The role of regulatory T cells in immune dysfunction during sepsis

BACKGROUND: Although regulatory T cells(Tregs) are key to the maintenance of immunologic homeostasis and tolerance, little is known about Treg-mediated immunosuppression in the stage of sepsis. This article aimed to review the current literature on the role of Tregs in the pathophysiology of septic response, attempting to investigate the role of Tregs in immune dysfunction during sepsis.DATA SOURCES: A literature search was conducted in January 2014 using the China National Knowledge Infrastructure and Pub Med. Articles on the role of Tregs in immune dysfunction during sepsis were identified.RESULTS: The identified articles indicated that Treg levels can be used for the assessment of the course of sepsis. The inhibition of Treg activity can promote the recovery of immune function.CONCLUSION: Since the mechanism of Tregs is complex during the sepsis, more studies are needed.

Role of immune dysfunction in drug induced liver injury

Drug-induced liver injury(DILI)is one of the leading causes of liver failure and withdrawal of drugs from the market.A poor understanding of the precipitating event aetiology and mechanisms of disease progression has rendered the prediction and subsequent treatment intractable.Recent literature suggests that some drugs can alter the liver’s repair systems resulting in injury.The pathophysiology of DILI is complex,and immune dysfunction plays an important role in determining the course and severity of the disease.Immune dysfunction is influenced by the host response to drug toxicity.A deeper understanding of these processes may be beneficial in the management of DILI and aid in drug development.This review provides a structured framework presenting DILI in three progressive stages that summarize the interplay between drugs and the host defence networks.

Immune Dysfunction in Cirrhosis

Cirrhosis due to any etiology disrupts the homeostatic role of liver in the body.Cirrhosis-associated immune dysfunction leads to alterations in both innate and acquired immunity,due to defects in the local immunity of liver as well as in systemic immunity.Cirrhosis-associated immune dysfunction is a dynamic phenomenon,comprised of both increased systemic inflammation and immunodeficiency,and is responsible for 30%mortality.It also plays an important role in acute as well as chronic decompensation.Immune paralysis can accompany it,which is characterized by increase in antiinflammatory cytokines and suppression of proinflammatory cytokines.There is also presence of increased gut permeability,reduced gut motility and altered gut flora,all of which leads to increased bacterial translocation.This increased bacterial translocation and consequent endotoxemia leads to increased blood stream bacterial infections that cause systemic inflammatory response syndrome,sepsis,multiorgan failure and death.The gut microbiota of cirrhotic patients has more pathogenic microbes than that of noncirrhotic individuals,and this disturbs the homeostasis and favors gut translocation.Prompt diagnosis and treatment of such infections are necessary for better survival.We have reviewed the various mechanisms of immune dysfunction and its consequences in cirrhosis.Recognizing the exact pathophysiology of immune dysfunction will help treating clinicians in avoiding its complications in their patients and can lead to newer therapeutic interventions and reducing the morbidity and mortality rates.

Immune dysfunction leads to mortality and organ injury in patients with COVID-19 in China:insights from ERS-COVID-19 study

Dear Editor,A series of novel coronavirus disease 2019(COVID-19)caused by severe acute respiratory syndrome coronavirus 2(SARS-CoV-2)since the end of 2019 is ongoing and triggering a global public health crisis.The estimated case fatality rate is approximately 3.4%in China.However,some patients experience dyspnea within 1 week and develop rapidly to organ injury and even death within 2 weeks after dyspnea.1 In addition,early organ injury could lead to higher risks of mortality.Thus,early identification of patients at risk of organ injury and death is crucial,which saves the patients from classified and invasive treatment,improving clinical outcome and prognosis.The human immune system plays significant roles in the resistance of foreign pathogens and the progress of pneumonia.Recent studies have mentioned that T cells were decreased in COVID-19 patients,excessive activated immune response was caused by pathogenic Th1 cells,and inflammatory CD14+CD16+monocytes may connect to pulmonary immunopathology,leading to deleterious clinical manifestations and even acute mortality after SARS-CoV-2 infections.2 SARS-CoV-2 might damage lymphocytes,especially T lymphocytes,and the immune system was impaired during the period of disease to cause tissue injury.

