The novel coronavirus SARS-CoV-2 enters into the human body mainly through the ACE2 + TMPRSS2+ nasal epithelial cells. The initial host response to this pathogen occurs in a peculiar immune ...microenvironment that, starting from the Nasopharynx-Associated Lymphoid Tissue (NALT) system, is the product of a long evolutionary process that is aimed to first recognize exogenous airborne agents. In the present work, we want to critically review the latest molecular and cellular findings on the mucosal response to SARS-CoV-2 in the nasal cavity and in NALT, and to analyze its impact in the subsequent course of COVID-19. Finally, we want to explore the possibility that the regulation of the systemic inflammatory network against the virus can be modulated starting from the initial phases of the nasal and nasopharyngeal response and this may have several clinical and epidemiological implications starting from a mucosal vaccine development.
The characterization of the adaptive immune response to COVID-19 vaccination in individuals who recovered from SARS-CoV- 2 infection may define current and future clinical practice. To determine the ...effect of the 2-dose BNT162b2 mRNA COVID-19 vaccination schedule in individuals who recovered from COVID-19 (COVID- 19-recovered subjects) compared with naive subjects, we evaluated SARS-CoV-2 Spike-specific T and B cell responses, as well as specific IgA, IgG, IgM, and neutralizing antibodies titers in 22 individuals who received the BNT162b2 mRNA COVID-19 vaccine, 11 of whom had a previous history of SARS-CoV-2 infection. Evaluations were performed before vaccination and then weekly until 7 days after second injection. Data obtained clearly showed that one vaccine dose is sufficient to increase both cellular and humoral immune response in COVID-19-recovered subjects without any additional improvement after the second dose. On the contrary, the second dose proved mandatory in naive subjects to further enhance the immune response. These findings were further confirmed at the serological level in a larger cohort of naive (n = 68) and COVID-19-recovered (n = 29) subjects, tested up to 50 days after vaccination. These results question whether a second vaccine injection in COVID-19-recovered subjects is required, and indicate that millions of vaccine doses may be redirected to naive individuals, thus shortening the time to reach herd immunity.
The current pandemic emergence of novel coronavirus disease (COVID-19) poses a relevant threat to global health. SARS-CoV-2 infection is characterized by a wide range of clinical manifestations, ...ranging from absence of symptoms to severe forms that need intensive care treatment. Here, plasma-EDTA samples of 30 patients compared with age- and sex-matched controls were analyzed via untargeted nuclear magnetic resonance (NMR)-based metabolomics and lipidomics. With the same approach, the effect of tocilizumab administration was evaluated in a subset of patients. Despite the heterogeneity of the clinical symptoms, COVID-19 patients are characterized by common plasma metabolomic and lipidomic signatures (91.7% and 87.5% accuracy, respectively, when compared to controls). Tocilizumab treatment resulted in at least partial reversion of the metabolic alterations due to SARS-CoV-2 infection. In conclusion, NMR-based metabolomic and lipidomic profiling provides novel insights into the pathophysiological mechanism of human response to SARS-CoV-2 infection and to monitor treatment outcomes.
Background Protection against helminths consists of adaptive responses by TH 2 cells and innate responses by group 2 innate lymphoid cells (ILC2s), with these latter being well characterized in mice ...but less so in human subjects. Objective We sought to characterize human circulating ILC2s and compare their functional profile with that of autologous TH 2 cells. Methods Circulating ILC2s and TH 2 cells were isolated by means of fluorescence-activated cell sorting and magnetic cell sorting and expanded in vitro . ILC2s were then stimulated with phorbol 12-myristate 13-acetate plus ionomycin, IL-25 plus IL-33 (IL-25/IL-33), or a mixture of Toll-like receptor ligands to evaluate their ability to produce cytokines, express CD154, and induce IgE production by autologous B cells. Cytokines and transcription factor gene methylation were assessed. Results ILC2s expressed GATA-3, retinoic acid orphan receptor (RORC) 2, and RORα; were able to produce IL-5, IL-13, and IL-4; and, accordingly, were characterized by demethylation of IL4 , IL13 , IL5 , GATA3 , and RORC2 , whereas the IFNG , IFNG promoter, and TBX21 regions of interest were methylated. ILC2s expressed TLR1 , TLR4 , and TLR6 , and TLR stimulation induced IL-5 and IL-13 production. Moreover, ILC2s expressed CD154 in response to phorbol 12-myristate 13-acetate plus ionomycin, IL-25/IL-33, or a mixture of TLR ligands. Stimulated ILC2s also induced IgM, IgG, IgA, and IgE production by B cells. Finally, circulating ILC2s from atopic patients were not different in numbers and frequency but expressed higher IL-4 levels than those from nonatopic subjects. Conclusion This study provides the first evidence that human ILC2s can express CD154 and stimulate the production of IgE by B lymphocytes through IL-25/IL-33 stimulation or TLR triggering.
Innate lymphoid cells type 2 (ILC2) are considered the innate counterpart of Th2 cells and cooperate with them in host protection against helminths and in the pathogenesis of allergic diseases. ILC2 ...are characterized by type 2 cytokines production (IL-13, IL-4 and IL-5) and by GATA-3 transcription factor expression. Belonging to innate immune system, ILC2 lack of antigen specific receptor and their activation is controlled mainly by epithelial derived cytokines, such as TSLP, IL-25, and IL-33. ILC2 are located in a strategic position in the airway mucosa and are important to patrol the airways, to recruit other immune system cells and to activate resident cells in response to pathogens injury and/or tissue damage.
