Mannose metabolism and immune regulation:Insights into its therapeutic potential in immunology-related diseases

Mannose,a different isomer of the hydroxyl group at the C-2 position of glucose,shares the same transport carrier protein with glucose to enter cells and participate in the regulation of glucose metabolism.It affects cell growth,differentiation,and function and plays an active role in tumor immunity and inflammatory processes.This paper provides theoretical support for expanding the clinical applications of mannose by exploring its constitution,metabolic pathways,and role in regulating immune cell function and treating immunology-related diseases.

Scientific connotation of “treating different diseases with the same method” from the perspective of metabolic-immune dysregulation in inflammation-mediated carcinogenesis of digestive organs

Inflammation-mediated carcinogenesis develops in the context of chronic inflammation and is a significant cause of cancer within the digestive system.In the chronic inflammation microenvironment,the metabolic activity of tissue cells undergoes extensive changes,which interfere with the normal function of immune cells.Dysregulation of cell metabolism and immune function has been identified as a key factor contributing to inflammation-mediated carcinogenesis within the major digestive organs,such as the stomach,liver,and colorectum.This metabolic-immune imbalance also corresponds to traditional Chinese medicine(TCM)theories of“yin-yang disharmony”and“disharmony between Ying-nutrients and Wei-defense.”The metabolic-immune imbalance has also been regarded as the key factor supporting“treatment of different diseases with the same method”,in which the same approach is adopted in the treatment of different conditions.In the TCM treatment process,it is necessary to first identify TCM patterns and then apply the corresponding TCM to correct the dysregulated metabolic and immune function,thereby blocking the progression from inflammation to malignancy.Our study findings deepen the TCM understanding of metabolic-immune dysregulation and the relationship between metabolic-immune dysregulation,pattern identification,and treatment method.They also provide new insights for the treatment of inflammation-mediated carcinogenesis in major digestive organs and help us further explore the scientific connotation of the TCM strategy of“treating different diseases with the same method”.

MUCOSAL IMMUNE SYSTEM AND FERTILITY REGULATION IN MAMMAL AND HUMAN

皮肤和粘膜是哺乳类动物和人体的内外环境之间的第一道屏障或第一道防线。粘膜是消化道,呼吸道和泌尿生殖道的重要组成部份。在粘膜系统大约集中了70％的淋巴组织。哺乳类动物的配子成熟,运输,精卵子的结合和融合,受精卵的运输,胚泡着床等等,都是在生殖道内进行的。因此,研究生殖道的粘膜免疫系统在不育的诊断和治疗,性传染疾病的控制,避孕疫苗的研究等方面,都有很重要的意义。 粘膜免疫系统有几个显著的特点:首先,在抗体成份方面,以IgA为主,IgA的分泌量约占全身各种抗体成份的60％以上。为了刺激粘膜的体液免疫反应,局部免疫的效果最佳。参与粘膜免疫调节的细胞有T辅助细胞,T杀伤和抑制细胞,反抑制细胞,抗抑制细胞。其次在细胞免疫方面,粘膜系统有许多TCR1 T细胞,它们在粘膜免疫方面可能具有重要的功能。粘膜系统的免疫细胞的特有分布是通过细胞表面的许多受体和配体的相互作用来实现的。雌性生殖道的粘膜免疫系统的反应常与激素水平有关,如雌二醇的升高常伴随IgA的升高,孕酮的存在常有抑制IgA产生的作用。此外,在妊娠子宫内发现有许多特殊的抑制细胞和其他许多抑制因子。 在某些不孕患者的精浆内可测定到抗精子的IgA和IgG。精浆内存在许多免疫细胞抑制因子和许多免疫细胞。

Antitumor and immune regulation activities of the extracts of some Chinese marine invertebrates