Effects of Chinese Medicine Shen-Fu Injection(参附注射液)on the Expression of Inflammatory Cytokines and Complements during Post-Resuscitation Immune Dysfunction in A Porcine Model

Objective：To investigate the action of Shen-Fu Injection（参附注射液,SFI） in regulating the expression of the serum complements and inflammatory cytokines synthesized and released in response to the stress of global ischemia accompanying cardiac arrest（CA） and resuscitation.Methods：Thirty pigs were randomly divided into the sham（n=6） and 3 returns of spontaneous circulation（ROSC） groups（n=24）.After 8-min untreated ventricular fibrillation and 2-min basic life support,24 pigs of the ROSC groups were randomized into three groups（n=8 per group）,which received central venous injection of SFI（SFI group）,epinephrine（EP group）,or saline（SA group）.Hemodynamic status and blood samples were obtained at 0,0.5,1,2,4,6,12,and 24 h after ROSC.Results：Serum concentrations of specific activation markers of the complement system C3,C4 and C5b-9 were increased during cardiopulmonary resuscitation th rough1 24 h after ROSC.There were intense changes of various pro-inflammatory cytokines and anti-inflammatory cytokines as early as 0.5 h after CA.Compared with the EP and SA groups,SFI treatment reduced the proinflammatory cytokines levels of interleukin（IL）-6,IL-8and tumor necrosis factor α（TNF-α,P〈0.05）,and increased the anti-inflammatory cytokine levels of IL-4 and IL-10（P〈0.05）.Further,SFI treatment decreased the values of C3,C4 and C5b-9 compared with the EP and SA groups.Conclusions：SFI,derived from the ancient Chinese medicine,has significant effects in attenuating post-resuscitation immune dysfunction by modulating the expression of complements and cytokines levels.The current study provided an experimental basis for the clinical application of a potential pharmacologic target for post resuscitation immune dysfunction.

Effects of Shen-Fu Injection (参附注射液) on Apoptosis of Regulatory T Lymphocytes in Spleen during Post-Resuscitation Immune Dysfunction in A Porcine Model of Cardiac Arrest

Objective： To investigate whether Shen-Fu Injection（参附注射液, SFI） reduces post-resuscitation immune dysfunction in a porcine model of cardiac arrest by modulating apoptosis of regulatory T lymphocytes（Treg） in the spleen. Methods： After 8-min untreated ventricular fibrillation and 2-min basic life support, 24 pigs were divided into 3 groups with a random number table, i.e. SFI group, epinephrine（EP） group, and saline（SA） group（8 in each group）, which received central venous injection of SFI（1.0 m L/kg）, EP（0.02 mg/kg） and SA, respectively. The same procedure without CA initiation was achieved in the sham-operated（sham） group（n=6）. After successful return of spontaneous circulation（ROSC）, apoptosis rate of splenic Treg was detected by flow cytometry; and the m RNA expression of forkhead/winged helix transcription factor（Foxp3） of splenic Treg was detected by real time-polymerase chain reaction; and the levels of interleukin-4（IL-4） and interferon-γ（IFN-γ） in porcine splenic Treg were detected by using enzyme-linked immunosorbent assay（ELISA）. Results： Compared with the sham group, the apoptosis rate of Treg was significantly decreased, and the levels of Foxp3 m RNA expression, IFN-γ, IL-4 and IFN-γ/IL-4 were increased in the SA group（P〈0.05 or P〈0.01）. Compared with the EP and SA groups, SFI treatment increased the apoptosis rate of Treg and reduced the levels of Foxp3 m RNA expression, IFN-γ and IFN-γ/IL-4（P〈0.05）. Conclusions： SFI has significant effects in attenuating post-resuscitation immune dysfunction by modulating apoptosis of Treg in the spleen.

