Regulatory T Cells: Angels or Demons in the Pathophysiology of Sepsis?

Gao, Yulei; Yao, Ying; Zhang, Xiang; Chen, Fang; Meng, Xianglong; Chen, Xin-sen; Wang, Chao-lan; Liu, Yan-Cun; Tian, Xin; Shou, Songtao; Chai, Yifeng

doi:10.3389/fimmu.2022.829210

Cited by 15 publications

(14 citation statements)

References 185 publications

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“…Abnormal CD4+ and CD8+ T cell responses are major components of a dysregulated acquired immune response, and the immune dysfunction of Tregs also contributes to pathogenesis ( 27 ). Improved outcomes in sepsis by increasing the heterogeneous characteristics of Tregs through intervention strategies has been reported ( 28 ). The investigation of associations between immune-related common genes and immune cell fractions in trauma and sepsis patients revealed that the identified immune-related common genes were more or less significantly related to the immune cells concurrently dysregulated in trauma and sepsis, indicating their possible roles in regulating the functions of these immune cells.…”

Section: Discussionmentioning

confidence: 99%

Identification of Immune-Related Genes Concurrently Involved in Critical Illnesses Across Different Etiologies: A Data-Driven Analysis

Peng

Zhou

et al. 2022

Front. Immunol.

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Severe trauma and sepsis can lead to multiple organ dysfunction syndrome, which is a leading cause of death in intensive care units with mortality rates in excess of 50%. In addition to infection, the degree of immuno-inflammatory response also influences the outcome. The genomic changes observed after a variety of pathophysiological insults, such as trauma, sepsis, burns are similar, and consist of innate immune activation and adaptive immunity suppression. However, the characteristics of the shared mechanisms of aforementioned critical illnesses and the clinical relevance remain less explored. In the present study, we performed a data analysis to identify functional genes concurrently involved in critical illnesses across differing etiologies (trauma and sepsis derived from community-acquired pneumonia/abdominal source) and explored the shared signaling pathways these common genes involved in to gain insight into the underlying molecular mechanisms. A number of immune-related biological functions were found to be dysregulated in both trauma and sepsis in the present study, so we continued to identify immune-related common genes, profiled the immune cell proportion, and explored the relationships between them. The diagnostic and prognostic value of the immune-related common genes was also evaluated to address their potential clinical utilization as novel biomarkers. Notably, we identified a list of 14 immune-related genes concurrently dysregulated in trauma and sepsis showing favorable diagnostic value, among which S100P can predict prognosis of sepsis patients. Moreover, a spectrum of immune cell subsets including naïve B cells, CD8+ T cells, CD4+ memory resting T cells, activated NK cells, resting dendritic cells, plasma cells, Tregs, macrophages M0 and macrophages M1 was found to be concurrently dysregulated in both trauma and sepsis, and a close relation between above identified immune-related genes and immune cell subsets was observed. Our data-driven findings lay a foundation for future research to elucidate the pathophysiology regarding the aspect of inflammatory and immune response in critical illnesses, and suggest future studies focus on interpreting the function roles of the identified immune-related genes, as well as the reactive immune cell subsets.

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Section: Discussionmentioning

confidence: 99%

Identification of Immune-Related Genes Concurrently Involved in Critical Illnesses Across Different Etiologies: A Data-Driven Analysis

Peng

Zhou

et al. 2022

Front. Immunol.

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“…It is noteworthy that the immunophenotype CD39 on CD39+ CD8br within the Tregs panel, predicted by genetics, has a negative correlation with the 28-day mortality rate. Tregs constitute a subset of CD4+ lymphocytes known for their negative immune regulatory functions (47). Given their broad regulatory role in the immune system, Tregs hold considerable therapeutic potential for various diseases (48,49).…”

Section: Discussionmentioning

confidence: 99%

The Relationship Between Circulating Immune Cell Phenotypes and Sepsis: A Mendelian Randomization Study