Extracts of 21 marine invertebrates belonging to Coelenterata, Mollusca, Annelida, Bryozoa, Echiura, Arthropoda, Echinodermata and Urochordata were screened for the studies on their antitumor and immune regulation activities. Antitumor activity was determined by MTT method and immune regulation activity was studied using T- and B-lymphocytes in mice spleen in vitro. It was found that the n-butanol part of Asterina pectinifera, the acetic ether part of Tubuaria marina,95% ethanol extract of Acanthochiton rubrolineatus have a high inhibition rate of 96.7%,63.9% and 50.5% respectively on tumor cell line HL-60 at the concentration of 0.063 mg/ml. The inhibition rate of the acetic ether part of Tubuaria marina on the tumor cell line A-549 is 65.4 % at concentration of 0.063 mg/mL. The 95% ethanol extract of Meretrix meretrix has so outstanding promoting effect on T-lymphocytes that their multiplication increases 25% when the sample concentration is only 1 μg/ml. On B-lymphocytes, the 95% extract of Rapana venosa, at concentration of 100 μg/ml, has a promotion percent- age of 60%. On the other hand, under the condition of no cytotoxic effect, the 95% ethanol extracts of Acantho- chiton rubrolineatus and Cellana toreum can reach 92% inhibition rate on T lymphocyte at concentration of 100 μg/ml, while the inhibition rate on B lymphocyte of the 95% extract of Acanthochiton rubrolineatus reaches 92% at the same concentration.

Initiation and Regulation of CNS Autoimmunity: Balancing Immune Surveillance and Inflammation in the CNS

While the central nervous system (CNS) was once thought to be immune privileged, more recent data support that certain areas of the healthy CNS are routinely patrolled by immune cells. Further, antigen drainage is another means by which the adaptive arm of the immune system can gain information about the health of the CNS. Altogether these ensure that the CNS is not beyond the scope of immune protection against viruses and tumors. However, immune surveillance in the CNS has to be tightly regulated, as CNS autoimmune disease and inflammation may arise from increased immune cell infiltration. In this review we discuss the concept and implications of CNS immune surveillance and introduce the CNS antigen-presenting cells (APCs) that potentially regulate neuroinflammation and autoimmunity. We also discuss novel animal models in which CNS disease initiation and the role of APCs in disease regulation can be tested.

Research Progress of Anti-tumor Effects of Curcuma zedoaria and its Active Ingredients Through Immune Regulation Mechanism

The continuous increase in the incidence rate of various fatal malignant tumors in the recent years warrants an imperative search for medications or drugs with obvious anti-tumor eflects and reliable curative effects.Previous studies have found that Curcuma zedoaria and its active ingredients,such as turmeric oil,curcumol,and P-elemene,have obvious antitumor effects,and they do not have the adverse reactions and side effects seen in the anti-tumor drugs of Western medicine.Based on the review and inductive analysis of related literature,we summarize in the present article the results of some researchers who investigated the anti-tumor effects of Curcuma zedoaria and its active ingredients through the immune regulation mechanism.

Immunoregulatory Effects of Ethyl-acetate Fraction of Extracts from Tetrastigma Hemsleyanum Diels et. Gilg on Immune Functions of ICR Mice

Objective To evaluate the effects of ethyl-acetate fraction （EAF） of extracts from Tetrastigma hemsleyanum Diels et. Gilg （TDG） on immune functions of ICR mice. Methods ICR mice were exposed to different doses of EAF for 15 or 30 days and then their immune functions were analyzed, including ConA-induced splenic lymphocyte transformation, SRBC- induced delayed type hypersensitivity response, serum hemolysin analysis, antibody-producing cells, peritoneal macrophage phagocytized chicken red blood cells, natural killer cell activity, and serum level of cytoldnes. Results EAF of extracts from TDG at different doses had various effects on immune functions of ICR mice. As compared with the controls, it increased the mouse spleen lymphocyte transformation induced by ConA, the left-hind voix pedis thickness and the number of plague forming cells （PFCs） at the dose of 1.82 mg/mL, 5.48 mg/mL, and 9.12 mg/mL, respectively; increased the ink clearance ability at the dose of 0.91 mg/mL, 1.82 mg/mL, 5.48 mg/mL, and 9.12 mg/mL, respectively; increased the phagocytosis index of mononuclear-macrophages and production of serum interferon-gamma （IFN-？） at the dose of 5.48 mg/mL; and could promote the production of serum tumor necrosis factor-alpha （TNF-α） at the dose of 9.12 mg/mL. Conclusion EAF of extracts from TDG can regulate mouse immune functions in vivo.