Treatment of immune dysfunction in intrauterine growth restriction piglets via supplementation with dimethylglycine sodium salt during the suckling period

This study aimed to investigate the mechanism of small intestinal immune dysfunction in intrauterine growth restriction(IUGR)newborn piglets and relieve this dysfunction via dimethylglycine sodium salt(DMG-Na)supplementation during the suckling period.Thirty sows(Duroc×[Landrace×Yorkshire])were selected,and 1 male newborn piglet with normal birth weight(NBW)and 1 male newborn piglet with IUGR were obtained from each sow.Among them,10 NBW and 10 IUGR newborns were euthanized without suckling.The other 20 NBW newborns were allocated to the group named NCON,which means NBW newborns fed a basic milk diet(BMD)(n=10),and the group named ND,which means NBW newborns fed BMD supplemented with 0.1%DMG-Na(n=10);the other 20 IUGR newborns were assigned to the group named ICON,which means IUGR newborns fed BMD(n=10),and the group named ID,which means IUGR newborns fed BMD supplemented with 0.1%DMG-Na(n=10).The newborns were fed BMD from 7 to 21 d of age and euthanized at 21 d of age to collect serum and small intestinal samples.The growth performance,small intestinal histological morphology and sub-organelle ultrastructure,serum immunoglobulin,small intestinal digestive enzyme activity,inflammatory cytokine level,and jejunum mRNA and protein expression of the toll-like receptor 4(TLR4)/nucleotide-binding oligomerization domain protein(NOD)/nuclear factor-k B(NF-k B)network deteriorated in the ICON group compared to that in the NCON group.The small intestinal histological morphology and suborganelle ultrastructure,serum immunoglobulin,small intestinal digestive enzyme activity,and inflammatory cytokine level improved(P<0.05)in the ID group compared to those in the ICON group.The jejunum mRNA and protein expression of the TLR4/NOD/NF-k B network improved(P<0.05)in the ID group compared to that in the ICON group.In conclusion,the activity of the TLR4/NOD/NF-k B pathway was inhibited in the IUGR newborns,which in turn led to their jejunum immune dysfunction and reduced their performance.By ingesting DMG-Na,the IUGR newborns activated the TLR4/NOD/NF-k B pathway,thereby improving their unfavorable body state during the suckling period.

Prognosis-related classifi cation and dynamic monitoring of immune status in patients with sepsis:A prospective observational study

BACKGROUND:The dynamic monitoring of immune status is crucial to the precise and individualized treatment of sepsis.In this study,we aim to introduce a model to describe and monitor the immune status of sepsis and to explore its prognostic value.METHODS:A prospective observational study was carried out in Zhongshan Hospital,Fudan University,enrolling septic patients admitted between July 2016 and December 2018.Blood samples were collected at days 1 and 3.Serum cytokine levels(e.g.,tumor necrosis factor-α[TNF-α],interleukin-10[IL-10])and CD14+monocyte human leukocyte antigen-D-related(HLA-DR)expression were measured to serve as immune markers.Classifi cation of each immune status,namely systemic inflammatory response syndrome(SIRS),compensatory anti-inflammatory response syndrome(CARS),and mixed antagonistic response syndrome(MARS),was defined based on levels of immune markers.Changes of immune status were classifi ed into four groups which were stabilization(SB),deterioration(DT),remission(RM),and non-remission(NR).RESULTS:A total of 174 septic patients were enrolled including 50 non-survivors.Multivariate analysis discovered that IL-10 and HLA-DR expression levels at day 3 were independent prognostic factors.Patients with MARS had the highest mortality rate.Immune status of 46.1%patients changed from day 1 to day 3.Among four groups of immune status changes,DT had the highest mortality rate,followed by NR,RM,and SB with mortality rates of 64.7%,42.9%,and 11.2%,respectively.CONCLUSIONS:Severe immune disorder defi ned as MARS or deterioration of immune status defi ned as DT lead to the worst outcomes.The preliminary model of the classifi cation and dynamic monitoring of immune status based on immune markers has prognostic values and is worthy of further investigation.

