Otitis media with effusion (OME) is a chronic inflammatory disease of the middle ear space characterized by the accumulation of fluid. Previous investigations have suggested that the immunopathologic ...mechanism underlying the development of middle ear effusion in patients with allergy is largely due to the effects of T
H2 mediators. The composition of the inflammatory substrate in the effusions of allergic otitis media is similar to the late-phase allergic response seen elsewhere in the respiratory tract, such as in asthma and in allergic rhinitis.
To determine whether the middle ear compartment may be a component of the united airways in allergic disease by comparing the inflammatory profiles of the middle ear to the upper airway.
Middle ear effusions, torus tubaris (Eustachian tube mucosa at the nasopharyngeal orifice), and adenoidal tissue biopsies were obtained from 45 patients undergoing simultaneous tympanostomy tube placement for OME and adenoidectomy for adenoid hypertrophy. The cellular and cytokine profiles of each site were investigated by using immunocytochemistry (elastase, CD3, major basic protein) and in situ hybridization (IL-4, IL-5, IFN-γ mRNA). Atopic status was determined for each patient by using skin prick testing.
Eleven of the 45 patients with OME (24%) were atopic. The middle ear effusions of atopic patients had significantly higher levels of eosinophils, T lymphocytes, and IL-4 mRNA
+ cells (
P < .01) and significantly lower levels of neutrophils and IFN-γ mRNA
+ cells (
P < .01) compared with nonatopic patients. The nasopharyngeal tissue biopsies revealed similar cellular and cytokine profiles.
In atopic patients with OME, the allergic inflammation occurs on both sides of the Eustachian tube, both in the middle ear and in the nasopharynx. The results of this study support the concept that the middle ear may be part of the united airway in atopic individuals.
Background IL-9 has been shown to affect the differentiation pathway of different cell types. However, its potential role in the maturation pathway of antigen-driven B-cell differentiation and its ...functional effects remain unknown. Objective To characterize IL-9 receptor α chain (IL-9Rα) expression on human tonsillar B cells at different maturational stages, and to assess its effect on IgE production. Methods Freshly purified human tonsillar B cells were fractionated into 3 populations: low-density (LD), medium-density, and high-density cells. Expression levels of IL-9Rα were determined by using immunohistochemistry and flow cytometry. IL-9Rαhigh –expressing cells were stimulated with IL-9 in the presence or absence of IL-4, and IgE release was measured by ELISA. Results IL-9Rα was expressed on human LD tonsillar B cells, with an ability to transduce signals through activation of signal transducer and activator of transcription 3 and 5. Although IL-9 was unable to induce IgE secretion by itself, it potentiated IL-4–mediated IgE production from LD cells. Moreover, increased IgE was paralleled by an upregulation of IL-9Rα and CD27, with the latter a memory B-cell marker implicated in increased IgE secretion. Conclusion These results highlight a crucial role for IL-9 in modulating T-cell–dependent B-cell differentiation and establish a new paradigm for understanding the synergistic role of TH 2 cytokines and their modulatory effect on B-cell maturation and IgE production. Clinical implications IL-9 appears to be involved in memory B-cell differentiation and TH 2-mediated allergic diseases such as asthma.
The use of COVID-19 vaccines has been prioritised to protect the most vulnerable—notably, older people. Because of fluctuations in vaccine availability, strategies such as delayed second dose and ...heterologous prime-boost have been used. However, the effectiveness of these strategies in frail, older people are unknown. We aimed to assess the antigenicity of mRNA-based COVID-19 vaccines in frail, older people in a real-world setting, with a rationed interval dosing of 16 weeks between the prime and boost doses.
This prospective observational cohort study was done across 12 long-term care facilities of the Montréal Centre-Sud – Integrated University Health and Social Services Centre in Montréal, Québec, Canada. Under a rationing strategy mandated by the provincial government, adults aged 65 years and older residing in long-term care facilities in Québec, Canada, with or without previously documented SARS-CoV-2 infection, were administered homologous or heterologous mRNA vaccines, with an extended 16-week interval between doses. All older residents in participating long-term care facilities who received two vaccine doses were eligible for inclusion in this study. Participants were enrolled from Dec 31, 2020, to Feb 16, 2021, and data were collected up to June 9, 2021. Clinical data and blood samples were serially collected from participants at the following timepoints: at baseline, before the first dose; 4 weeks after the first dose; 6–10 weeks after the first dose; 16 weeks after the first dose, up to 2 days before administration of the second dose; and 4 weeks after the second dose. Sera were tested for SARS-CoV-2-specific IgG antibodies (to the trimeric spike protein, the receptor-binding domain RBD of the spike protein, and the nucleocapsid protein) by automated chemiluminescent ELISA. Two cohorts were used in this study: a discovery cohort, for which blood samples were collected before administration of the first vaccine dose and longitudinally thereafter; and a confirmatory cohort, for which blood samples were only collected from 4 weeks after the prime dose. Analyses were done in the discovery cohort, with validation in the confirmatory cohort, when applicable.