B Cells with Regulatory Function in Animal Models of Autoimmune and Non-Autoimmune Diseases

Although the identification of B cell subsets with negative regulatory functions and the definition of their mechanisms of action are recent events, the important negative regulatory roles of B cells in immune responses are now broadly recognized. There is an emerging appreciation for the pivotal role played by B cells in several areas of human diseases including autoimmune diseases and non-autoimmune diseases such as parasite infections and cancer. The recent research advancement of regulatory B cells in human disease coincides with the vastly accelerated pace of research on the bridging of innate and adaptive immune system. Current study and our continued research may provide better understanding of the mechanisms that promote regulatory B10 cell function to counteract exaggerated immune activation in autoimmune as well as non-autoimmune conditions. This review is focused on the current knowledge of BREG functions studied in animal models of autoimmune and non-autoimmune diseases.

Annual advances of traditional medicine on tumor immunity regulation in 2020

Tumor burden remains a global health problem that threatens human life worldwide.Over the past few years,the evolution of immune checkpoint inhibitors has represented one of the most successful approaches in the field of tumor therapy.Drugs regulating tumor immune microenvironment or enhancing body immunity have indicated a novel perspective to treat tumors.Therefore,an increased number of scientists have been shifting their research focus to explore the immunity regulation effects of anti-tumor traditional medicine or natural products.In this review,we summarize the research progress of traditional medicines on tumor immunity regulation in 2020.Our findings suggest that more herbal medicine-derived phytochemicals and formulas were derived from traditional Chinese medicine,and more papers were published in comprehensive journals.Traditional medicine can comprehensively regulate the tumor immune microenvironment,including natural killer cells,dendritic cells,CD4+/CD8+T lymphocytes,regulatory T cells,myeloid-derived suppressor cells,tumor-associated macrophages,immunosuppressive factors,and immune checkpoints.In 2020,a greater number of research papers focused on active ingredients and formulas that regulate tumor-associated macrophages and immune checkpoints.Active ingredients such as flavonoids became a global hotspot in 2020.Certain natural products were also found to exert synergistic anti-tumor activity with immune checkpoint inhibitors,such as curcumin.However,a distinct lack of high-quality experimental and clinical studies remains a prevalent and challenging issue that hinders the further development of traditional medicine.

Two new lncRNAs regulate the key immune factor NOD1 and TRAF5 in chicken lymphocyte

Reticuloendotheliosis virus(REV)causes the atrophy of immune organs and immuno-suppression in chickens,but the underlying molecular mechanism of the immune response after infection by REV is not well understood.Presently,the RNA-seq was used to analyze the regulation of immune response to REV in chicken lymphocytes from peripheral blood.Overall,134 differentially expressed long non-coding RNAs(lncRNAs)between cells with REV infection or without in vitro were screened.Based on the differentially expressed protein-coding genes,the nucleotide-binding oligomerization domain(NOD)-like receptor pathway related to immune regulation was enriched.Two lncRNAs(L11530 and L09863)were predicted to target the NOD1 and tumor necrosis factor receptor-associated factor 5(TRAF5)gene,respectively,which are involved in the NOD-like receptor pathway with cis-regulation way.The in vitro results revealed the significantly up-regulated(P<0.01)levels of lncRNA-L11530 and its target gene,NOD1,and the significantly down-regulated(P<0.05)levels of lncRNA-L09863 and its target gene,TRAF5,in lymphocytes after REV infection.These changes also occurred in vivo in blood lymphocytes of chickens infected with REV.Further,L09863 and L11530 were respectively interfered,the expression levels of their target genes NOD1 or TRAF5 were significantly down-regulated,accompanied by the change of IL-8 and IL-18 secretions in lymphocytes.The NOD-like receptor pathway appears to be important in the immune response to REV,LncRNA-11530 and lncRNA-09863 might involve in the immune regulation on REV infection by targeting NOD1 or TRAF5 in blood lymphocytes of chickens.Our findings reveal a new regulation of lncRNAs(L11530 and L09863)on immunity in chicken peripheral blood lymphocytes for REV infection by changing the expression of the target genes via the NOD-like receptor pathway.