Dynamic changes in the systemic immune responses of spinal cord injury model mice

Intraspinal inflammatory and immune responses are considered to play central roles in the pathological development of spinal cord injury.This study aimed to decipher the dynamics of systemic immune responses,initiated by spinal cord injury.The spinal cord in mice was completely transected at T8.Changes in the in vivo inflammatory response,between the acute and subacute stages,were observed.A rapid decrease in C-reactive protein levels,circulating leukocytes and lymphocytes,spleen-derived CD4~+interferon-γ+T-helper cells,and inflammatory cytokines,and a marked increase in neutrophils,monocytes,and CD4~+CD25~+FOXP3~+regulatory T-cells were observed during the acute phase.These systemic immune alterations were gradually restored to basal levels during the sub-acute phase.During the acute phase of spinal cord injury,systemic immune cells and factors showed significant inhibition;however,this inhibition was transient,and the indicators of these serious disorders gradually returned to baseline levels during the subacute phase.All experiments were performed in accordance with the institutional animal care guidelines,approved by the Institutional Animal Care and Use Committee of Experimental Animal Center of Drum Tower Hospital,China(approval No.2019 AE01040)on June 25,2019.

The immune response to SARS-CoV-2 in people with HIV

This review examines the intersection of the HIV and SARS-CoV-2 pandemics.People with HIV(PWH)are a heterogeneous group that differ in their degree of immune suppression,immune reconstitution,and viral control.While COVID-19 in those with wellcontrolled HIV infection poses no greater risk than that for HIV-uninfected individuals,people with advanced HIV disease are more vulnerable to poor COVID-19 outcomes.COVID-19 vaccines are effective and well tolerated in the majority of PWH,though reduced vaccine efficacy,breakthrough infections and faster waning of vaccine effectiveness have been demonstrated in PWH.This is likely a result of suboptimal humoral and cellular immune responses after vaccination.People with advanced HIV may also experience prolonged infection that may give rise to new epidemiologically significant variants,but initiation or resumption of antiretroviral therapy(ART)can effectively clear persistent infection.COVID-19 vaccine guidelines reflect these increased risks and recommend prioritization for vaccination and additional booster doses for PWH who are moderately to severely immunocompromised.We recommend continued research and monitoring of PWH with SARS-CoV-2 infection,especially in areas with a high HIV burden.

Role of systemic inflammation in cirrhosis:From pathogenesis to prognosis

The natural history of cirrhosis can be divided into an initial stage, known as compensated cirrhosis, and an advanced stage which encompasses both decompensated cirrhosis and acute-on-chronic liver failure(ACLF). The latter syndrome has been recently described as an acute deterioration of liver function in patients with cirrhosis, which is usually triggered by a precipitating event and results in the failure of one or more organs and high short-term mortality rates. Each stage is characterized by distinctive clinical manifestations and prognoses. One of the key elements involved in cirrhosis physiopathology is systemic inflammation, recently described as one of the components in the cirrhosis-associated immune dysfunction syndrome. This syndrome refers to the combination of immune deficiency and exacerbated inflammation that coexist during the course of cirrhosis and relates to the appearance of clinical complications. Since systemic inflammation is often difficult to assess in cirrhosis patients, new objective, reproducible and readily-available markers are needed in order to optimize prognosis and lengthen survival. Thus, surrogate serum markers and clinical parameters of systemic inflammation have been sought to improve disease follow-up and management, especially in decompensated cirrhosis and ACLF. Leukocyte counts(evaluated as total leukocytes, total eosinophils or neutrophil:lymphocyte ratio) and plasma levels of procalcitonin or C-reactive protein have been proposed as prognostic markers, each with advantages and shortcomings. Research and prospective randomized studies that validate these and other markers are clearly warranted.

Better therapy for combat injury

In modern warfare,therapy for combat injury is a critical issue to improve personnel survival and battle effectiveness.Be limited to the severe circumstance in the distant battlefield,quick and effective treatment cannot be supplied that leads infections,sepsis,multiple organ dysfunction syndrome(MODS)and high mortality.To get a better therapy for combat injury,we summarized several reports that associated with the mechanisms of sepsis and MODS,those published on MMR recently.Chaudry and colleagues reported gender difference in the outcomes of trauma,shock and sepsis.The advantageous outcome in female is due to their hormone milieu.Their accumulating reports indicated estrogen as a beneficial factor for multiple system and organs,including the central nervous system,the cardiopulmonary system,the liver,the kidneys,the immune system,and leads to better survival from sepsis.Thompson et al.reviewed the underlying mechanisms in trauma induced sepsis,which can be concluded as an imbalance of immune response triggered by damage-associated molecular patterns(DAMPs)and other immune modifying agents.They also emphasize immunomodulation as a better therapeutic strategy that might be a potential benefit in regulating the host immune response.Fan et al.have revealed a crucial mechanism underlying lung epithelial and macrophage crosstalk,which involves IL-25 as a mediator.After the injury,lung epithelial secreted IL-25 promotes TNF-αproduction in macrophage leading to acute lung injury(ALI).In addition to a mountain of cytokines,mitochondrial dysfunction in immune cell is another critical risk factor for immune dysfunction during sepsis.Both morphology and function alterations in mitochondria are closely associated with inadequate ATP production,insufficient metabolism process and overloaded ROS production,which lead harm to immune cells and other tissues by triggering oxidative stress.All the above reports discussed mechanisms of sepsis induction after trauma and provided evidence to improve better therapy strategies targeting diverse risk factors.

