BackgroundThe immune response plays a pivotal role in dictating the clinical outcome in severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)-infected adults, but it is still poorly investigated in the pediatric population.MethodsOf 209 enrolled subjects, 155 patients were confirmed by PCR and/or serology as having coronavirus disease 2019 (COVID-19). Blood samples were obtained at a median of 2.8 (interquartile, 2.1–3.7) and 6.1 (5.3–7.2) months after baseline (symptom onset and/or first positive virus detection). The immune profiles of activation, senescence, exhaustion, and regulatory cells were analyzed by flow cytometry. Neutralizing antibodies (nAbs) were detected by a plaque reduction neutralization test. In available nasopharyngeal swabs at baseline, SARS-CoV-2 levels were quantified by digital droplet PCR (ddPCR).ResultsOverall, COVID-19 patients had higher levels of immune activation, exhaustion, and regulatory cells compared to non-COVID-19 subjects. Within the COVID-19 group, activated and senescent cells were higher in adults than in children and inversely correlated with the nAbs levels. Conversely, Tregs and Bregs regulatory cells were higher in COVID-19 children compared to adults and positively correlated with nAbs. Higher immune activation still persisted in adults after 6 months of infection, while children maintained higher levels of regulatory cells. SARS-CoV-2 levels did not differ among age classes.ConclusionsAdults displayed higher immune activation and lower production of anti-SARS-CoV-2 nAbs than children. The different immune response was not related to different viral load. The higher expression of regulatory cells in children may contribute to reduce the immune activation, thus leading to a greater specific response against the virus.

Tunicates are the unique chordates to possess species reproducing sexually and asexually. Among them, the colonial ascidian Botryllus schlosseri is a reference model for the study of similarities and differences in these two developmental pathways. We here illustrate the characterization and expression pattern during both pathways of a transcript for a gene orthologous to Dazap1. Dazap1 genes encode for RNA-binding proteins and fall into the Musashi-like (Msi-like) group. Our phylogenetic analysis shows that these are related to other RNA-binding proteins (Tardbp and several heterogeneous nuclear ribonucleoproteins types) that share the same modular domain structure of conserved tandem RNA Recognition Motifs (RRMs). We also classify the whole group as derived from a single ancient duplication of the RRM. Our results also show that Dazap1 is expressed with discrete spatiotemporal pattern during embryogenesis and blastogenesis of B. schlosseri. It is never expressed in wholly differentiated tissues, but it is located in all bud tissues and in different spatiotemporally defined territories of embryos and larva. These expression patterns could indicate different roles in the two processes, but an intriguing relationship appears if aspects of cell division dynamics are taken into account, suggesting that it is related to the proliferative phases in all tissues, and raising a similarity with known Dazap1 orthologs in other metazoans.

Liver transplanted (LT) patients for hepatocellular carcinoma (LT-HCC) or for other causes (LT-no-HCC) may develop post-transplantation malignancies. Although immune activation and senescence are frequently implicated in cancer development, no data is available on their possible role as biomarkers predictive of tumor onset in this setting. A total of 116 patients were investigated: the 45 LT-HCC patients were older than the 71 LT-non-HCC (p=0.011), but comparable for sex, HCV, HBV infection and immunosuppressive treatment. At baseline, the numbers of activated and senescent-like circulating cells were significantly higher in LT-HCC patients than in LT-no-HCC ones. After a median follow-up of 26.8 months, 6 post-transplant malignancies (PTM) occurred: 4 in LT-HCC (8.9%) and 2 in LT-no-HCC (2.8%) patients. Overall, subjects with high percentages of activated and exhausted T and B cells at baseline were at higher risk of PTM. Notably, within the LT-HCC group, a higher percentage of senescence-like T cells was also associated with cancer development. Moreover, patients with PTM had higher telomere erosion and higher levels of circulating PAMPs (16S rDNA) and DAMPs (mtDNA) when compared with matched patients without PTM. Overall, these findings suggest that immune activation and exhaustion may be useful to predict the risk of PTM occurrence, regardless of the cause of transplantation. In LT-HCC, T-cell senescence represents an additional risk factor for tumor onset.

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Purpose: Antibody-mediated rejection (AMR) following lung transplantation (LTX) is an evolving concept that may explain persistent graft dysfunction or organ failure in a subset of patients. The incidence of lung AMR is unknown and the clinical outcome has been reported only in a few studies. Methods: Forty-one lung recipients were included in the study: 24 with clinical dysfunction and/or histological indications for AMR immunopathologic evaluation and 17 controls (without signs of clinical dysfunction and histological damage). All patients underwent scheduled transbronchial biopsies or biopsies for clinical indication, associated with screening for the detection of donor-specific anti-HLA antibodies (DSA) by luminex. AMR was defined according the latest AMR update from the ISHLT Pathology Council [Berry G et al., 2013]. Patients with AMR were treated with high-dose steroids, plasmapheresis and CMV-Ig. Results: During the follow up, 59 biopsies and DSA measurements were performed; 3 patients showed acute AMR (defined as high DSA levels and C4d immunostaining in more than 50% of interstitial capillaries) and one showed probable AMR (C4d > 50% but no DSA). AMR occurred very early (within 4 months after LTX) and these patients elicited a de novo anti-DQ immune response. They were followed for a mean follow-up time of 17 months (range: 10-24 months) and 7 biopsies and blood samples taken at the same time for each patient were analyzed. One patient died 4 weeks after diagnosis for untreatable AMR; in one patient AMR lasted for 6 months and one patient showed clinical improvement with considerable DSA reduction after 5 weeks. The 17 control patients without clinical or histological signs of graft damage had no pathological C4d deposition or DSA in the measurements performed to date. Conclusion: Our data show that, in lung transplant recipients with clinical dysfunction and/or histological damage, AMR is not a rare event as it has a prevalence of 12.5%. In these patients a full clinical, pathological and immunological assessment should be performed to enable a timely diagnosis and a better therapeutic approach of this challenging form of rejection.