Activation or exhaustion of CD8 + T cells in patients with COVID-19

In addition to CD4+ T cells and neutralizing antibodies, CD8+ T cells contribute to protective immune responses against SARS-CoV-2 in patients with coronavirus disease 2019 (COVID-19), an ongoing pandemic disease. In patients with COVID-19, CD8+ T cells exhibiting activated phenotypes are commonly observed, although the absolute number of CD8+ T cells is decreased. In addition, several studies have reported an upregulation of inhibitory immune checkpoint receptors, such as PD-1, and the expression of exhaustion-associated gene signatures in CD8+ T cells from patients with COVID-19. However, whether CD8+ T cells are truly exhausted during COVID-19 has been a controversial issue. In the present review, we summarize the current understanding of CD8+ T-cell exhaustion and describe the available knowledge on the phenotypes and functions of CD8+ T cells in the context of activation and exhaustion. We also summarize recent reports regarding phenotypical and functional analyses of SARS-CoV-2-specific CD8+ T cells and discuss long-term SARS-CoV-2-specific CD8+ T-cell memory.ope

SARS-CoV-2-specific T cell memory is sustained in COVID-19 convalescent patients for 10 months with successful development of stem cell-like memory T cells

Memory T cells contribute to rapid viral clearance during re-infection, but the longevity and differentiation of SARS-CoV-2-specific memory T cells remain unclear. Here we conduct ex vivo assays to evaluate SARS-CoV-2-specific CD4+ and CD8+ T cell responses in COVID-19 convalescent patients up to 317 days post-symptom onset (DPSO), and find that memory T cell responses are maintained during the study period regardless of the severity of COVID-19. In particular, we observe sustained polyfunctionality and proliferation capacity of SARS-CoV-2-specific T cells. Among SARS-CoV-2-specific CD4+ and CD8+ T cells detected by activation-induced markers, the proportion of stem cell-like memory T (TSCM) cells is increased, peaking at approximately 120 DPSO. Development of TSCM cells is confirmed by SARS-CoV-2-specific MHC-I multimer staining. Considering the self-renewal capacity and multipotency of TSCM cells, our data suggest that SARS-CoV-2-specific T cells are long-lasting after recovery from COVID-19, thus support the feasibility of effective vaccination programs as a measure for COVID-19 control.ope

Current status and trend in training for endoscopic submucosal dissection: A nationwide survey in Korea

Background: Although endoscopic submucosal dissection (ESD) is widely used, the current status and trend in its training have yet to be fully evaluated. We aimed to investigate how ESD endoscopists have been trained in actual clinical practice. Methods: Endoscopists aged <45 years who have completed a gastroenterology fellowship or were currently in a fellowship for ≥2 years were included. We conducted a nationwide survey on the ESD training experiences of these endoscopists. Results: Among 79 young Korean endoscopists invited to participate in the survey, 68 (86.1%) trained in 24 major hospitals responded to the questionnaire. Twenty, 25, and 23 participants belonged to the second-year fellow, <5 years after training, and ≥5 years after training groups, respectively. Sixty-nine percent of the participants observed ≥50 ESD cases before starting ESD under supervision by an expert endoscopist. Additionally, 22% experienced ≥20 supervised ESDs during the training period. The proportion of the participants who underwent a hands-on course differed among the groups (≥5 years after training, 13.0%; <5 years after training, 40.0%; and second-year fellow, 50.0%; P = 0.027). ESD under supervision, observation, and hands-on course were the preferred methods for learning ESD (91.1%, 80.9%, and 35.3%, respectively). Overall, 42.6% of the participants were satisfied with their training program. More experience in supervised ESD (≥20 cases) was associated with an increased satisfaction (odds ratio, 6.65; 95% confidence interval, 1.62-36.31). Conclusions: Observation and performance of ESD under the supervision of an expert endoscopist are the primary methods for learning ESD. Hands-on course program has been used more frequently in recent years.ope

Are Electronic Cigarettes Harmful? Mucin May Be the Key

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A Case of Recurred Cholesteatoma Removal via Middle Cranial Fossa Approach

Cholesteatoma is a benign disease but it has an aggressive feature that may lead to serious conditions. Many strategies have been introduced for the treatment cholesteatoma, yet no definite single method has been established: it should be treated respectively regarding the completion of cholesteatoma, conservation of tympanic mucosa, proper ventilation of middle ear and preservation of hearing. A 25-year old patient visited our clinic for right-sided facial paralysis of 5 days. The patient underwent canal wall down mastoidectomy 10 years ago due to cholesteatoma and a few revision surgeries under local anesthesia for recurrence. Pre-operative temporal bone CT showed suspected recurred cholesteatoma in internal auditory canal and labyrinthine segment of facial nerve nearby. The patient underwent a removal of cholesteatoma via middle cranial fossa approach. This case report is a successful completion of recurred cholesteatoma, for which no recurrence is shown. Facial nerve function is improved at postoperative 1 year.ope

Identification of a distinct NK-like hepatic T-cell population activated by NKG2C in a TCR-independent manner