Minimally invasive surgery vs laparotomy in patients with colon cancer residing in high-altitude areas

BACKGROUND Colon cancer is associated with a higher incidence among residents in highaltitude areas.Hypoxic environment at high altitudes inhibits the phagocytic and oxygen-dependent killing function of phagocytes,thereby increasing the inflammatory factors,inhibiting the body’s innate immunity and increasing the risk of colon cancer.AIM To examine the effect of minimally invasive surgery vs laparotomy in patients with colon cancer residing in high-altitude areas.METHODS Ninety-two patients with colon cancer in our hospital from January 2019 to February 2021 were selected and divided into the minimally invasive surgery and laparotomy groups using the random number table method,with 46 patients in each group.Minimally invasive surgery was performed in the minimally invasive group and laparotomy in the laparotomy group.Operative conditions,inflammatory index pre-and post-surgery,immune function index and complication probability were measured.RESULTS Operative duration was significantly longer and intraoperative blood loss and recovery time of gastrointestinal function were significantly less(all P<0.05)in the minimally invasive group than in the laparotomy group.The number of lymph nodes dissected was not significantly different.Before surgery,there were no significant differences in serum C-reactive protein,interleukin-6 and tumor necrosis factor-αlevels between the groups,whereas after surgery,the levels were significantly higher in the minimally invasive group(26.98±6.91 mg/L,146.38±11.23 ng/mL and 83.51±8.69 pg/mL vs 41.15±8.39 mg/L,186.79±15.36 ng/mL and 110.65±12.84 pg/mL,respectively,P<0.05).Furthermore,before surgery,there were no significant differences in CD3+,CD4+and CD4+/CD8+levels between the groups,whereas after surgery,the levels decreased in both groups,being significantly higher in the minimally invasive group(55.61%±4.39%,35.45%±3.67%and 1.30±0.35 vs 49.68%±5.33%,31.21%±3.25%and 1.13±0.30,respectively,P<0.05).Complication probability was significantly lower in the minimally invasive group(4.35%vs 17.39%,P<0.05).CONCLUSION Laparoscopic minimally invasive procedures reduce surgical trauma and alleviate the inflammatory response and immune dysfunction caused by invasive operation.It also shortens recovery time and reduces complication probability.

Glycolytic and fatty acid oxidation genes affect the treatment and prognosis of liver cancer

BACKGROUND Metabolic reprogramming is a feature of tumour cells and is essential to support their rapid proliferation.The glycolytic activity of liver cancer cells is significantly higher than that of normal liver cells,and the rapidly proliferating tumour cells are powered by aerobic glycolysis.Lipid metabolism reprogramming enables tumour cells to meet their needs for highly proliferative growth and is an important driving force for the development of hepatocellular carcinoma(HCC).AIM To explore the influence of different metabolic subtypes of HCC and analyse their significance in guiding prognosis and treatment based on the molecular mechanism of glycolysis and fatty acid oxidation(FAO).METHODS By downloading related data from public databases including the Cancer Genome Atlas(TCGA),the Molecular Signatures Database,and International Cancer Genome Consortium,we utilised unsupervised consensus clustering to divide TCGA Liver Hepatocellular Carcinoma samples into four metabolic subgroups and compared single nucleotide polymorphism,copy number variation,tumour microenvironment,and Genomics of Drug Sensitivity in Cancer and Tumour Immune Dysfunction and Exclusion between different metabolites.The differences and causes of survival and the clinical characteristics between them were analysed,and a prognostic model was established based on glycolysis and FAO genes.Combined with the clinical features,a Norman diagram was created to compare the pros and cons of each model.RESULTS In the four metabolic subgroups,with the increase in glycolytic expression,the median survival of patients showed the worst results,while FAO showed the best.When comparing the follow-up analysis of each group,we considered that the differences between them might be related to reactive oxygen species,somatic copy number variation of key genes,and immune microenvironment.It was also found that the FAO group and the low-risk group had better efficacy and response to immune checkpoint blockade treatment and anti-tumour drugs.CONCLUSION There are obvious differences in genes,chromosomes,and clinical characteristics between metabolic subgroups.The establishment of a prognostic model could predict patient prognosis and guide clinical treatment.

