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Acute infection of bovine viral diarrhea virus (BVDV) is associated with immune dysfunction and can cause peripheral blood lymphopenia and lymphocyte apoptosis. Our previous study has confirmed that programmed death-1 (PD-1) blockade inhibits peripheral blood lymphocytes (PBL) apoptosis and restores proliferation and anti-viral immune functions of lymphocytes after BVDV infection in vitro. However, the situation in vivo remains to be further studied and confirmed. Therefore, in this study, we established a BALB/c mouse model of acute BVDV infection with cytopathic (CP) BVDV (strain NADL) and non-cytopathic (NCP) BVDV (strain NY-1). Then, we examined the mRNA and protein levels of PD-1 and programmed death-ligand 1 (PD-L1) in peripheral blood mononuclear cells (PBMC) from BVDV-infected mice and analyzed the effects of PD-1 blockade on the proportions of CD3+, CD4+, and CD8+ T cell subsets, the apoptosis and proliferation of PBL, and the production of IL-2 and IFN-γ. We found that leukopenia, lymphocytopenia, and thrombocytopenia were developed in both CP and NCP BVDV-infected mice at day 7 of post-infection. The mRNA and protein expression of PD-1 and PD-L1 were significantly upregulated in CP and NCP BVDV-infected mice. Moreover, PD-1/PD-L1 upregulation was accompanied by leukopenia and lymphopenia. Additionally, PD-1 blockade inhibited PBL apoptosis and virus replication, restored the proportions of CD3+, CD4+, and CD8+ T cell subsets, and increased IFN-γ production and p-ERK expression in BVDV-infected mice. However, blocking PD-1 did not significantly affect PBL proliferation and IL-2 production in NCP BVDV-infected mice. Our findings further confirmed the immunomodulatory role of PD-1 in peripheral blood lymphocytopenia in vivo and provided a scientific basis for exploring the molecular mechanism of immune dysfunction caused by acute BVDV infection.

Congenital disorders of glycosylation are a group of rare monogenic inborn errors of metabolism caused by defective glycoprotein and glycolipid glycan synthesis and attachment. Here, we present a patient with galactose epimerase deficiency, also known as GALE deficiency, accompanied by pancytopenia and immune dysregulation. She was first identified by an abnormal newborn screen for galactosemia with subsequent genetic evaluation due to pancytopenia and immune dysregulation. The evaluation ultimately revealed that her known diagnosis of GALE deficiency was the cause of her hematologic and immune abnormalities. These findings further expand the clinical spectrum of disease of congenital disorders of glycosylation. [ABSTRACT FROM AUTHOR]

Acute infection of bovine viral diarrhea virus (BVDV) is associated with immune dysfunction and can cause peripheral blood lymphopenia and lymphocyte apoptosis. Our previous study has confirmed that programmed death-1 (PD-1) blockade inhibits peripheral blood lymphocytes (PBL) apoptosis and restores proliferation and anti-viral immune functions of lymphocytes after BVDV infection in vitro. However, the situation in vivo remains to be further studied and confirmed. Therefore, in this study, we established a BALB/c mouse model of acute BVDV infection with cytopathic (CP) BVDV (strain NADL) and non-cytopathic (NCP) BVDV (strain NY-1). Then, we examined the mRNA and protein levels of PD-1 and programmed death-ligand 1 (PD-L1) in peripheral blood mononuclear cells (PBMC) from BVDV-infected mice and analyzed the effects of PD-1 blockade on the proportions of CD3+, CD4+, and CD8+ T cell subsets, the apoptosis and proliferation of PBL, and the production of IL-2 and IFN-γ. We found that leukopenia, lymphocytopenia, and thrombocytopenia were developed in both CP and NCP BVDV-infected mice at day 7 of post-infection. The mRNA and protein expression of PD-1 and PD-L1 were significantly upregulated in CP and NCP BVDV-infected mice. Moreover, PD-1/PD-L1 upregulation was accompanied by leukopenia and lymphopenia. Additionally, PD-1 blockade inhibited PBL apoptosis and virus replication, restored the proportions of CD3+, CD4+, and CD8+ T cell subsets, and increased IFN-γ production and p-ERK expression in BVDV-infected mice. However, blocking PD-1 did not significantly affect PBL proliferation and IL-2 production in NCP BVDV-infected mice. Our findings further confirmed the immunomodulatory role of PD-1 in peripheral blood lymphocytopenia in vivo and provided a scientific basis for exploring the molecular mechanism of immune dysfunction caused by acute BVDV infection. [ABSTRACT FROM AUTHOR]

Diabetes and sepsis are important causes of morbidity and mortality worldwide, and diabetic patients represent the largest population experiencing post-sepsis complications and rising mortality. Dysregulated immune pathways commonly found in both sepsis and diabetes contribute to worsen the host response in diabetic patients with sepsis. The impact of diabetes on mortality from sepsis is still controversial. Whereas a substantial proportion of severe infections can be attributed to poor glycemic control, treatment with insulin, metformin and thiazolidinediones may be associated with lower incidence and mortality for sepsis. It has been suggested that chronic exposure to high glucose might enhance immune adaptation, leading to reduced mortality rate in septic diabetic patients. On the other hand, higher risk of acute kidney injury has been extensively documented and a suggested lower risk of acute respiratory distress syndrome has been recently questioned. Additional investigations are ongoing to confirm the protective role of some anti-diabetic treatments, the occurrence of acute organ dysfunction, and the risk/benefit of less stringent glycemic control in diabetic patients experiencing sepsis. Based on a MEDLINE/PubMed search from inception to December 31, 2020, the aim of this review is therefore to summarize the strengths and weaknesses of current knowledge on the interplay between diabetes and sepsis. [ABSTRACT FROM AUTHOR]

Aims: Previous studies have indicated that heavy alcohol intake stimulates inflammation and impairs the body's ability to regulate inflammation. The aim of this study was to compare changes in neutrophil calprotectin and a wide spectrum of other inflammatory mediators in response to heavy alcohol drinking.Methods: Serum calprotectin (a marker of neutrophil activation), suPAR, CD163, and pro- (IL-6, IL-8, TNF-α) and anti-inflammatory (IL-10, TGF-β) cytokines were measured from 61 alcohol-dependent subjects (46 men, 15 women, mean age 43.6 ± 11.0 years) at the time of admission for detoxification and after 8 ± 2 days of abstinence. These biomarkers were also measured from age- and sex-matched healthy controls representing abstainers or light drinkers. The clinical assessments included detailed clinical interviews on the amounts and patterns of alcohol consumption and assays for biomarkers of alcohol consumption (GGT, CDT, MCV, GGT-CDT) and liver function (AST, ALT).Results: The subjects with alcohol use disorder showed significantly higher concentrations of serum calprotectin (p < 0.0005), suPAR (p < 0.01), CD163 (p < 0.01), IL-6 (p < 0.0005), IL-8 (p < 0.0005), TNF-α (p < 0.001), and IL-10 (p < 0.0005) than healthy controls. These inflammatory mediators, except for CD163, remained elevated after the 8 ± 2-day period of supervised abstinence, which resulted in significant decreases in the biomarkers of alcohol consumption and indices of liver status. The AUC (0.855) for serum calprotectin in differentiating between the heavy drinkers and healthy controls was equal or equivalent with those of the conventional biomarkers of alcohol consumption (GGT:0.835 or CDT:0.803).Conclusions: The data indicate that neutrophil calprotectin is released in response to heavy alcohol intake in a sensitive manner and may be associated with perpetuation of inflammation in patients with alcohol use disorder. Serum calprotectin may also prove to be a useful biomarker for inflammatory activity in alcohol-consuming patients. [ABSTRACT FROM AUTHOR]

