Differential Effects of Yin- and Yang-Chinese Tonifying Herbs on Innate and Adaptive Immunity

The present study investigated the effect of treatment with methanolic extracts of Yin- and Yang-Chinese tonifying herbs on concanavalin A (Con A)/lipopolysaccharide (LPS)-stimulated splenocyte proliferation (adaptive immunity) and natural killer (NK) cell activity (innate immunity) in an ex vivo mouse model. The results indicated that while treatment with most Yin herbal extracts potentiated the Con A/LPS-stimulated splenocyte proliferation, only Yang (but not Yin) herbal extracts stimulated NK cell activity. The differential effects of Yin- and Yang-Chinese tonifying herbs on innate and adaptive immunity are consistent with the Chinese medicine theory which depicts the Yin and Yang functional components of Zheng Qi (vital energy), with the Yang component being responsible for the first line of defense against invading microorganisms (i.e., innate immunity) and the Yin oner serving as a follow-up defensive response (adaptive immunity).

Tetrahedral Framework Nucleic Acid-Based Delivery of Resveratrol Alleviates Insulin Resistance:From Innate to Adaptive Immunity

Obesity-induced insulin resistance is the hallmark of metabolic syndrome,and chronic,low-grade tissue inflammation links obesity to insulin resistance through the activation of tissue-infiltrating immune cells.Current therapeutic approaches lack efficacy and immunomodulatory capacity.Thus,a new therapeutic approach is needed to prevent chronic inflammation and alleviate insulin resistance.Here,we synthesized a tetrahedral framework nucleic acid(tFNA)nanoparticle that carried resveratrol(RSV)to inhibit tissue inflammation and improve insulin sensitivity in obese mice.The prepared nanoparticles,namely tFNAs-RSV,possessed the characteristics of simple synthesis,stable properties,good water solubility,and superior biocompatibility.The tFNA-based delivery ameliorated the lability of RSV and enhanced its therapeutic efficacy.In high-fat diet(HFD)-fed mice,the administration of tFNAs-RSV ameliorated insulin resistance by alleviating inflammation status.tFNAs-RSV could reverse M1 phenotype macrophages in tissues to M2 phenotype macrophages.As for adaptive immunity,the prepared nanoparticles could repress the activation of Th1 and Th17 and promote Th2 and Treg,leading to the alleviation of insulin resistance.Furthermore,this study is the first to demonstrate that tFNAs,a nucleic acid material,possess immunomodulatory capacity.Collectively,our findings demonstrate that tFNAs-RSV alleviate insulin resistance and ameliorate inflammation in HFD mice,suggesting that nucleic acid materials or nucleic acid-based delivery systems may be a potential agent for the treatment of insulin resistance and obesity-related metabolic diseases.

Intelligent direct analysis of physical and mechanical parameters of tunnel surrounding rock based on adaptive immunity algorithm and BP neural network

Because of complexity and non-predictability of the tunnel surrounding rock, the problem with the determination of the physical and mechanical parameters of the surrounding rock has become a main obstacle to theoretical research and numerical analysis in tunnel engineering. During design, it is a frequent practice, therefore, to give recommended values by analog based on experience. It is a key point in current research to make use of the displacement back analytic method to comparatively accurately determine the parameters of the surrounding rock whereas artificial intelligence possesses an exceptionally strong capability of identifying, expressing and coping with such complex non-linear relationships. The parameters can be verified by searching the optimal network structure, using back analysis on measured data to search optimal parameters and performing direct computation of the obtained results. In the current paper, the direct analysis is performed with the biological emulation system and the software of Fast Lagrangian Analysis of Continua (FLAC3D. The high non-linearity, network reasoning and coupling ability of the neural network are employed. The output vector required of the training of the neural network is obtained with the numerical analysis software. And the overall space search is conducted by employing the Adaptive Immunity Algorithm. As a result, we are able to avoid the shortcoming that multiple parameters and optimized parameters are easy to fall into a local extremum. At the same time, the computing speed and efficiency are increased as well. Further, in the paper satisfactory conclusions are arrived at through the intelligent direct-back analysis on the monitored and measured data at the Erdaoya tunneling project. The results show that the physical and mechanical parameters obtained by the intelligent direct-back analysis proposed in the current paper have effectively improved the recommended values in the original prospecting data. This is of practical significance to the appraisal of stability and informationization design of the surrounding rock.