Research Progress on the Immunomodulatory Effect of Mesenchymal Stem Cells on Chronic Periodontitis

Periodontal disease is an inflammatory and destructive disease of periodontal support tissue caused by microorganisms in dental plaque. During the development of periodontal disease, host immune regulation plays an important role, and unnecessary excessive immune regulation often exacerbates the course of chronic periodontal disease. Mesenchymal stem cells (MSCs) are adult stem cells with self replication ability and multi-directional differentiation potential. Many studies have found that MSCs have strong immunosuppressive effects on both adaptive and innate immunity. In recent years, literature has reported that MSCs are involved in the immune regulatory effect of chronic periodontal disease, inhibiting its inflammatory response and alveolar bone resorption, but the specific regulatory mechanism has not been elucidated. This article reviews the current research status of the immune regulatory effects of MSCs on chronic periodontitis.

Effect of FasL High Expression on Immune Regulative Function of Sertoli Cell in Transgenic Mouse

Objective To study the immune regulative function of Sertoli cell on testis local infection Methods Ureaplasma urealyticum （UU） was directly injected into bladders of FasL transgenic mice and wild-type mice, which mimicked an ascending infectious way. At week 1, 2 and 3 after injection respectively, the mice were killed to observe the pathological alterations in testis section. And at the same time cytokines was tested by immunohistochemistry. Comparison of levels of FasL, TGF-β, IL-1α and IL-6 between UU-infected and control groups of wild mice and FasL transgenic mice was made respectively. Then the capability of Sertoli cell （FasL^＋） to mediate apoptosis of Fas^＋ cells between wild control and wild UU-infected groups was analyzed. Results The pathological changes of testis in FasL transgenic mice were more seriously compared with wild counterpart and the changing mode of cytokines secreted by Sertoli cells were different between the two kinds of mice. The UU-infected Sertoli cells increased Fas^＋ Jurkat cell apoptosis. Conclusions High expression of FasL in FasL transgenic mice can influence the cytokines secretion during anti-infection, thus affecting the testis immune response to infection and immune balance. The high expression of FasL is not beneficial for body＇s anti-inflection immune response.

Regulatory roles of extracellular vesicles in immune responses against Mycobacterium tuberculosis infection

Extracellular vesicles(EVs)are cystic vesicles naturally released by most mammalian cells and bacteria.EV contents include proteins,lipids,and nucleic acids.EVs can act as messengers to transmit a variety of molecules to recipient cells and thus play important regulatory roles in intercellular signal transduction.EVs,released by either a host cell or a pathogen,can carry pathogen-associated antigens and thus act as modulators of immune responses.EVs derived from Mycobacterium tuberculosis(Mtb)-infected cells can regulate the innate immune response through various pathways,such as regulating the release of inflammatory cytokines.In addition,EVs can mediate antigen presentation and regulate the adaptive immune response by transmitting immunoregulatory molecules to T helper cells.In this review,we summarize the regulatory roles of EVs in the immune response against Mtb.