Immunological aspects of age-related diseases

The proportion of elderly people rises in the developed countries. The increased susceptibility of the elderly to infectious diseases is caused by immune dysfunction, especially T cell functional decline. Age-related hematopoietic stem cells deviate from lymphoid lineage to myeloid lineage. Thymus shrinks early in life, which is followed by the decline of na?ve T cells. T-cell receptor repertoire diversity declines by aging, which is caused by cytomegalovirus-driven T cell clonal expansion. Functional decline of B cell induces antibody affinity declines by aging. Many effector functions including phagocytosis of myeloid cells are down regulated by aging. The studies of aging of myeloid cells have some controversial results. Although M1 macrophages have been shown to be replaced by antiinflammatory(M2) macrophages by advanced age, many human studies showed that pro-inflammatory cytokines are elevated in older human. To solve this discrepancy here we divide age-related pathological changes into two categories. One is an aging of immune cell itself. Second is involvement of immune cells to age-related pathological changes. Cellular senescence and damaged cells in aged tissue recruit pro-inflammatory M1 macrophages, which produce pro-inflammatory cytokines and proceed to agerelated diseases. Underlying biochemical and metabolic studies will open nutritional treatment.

Potential biomarkers for diagnosis and disease evaluation of idiopathic pulmonary fibrosis

Idiopathic pulmonary fibrosis(IPF)is a chronic progressive lung disease characterized by progressive lung fibrogenesis and histological features of usual interstitial pneumonia.IPF has a poor prognosis and presents a spectrum of disease courses ranging from slow evolving disease to rapid deterioration;thus,a differential diagnosis remains challenging.Several biomarkers have been identified to achieve a differential diagnosis;however,comprehensive reviews are lacking.This review summarizes over 100 biomarkers which can be divided into six categories according to their functions:differentially expressed biomarkers in the IPF compared to healthy controls;biomarkers distinguishing IPF from other types of interstitial lung disease;biomarkers differentiating acute exacerbation of IPF from stable disease;biomarkers predicting disease progression;biomarkers related to disease severity;and biomarkers related to treatment.Specimen used for the diagnosis of IPF included serum,bronchoalveolar lavage fluid,lung tissue,and sputum.IPF-specific biomarkers are of great clinical value for the differential diagnosis of IPF.Currently,the physiological measurements used to evaluate the occurrence of acute exacerbation,disease progression,and disease severity have limitations.Combining physiological measurements with biomarkers may increase the accuracy and sensitivity of diagnosis and disease evaluation of IPF.Most biomarkers described in this review are not routinely used in clinical practice.Future large-scale multicenter studies are required to design and validate suitable biomarker panels that have diagnostic utility for IPF.