Radiation-based immunogenic vaccine combined with a macrophage“checkpoint inhibitor”for boosting innate and adaptive immunity against metastatic colon cancers

Immunogenic dying tumor cells hold promising prospects as cancer vaccines to activate systemic immunity against both primary and metastatic tumors.Especially,X-ray-induced dying tumor cells are rich in highly immunogenic tumor-associated antigens and self-generated dsDNA as potent adjuvants.However,we found that the X-ray induction process can result in the excessive exposure of phosphatidylserine in cancer vaccines,which can specifically bind with the MerTK receptor on macrophages,acting as a“checkpoint”to facilitate immune silence in the tumor microenvironment.Therefore,we developed a novel strategy combining X-ray-induced cancer vaccines with UNC2250,a macrophage MerTK“checkpoint inhibitor,”for treating peritoneal carcinomatosis in colon cancer.By incorporating UNC2250 into the treatment regimen,immunosuppressive efferocytosis of macrophages,which relies on MerTK-directed recognition of phosphatidylserine on vaccines,was effectively blocked.Consequently,the immune analysis revealed that this combination strategy promoted the maturation of dendritic cells and M1-like repolarization of macrophages,thereby simultaneously eliciting robust adaptive and innate immunity.This innovative approach utilizing X-ray-induced vaccines combined with a checkpoint inhibitor may provide valuable insights for developing effective cancer vaccines and immunotherapies targeting colon cancer.

Pharmacological Investigation on the Qi-Invigorating Action of Schisandrin B: Effects on Mitochondrial ATP Generation in Multiple Tissues and Innate/Adaptive Immunity in Mice

Schisandrae Fructus, containing schisandrin B (Sch B) as its main active component, is recognized in traditional Chinese medicine (TCM) for its Qi-invigorating properties in the five visceral organs. Our laboratory has shown that the Qi-invigorating action of Chinese tonifying herbs is linked to increased mitochondrial ATP generation and an enhancement in mitochondrial glutathione redox status. To explore whether Sch B can exert Qi-invigorating actions across various tissues, we investigated the effects of Sch B treatment on mitochondrial ATP generation and glutathione redox status in multiple mouse tissues ex vivo. In line with TCM theory, which posits that Zheng Qi generation relies on the Qi function of the visceral organs, we also examined Sch B’s impact on natural killer cell activity and antigen-induced splenocyte proliferation, both serving as indirect measures of Zheng Qi. Our findings revealed that Sch B treatment consistently enhanced mitochondrial ATP generation and improved mitochondrial glutathione redox status in mouse tissues. This boost in mitochondrial function was associated with stimulated innate and adaptive immune responses, marked by increased natural killer cell activity and antigen-induced T/B cell proliferation, potentially through the increased generation of Zheng Qi.

The functions of tumor suppressor PTEN in innate and adaptive immunity

The tumor suppressor phosphatase and tensin homolog(PTEN)is a lipid and protein phosphatase that is able to antagonize the PI3K/AKT pathway and inhibit tumor growth.PTEN also possesses phosphatase-independent functions.Genetic alterations of PTEN may lead to the deregulation of cell proliferation,survival,differentiation,energy metabolism and cellular architecture and mobility.Although the role of PTEN in tumor suppression is extensively documented and well established,the evidence for its roles in immunity did not start to accumulate until recently.In this review,we will focus on the newly discovered functions of PTEN in the regulation of innate and adaptive immunity,including antiviral responses.

The Role of the p38 Pathway in Adaptive Immunity

Since its discovery in 1993, the mitogen-activated protein （MAP） kinase p38 has attracted much attention for its role in a wide range of cellular processes, many of which involve the immune system. Although p38 has been heavily implicated in the function of all type immune cells, research has tended focus on its role in innate immunity. In this review we attempt to highlight some of the major discoveries that have been made regarding p38＇s role in adaptive immunity, and also to discuss the possible future implications of these discoveries.