Neuroimmune dysfunction is thought to promote the development of several acute and chronic complications in spinal cord injury (SCI) patients. Putative roles for adrenal stress hormones and catecholamines are increasingly being recognized, yet how these adversely affect peripheral tissue homeostasis and repair under SCI conditions remains elusive. Here, we investigated their influence in a mouse model of SCI with acquired neurogenic heterotopic ossification. We show that spinal cord lesions differentially influence muscular regeneration in a level-dependent manner and through a complex multi-step process that creates an osteopermissive environment within the first hours of injury. This cascade of events is shown to critically involve adrenergic signals and drive the acute release of the neuropeptide, substance P. Our findings generate new insights into the kinetics and processes that govern SCI-induced deregulations in skeletal muscle homeostasis and regeneration, thereby aiding the development of sequential therapeutic strategies that can prevent or attenuate neuromusculoskeletal complications in SCI patients. [ABSTRACT FROM AUTHOR]

The coexistence of Parkinson's disease (PD) and myasthenia gravis (MG) is rare. When similar symptoms of both diseases overlap, it is challenging to make a concomitant diagnosis of PD and MG. The present study describes the case of a patient with concomitant PD and MG. In addition, a systematic literature review was conducted by searching PubMed and Embase for reports on all patients with concomitant PD and MG, which were then grouped and compared according to different preexisting diseases. Finally, a total of 47 cases of concomitant PD and MG (35 men; 12 women), including the present case, were analyzed. The median age of the patients at first diagnosis was 66.59±9.91 years. The interval between the two diseases varied from 2 months to 22 years. Based on the sequential occurrence of these two diseases, the patients were categorized into three groups: The prePD-MG (30 cases), preMG-PD (12 cases), and coPD-MG (5 cases) groups. In the prePD-MG group, the onset age of MG was older and head drop was more common. In the preMG-PD group, the patients were more likely to have comorbid immune diseases. [ABSTRACT FROM AUTHOR]

The current study aimed to explore whether bisphenol A (BPA) exposure aggravated the decrease in Tregs induced by ovalbumin (OVA) in adolescent female mouse models of asthma, and whether the process was associated with mTOR-mediated signaling pathways and DNA methylation levels. A total of 40 female C57BL/6 mice at the age of four weeks were used and divided into five groups after 1 week of domestication. Each group consisted of eight mice: the control group, OVA group, OVA + BPA (0.1 μg mL−1) group, OVA + BPA (0.2 μg mL−1) group, and OVA + BPA (0.4 μg mL−1) group. Results revealed that Foxp3 protein levels decreased in the spleens of mice exposed to BPA compared to those in the OVA group. After an elevation in BPA dose, the mRNAs of methyltransferases (Dnmt1 , Dnmt3a , and Dnmt3b) were gradually upregulated. The mechanism was related to the activity of TLR4/NF-κB and PI3K/Akt/mTOR signaling pathways and the enhancement of Foxp3 DNA methylation. Our results, collectively, provided a new view for studying the mechanisms underlying BPA exposure-induced immune dysfunction. Investigation of the regulatory mechanisms of DNA methylation in the abnormal Th immune response caused by BPA exposure could help reveal the causes and molecular mechanisms underlying the high incidence of allergic diseases in children in recent years. [Display omitted] • Decreased Treg cells in asthmatic mice are associated with the mTOR signaling pathway. • Reduced Treg cells induced by BPA related to increased Fox p 3 gene methylation. • Fox p 3 hypermethylation is associated with the up-regulation of DNA methyltransferase. [ABSTRACT FROM AUTHOR]

Recognizing immune dysregulation as a hallmark of sepsis pathophysiology, leukocytes have attracted major attention of investigation. While adult and pediatric sepsis are clinically distinct, their immunological delineation remains limited. Single cell technologies facilitated the characterization of immune signatures. We tackled to delineate immunological profiles of pediatric sepsis at a single-cell level by analyzing blood samples from six septic children, at both acute and recovery phases, and four healthy children. 16 single-cell transcriptomic datasets were analyzed and compared to adult sepsis dataset. We showed a unique shift in neutrophil subpopulations and functions between acute and recovery phases, along with the regulatory role of resistin. Neutrophil signatures were comparable between adult and pediatric sepsis. Innate-like CD4 T cells were predominantly and uniquely observed in acute phase of pediatric sepsis. Our study serves as a rich source of information about the phenotypic diversity and trajectory of circulating immune cells during pediatric sepsis. [ABSTRACT FROM AUTHOR]

Increasing numbers of studies implicate abnormal DNA methylation in cancer and many non-malignant diseases. This is consistent with numerous findings about differentiation-associated changes in DNA methylation at promoters, enhancers, gene bodies, and sites that control higher-order chromatin structure. Abnormal increases or decreases in DNA methylation contribute to or are markers for cancer formation and tumour progression. Aberrant DNA methylation is also associated with neurological diseases, immunological diseases, atherosclerosis, and osteoporosis. In this review, I discuss DNA hypermethylation in disease and its interrelationships with normal development as well as proposed mechanisms for the origin of and pathogenic consequences of disease-associated hypermethylation. Disease-linked DNA hypermethylation can help drive oncogenesis partly by its effects on cancer stem cells and by the CpG island methylator phenotype (CIMP); atherosclerosis by disease-related cell transdifferentiation; autoimmune and neurological diseases through abnormal perturbations of cell memory; and diverse age-associated diseases by age-related accumulation of epigenetic alterations.

Clostridium Difficile Infection (CDI) has registered a dramatically increasing incidence in the general population over the past decades. Nowadays, Clostridium Difficile is the leading cause of hospital-acquired diarrhea in Europe and North America. Liver cirrhosis is the final stage of any chronic liver disease (CLD). The most common causes are chronic hepatitis C or B and viral coinfections, alcohol misuse, and nonalcoholic fatty liver disease (NAFLD). CLD and cirrhosis are listed among the ten leading causes of death in the US. Cirrhosis due to any etiology disrupts the homeostatic role of the liver in the body. Cirrhosis-associated immune dysfunction (CAID) leads to alterations in both inherited and acquired systemic and local liver immunity. CAID is caused by increased systemic inflammation and immunodeficiency and it is responsible for 30% of mortality rates all over the world. Clostridium Difficile infection frequently affects patients suffering from liver cirrhosis because of the high number of prolonged hospitalizations, regular use of antibiotics for the prevention or treatment of SBP, proton pump inhibitor (PPI) use, and an overall immunocompromised state. Clostridium Difficile is a Gram-positive bacterium responsible for the high morbidity and mortality rates in patients with cirrhosis, with an essential increase in a 30-day mortality.