Non-severe burn injury increases cancer incidence in mice and has long-term impacts on the activation and function of T cells

Background:Recent evidence suggests that burn patients are at increased risk of hospital admission for infection,mental health conditions,cardiovascular disease and cancer for many years after discharge for the burn injury itself.Burn injury has also been shown to induce sustained immune system dysfunction.This change to immune function may contribute to the increased risk of chronic disease observed.However,the mechanisms that disrupt long-term immune function in response to burn trauma,and their link to long-term morbidity,remain unknown.In this study we investigated changes to immune function after burn injury using a murine model of non-severe injury.Methods:An established mouse model of non-severe burn injury(full thickness burn equivalent to 8%total body surface area)was used in combination with an orthotopic model of B16 melanoma to investigate the link between burns and cancer.Considering that CD8^(+)T cells are important drivers of effective tumour suppression in this model,we also investigated potential dysregulation of this immune population using mouse models of burn injury in combination with herpes simplex virus infection.Flow cytometry was used to detect and quantify cell populations of interest and changes in immune function.Results:We demonstrate that 4 weeks after a non-severe burn injury,mice were significantly more susceptible to tumour development than controls using an orthotopic model of B16 melanoma.In addition,our results reveal that CD8^(+)T cell expansion,differentiation and memory potential is significantly impaired at 1 month post-burn.Conclusions:Our data suggests that CD8^(+)T cell-mediated immunity may be dysfunctional for a sustained period after even non-severe burn injury.Further studies in patients to validate these findings may support clinical intervention to restore or protect immunity in patients after burn injury and reduce the increased risk of secondary morbidities observed.

Role of Epigenetics in the Pathogenesis of Systemic Sclerosis

Systemic sclerosis(SSc)is characterized by immune dysfunction,vasculopathy,chronic fibrosis of skin and internal organs with complex etiology.With the rapid development and the application in biomedicine of epigenetics,accumulating evidence has shown that epigenetics plays an important role in the pathogenesis of SSc.Environmental factors via epigenetics are needed to trigger and maintain for the disease in the subjects with genetic predisposition to SSc.The role of epigenetics in the pathogenesis of SSc includes hypermethylation of the promoter region of nitric oxide synthase and bone morphogenetic protein receptors II,up-regulation of histone deacetylases 4 and 5 expression,and down-regulation of miR-193b and miR-152 in endothelial cells inducing vascular dysfunction;DNA hypermethylation and hypoacetylation of histone H3 and H4 in Friend leukemia virus integration 1 and Kruppel-like factor 5 genes,and the abnormal expression of miR-29,miR-129-5p and miR-135b in fibroblasts causing excessive fibrosis;DNA hypomethylation in the promoter regions of CD11a and CD70 genes in CD4+T cells resulting in immune dysfunction.Studies on the role of epigenetics in SSc are of great significance for better understanding the pathogenic machanism of SSc,which is helpful to find new molecular targets for treating SSc,and consequently,improve the prognosis of SSc.

用于结直肠癌预后评估和精准免疫治疗的肿瘤免疫微环境转录组学分型

背景:基于免疫环境的生物学标志物或许可以指导预后评估。T细胞失活、T细胞排斥以及T细胞功能障碍均会损害肿瘤微环境进而影响免疫治疗的效果及预后。然而,截至目前尚未见利用免疫相关生物标记物来对结直肠癌患者进行分类的报道。因此,本研究旨在根据肿瘤微环境中的T细胞失活、T细胞排斥和T细胞功能障碍的程度来对结直肠癌患者进行分类。方法:通过肿瘤免疫功能障碍和排斥(TIDE)算法,对TCGA数据库中的618例结直肠癌患者的RNAseq数据和GEO数据库中的316例结直肠癌患者的基因芯片数据进行分析。采用无监督聚类法对患者进行分类。结果:基于骨髓来源抑制细胞、癌相关成纤维细胞、M2型肿瘤相关巨噬细胞、细胞毒性T细胞和PD-L1的表达,将患者聚类分为4型:1型为高度免疫功能障碍,2型为低度免疫激活,3型为强烈免疫排斥,4型为高度免疫激活、中度免疫功能障碍及中度免疫排斥。多因素Cox分析结果显示,与1型相比,2、3、4型患者总体生存的风险比(95%可信区间)分别为0.63(0.35-1.13)、0.55(0.29-1.03)和0.30(0.14-0.64)。利用GSE39582队列进行验证,也得到了相似的聚类分型和预后模式。亚组分析中,在I/II期、微卫星稳定和未接受辅助治疗的患者中,免疫聚类分型与总体生存显著相关。结论:本研究结果表明,免疫分型可作为结直肠癌患者一项可靠的预后指标,且有助于个体化免疫治疗的病例选择。