Effects of Oleanolic Acid on the Immune Complex Allergic Reaction and Inflammation

When oleanolic acid (OA) was administered ig before and after sensitization on d 1 to d 5 and d 11 to d 17,it had no apparent effect on Arthus reaction.When it was administered at 48,24 and 1 h before challenge,however,Arthus reaction was significantly inhibited.OA showed markedly suppressive effects on reversible passive Arthus reaction and leukocyte migratory response.It could significantly stabilize erythrocyte membrane,inhibit the swelling of the rat's hind paw induced by in- jecting mycostatin,reduce the acid phosphatase content in the inflammatory exudate,suppress the syn- thesis or release of PGE,histamine,LTB4 and kinin,and the phlogistic action of PGE_2,histamine,5- HT and kinin.In addition,it could decrease the content of malonyldialdehyde (MDA) in hepatic tissue of alcohol-intoxicated mice,and increase the activity of catalase (CAT) in hepatic tissue of mice.OA had no apparent effect on the activity of super-oxide dismutase (SOD) in rat serum,on the content of immune complex in serum of rat with Arthus reaction,on the phagocytosis of monocytc-macrophage system,on the clearance of enzyme-containing immune complex by macrophage,or on the activity of total complement.

Gas-propelled nanomotors alleviate colitis through the regulation of intestinal immunoenvironment-hematopexis-microbiota circuits

The progression of ulcerative colitis(UC)is associated with immunologic derangement,intestinal hemorrhage,and microbiota imbalance.While traditional medications mainly focus on mitigating inflammation,it remains challenging to address multiple symptoms.Here,a versatile gas-propelled nanomotor was constructed by mild fusion of post-ultrasonic CaO_(2) nanospheres with Cu_(2)O nanoblocks.The resulting CaO_(2)–Cu_(2)O possessed a desirable diameter(291.3 nm)and a uniform size distribution.It could be efficiently internalized by colonic epithelial cells and macrophages,scavenge intracellular reactive oxygen/nitrogen species,and alleviate immune reactions by pro-polarizing macrophages to the anti-inflammatory M2 phenotype.This nanomotor was found to penetrate through the mucus barrier and accumulate in the colitis mucosa due to the driving force of the generated oxygen bubbles.Rectal administration of CaO_(2)–Cu_(2)O could stanch the bleeding,repair the disrupted colonic epithelial layer,and reduce the inflammatory responses through its interaction with the genes relevant to blood coagulation,anti-oxidation,wound healing,and anti-inflammation.Impressively,it restored intestinal microbiota balance by elevating the proportions of beneficial bacteria(e.g.,Odoribacter and Bifidobacterium)and decreasing the abundances of harmful bacteria(e.g.,Prevotellaceae and Helicobacter).Our gas-driven CaO_(2)–Cu_(2)O offers a promising therapeutic platform for robust treatment of UC via the rectal route.

Profiling of hepatocellular carcinoma neoantigens reveals immune microenvironment and clonal evolution related patterns

Objective: Neoantigens derived from tumor-specific genomic alterations have demonstrated great potential for immunotherapeutic interventions in cancers. However, the comprehensive profile of hepatocellular carcinoma(HCC) neoantigens and their complex interplay with immune microenvironment and tumor evolution have not been fully addressed.Methods: Here we integrated whole exome sequencing data, transcriptome sequencing data and clinical information of 72 primary HCC patients to characterize the HCC neoantigen profile, and systematically explored its interactions with tumor clonal evolution, driver mutations and immune microenvironments.Results: We observed that higher somatic mutation/neoantigen load was associated with better clinical outcomes and HCC patients could be further divided into two subgroups with distinct prognosis based on their neoantigen expression patterns. HCC subgroup with neoantigen expression probability high(NEP-H) showed more aggressive pathologic features including increased incidence of tumor thrombus(P=0.038), higher recurrence rate(P=0.029),more inclined to lack tumor capsule(P=0.026) and with more microsatellite instability sites(P=0.006). In addition,NEP-H subgroup was also characterized by higher chance to be involved in tumor clonal evolution [odds ratio(OR)=46.7, P<0.001]. Gene set enrichment analysis revealed that upregulation of MYC and its targets could suppress immune responses, leading to elevated neoantigen expression proportion in tumor cells. Furthermore, we discovered an immune escape mechanism that tumors could become more inconspicuous by evolving subclones with less immunogenicity. We observed that smaller clonal mutation clusters with higher immunogenicity in tumor were more likely to involve in clonal evolution. Based on identified neoantigen profiles, we also discovered series of neoantigenic hotspot genes, which could serve as potential actionable targets in future.Conclusions: Our results revealed the landscape of HCC neoantigens and discovered two clinically relevant subgroups with distinct neoantigen expression patterns, suggesting the neoantigen expression should be fully considered in future immunotherapeutic interventions.