It is known that functional activity of complement system depends not only on balance and concentration of components participating in formation of the system end products, but also on levels of inhibitory activities. Numerous relations with hemostasis also substantially contribute to general level of complement system activity. Changes in complement system functioning are inevitable during chronic diseases accompanied with immune system dysregulation. All mental diseases tend to be chronic and are they aggravated by patients’ immune system changes. Autism spectrum disorders in children is a group of mental disorders. Immune system dysregulation is usually detected in such patients, manifesting as excessive susceptibility to viral and bacterial infections. Therefore, the level of its functional activity is diagnostically and prognostically significant in this pathology, since the complement system is a key element of immune system.We have evaluated functional activity of complement system in patients with autistic spectrum disorders, using the method which was developed earlier. It is based on the reaction of the protozoa (Tetrahymena pyriformis) which are both targets and activators for the complement system. The complement system capacity (cSC) was used as the main parameter of complement evaluation. The half-time of protozoa survival (T50) was defined using the BioLat device for each serum specimen added at four concentrations (1/20, 1/40, 1/80, 1/160 dilution). The complement capacity was calculated as the area enclosed by influence curve of the reciprocals of T50 and the serum dilution. According to Mann–Whitney U test, the difference between patients’ and healthy volunteers’ groups was established as Z = 4.43 (by T50 at 1/160 dilution), p < 0.001 and by cSCas Z = 5.8, p < 0.001. cSC was calculated from the results obtained at each serum concentration measured. The difference between the two groups according to Mann–Whitney U test appeared to be more significant than the difference according to T50. Therefore, cSC was taken as the main characteristic of complement system function.The contribution of hemostasis plasma components to complement system functional activity level was estimated by determination of complement capacity in plasma and serum of each blood sample from 6 patients with autism spectrum disorders and 5 healthy donors. All healthy donors showed small difference between plasma and serum complement capacity, and their complement activity was higher in plasma. In patients’ group, the complement capacity levels in plasma and serum differed significantly. The cSC levels of two patients were higher in serum than in plasma, and the cSC levels of three other patients were significantly higher in plasma than in serum. Differential involvement of coagulation into the complement system activation may be indicative for the immune system dysfunction which is observed in patients with autistic spectrum disorders of different etiology.

Mass vaccination is an essential element of immunoprophylaxis of infectious diseases, and the global community has agreed that it is crucial for preserving the lives and health of children and adults. The objective of this study was to analyse the current state of vaccination of infants under one year old against bacterial infections, given that the National Immunisation Schedule is overladen with various vaccines, and there are apparent inconsistencies between the types of marketed vaccines and recommendations on their use. The article summarises the types of antibacterial vaccines marketed in the Russian Federation, analyses some aspects of combination of different antigens and interchangeability of vaccines. The authors justify the need to amend recommendations on antibacterial vaccination and to develop common rules for the use and combination of vaccines, as well as for their interchangeability. Another important issue is adoption of requirements for the contents of patient information leaflets. The article summarises the main safety concerns regarding the use of polyvalent vaccines and simultaneous vaccination against several pathogens. It discusses safety issues of multiple immunisation and the strategy to reduce potential risks associated with an intensive vaccination schedule. The authors highlight the safety of current immunisations schedules and the need to update vaccination standards. They also demonstrate the need to harmonise national recommendations on the use of vaccines based on clinical data and the results of international clinical trials.

Abstract With improvements in personnel and vehicular body armor, robust casualty evacuation capabilities, and damage control resuscitation strategies, more combat casualties are surviving to reach higher levels of care throughout the casualty evacuation system. As such, medical centers are becoming more accustomed to managing the deleterious late consequences of combat trauma related to the dysregulation of the immune system. In this review, we aim to highlight these late consequences and identify areas for future research and therapeutic strategies. Trauma leads to the dysregulation of both the innate and adaptive immune responses, which places the injured at risk for several late consequences, including delayed wound healing, late onset sepsis and infection, multi-organ dysfunction syndrome, and acute respiratory distress syndrome, which are significant for their association with the increased morbidity and mortality of wounded personnel. The mechanisms by which these consequences develop are complex but include an imbalance of the immune system leading to robust inflammatory responses, triggered by the presence of damage-associated molecules and other immune-modifying agents following trauma. Treatment strategies to improve outcomes have been difficult to develop as the immunophenotype of injured personnel following trauma is variable, fluid and difficult to determine. As more information regarding the triggers that lead to immune dysfunction following trauma is elucidated, it may be possible to identify the immunophenotype of injured personnel and provide targeted treatments to reduce the late consequences of trauma, which are known to lead to significant morbidity and mortality.

Abstract Background Cirrhosis-associated immune dysfunction syndrome (CAIDS) has been identified in patients with liver cirrhosis (LC), predisposing them to a wide variety of infections. In patients with LC, healthcare-associated infections involving multi-drug resistant (MDR) bacteria have increased significantly over the last decades. Among them, hospital-acquired urinary tract infections (HA-UTI) are the most common. This study aimed to investigate the rates of antimicrobial resistance among patients with LC and HA-UTI and to determine risk factors associated with their development among patients hospitalized in tertiary care facility in Serbia. Methods This retrospective study included 65 hospitalized patients with LC who had developed HA-UTI. We examined the epidemiology of these infections concerning resistance to the most commonly used antimicrobials and patient-specific risk factors associated with HA-UTI development by MDR pathogens. Results The most frequently isolated organisms were Enterococcus spp. (n = 34, 52.3%), Klebsiella spp. (n = 10, 15.4%), and E.coli (n = 6, 9.2%). Thirty-five isolates (53.8%) were identified as MDR, and 30 (46.2%) were non-MDR.We found a statistically significant difference in the distribution of MDR and non-MDR strains, based on Gram staining, with the majority of Gram-negative pathogens being MDR (p = 0.005). We identified age ≥ 65 years (p = 0.007), previous use of cephalosporins as empiric therapy (p = 0.042), and the presence of hepatic encephalopathy (p = 0.011) as independent risk factors for the development of MDR UTIs. Conclusion This is the first study from Serbia and the Balkans concerning the changing epidemiology of MDR UTI in patients with LC. Our study showed that more than half of HA-UTI was caused by MDR and the most common pathogen was Enterococcus spp. The overall resistance to ceftriaxone was 92%. Our findings underscore the need for institutions to individualize protocols for treatment of hospital-acquired infections, particularly in immunocompromised populations.