Background & aims: The liver provides a unique niche of lymphocytes enriched with a large proportion of innate-like T cells. However, the heterogeneity and functional characteristics of the hepatic T-cell population remain to be fully elucidated. Methods: We obtained liver sinusoidal mononuclear cells from the liver perfusate of healthy donors and recipients with HBV-associated chronic liver disease (CLD) during liver transplantation. We performed a CITE-seq analysis of liver sinusoidal CD45+ cells in combination with T cell receptor (TCR)-seq and flow cytometry to examine the phenotypes and functions of liver sinusoidal CD8+ T cells. Results: We identified a distinct CD56hiCD161-CD8+ T-cell population characterized by natural killer (NK)-related gene expression and a uniquely restricted TCR repertoire. The frequency of these cells among the liver sinusoidal CD8+ T-cell population was significantly increased in patients with HBV-associated CLD. Although CD56hiCD161-CD8+ T cells exhibit weak responsiveness to TCR stimulation, CD56hiCD161-CD8+ T cells highly expressed various NK receptors, including CD94, killer immunoglobulin-like receptors, and NKG2C, and exerted NKG2C-mediated NK-like effector functions even in the absence of TCR stimulation. In addition, CD56hiCD161-CD8+ T cells highly respond to innate cytokines, such as IL-12/18 and IL-15, in the absence of TCR stimulation. We validated the results from liver sinusoidal CD8+ T cells using intrahepatic CD8+ T cells obtained from liver tissues. Conclusions: In summary, the current study found a distinct CD56hiCD161-CD8+ T-cell population characterized by NK-like activation via TCR-independent NKG2C ligation. Further studies are required to elucidate the roles of liver sinusoidal CD56hiCD161-CD8+ T cells in immune responses to microbial pathogens or liver immunopathology. Lay summary: The role of different immune cell populations in the liver is becoming an area of increasing interest. Herein, we identified a distinct T-cell population that had features similar to those of natural killer (NK) cells - a type of innate immune cell. This distinct population was expanded in the livers of patients with chronic liver disease and could thus have pathogenic relevance.ope

Association between the neutrophil-to-lymphocyte ratio and obstructive sleep apnea: a meta-analysis

This meta-analysis is aimed to investigate the association between the neutrophil-to-lymphocyte ratio (NLR) and obstructive sleep apnea (OSA). The PubMed, Web of Science, Google Scholar, and Cochrane Library databases were searched to collect all relevant articles. The pooled standardized mean difference (SMD) with a 95% confidence interval (CI) was calculated using the random effects model. In addition, subgroup analysis and meta-regression analysis were performed. Eleven eligible articles containing 2,259 patients with OSA were included in this study. Pooled outcomes revealed that the NLR was significantly higher in patients with OSA than in controls (SMD 0.62, 95% CI 0.29-0.94, P = 0.002). In subgroup analyses, differences in the NLR between patients and controls increased with worsening OSA grades. Furthermore, meta-regression analysis showed that differences in mean BMI exerted a significant effect on differences in the NLR (P = 0.0003). In summary, our meta-analysis demonstrated that the NLR in OSA patients was significantly higher than that in controls, and the difference was larger in patients with severe OSA. These results indicate that the NLR may be a reliable marker for detecting systemic inflammation and predicting disease severity in patients with OSA.ope

Is obstructive sleep apnea associated with erythrocytosis? A systematic review and meta-analysis

Objective: The aim of this systematic review and meta-analysis was to investigate the association between obstructive sleep apnea (OSA) and erythrocytosis. Methods: The PubMed, Web of Science, and Cochrane Library databases were searched for articles examining hematocrit values in patients with OSA and control individuals published till September 1, 2021. The pooled standardized mean difference (SMD) with 95% confidence interval (CI) was calculated, and subgroup analyses were performed. Results: Eleven eligible studies with a total of 4608 patients with OSA were included in this meta-analysis. Pooled outcomes revealed that hematocrit values were significantly higher in patients with OSA than in controls (SMD, 0.19; 95% CI, 0.08-0.29; p < .01). When studies were stratified by disease severity, the significant differences in hematocrit values between patients and controls were only observed in the severe OSA group (SMD, 0.34; 95% CI, 0.08-0.59; p < .01), but not in the mild and moderate OSA groups. In subgroup analyses according to sex and publication year, significant differences in hematocrit values between patients and controls remained stable in studies with only female patients (SMD, 0.25; 95% CI, 0.12-0.38; p < .01) and in studies published after 2012 (SMD, 0.17; 95% CI, 0.06-0.28, p < .01). Conclusion: Our meta-analysis revealed that the hematocrit value was significantly increased in patients with OSA, particularly in severe patients, compared with that in controls. However, the elevation was modest, and the hematocrit value is expected to be within the normal range in patients with OSA. These data suggest that OSA leads to slight increases in hematocrit but does not cause clinically significant erythrocytosis.ope

The mechanism of Influenza A virus-induced cell death in primary human nasal epithelial cells