Adaptive immunity in the liver

The anatomical architecture of the human liver and the diversity of its immune components endow the liver with its physiological function of immune competence. Adaptive immunity is a major arm of the immune system that is organized in a highly specialized and systematic manner, thus providing long-lasting protection with immunological memory. Adaptive immunity consists of humoral immunity and cellular immunity. Cellular immunity is known to have a crucial role in controlling infection, cancer and autoimmune disorders in the liver. In this article, we will focus on hepatic virus infections, hepatocellular carcinoma and autoimmune disorders as examples to illustrate the current understanding of the contribution of T cells to cellular immunity in these maladies. Cellular immune suppression is primarily responsible for chronic viral infections and cancer. However, an uncontrolled auto-reactive immune response accounts for autoimmunity. Consequently, these immune abnormalities are ascribed to the quantitative and functional changes in adaptive immune cells and their subsets, innate immunocytes, chemokines, cytokines and various surface receptors on immune cells. A greater understanding of the complex orchestration of the hepatic adaptive immune regulators during homeostasis and immune competence are much needed to identify relevant targets for clinical intervention to treat immunological disorders in the liver.

Current Advances of Innate and Adaptive Immunity in Acute-on-Chronic Hepatitis B Liver Failure

Acute-on-chronic hepatitis B liver failure(ACHBLF)is a term used to define the acute deterioration of liver function that occurs in patients with chronic hepatitis B virus infection or hepatitis B virus-related liver cirrhosis.The specific pathogenesis of ACHBLF is still not completely understood.Current research has shown that an intense systemic inflammation is involved in the development of acute-on-chronic liver failure(ACLF).Meanwhile,a subsequent immune paresis over the course of ACLF favors the development of infection and sepsis.Deregulation in both the innate and adaptive immunity is the notable feature of ACLF.The dysregulated immune responses play a crucial role in disease progression and potentially drive organ failure and mortality in ACHBLF.In this review,we highlight the current knowledge of innate and adaptive immune cells in ACHBLF.

Interplay between mesenchymal stromal cells and the immune system after transplantation: implications for advanced cell therapy in the retina

Advanced mesenchymal stromal cell-based therapies for neurodegenerative diseases are widely investigated in preclinical models.Mesenchymal stromal cells are well positioned as therapeutics because they address the underlying mechanisms of neurodegeneration,namely trophic factor deprivation and neuroinflammation.Most studies have focused on the beneficial effects of mesenchymal stromal cell transplantation on neuronal survival or functional improvement.However,little attention has been paid to the interaction between mesenchymal stromal cells and the host immune system due to the immunomodulatory properties of mesenchymal stromal cells and the long-held belief of the immunoprivileged status of the central nervous system.Here,we review the crosstalk between mesenchymal stromal cells and the immune system in general and in the context of the central nervous system,focusing on recent work in the retina and the importance of the type of transplantation.

Full T-cell activation and function in teleosts require collaboration of first and co-stimulatory signals

Mammalian T-cell responses require synergism between the first signal and co-stimulatory signal.However,whether and how dual signaling regulates the T-cell response in early vertebrates remains unknown.In the present study,we discovered that the Nile tilapia(Oreochromis niloticus)encodes key components of the LAT signalosome,namely,LAT,ITK,GRB2,VAV1,SLP-76,GADS,and PLC-γ1.These components are evolutionarily conserved,and CD3εmAb-induced T-cell activation markedly increased their expression.Additionally,at least ITK,GRB2,and VAV1 were found to interact with LAT for signalosome formation.Downstream of the first signal,the NF-κB,MAPK/ERK,and PI3K-AKT pathways were activated upon CD3εmAb stimulation.Furthermore,treatment of lymphocytes with CD28 mAbs triggered the AKT-mTORC1 pathway downstream of the co-stimulatory signal.Combined CD3εand CD28 mAb stimulation enhanced ERK1/2 and S6 phosphorylation and elevated NFAT1,c-Fos,IL-2,CD122,and CD44 expression,thereby signifying T-cell activation.Moreover,rather than relying on the first or co-stimulatory signal alone,both signals were required for T-cell proliferation.Full T-cell activation was accompanied by marked apoptosis and cytotoxic responses.These findings suggest that tilapia relies on dual signaling to maintain an optimal T-cell response,providing a novel perspective for understanding the evolution of the adaptive immune system.