Substantial morbidity results from pituitary pars intermedia dysfunction (PPID) which is often underestimated by owners and veterinarians. Clinical signs, pathophysiology, diagnostic tests, and treatment protocols of this condition are reviewed. The importance of improved recognition of early clinical signs and diagnosis are highlighted, as initiation of treatment will result in improved quality of life. Future research should be targeted at improving the accuracy of the diagnosis of PPID, as basal adrenocorticotropic hormone (ACTH) concentration can lack sensitivity and thyrotropin releasing hormone (TRH) used to assess ACTH response to TRH stimulation is not commercially available as a sterile registered product in many countries. The relationship between PPID and insulin dysregulation and its association with laminitis, as well as additional management practices and long-term responses to treatment with pergolide also require further investigation.

Poor recognition of subtle clinical abnormalities and equivocal ACTH concentrations make early diagnosis of PPID difficult. Progressive clinical findings and corresponding ACTH concentrations in horses transitioning to PPID over time have not been documented. Seven horses with ACTH concentrations equivocal for PPID (utilizing locally derived, seasonally adjusted diagnostic-cut off values (DCOV)) and no clinical signs of PPID were selected. Sequential measurement of basal and thyrotropin-releasing hormone (TRH)-stimulated ACTH concentrations and recording of clinical findings occurred from October 2017 to November 2021 in a prospective case series. In two horses, marked hypertrichosis developed. Although 1/11 basal ACTH concentrations were below DCOV in 2018, subsequently all basal ACTH concentrations in these two horses without treatment were greater than DCOV. One horse was treated with pergolide which normalized basal ACTH concentrations. Four horses developed intermittent, mild hypertrichosis, and one horse never developed hypertrichosis. Basal ACTH concentrations in these five horses were greater than DCOV in 63/133 (47.4%) of testing points. TRH-stimulated ACTH concentrations in these five horses were greater than DCOV in 77/133 (57.9%) of testing points, sometimes markedly increased and greater than the assay upper limit of detection (LoD) of 1250pg/mL. TRH-stimulated ACTH concentrations were most frequently positive in late summer and early autumn, with 24/37 (64.9%) of TRH-stimulated ACTH concentrations greater than the DCOV in February and March. Horses transitioning to PPID can have subtle clinical signs and equivocal ACTH concentrations. However, TRH-stimulated ACTH concentrations can be markedly greater than DCOV, especially in late summer and early autumn (February and March) allowing for identification of subclinical and transitional cases.

Ammonia (NH3) is a major gaseous pollutant in livestock production and has adverse effects on production, health and welfare of animals. The liver is one of the target organs of NH3, and excessive NH3 inhalation can induce liver damage. However, the toxicity assessment of NH3 on pig liver and its mechanism have not been reported yet. Recently, transcriptome analysis has become a major method to study the toxic mechanism of pollutants in environmental toxicology. Therefore, in the present study, we examined the effects of excessive NH3 inhalation on the liver of fattening pig through chemical analysis, ELISA, transcriptome analysis and real-time quantitative PCR (qRT-PCR). Our results showed that the transcriptome analysis database of fattening pig liver under excessive NH3 exposure, and 449 differentially expressed genes (DEGs) (including 181 up-regulated DEGs and 168 down-regulated DEGs) were found. Some genes associated with the 3 Gene Ontology (GO) terms (liver function, immune, antioxidant defense) were validated by quantitative real-time PCR. In addition, the activities of GPT and GOT in NH3 group were significantly increased by 63.5% and 37.4% (P

Acute myeloid leukemia (AML) refers to a heterogeneous group of hematopoietic malignancies. The well-known European Leukemia Network (ELN) stratifies AML patients into three risk groups, based primarily on the detection of cytogenetic abnormalities. However, the prognosis of cytogenetically normal AML (CN-AML), which is the largest AML subset, can be hard to define. Moreover, the clinical outcomes associated with this subgroup are diverse. In this study, using transcriptome profiles collected from CN-AML patients in the BeatAML cohort, we constructed a robust prognostic Cox model named NEST (Nine-gEne SignaTure). The validity of NEST was confirmed in four external independent cohorts. Moreover, the risk score predicted by the NEST model remained an independent prognostic factor in multivariate analyses. Further analysis revealed that the NEST model was suitable for bone marrow mononuclear cell (BMMC) samples but not peripheral blood mononuclear cell (PBMC) samples, which indirectly indicated subtle differences between BMMCs and PBMCs. Our data demonstrated the robustness and accuracy of the NEST model and implied the importance of the immune dysfunction in the leukemogenesis that occurs in CN-AML, which shed new light on the further exploration of molecular mechanisms and treatment guidance for CN-AML.

Hypoxia is a pathological condition common to many diseases, although multiple organ injuries induced by hypoxia are often overlooked. There is increasing evidence to suggest that the hypoxic environment may activate innate immune cells and suppress adaptive immunity, further stimulating inflammation and inhibiting immunosurveillance. We found that dysfunctional immune regulation may aggravate hypoxia-induced tissue damage and contribute to secondary injury. Among the diverse mechanisms of hypoxia-induced immune dysfunction identified to date, the role of programmed death-ligand 1 (PD-L1) has recently attracted much attention. Besides leading to tumour immune evasion, PD-L1 has also been found to participate in the progression of the immune dysfunction which mediates hypoxia-induced multiple organ injury. In this review, we aimed to summarise the role of immune dysfunction in hypoxia-induced multiple organ injury, the effects of hypoxia on the cellular expression of PD-L1, and the effects of upregulated PD-L1 expression on immune regulation. Furthermore, we summarise the latest information pertaining to the involvement, diagnostic value, and therapeutic potential of immunosuppression induced by PD-L1 in various types of hypoxia-related diseases, including cancers, ischemic stroke, acute kidney injury, and obstructive sleep apnoea. 61Qdns8RY7g31YGFsWcfG1 Video Abstract [ABSTRACT FROM AUTHOR]

Infections, due to a dysfunctional immune response, pose a great risk to patients with decompensated cirrhosis and herald the beginning of the terminal phase of this disease. Infections typically result from breaches in innate immune barriers and inadequate clearance by immune cells. This leads to bacterial and bacterial product translocation to the systemic circulation, which is already primed by ongoing hepatic inflammation in patients with cirrhosis, who are particularly prone to developing organ failure in the presence of an infection. Early identification of bacterial infection, along with the prompt use of appropriate antibiotics, have reduced the mortality associated with certain infections in patients with decompensated cirrhosis. Judicious use of antibiotic therapy remains imperative given the emergence of multidrug-resistant infections in the cirrhotic population. Important research over the last few years has identified molecular targets on immune cells that may enhance their function, and theoretically prevent infections. Clinical trials are ongoing to delineate the beneficial effects of targeted molecules from their off-target effects. Herein, we review the mechanisms that predispose patients with cirrhosis to bacterial infections, the clinical implications of infections and potential targets for the prevention or treatment of infections in this vulnerable population. [ABSTRACT FROM AUTHOR]

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 classified 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 defined 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. [ABSTRACT FROM AUTHOR]