Liu,

Zhou

et al. 2024

Shock

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Objective The role of immune cells in sepsis remains unclear, and there is some controversy. Here, we aim to systematically assess whether distinct immune cell phenotypes impact the susceptibility to sepsis. Methods In this study, we harnessed publicly available summary-level data from genome-wide association studies (GWAS). The selection of genetic variations strongly associated with 731 phenotypes of circulating immune cells served as instrumental variables (IVs). Using a two-sample Mendelian randomization (MR) analysis, we investigated the relationships between different immunophenotypes and the occurrence of sepsis, as well as the 28-day mortality. The MR study utilized the Inverse Variance Weighting (IVW) method as the main analytical approach. Additionally, we incorporated four other MR methods for supplementary causal inference, including Weighted Median (WME), MR-Egger regression, Simple Mode, and Weighted Mode. Furthermore, the robustness of the results was affirmed through multiple sensitivity analyses. Results The results of the IVW method indicated that a total of 36 immunophenotypes are associated with the risk of sepsis. we also identified 34 immunophenotypes with a causal association with the 28-day mortality. Interestingly, before multiple testing corrections, 11 immunophenotypes were determined to have consistent causal relationships with both the occurrence of sepsis and the 28-day mortality. Notably, after False Discovery Rate (FDR) correction, four immunophenotypes were found to be significantly correlated with susceptibility to sepsis: CD45RA− CD4+ %CD4 + (OR = 1.355, 95% CI = 1.139 ~ 1.611, P < 0.001, P FDR = 0.192), HLA DR on HLA DR+ NK(OR = 0.818, 95% CI = 0.726 ~ 0.922, P = 0.001, PFDR = 0.192), IgD+ CD24+ %B cell(OR = 0.626, 95% CI = 0.473 ~ 0.828, P = 0.001, PFDR = 0.192), TD DN (CD4 − CD8−) AC(OR = 0.655, 95% CI = 0.510 ~ 0.840, P < 0.001, PFDR = 0.192). Following FDR correction, only one immunophenotype was confirmed to be negatively correlated with the 28-day mortality: CD39 on CD39+ CD8br(OR = 0.820, 95% CI = 0.737 ~ 0.912, P < 0.001, PFDR = 0.184). Conclusion This study, for the first time, has uncovered indicative evidence of a causal relationship between circulating immune cell phenotypes and varying degrees of sepsis through genetic means. These findings underscore the significance of immune cells in the pathogenesis of sepsis.

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“…As with most S. aureus immune responses, the Treg response is complex. Hence, more work is needed to sort out their exact role in patients with low IL-2 ( Gaborit et al., 2020 ; Gao et al., 2022 ). Similarly, IL-17-producing T cells that are associated with hyperactive and pathogenic immune responses are induced in the presence of commensals such as staphylococcal species specifically upon the use of immune checkpoint inhibitors ( Hu et al., 2022 ).…”

Section: Immune Dysfunctions Imposed By S Aureusmentioning

confidence: 99%

Staphylococcus aureus adaptive evolution: Recent insights on how immune evasion, immunometabolic subversion and host genetics impact vaccine development

Lung

Chan

Prince

et al. 2022

Front. Cell. Infect. Microbiol.

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Despite meritorious attempts, a S. aureus vaccine that prevents infection or mitigates severity has not yet achieved efficacy endpoints in prospective, randomized clinical trials. This experience underscores the complexity of host-S. aureus interactions, which appear to be greater than many other bacterial pathogens against which successful vaccines have been developed. It is increasingly evident that S. aureus employs strategic countermeasures to evade or exploit human immune responses. From entering host cells to persist in stealthy intracellular reservoirs, to sensing the environmental milieu and leveraging bacterial or host metabolic products to reprogram host immune responses, S. aureus poses considerable challenges for the development of effective vaccines. The fact that this pathogen causes distinct types of infections and can undergo transient genetic, transcriptional or metabolic adaptations in vivo that do not occur in vitro compounds challenges in vaccine development. Notably, the metabolic versatility of both bacterial and host immune cells as they compete for available substrates within specific tissues inevitably impacts the variable repertoire of gene products that may or may not be vaccine antigens. In this respect, S. aureus has chameleon phenotypes that have alluded vaccine strategies thus far. Nonetheless, a number of recent studies have also revealed important new insights into pathogenesis vulnerabilities of S. aureus. A more detailed understanding of host protective immune defenses versus S. aureus adaptive immune evasion mechanisms may offer breakthroughs in the development of effective vaccines, but at present this goal remains a very high bar. Coupled with the recent advances in human genetics and epigenetics, newer vaccine technologies may enable such a goal. If so, future vaccines that protect against or mitigate the severity of S. aureus infections are likely to emerge at the intersection of precision and personalized medicine. For now, the development of S. aureus vaccines or alternative therapies that reduce mortality and morbidity must continue to be pursued.

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Regulatory T Cells: Angels or Demons in the Pathophysiology of Sepsis?

Cited by 15 publications

References 185 publications

Identification of Immune-Related Genes Concurrently Involved in Critical Illnesses Across Different Etiologies: A Data-Driven Analysis

Identification of Immune-Related Genes Concurrently Involved in Critical Illnesses Across Different Etiologies: A Data-Driven Analysis

The Relationship Between Circulating Immune Cell Phenotypes and Sepsis: A Mendelian Randomization Study

Staphylococcus aureus adaptive evolution: Recent insights on how immune evasion, immunometabolic subversion and host genetics impact vaccine development

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