CD3ε of a pan T cell marker involved in mouse Aspergillus fumigatus keratitis

AIM:To explore whether CD3ε is involved in the adaptive immunity of Aspergillus fumigatus(A.fumigatus)keratitis in mice and the role of innate and adaptive immunity in it.METHODS:Mice models of A.fumigatus keratitis were established by intra-stromal injection and corneal epithelial scratching.Subconjunctival injections of natamycin,wedelolactone,LOX-1 inhibitor(poly I)or Dectin-1 inhibitor(laminarin)were used to treat mice with A.fumigatus keratitis.Mice were pretreated by intraperitoneal injection of anti-mouse CD3ε.We observed the corneal infection of mice under the slit lamp microscope and made a clinical score.The protein expression of CD3ε and interleukin-10(IL-10)was determined by Western blotting.RESULTS:With the disease progresses,the degree of corneal opacity and edema augmented.In the intrastromal injection models,CD3εprotein expression began to increase significantly on the 2^(nd) day.However,in the scraping epithelial method models,CD3ε only began to increase on the 3^(rd) day.After natamycin treatment,the degree of corneal inflammation in mice was significantly attenuated on the 3^(rd) day.After wedelolactone treatment,the severity of keratitis worsened.And the amount of CD3ε protein was also reduced,compared with the control group.By inhibiting LOX-1 and Dectin-1,there was no significant difference in CD3ε production compared with the control group.After inhibiting CD3ε,corneal ulcer area and clinical score increased,and IL-10 expression was downregulated.CONCLUSION:As a pan T cell marker,CD3ε participate in the adaptive immunity of A.fumigatus keratitis in mice.In our mice models,the corneas will enter the adaptive immune stage faster.By regulating IL-10,CD3ε exerts antiinflammatory and repairs effects in the adaptive immune stage.

Innate and adaptive immune escape mechanisms of hepatitis B virus

Chronic hepatitis B virus(HBV)infection is an international health problem with extremely high mortality and morbidity rates.Although current clinical chronic hepatitis B(CHB)treatment strategies can partly inhibit and eliminate HBV,viral breakthrough may result due to non-adherence to treatment,the emergence of viral resistance,and a long treatment cycle.Persistent CHB infection arises as a consequence of complex interactions between the virus and the host innate and adaptive immune systems.Therefore,understanding the immune escape mechanisms involved in persistent HBV infection is important for designing novel CHB treatment strategies to clear HBV and achieve long-lasting immune control.This review details the immunological and biological characteristics and escape mechanisms of HBV and the novel immune-based therapies that are currently used for treating HBV.

Innate and adaptive immune responses against picornaviruses and their counteractions: An overview

Picornaviruses, small positive-stranded RNA viruses, cause a wide range of diseases which is based on their differential tissue and cell type tropisms. This diversity is reflected by the immune responses, both innate and adaptive, induced after infection, and the subsequent interactions of the viruses with the immune system. The defense mechanisms of the host and the countermeasures of the virus significantly contribute to the pathogenesis of the infections. Important human pathogens are poliovirus, coxsackievirus, human rhinovirus and hepatitis A virus. These viruses are the beststudied members of the family, and in this review we want to present the major aspects of the reciprocal effects between the immune system and these viruses.

Adaptive immune response during hepatitis C virus infection

Hepatitis C virus(HCV)infection affects about 170 million people worldwide and it is a major cause of liver cirrhosis and hepatocellular carcinoma.HCV is a hepatotropic non-cytopathic virus able to persist in a great percentage of infected hosts due to its ability to escape from the immune control.Liver damage and disease progression during HCV infection are driven by both viral and host factors.Specifically,adaptive immune response carries out an essential task in controllingnon-cytopathic viruses because of its ability to recognize infected cells and to destroy them by cytopathic mechanisms and to eliminate the virus by non-cytolytic machinery.HCV is able to impair this response by several means such as developing escape mutations in neutralizing antibodies and in T cell receptor viral epitope recognition sites and inducing HCV-specific cytotoxic T cell anergy and deletion.To impair HCV-specific T cell reactivity,HCV affects effector T cell regulation by modulating T helper and Treg response and by impairing the balance between positive and negative co-stimulatory molecules and between pro-and antiapoptotic proteins.In this review,the role of adaptive immune response in controlling HCV infection and the HCV mechanisms to evade this response are reviewed.

Harnessing and honing mesenchymal stem/stromal cells for the amelioration of graft-versus-host disease

Allogeneic hematopoietic stem cell transplantation is a deterministic curative procedure for various hematologic disorders and congenital immunodeficiency.Despite its increased use,the mortality rate for patients undergoing this procedure remains high,mainly due to the perceived risk of exacerbating graft-versushost disease(GVHD).However,even with immunosuppressive agents,some patients still develop GVHD.Advanced mesenchymal stem/stromal cell(MSC)strategies have been proposed to achieve better therapeutic outcomes,given their immunosuppressive potential.However,the efficacy and trial designs have varied among the studies,and some research findings appear contradictory due to the challenges in characterizing the in vivo effects of MSCs.This review aims to provide real insights into this clinical entity,emphasizing diagnostic,and therapeutic considerations and generating pathophysiology hypotheses to identify research avenues.The indications and timing for the clinical application of MSCs are still subject to debate.