In the first 3 years of life, respiratory illnesses are the commonest reason for admission to hospital for children with Down syndrome (DS). Providing respiratory care for children with DS requires a long term multidisciplinary approach. Children have multiple respiratory complications from the mouth to the alveoli, with co-morbidities of the cardiac and gastrointestinal systems also impacting upon respiratory disease. Respiratory morbidity can be serious and frequently leads to intensive care admission. In this brief article we summarize the respiratory conditions frequently encountered and give recommendations for management. [ABSTRACT FROM AUTHOR]

Cirrhosis contributes significantly to morbidity and mortality worldwide. Infections in patients with cirrhosis are common and significantly impact health-related quality of life. As our understanding of immune dysfunction associated with cirrhosis grows and as rates of drug-resistant organisms increase, the management of infections in cirrhosis has become increasingly nuanced. In this review, we discuss the current understanding of cirrhosis-associated immune deficiency, review the most common infections in patients with cirrhosis, and highlight techniques for the general clinician in the prevention and treatment of infections in this high-risk population. [ABSTRACT FROM AUTHOR]

Introduction: Early identification of severe disease in Coronavirus Disease-2019 (COVID-19) infection is important to reduce mortality and for the efficient allocation of medical resources. Several studies have established that severe cases of COVID- 19 infections tend to have a higher Neutrophil Lymphocyte Ratio (NLR) and is an independent predictor of mortality. Aim: This study aimed to determine whether NLR can serve as a predictor of the prognosis of COVID-19 infections in Indian patients. Materials and Methods: This study was an ambispective observational single centre study conducted in Tirunelveli Medical College from March 2020 to July 2020. Clinical and laboratory data of 1100 laboratory-confirmed COVID-19 infected patients were reviewed in this study. The patients were categorised as, asymptomatic, mild, moderate, and severe cases based on their clinical presentation. The demographic, clinical characteristics and laboratory data on the day of admission were analysed and compared by tertiles of the NLR. The receiver operating curve was applied to determine the threshold of NLR and the prognostic value was assessed via the Kaplan-Meier curve and regression models. Results: A total of 1100 cases were included in the study and were subdivided based on the clinical presentation into mild (n=226), moderate (n=27), severe (n=67), and asymptomatic (n=780) cases. The overall mortality rate was 4.9%. The ROC curve indicated that NLR is a better predictor of severe disease than other haematological parameters, with 89.3% Area Under the Curve (AUC) at the cut-off value of 2.81 with 80.6% sensitivity and 87.1% specificity. Multivariate analysis established that patients with NLR >2.8 had higher odds (OR=19.809, 95% CI-10.159-38.622) of severe infection and mortality (HR=1.110, 95% CI-1.088-1.113). Kaplan-Meier curve showed a significant difference (p-value<0.001) in the duration of hospital stay between patients with NLR <2.8 (Mean=10.4 days) and NLR >2.8 (13.1 days). Conclusion: Early identification of COVID-19 patients with severe disease is important to reduce mortality. Elevated NLR is associated with severe disease in Severe Acute Resiratory Syndrome Coronavirus-2 (SARS-CoV-2) infection. NLR >2.8 in Indian population, may aid in identification of severe illness necessitating early access to intensive care unit and requirement of respiratory support. [ABSTRACT FROM AUTHOR]

High mobility group box 1 protein (HMGB1) has been suggested to be involved in the immune dysfunction and inflammation reported in autism spectrum disorder (ASD). We aimed to assess HMGB1 serum concentrations (SCs) in high-functioning ASD children compared to typically developing (TD) controls and to explore their associations with the autism spectrum quotient (AQ), the empathy quotient (EQ), and the systemizing quotient (SQ). The study involved 42 ASD children and 38 TD children, all-male, aged between 6.1 and 13.3 years old. HMGB1 SCs were measured by enzyme-linked immunosorbent assay (ELISA). Groups were comparable regarding age, general IQ, birth weight, and maternal age at birth. ASD children showed significantly higher HMGB1 SCs compared to TD children (1.25 ± 0.84 ng/mL versus 1.13 ± 0.79 ng/mL, respectively, p = 0.039). The Spearman’s rho revealed that HMGB1 SCs were positively correlated with the AQ attention to detail subscale (rs = 0.46, p = 0.045) and with the SQ total score (rs = 0.42, p = 0.04) in the ASD group. These results show that HMGB1 serum concentrations are altered in ASD children, and suggest that inflammatory processes mediated by HMGB1 may be associated with specific cognitive features observed in ASD. [ABSTRACT FROM AUTHOR]

Acute myeloid leukemia (AML) refers to a heterogeneous group of hematopoietic malignancies. The well-known European Leukemia Network (ELN) stratifies AML patients into three risk groups, based primarily on the detection of cytogenetic abnormalities. However, the prognosis of cytogenetically normal AML (CN-AML), which is the largest AML subset, can be hard to define. Moreover, the clinical outcomes associated with this subgroup are diverse. In this study, using transcriptome profiles collected from CN-AML patients in the BeatAML cohort, we constructed a robust prognostic Cox model named NEST (Nine-gEne SignaTure). The validity of NEST was confirmed in four external independent cohorts. Moreover, the risk score predicted by the NEST model remained an independent prognostic factor in multivariate analyses. Further analysis revealed that the NEST model was suitable for bone marrow mononuclear cell (BMMC) samples but not peripheral blood mononuclear cell (PBMC) samples, which indirectly indicated subtle differences between BMMCs and PBMCs. Our data demonstrated the robustness and accuracy of the NEST model and implied the importance of the immune dysfunction in the leukemogenesis that occurs in CN-AML, which shed new light on the further exploration of molecular mechanisms and treatment guidance for CN-AML. [ABSTRACT FROM AUTHOR]

Background: Endometriosis is a refractory and recurrent disease and it affects nearly 10% of reproductive-aged women and 40% of infertile patients. The commonly accepted theory for endometriosis is retrograde menstruation where endometrial tissues invade into peritoneal cavity and fail to be cleared due to immune dysfunction. Therefore, the comprehensive understanding of immunologic microenvironment of peritoneal cavity deserves further investigation for the previous studies mainly focus on one or several immune cells. Results: High-quality transcriptomes were from peritoneal fluid samples of patients with endometriosis and control, and firstly subjected to 10 × genomics single-cell RNA-sequencing. We acquired the single-cell transcriptomes of 10,280 cells from endometriosis sample and 7250 cells from control sample with an average of approximately 63,000 reads per cell. A comprehensive map of overall cells in peritoneal fluid was first exhibited. We unveiled the heterogeneity of immune cells and discovered new cell subtypes including T cell receptor positive (TCR+) macrophages, proliferating macrophages and natural killer dendritic cells in peritoneal fluid, which was further verified by double immunofluorescence staining and flow cytometry. Pseudo-time analysis showed that the response of macrophages to the menstrual debris might follow the certain differentiation trajectory after endometrial tissues invaded into the peritoneal cavity, that is, from antigen presentation to pro-inflammation, then to chemotaxis and phagocytosis. Our analyses also mirrored the dysfunctions of immune cells including decreased phagocytosis and cytotoxic activity and elevated pro-inflammatory and chemotactic effects in endometriosis. Conclusion: TCR+ macrophages, proliferating macrophages and natural killer dendritic cells are firstly reported in human peritoneal fluid. Our results also revealed that immune dysfunction happens in peritoneal fluid of endometriosis, which may be responsible for the residues of invaded menstrual debris. It provided a large-scale and high-dimensional characterization of peritoneal microenvironment and offered a useful resource for future development of immunotherapy. [ABSTRACT FROM AUTHOR]