In the last decade, many studies, in both humans and mice, focused on ILC2, fully investigating their main features such as the development from the precursor, the stimuli for their activation or inhibition, their plasticity, their classification in different subsets, and finally, their pathogenetic role in type 2 immune-mediated disorders.
In this review we performed an excursus on phenotypical and functional properties on both human and mouse ILC2, in physiological and pathological conditions (mainly in type 2 asthma), considering this cell subset as target for specific therapeutic strategies.
Overwhelming inflammatory reactions contribute to respiratory distress in patients with COVID-19. Ruxolitinib is a JAK1/JAK2 inhibitor with potent anti-inflammatory properties. We report on a ...prospective, observational study in 34 patients with COVID-19 who received ruxolitinib on a compassionate-use protocol. Patients had severe pulmonary disease defined by pulmonary infiltrates on imaging and an oxygen saturation ≤ 93% in air and/or PaO2/FiO2 ratio ≤ 300 mmHg. Median age was 80.5 years, and 85.3% had ≥ 2 comorbidities. Median exposure time to ruxolitinib was 13 days, median dose intensity was 20 mg/day. Overall survival by day 28 was 94.1%. Cumulative incidence of clinical improvement of ≥2 points in the ordinal scale was 82.4% (95% confidence interval, 71-93). Clinical improvement was not affected by low-flow versus high-flow oxygen support but was less frequent in patients with PaO2/FiO2 < 200 mmHg. The most frequent adverse events were anemia, urinary tract infections, and thrombocytopenia. Improvement of inflammatory cytokine profile and activated lymphocyte subsets was observed at day 14. In this prospective cohort of aged and high-risk comorbidity patients with severe COVID-19, compassionate-use ruxolitinib was safe and was associated with improvement of pulmonary function and discharge home in 85.3%. Controlled clinical trials are necessary to establish efficacy of ruxolitinib in COVID-19.
In the last years much attention has focused on the Th17 and Th1 phenotypes and on their pathogenic role in juvenile idiopathic arthritis, investigating how the cytokines produced by T helper cells ...act on resident cells on the synovia and which signal transduction pathways regulate Th17 cells proliferation and plasticity. In this context, an important milestone was represented by the identification of the non-classic Th1 phenotype, developed from the shift of Th17 cells. The cytokine TNF-α, beyond its well-known proinflammatory activity is involved in this process and this is one of the reasons why the TNF-α inhibitors are widely used in the treatment of juvenile idiopathic arthritis patients.
BACKGROUNDImmunization against SARS-CoV-2, the causative agent of COVID-19, occurs via natural infection or vaccination. However, it is currently unknown how long infection- or vaccination-induced ...immunological memory will last.METHODSWe performed a longitudinal evaluation of immunological memory to SARS-CoV-2 up to 1 year after infection and following mRNA vaccination in naive individuals and individuals recovered from COVID-19 infection.RESULTSWe found that memory cells are still detectable 8 months after vaccination, while antibody levels decline significantly, especially in naive individuals. We also found that a booster injection is efficacious in reactivating immunological memory to spike protein in naive individuals, whereas it was ineffective in previously SARS-CoV-2-infected individuals. Finally, we observed a similar kinetics of decay of humoral and cellular immunity to SARS-CoV-2 up to 1 year following natural infection in a cohort of unvaccinated individuals.CONCLUSIONShort-term persistence of humoral immunity, together with the reduced neutralization capacity versus the currently prevailing SARS-CoV-2 variants, may account for reinfections and breakthrough infections. Long-lived memory B and CD4+ T cells may protect from severe disease development. In naive individuals, a booster dose restored optimal anti-spike immunity, whereas the needs for vaccinated individuals who have recovered from COVID-19 have yet to be defined.FUNDINGThis study was supported by funds to the Department of Experimental and Clinical Medicine, University of Florence (Project Excellence Departments 2018-2022), the University of Florence (project RICTD2122), the Italian Ministry of Health (COVID-2020-12371849), and the region of Tuscany (TagSARS CoV 2).
It is well accepted that Th17 cells are a highly plastic cell subset that can be easily directed toward the Th1 phenotype in vitro and also in vivo during inflammation. However, there is an ongoing ...debate regarding the reverse plasticity (conversion from Th1 to Th17). We show here that ectopic ROR‐γt expression can restore or initiate IL‐17 expression by non‐classic or classic Th1 cells, respectively, while common pro‐Th17 cytokine cocktails are ineffective. This stability of the Th1 phenotype is at least partially due to the presence of a molecular machinery governed by the transcription factor Eomes, which promotes IFN‐γ secretion while inhibiting the expression of ROR‐γt and IL‐17. By using a mouse model of T cell‐dependent colitis we demonstrate that Eomes controls non‐classic Th1 cell development also in vivo and promotes their pathogenic potential. Eomes expression associates to a highly inflammatory phenotype also in patients with juvenile idiopathic arthritis. Indeed, it favors the acquisition of a cytotoxic signature, and promotes the development of IFN‐γ+GM‐CSF+ cells that have been described to be pathogenic in chronic inflammatory disorders.
Chronic inflammation leads to conversion of Th17 cells towards a non‐classic Th1 phenotype. We show in vitro and in vivo in a mouse model of colitis and in juvenile idiopathic arthritis patients that this process is Eomes‐dependent. Eomes acts inhibiting RORC2 and IL17 expression, while contemporary promoting IFNG and CSF2.
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