Immunologic mechanism of fungal keratitis

Fungal keratitis(FK)is a refractory disease that poses a serious threat to vision,with common risk factors like eye trauma,contact lens wearing,topical corticosteroids and antibiotic abuse.Nowadays,topical and systemic anti-fungal drugs and ocular surgeries are still the main therapeutic modalities.However,the pathogenesis of FK,especially the immunologic mechanism within it,has not yet been deeply clarified.A better understanding of the pathogenesis of FK is imperative for more effective therapies and prognosis.Meanwhile,the immune protection strategies are also urgently required to manage FK.This review highlights recent advances in the immunologic mechanism in the pathogenesis of FK,in hope of providing valuable reference information for more effective anti-fungal treatment.

Role of interleukin-1-family cytokines on effector CD4 T cell differentiation

The ability of CD4 T cells to differentiate into various effector or regulatory T cell subsets explains the successful adaptation of immune responses to different types of infectious pathogens. Immune responses in the context of cancer are also shaped by CD4 T cells, which can directly affect cancer prognosis in patients. While the proinflammatory mediator interleukin(IL)-1β was initially shown to enhance Th2 cell responses, recent findings support a predominant role of two other members of the IL-1 family, IL-18 and IL-33, on the production of Th1 and Th2-derived cytokines. In addition, IL-1β was found to profoundly affect the biology of two recently identified CD4 T cell subsets, Th17 and Th9 cells. IL-1β is critical for Th17 cell differentiation and it enhances the production of IL-9 and IL-21 by Th9 cells, thus increasing their anticancer properties. We will here review the mechanisms accounting for the ability of IL-1 cytokines to affect the differentiation of CD4 effector T cells with a focus on Th17 and Th9 cells. The physiopathological relevance of IL-1-driven effects on CD4 T cells will also be discussed.

Old game, new players: Linking classical theories to new trends in transplant immunology

The evolutionary emergence of an efficient immune system has a fundamental role in our survival against pathogenic attacks. Nevertheless, this same protective mechanism may also establish a negative consequence in the setting of disorders such as autoimmunity and transplant rejection. In light of the latter, although research has long uncovered main concepts of allogeneic recognition, immune rejection is still the main obstacle to long-term graft survival. Therefore, in order to define effective therapies that prolong graft viability, it is essential that we understand the underlying mediators and mechanisms that participate in transplant rejection. This multifaceted process is characterized by diverse cellular and humoral participants with innate and adaptive functions that can determine the type of rejection or promote graft acceptance. Although a number of mediators of graft recognition have been described in traditional immunology, recent studies indicate that defining rigid roles for certain immune cells and factors may be more complicated than originally conceived. Current research has also targeted specific cells and drugs that regulate immune activation and induce tolerance. This review will give a broad view of the most recent understanding of the allogeneic inflammatory/tolerogenic response and current insights into cellular and drug therapies that modulate immune activation that may prove to be useful in the induction of tolerance in the clinical setting.

Innate and adaptive immune abnormalities underlying autoimmune diseases:the genetic connections

With the exception of an extremely small number of cases caused by single gene mutations,most autoimmune diseases result from the complex interplay between environmental and genetic factors.In a nutshell,etiology of the common autoimmune disorders is unknown in spite of progress elucidating certain effector cells and molecules responsible for pathologies associated with inflammatory and tissue damage.In recent years,population genetics approaches have greatly enriched our knowledge regarding genetic susceptibility of autoimmunity,providing us with a window of opportunities to comprehensively re-examine autoimmunity-associated genes and possible pathways.In this review,we aim to discuss etiology and pathogenesis of common autoimmune disorders from the perspective of human genetics.An overview of the genetic basis of autoimmunity is followed by3 chapters detailing susceptibility genes involved in innate immunity,adaptive immunity and inflammatory cell death processes respectively.With such attempts,we hope to expand the scope of thinking and bring attention to lesser appreciated molecules and pathways as important contributors of autoimmunity beyond the‘usual suspects’of a limited subset of validated therapeutic targets.