Sepsis is a life-threatening complication of pneumonia, including coronavirus disease-2019 (COVID-19)-induced pneumonia. Evidence of the benefits of vitamin C (VC) for the treatment of sepsis is accumulating. However, data revealing the targets and molecular mechanisms of VC action against sepsis are limited. In this report, a bioinformatics analysis of network pharmacology was conducted to demonstrate screening targets, biological functions, and the signaling pathways of VC action against sepsis. As shown in network assays, 63 primary causal targets for the VC action against sepsis were identified from the data, and four optimal core targets for the VC action against sepsis were identified. These core targets were epidermal growth factor receptor (EGFR), mitogen-activated protein kinase-1 (MAPK1), proto-oncogene c (JUN), and signal transducer and activator of transcription-3 (STAT3). In addition, all biological processes (including a top 20) and signaling pathways (including a top 20) potentially involved in the VC action against sepsis were identified. The hub genes potentially involved in the VC action against sepsis and interlaced networks from the Kyoto Encyclopedia of Genes and Genomes Mapper assays were highlighted. Considering all the bioinformatic findings, we conclude that VC antisepsis effects are mechanistically and pharmacologically implicated with suppression of immune dysfunction-related and inflammation-associated functional processes and other signaling pathways. These primary predictive biotargets may potentially be used to treat sepsis in future clinical practice. [ABSTRACT FROM AUTHOR]

Objectives: Despite its importance as an HIV anatomic sanctuary, little is known about the characteristics of the HIV reservoir in the terminal ileum (TI). In blood, the immune checkpoint inhibitor programmed‐death‐1 (PD‐1) has been linked to the HIV reservoir and T‐cell immune dysfunction. We thus evaluated PD‐1 expression and cell‐associated HIV DNA in memory CD4 T‐cell subsets from TI, peripheral blood (PB) and rectum (RE) of untreated and treated HIV‐positive patients to identify associations between PD‐1 and HIV reservoir in other sites. Methods: Using mononuclear cells from PB, TI and RE of untreated HIV‐positive (N = 6), treated (n = 18) HIV‐positive and uninfected individuals (n = 16), we identified and sorted distinct memory CD4 T‐cell subsets by flow cytometry, quantified their cell‐associated HIV DNA using quantitative PCR and assessed PD‐1 expression levels using geometric mean fluorescence intensity. Combined HIV‐1 RNA in situ hybridization and immunohistochemistry was performed on ileal biopsy sections. Results: Combined antiretroviral therapy (cART)‐treated patients with undetectable HIV RNA and significantly lower levels of HIV DNA in PB showed particularly high PD‐1 expression in PB and TI, and high HIV DNA levels in TI, irrespective of clinical characteristics. By contrast, in treatment‐naïve patients HIV DNA levels in memory CD4 T‐cell subsets were high in PB and TI. Conclusion: Elevated PD‐1 expression on memory CD4 T‐cells in PB and TI despite treatment points to continuous immune dysfunction and underlines the importance of evaluating immunotherapy in reversing HIV latency and T‐cell reconstitution. As HIV DNA particularly persists in TI despite cART, investigating samples from TI is crucial in understanding HIV immunopathogenesis. [ABSTRACT FROM AUTHOR]

Duck-origin parvovirus disease is an epidemic disease mainly caused by duck-origin goose parvovirus (D-GPV), which is characterized by beak atrophy and dwarfism syndrome. Its main symptoms are persistent diarrhea, skeletal dysplasia, and growth retardation. However, the pathogenesis of Cherry Valley ducks infected by D-GPV has not been studied thoroughly. To perceive the distribution of D-GPV in the intestinal tract, intestinal morphological development, intestinal permeability, inflammatory cytokines in Cherry Valley ducks, and expression of tight junction protein, the D-GPV infection was given intramuscularly. Illumina MiSeq sequencing technology was used to analyze the diversity and structure of ileum flora and content of short-chain fatty acids of its metabolites. To investigate the relationship between intestinal flora changes and intestinal barrier function after D-GPV infection on Cherry Valley ducks is of great theoretical and practical significance for further understanding the pathogenesis of D-GPV and the structure of intestinal flora in ducks. The results showed that D-GPV infection was accompanied by intestinal inflammation and barrier dysfunction. At this time, the decrease of a large number of beneficial bacteria and the content of short-chain fatty acids in intestinal flora led to the weakening of colonization resistance of the intestinal flora and the accumulation of potentially pathogenic bacteria, which would aggravate the negative effect of D-GPV damage to the intestinal tract. Furthermore, a significant increase in Unclassified_S24-7 and decrease in Streptococcus was observed in D-GPV persistent, indicating the disruption in the structure of gut microbiota. Notably, the shift of microbiota was associated with the transcription of tight-junction protein and immune-associated cytokines. These results indicate that altered ileum microbiota, intestinal barrier, and immune dysfunction are associated with D-GPV infection. Therefore, there is a relationship between the intestinal barrier dysfunction and dysbiosis caused by D-GPV, but the specific mechanism needs to be further explored.

The study of the use of nanotechnology for drug delivery has been extensive. Nanomedical approaches for therapeutics; drug delivery in particular is superior to conventional methods in that it allows for controlled targeted delivery and release, higher stability, extended circulation time, minimal side-effects, and improved pharmacokinetic clearance (of the drug) form the body, to name a few. The magnitude of COVID-19, the current ongoing pandemic has been severe; it has caused widespread the loss of human life. In individuals with severe COVID-19, immune dysregulation and a rampant state of hyperinflammation is observed. This kind of an immunopathological response is detrimental and results in rapid disease progression, development of secondary infections, sepsis and can be fatal. Several studies have pin-pointed the reason for this immune dysregulation; deviations in the signaling pathways involved in the mediation and control of immune responses. In severe COVID-19 patients, many signaling cascades including JAK/STAT, NF-κB, MAPK/ERK, TGF beta, VEGF, and Notch signaling were found to be either upregulated or inactivated. Targeting these aberrant signaling pathways in conjunction with antiviral therapy will effectuate mitigation of the hyperinflammation, hypercytokinemia, and promote faster recovery. The science of the use of nanocarriers as delivery agents to modulate these signaling pathways is not new; it has already been explored for other inflammatory diseases and in particular, cancer therapy. Numerous studies have evaluated the efficacy and potential of nanomedical approaches to modulate these signaling pathways and have been met with positive results. A treatment regime, that includes nanotherapeutics and antiviral therapies will prove effective and holds great promise for the successful treatment of COVID-19. In this article, we review different nanomedical approaches already studied for targeting aberrant signaling pathways, the host immune response to SARS-CoV-2, immunopathology and the dysregulated signaling pathways observed in severe COVID-19 and the current treatment methods in use for targeting signaling cascades in COVID-19. We then conclude by suggesting that the use of nanomedical drug delivery systems for targeting signaling pathways can be extended to effectively target the aberrant signaling pathways in COVID-19 for best treatment results.

