpMMR contain a significantly increased fraction of CD163+ macrophages (TAMs) expressing TREM2 and CD66+ neutrophils (TANs) together with decrease in CD4−CD8−CD3+ double negative T lymphocytes (DNTs); no differences were revealed by the analysis of conventional and plasmacytoid dendritic cell populations. A fraction of tumor-infiltrating T-cells displays an exhausted phenotype, co-expressing PD-1 and TIM-3. Remarkably, expression of PD-L1 on fresh tumor cells and TAMs was undetectable even after in vitro stimulation with interferon-γ. These findings confirm the immune suppressive microenvironment of CRCpMMR characterized by dense infiltration of TAMs, occurrence of TANs, lack of DNTs, T-cell exhaustion, and interferon-γ unresponsiveness by host and tumor cells. Appropriate bypass strategies should consider these combinations of immune escape mechanisms in CRCpMMR.
TL;DR: An overview of anti-cytokine autoantibodies identified to date and their clinical associations can be found in this article , where the authors discuss whether they can act as enemies or friends and if they may be linked to gender or immunosenescence.
Abstract: Anti-cytokine autoantibodies and, in particular, anti-type I interferons are increasingly described in association with immunodeficient, autoimmune, and immune-dysregulated conditions. Their presence in otherwise healthy individuals may result in a phenotype characterized by a predisposition to infections with several agents. For instance, anti-type I interferon autoantibodies are implicated in Coronavirus Disease 19 (COVID-19) pathogenesis and found preferentially in patients with critical disease. However, autoantibodies were also described in the serum of patients with viral, bacterial, and fungal infections not associated with COVID-19. In this review, we provide an overview of anti-cytokine autoantibodies identified to date and their clinical associations; we also discuss whether they can act as enemies or friends, i.e., are capable of acting in a beneficial or harmful way, and if they may be linked to gender or immunosenescence. Understanding the mechanisms underlying the production of autoantibodies could improve the approach to treating some infections, focusing not only on pathogens, but also on the possibility of a low degree of autoimmunity in patients.