The total study sample consisted of 185 participants. 65 participants received two doses of mRNA-1273 (Spikevax; Moderna), 36 received two doses of BNT162b2 (Comirnaty; Pfizer–BioNTech), and 84 received mRNA-1273 followed by BNT162b2. In the discovery cohort, after a significant increase in anti-RBD and anti-spike IgG concentrations 4 weeks after the prime dose (from 4·86 log binding antibody units BAU/mL to 8·53 log BAU/mL for anti-RBD IgG and from 5·21 log BAU/mL to 8·05 log BAU/mL for anti-spike IgG), there was a significant decline in anti-RBD and anti-spike IgG concentrations until the boost dose (7·10 log BAU/mL for anti-RBD IgG and 7·60 log BAU/mL for anti-spike IgG), followed by an increase 4 weeks later for both vaccines (9·58 log BAU/mL for anti-RBD IgG and 9·23 log BAU/mL for anti-spike IgG). SARS-CoV-2-naive individuals showed lower antibody responses than previously infected individuals at all timepoints tested up to 16 weeks after the prime dose, but achieved similar antibody responses to previously infected participants by 4 weeks after the second dose. Individuals primed with the BNT162b2 vaccine showed a larger decrease in mean anti-RBD and anti-spike IgG concentrations with a 16-week interval between doses (from 8·12 log BAU/mL to 4·25 log BAU/mL for anti-RBD IgG responses and from 8·18 log BAU/mL to 6·66 log BAU/mL for anti-spike IgG responses) than did those who received the mRNA-1273 vaccine (two doses of mRNA-1273: from 8·06 log BAU/mL to 7·49 log BAU/mL for anti-RBD IgG responses and from 6·82 log BAU/mL to 7·56 log BAU/mL for anti-spike IgG responses; mRNA-1273 followed by BNT162b2: from 8·83 log BAU/mL to 7·95 log BAU/mL for anti-RBD IgG responses and from 8·50 log BAU/mL to 7·97 log BAU/mL for anti-spike IgG responses). No differences in antibody responses 4 weeks after the second dose were noted between the two vaccines, in either homologous or heterologous combinations.
Interim results of this ongoing longitudinal study show that among frail, older people, previous SARS-CoV-2 infection and the type of mRNA vaccine influenced antibody responses when used with a 16-week interval between doses. In these cohorts of frail, older individuals with a similar age and comorbidity distribution, we found that serological responses were similar and clinically equivalent between the discovery and confirmatory cohorts. Homologous and heterologous use of mRNA vaccines was not associated with significant differences in antibody responses 4 weeks following the second dose, supporting their interchangeability.
Public Health Agency of Canada, Vaccine Surveillance Reference Group; and the COVID-19 Immunity Task Force.
For the French translation of the abstract see Supplementary Materials section.
B lymphocytes convert arachidonic acid (AA) to the 5-lipoxygenase products leukotriene B4 (LTB4) and 5-hydroxy-6,8,11,14-eicosatetraenoic acid (5-HETE) when subjected to oxidative stress. 5-HETE has ...little biological activity, but can be oxidized by a selective dehydrogenase in some cells to 5-oxo-6,8,11,14-eicosatetraenoic acid (5-oxo-ETE), a potent eosinophil chemoattractant. We found that CESS cells, a B lymphocyte cell line, convert AA to 5-oxo-ETE and this is selectively stimulated by oxidative stress. In the presence of H2O2, 5-oxo-ETE is a major AA metabolite in these cells (5-oxo-ETE≈5-HETE>LTB4). The cyclooxygenase product 12-hydroxy-5,8,10-heptadecatrienoic acid is also formed, but is not affected by H2O2. Diamide had effects similar to those of H2O2 and both substances had similar effects on human tonsillar B cells. H2O2 also stimulated 5-oxo-ETE formation from its direct precursor 5-HETE in tonsillar B and CESS cells, and this was inhibited by the glutathione reductase inhibitor carmustine. H2O2 concomitantly induced rapid increases in GSSG and NADP+ and reductions in GSH and NADPH. We conclude that oxidative stress stimulates 5-oxo-ETE synthesis in B lymphocytes by two mechanisms: activation of 5-lipoxygenase and increased oxidation of 5-HETE by NADP+-dependent 5-hydroxyeicosanoid dehydrogenase. B lymphocyte-derived 5-oxo-ETE could contribute to eosinophilic inflammation in asthma and other allergic diseases.
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