Chinese medicine in the treatment of autoimmune hepatitis:Progress and future opportunities

Autoimmune hepatitis(AIH)is a chronic inflammatory liver disease occurring in indi-viduals of all ages with a higher incidence in females and characterized by hypergam-maglobulinemia,elevated serum autoantibodies and histological features of interface hepatitis.AIH pathogenesis remains obscure and still needs in-depth study,which is likely associated with genetic susceptibility and the loss of immune homeostasis.Steroids alone and in combination with other immunosuppressant agents are the pri-mary choices of AIH treatment in the clinic,whereas,in some cases,severe adverse effects and disease relapse may occur.Chinese medicine used for the treatment of AIH has proven its merits over many years and is well tolerated.To better under-stand the pathogenesis of AIH and to evaluate the efficacy of novel therapies,several animal models have been generated to recapitulate the immune microenvironment of patients with AIH.In the current review,we summarize recent advances in the study of animal models for AIH and their application in pharmacological research of Chinese medicine-based therapies and also discuss current limitations.This review aims to provide novel insights into the discovery of Chinese medicine-originated therapies for AIH using cutting-edge animal models.

Role of myeloid-derived suppressor cells in autoimmune disease

Myeloid-derived suppressor cells(MDSCs) represent an important class of immunoregulatory cells that can be activated to suppress T cell functions. These MDSCs can inhibit T cell functions through cell surface interactions and the release of soluble mediators. MDSCs accumulate in the inflamed tissues and lymphoid organs of patients with autoimmune diseases. Much of our knowledge of MDSC function has come from studies involving cancer models, however many recent studies have helped to characterize MDSC involvement in autoimmune diseases. MDSCs are a heterogeneous group of immature myeloid cells with a number of different functions for the suppression of T cell responses. However, we have yet to fully understand their contributions to the development and regulation of autoimmune diseases. A number of studies have described beneficial functions of MDSCs during autoimmune diseases, and thus there appears to be a potential role for MDSCs in the treatment of these diseases. Nevertheless, many questions remain as to the activation, differentiation, and inhibitory functions of MDSCs. This review aims to summarize our current knowledge of MDSC subsets and suppressive functions in tissue-specific autoimmune disorders. We also describe the potential of MDSC-basedcell therapy for the treatment of autoimmune diseases and note some of hurdles facing the implementation of this therapy.

Treatment Effect of Fermentation of Ganoderma lucidum to Immune and Antioxidant Functions in Immunosuppressed Mice

The immune regulatory and antioxidant roles of Ganoderma lucidum were investigated using cyclophosphamide(CTX)-induced immunosuppressed mice. Mice were randomly divided into groups: untreated(groupⅠ), immunosuppressed(groupⅡ), unfermented G. lucidum polysaccharide(groupⅢ) and fermented G. lucidum polysaccharide(group Ⅳ). After seven consecutive days of treatments, the serum concentration of IL-4, IFN-gamma, IgG, IgA and IgM and the liver activity of GSH-Px, SOD, CAT and MDA enzymes were analyzed. The contents of IL-4, IFN-γ in serum and GSH-Px, SOD and CAT in liver tissues were significantly reduced in groupⅡ compared with those in group I, indicating successful CTX-induced immunosuppression. Interestingly, the results showed that the above immune and antioxidant indicators were significantly improved after G. lucidum polysaccharide treatment, regardless of fermentation. However, fermentation caused changes in polysaccharide structure, which might have a significant impact on immune regulation and antioxidant functions in immunosuppressed mice.