의학과/석사A형 인플루엔자 바이러스는 인체 기도의 흔한 병원체로 범유행 감염을 야기 하고 폐렴과 같은 심각한 질병을 일으킨다. 코점막 상피의 선천성 면역체계는 침입하는 인플루엔자 바이러스에 대해 최전선 방어막으로 작용을 하고 항바이러스 면역 반응에 중요한 역할을 한다고 알려져 있다. 그러나, 아직까지 인플루엔자 바이러스 감염 시 발생하는 코점막 상피세포의 사멸이 바이러스의 증식과 면역 회피에 있어서 어떠한 역할을 하는 지에 대한 이해는 불충분하다. 이번 연구를 통해 인플루엔자 바이러스로 인한 코점막 상피세포 사멸의 기전과 역할에 대해 알아보고자 하였다. 계대 2의 코점막 상피세포에 인플루엔자 바이러스를 감염시키고 유세포분석과 실시간 중합효소연쇄반응을 통해 세포사멸과 세포 내 바이러스 증식이 시간이 지남에 따라 증가하는 것을 확인하였다. 미토콘드리아 표적 항산화제, 미토콘드리아 활성 산소에 의해 유도되는 세포괴사의 억제제를 각각 처리한 군들에서는 대조군에 비해 상피세포 사멸이 감소하고 인플루엔자 바이러스 증식이 억제되는 결과를 보였다. 실시간 중합효소연쇄반응과 효소면역측정법을 통해 확인한 interferon-β, interferon-λ1의 mRNA, 단백질 발현 모두 대조군에 비해 미토콘드리아 활성 산소를 억제한 군들에서 감소하였다. 본 연구를 통해 인플루엔자 바이러스에 의해 유도되는 미토콘드리아 활성 산소가 코점막 상피세포의 사멸을 유발함을 알 수 있었다. 또한, 미토콘드리아 활성 산소의 억제를 통해서 코점막 상피세포의 사멸을 감소시킬 경우, 인플루엔자 바이러스의 증식을 완화시킬 수 있음을 제시할 수 있다. 따라서, 미토콘드리아 활성 산소의 억제를 통해 코점막 상피세포의 사멸을 감소시키는 것이 기존의 치료법들에 더해서 인플루엔자 바이러스 감염의 새로운 치료 전략으로 이용될 수 있을 것으로 기대된다. Influenza A virus (IAV) is a common pathogen of the human airway, and it can cause severe viral infection or an epidemic of respiratory diseases. The innate immune system of the nasal epithelium serves as a first-line barrier and has an important role in antiviral defense against invading IAV. However, there is an incomplete understanding of the role of nasal epithelial cell death in regulation of viral replication and immune evasion during IAV infection. This study is focused on elucidating the mechanism of IAV-induced cell death in nasal epithelial cells and its role. Passage-2 primary human nasal epithelial cells were inoculated with IAV. Cell death was induced predominantly one and two days after infection and viral mRNA levels also showed a remarkable increase. The inhibition of mitochondrial ROS generation by treating cells with the inhibitor of the mitochondrial respiratory chain reaction and the inhibitor of oxidative stress-induced necrosis significantly decreased the death of nasal epithelial cells and restricted viral replication. In real-time PCR and ELISA, expression levels of interferon-β, interferon-λ1 were reduced in cells treated with inhibitors when compared to the control group. The results showed that IAV-generated mitochondrial ROS induced cell death in nasal epithelial cells. And viral replication was restricted by suppression of IAV-generated mitochondrial ROS in nasal epithelial cells. These findings suggest that inhibition of cell death in nasal epithelial cells might be a therapeutic target for treating an IAV infection.ope

IL-17A-producing sinonasal MAIT cells in patients with chronic rhinosinusitis with nasal polyps

Background: Diverse immune cells contribute to the pathogenesis of chronic rhinosinusitis (CRS), an inflammatory disease of the nasal cavity and paranasal sinuses. However, whether mucosal-associated invariant T (MAIT) cells are present in human sinonasal tissues remains unclear. Furthermore, the characteristics of sinonasal MAIT cells have not been studied in patients with CRS. Objective: We investigated the phenotype, function, and clinical implications of MAIT cells in patients with CRS. Methods: Peripheral blood and sinonasal tissue were obtained from patients with CRS with (CRSwNP) or without nasal polyps (CRSsNP) and healthy controls. MAIT cells were analyzed by flow cytometry. Results: We found that MAIT cells are present in human sinonasal tissues from healthy controls and patients with CRS. The sinonasal MAIT cell population, but not peripheral blood MAIT cells, from patients with CRSsNP, noneosinophilic CRSwNP (NE-NP), or eosinophilic CRSwNP (E-NP) had a significantly higher frequency of activated cells marked by CD38 expression. In functional analysis, the sinonasal MAIT cell population from NE-NP and E-NP had a significantly higher frequency of IL-17A+ cells but lower frequency of IFN-γ+ or TNF+ cells than control sinonasal tissues. Furthermore, CD38 expression and IL-17A production by sinonasal MAIT cells significantly correlated with disease extent evaluated by the Lund-Mackay computed tomography score in patients with E-NP. Conclusions: Sinonasal MAIT cells exhibit an activated phenotype and produce higher levels of IL-17A in patients with CRSwNP. These alterations are associated with the extent of disease in patients with E-NP.restrictio