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to an infection. It is a disease with a high incidence, mortality, and recurrence rate and frequently results in its survivors requiring readmission into hospitals. The readmission is mainly due to recurrent sepsis. Patients with recurrent sepsis are more susceptible to secondary infections partly due to immune dysfunction, leading to a higher mortality in the long term. However, there remains a gap in the understanding of immunological characteristics and underlying mechanisms of recurrent sepsis. In this study, we used mouse models of acute and recurrent sepsis to investigate their different immunological characteristics. And then we subjected the two mouse models to a secondary influenza A virus (H1N1) infection and characterized the different immune responses. Here, we demonstrated that CD4+ T cells present an exacerbated exhaustion phenotype in response to recurrent sepsis as illustrated by the decreased frequency of CD4+ T cells, reduced co-stimulatory CD28 and increased inhibitory PD-1 and Tim-3 expression on CD4+ T cells, increased frequency of regulatory T cells, and reduced MHC-II expression on antigen-presenting cells. Moreover, we showed that antiviral immune responses decrease in the recurrent sepsis mouse model subjected to a secondary infection as illustrated by the reduced pathogen clearance and inflammatory response. This may be a consequence of the exacerbated CD4+ T cell exhaustion. In summary, recurrent sepsis exacerbates CD4+ T cell exhaustion and decreases antiviral immune responses, contributing to significant morbidity, increased late mortality, and increased health care burden in recurrent sepsis patients.

Foot-and-mouth disease (FMD) is a highly contagious disease of cloven-hoofed animals, which has been regarded as a persistent challenge for the livestock industry in many countries. Foot-and-mouth disease virus (FMDV) is the etiological agent of FMD that can spread rapidly by direct and indirect transmission. FMDV is internalized into host cell by the interaction between FMDV capsid proteins and cellular receptors. When the virus invades into the cells, the host antiviral system is quickly activated to suppress the replication of the virus and remove the virus. To retain fitness and host adaptation, various viruses have evolved multiple elegant strategies to manipulate host machine and circumvent the host antiviral responses. Therefore, identification of virus-host interactions is critical for understanding the host defense against virus infections and the pathogenesis of the viral infectious diseases. This review elaborates on the virus-host interactions during FMDV infection to summarize the pathogenic mechanisms of FMD, and we hope it can provide insights for designing effective vaccines or drugs to prevent and control the spread of FMD and other diseases caused by picornaviruses.

MicroRNAs (miRNAs) are 19-24 nucleotide long non-coding RNA species that regulate the expression of multiple target genes at the post-transcriptional level. They are required for normal immune system development and function, and their expression is dynamically regulated in different immune cell subsets during lineage differentiation and immune response. Aberrant expression of miRNAs results in dysregulated innate and adaptive immunity. This in turn can lead to failure to fight against invading pathogens and the development of autoimmune diseases and hematopoietic malignancies. In this article, we review current progress in miRNA research in immunity in both physiological and pathological settings. We also discuss research limitations and challenges that researchers are just beginning to solve.

Inflammation is an indispensable biological process stimulated by infection and injuries. Inflammatory mechanisms related to extracellular vesicles (EVs), which are small membrane structures carrying various molecules, were summarized in this review. Emerging evidence from animal studies has highlighted the role of EVs in modulating inflammatory responses, by transporting various molecules involved in host defense. In this review, we have discussed the role of EV miRNAs in inflammation. Rodent studies associated with extracellular miRNAs in inflammatory diseases, published from 2012 to 2022, were explored from PUBMED, EMBASE, and MEDLINE. A total of 95 studies were reviewed. In summary, EV-associated miRNAs play a key role in various diseases, including organ injury, immune dysfunction, neurological disease, metabolic syndrome, vesicular disease, arthritis, cancer, and other inflammatory diseases. Diverse EV-associated miRNAs regulate inflammasome activation and pro- and anti-inflammatory cytokine levels by targeting genes.

Age-related T cell dysfunction contributes to immunosenescence and chronic inflammation. Aging is also associated with a progressive decline in zinc status. Zinc is an essential micronutrient critical for immune function. A significant portion of the older populations are at risk for marginal zinc deficiency. The combined impact of dietary zinc deficiency and age on immune dysfunction has not been well explored despite the common occurrence together in the elderly population. We hypothesize that age-related zinc loss contributes to T cell dysfunction and chronic inflammation in the elderly and is exacerbated by inadequate dietary intake and improved with zinc supplementation. Using an aging mouse model, the effects of marginal zinc deficiency and zinc supplementation on Th1/Th17/proinflammatory cytokine profiles and CD4+ T cell naïve/memory phenotypes were examined. In the first study, young (2 months) and old (24 months) C57BL/6 mice were fed a zinc adequate (ZA) or marginally zinc deficient (MZD) diets for 6 weeks. In the second study, mice were fed a ZA or zinc supplemented (ZS) diet for 6 weeks. MZD old mice had significant increase in LPS-induced IL6 compared to ZA old mice. In contrast, ZS old mice had significantly reduced plasma MCP1 levels, reduced T cell activation-induced IFNγ, IL17, and TNFα response, as well as increased naïve CD4+ T-cell subset compared to ZA old mice. Our data suggest that zinc deficiency is an important contributing factor in immune aging, and improving zinc status can in part reverse immune dysfunction and reduce chronic inflammation associated with aging. [ABSTRACT FROM AUTHOR]

Atopic dermatitis (AD) is a chronic relapsing inflammatory cutaneous disease that is often associated with other atopic symptoms, such as food allergy, allergic rhinitis and asthma, leading to significant morbidity and healthcare costs. The pathogenesis of AD is complicated and multifactorial. Although the aetiology of AD remains incompletely understood, recent studies have provided further insight into AD pathophysiology, demonstrating that the interaction among genetic predisposition, immune dysfunction and environmental provocation factors contributes to its development. However, the increasing prevalence of AD suggests that environmental factors such as irritation and cutaneous infection play a crucial role in triggering and/or aggravating the disease. Of note, AD skin is susceptible to bacterial, fungal and viral infections, and microorganisms may colonize the skin and aggravate AD symptoms. Overall, understanding the mechanisms by which these risk factors affect the cutaneous immunity of patients with AD is of great importance for developing a precision medicine approach for treatment. This review summarizes recent developments in exogenous factors involved in the pathogenesis of AD, with special emphasis on irritants and microbial infections. [ABSTRACT FROM AUTHOR]

Multiple sclerosis (MS) is a multifactorial, central nervous system, immune-mediated disease characterized by inflammation, demyelination, and neurodegeneration. Evidence suggests a steady rise in MS prevalence over the past five decades in the United States and around the world. Even with increased understanding of immunology, the specific etiological trigger of MS remains unknown. Evidence suggests that oxidative/nitroxidative stress is an important contributor to MS etiology, progression, and clinical symptoms. A multifaceted treatment approach aimed at counteracting oxidative/nitroxidative stress including MS disease–modifying medications, Mediterranean style diet, stress-relieving activities, smoking and alcohol cessation, exercise, and peer support programs is the best way to treat the disease. [ABSTRACT FROM AUTHOR]

Foot-and-mouth disease (FMD) is a highly contagious disease of cloven-hoofed animals, which has been regarded as a persistent challenge for the livestock industry in many countries. Foot-and-mouth disease virus (FMDV) is the etiological agent of FMD that can spread rapidly by direct and indirect transmission. FMDV is internalized into host cell by the interaction between FMDV capsid proteins and cellular receptors. When the virus invades into the cells, the host antiviral system is quickly activated to suppress the replication of the virus and remove the virus. To retain fitness and host adaptation, various viruses have evolved multiple elegant strategies to manipulate host machine and circumvent the host antiviral responses. Therefore, identification of virus-host interactions is critical for understanding the host defense against virus infections and the pathogenesis of the viral infectious diseases. This review elaborates on the virus-host interactions during FMDV infection to summarize the pathogenic mechanisms of FMD, and we hope it can provide insights for designing effective vaccines or drugs to prevent and control the spread of FMD and other diseases caused by picornaviruses. [ABSTRACT FROM AUTHOR]

Sepsis is a life-threatening organ dysfunction caused by a dysregulated host response to an infection. It is a disease with a high incidence, mortality, and recurrence rate and frequently results in its survivors requiring readmission into hospitals. The readmission is mainly due to recurrent sepsis. Patients with recurrent sepsis are more susceptible to secondary infections partly due to immune dysfunction, leading to a higher mortality in the long term. However, there remains a gap in the understanding of immunological characteristics and underlying mechanisms of recurrent sepsis. In this study, we used mouse models of acute and recurrent sepsis to investigate their different immunological characteristics. And then we subjected the two mouse models to a secondary influenza A virus (H1N1) infection and characterized the different immune responses. Here, we demonstrated that CD4+ T cells present an exacerbated exhaustion phenotype in response to recurrent sepsis as illustrated by the decreased frequency of CD4+ T cells, reduced co-stimulatory CD28 and increased inhibitory PD-1 and Tim-3 expression on CD4+ T cells, increased frequency of regulatory T cells, and reduced MHC-II expression on antigen-presenting cells. Moreover, we showed that antiviral immune responses decrease in the recurrent sepsis mouse model subjected to a secondary infection as illustrated by the reduced pathogen clearance and inflammatory response. This may be a consequence of the exacerbated CD4+ T cell exhaustion. In summary, recurrent sepsis exacerbates CD4+ T cell exhaustion and decreases antiviral immune responses, contributing to significant morbidity, increased late mortality, and increased health care burden in recurrent sepsis patients. [ABSTRACT FROM AUTHOR]

Diffuse large B-cell lymphoma (DLBCL) is the most frequent type of lymphoma. Our retrospective study included 553 newly diagnosed DLBCL patients from May 2009 to October 2019. The relationships between hypogammaglobulinemia, hypocomplementemia and progression-free survival (PFS) and overall survival (OS) were assessed. In our center, 19.0% of patients had hypogammaglobulinemia, and 7.7% had hypocomplementemia at diagnosis. Immunoglobulin and complement deficiencies were associated with advanced disease and displayed inferior PFS and OS. Then, we designed a new immunization cumulative prognostic score (ICPS) model to comprehensively clarify the effect of these two variables on prognosis. Multivariate analysis showed that ICPS was an independent prognostic indicator for inferior clinical outcomes (PFS: p = 0.007, OS: p = 0.003). Furthermore, the predictive effect of ICPS combined with the International Prognostic Index (IPI) was superior to that of IPI alone (PFS: p = 0.016, OS: p = 0.037). In conclusion, hypogammaglobulinemia and hypocomplementemia could be regarded as adverse prognostic indicators in DLBCL. [ABSTRACT FROM AUTHOR]

Background: Epigenetic changes are plausible molecular sources of clinical heterogeneity in schizophrenia. A subgroup of schizophrenia patients with elevated inflammatory or immune-dysregulation has been reported by previous studies. However, little is known about epigenetic changes in genes related to immune activation in never-treated first-episode patients with schizophrenia (FES) and its consistency with that in treated long-term ill (LTS) patients., Methods: In this study, epigenome-wide profiling with a DNA methylation array was applied using blood samples of both FES and LTS patients, as well as their corresponding healthy controls. Non-negative matrix factorization (NMF) and k -means clustering were performed to parse heterogeneity of schizophrenia, and the consistency of subtyping results from two cohorts. was tested., Results: This study identified a subtype of patients in FES participants (47.5%) that exhibited widespread methylation level alterations of genes enriched in immune cell activity and a significantly higher proportion of neutrophils. This clustering of FES patients was validated in LTS patients, with high correspondence in epigenetic and clinical features across two cohorts., Conclusions: In summary, this study demonstrated a subtype of schizophrenia patients across both FES and LTS cohorts, defined by widespread alterations in methylation profile of genes related to immune function and distinguishing clinical features. This finding illustrates the promise of novel treatment strategies targeting immune dysregulation for a subpopulation of schizophrenia patients.

Evidence from epidemiological, clinical, and biological research resulted in the immune hypothesis: the hypothesis that immune system dysfunction is involved in the pathophysiology of schizophrenia spectrum disorders (SSD). The promising implication of this hypothesis is the potential to use existing immunomodulatory treatment for innovative interventions for SSD. Here, we provide a selective historical review of important discoveries that have shaped our understanding of immune dysfunction in SSD. We first explain the basic principles of immune dysfunction, after which we travel more than a century back in time. Starting our journey with neurosyphilis-associated psychosis in the nineteenth century, we continue by evaluating the role of infections and autoimmunity in SSD and findings from assessment of immune function using new techniques, such as cytokine levels, microglia density, neuroimaging, and gene expression. Drawing from these findings, we discuss anti-inflammatory interventions for SSD, and we conclude with a look into the future.

Diabetes is associated with numerous comorbidities, one of which is increased vulnerability to infections. This review will focus on how diabetes mellitus (DM) affects the immune system and its various components, leading to the impaired proliferation of immune cells and the induction of senescence. We will explore how the pathology of diabetes-induced immune dysfunction may have similarities to the pathways of "inflammaging", a persistent low-grade inflammation common in the elderly. Inflammaging may increase the likelihood of conditions such as rheumatoid arthritis (RA) and periodontitis at a younger age. Diabetes affects bone marrow composition and cellular senescence, and in combination with advanced age also affects lymphopoiesis by increasing myeloid differentiation and reducing lymphoid differentiation. Consequently, this leads to a reduced immune system response in both the innate and adaptive phases, resulting in higher infection rates, reduced vaccine response, and increased immune cells' senescence in diabetics. We will also explore how some diabetes drugs induce immune senescence despite their benefits on glycemic control.