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Molecular Immunology
Pergamon Press
Molecular Immunology

Pergamon Press

0161-5890

Molecular Immunology/Journal Molecular ImmunologySCIISTP
正式出版
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    CD40 signaling-mediated delay in terminal differentiation of B cells enables alternate fate choices during early divisions

    Vijayashankar, Devi PrasadVaidya, Tushar
    15页
    查看更多>>摘要：Memory B cells and differentiated plasma cells combine to confer sustained humoral immunity. Nonetheless, we are yet to understand how B cells decide between these fates. Although pan-T cell help augments plasma cell differentiation, signaling via CD40 alone is considered to be inhibitory. Here, we examine the capacity of CD40 signaling to interfere with lipopolysaccharide-induced differentiation. Whereas lipopolysaccharide stimulation yielded only short-lived plasmablasts, co-stimulation of CD40 enhanced activation, proliferation, survival, and isotype-switching, leading to alternate fate choices such as germinal center and memory B cells during early divisions. Contrary to the notion that CD40 signaling simply arrests differentiation, the survivors, at later time points, developed into long-lived mature plasma cells, after progressively losing their ability to get restimulated. Counterintuitively, as constitutive lipopolysaccharide stimulation itself hampered differentiation, we identified that the proliferation potential of cells acted alongside CD40 signaling. Accordingly, we propose a bi-layered regulation of differentiation - CD40 signaling and proliferation potential of cells independently inhibit the commitment to and maturation of differentiation, respectively. Elucidating such cell fate decision mechanisms will aid in better vaccine design and disease management.
      原文链接:
    • NSTL
    • Elsevier

    Macrophage M1 regulatory diabetic nephropathy is mediated by m6A methylation modification of lncRNA expression

    Li, ChangYanSu, FengLiang, ZhangZhang, Le...
    10页
    查看更多>>摘要：Immune and inflammatory responses have been identified to play an important role in diabetic nephropathy (DN) (H. Zhou et al. (2021)). It was found that the part of long non-coding RNA (LncRNA) in nephrosis is related to the negative regulation of MicroRNA (miRNA) (C. Gao et al., 2020), which mechanism is unclear; N6-methyladenosine (m6A) is one of the most common mRNA modifications in eukaryotes (Gu et al. (2020)). m6A has been proved in many works of literature can act on the triple helix structure of RNA-DNA and regulate the relationship between lncRNA and specific DNA sites (Fico et al. (2020); Lobos ' and Regulska-Ilow (2021); Xu et al. (2021)). Other studies have shown that m6A methylation modification plays a vital role in developing metabolic diseases such as obesity and type 2 diabetes by regulating glucose and lipid metabolism and immune inflammation. In this study, we performed a subgroup analysis of m6A-modified LncRNA expression in the DN transcriptome dataset (LncRNA high-low expression group); the results showed that the presence of Macrophage M1-related lncRNA (LINC00342, LINC00667, and LNC00963) in the process of m6A methylation recognition and metastasis was indirectly related to the downstream demethylase FTO, at the same time, we analyzed the interaction between m6A and RBM15, which is involved in the immune regulation of macrophage M1, and found that there might be a potential interaction between RBM15 and WTAP, which may play a role in regulating the methylation of lncRNA in macrophage M1, the DN was mediated by macrophage M1 immunoreaction of macrophages.
      原文链接:
    • NSTL
    • Elsevier

    An adeno-associated virus-mediated immunotherapy for Alzheimer's disease

    Zhang, YuQian, LinKuang, YuzhuLiu, Junting...
    9页
    查看更多>>摘要：Disease-modifying passive immunotherapies focusing on removal of abnormal phosphorylated Tau (p-Tau) constitute promising treatments for Alzheimer's disease (AD). Although several prior immunotherapies targeting p-Tau appear to be beneficial against AD, they have limitations such as the low blood-brain barrier (BBB) penetration rate, short half-life of antibodies, and the likelihood of inflammation. To address these issues, we designed a novel immunotherapy for AD. To this end, a single chain antibody (scFv) targeting p-Tau was generated, and a recombinant adeno-associated virus that can cross the BBB (rAAV/BBB) was used as a vector to express scFv for at least 22 weeks in the mouse brain. Results showed that the scFv constructed in this study had a high affinity to p-Tau and could bind to neuronal tangles in the section of brains of AD model mice. Moreover, the rAAV/BBB could cross the BBB, infect neuronal cells, and express scFv. This novel immunotherapy could effectively deliver scFv into the brain and resulted in a continuous expression of scFv in vivo, suggesting its potential for the treatment of AD.
      原文链接:
    • NSTL
    • Elsevier

    Analysis of rainbow trout TCR alpha beta/CD3 complex: An in-silico modeling approach

    Maisey, K.Flores-Kossack, C.Munoz, C.Fuentes, N....
    9页
    查看更多>>摘要：In mammals, the T lymphocyte receptor (TCR) is a multiprotein complex formed by the proteins TCR alpha, TCR beta, CD3 epsilon, CD3 gamma, CD3 delta, and CD3 zeta. It is responsible for recognizing antigens processed and presented by antigen presenting cells (APC). The TCR is located at the cytoplasmic membrane of the T lymphocyte but is functional assembled in the rough endoplasmic reticulum (RER).Most of the available information on TCR constituents in salmonids comes from numerous nucleotide sequences available in different databases. In this work, by in silico homology modeling, we generated the TCR alpha beta/ CD3 complex of rainbow trout (Oncorhynchus mykiss) and characterized the structure of the different proteins and their potential interactions.The results show that the main structural features described in mammalian TCR/CD3 are present in the model predicted for trout. Furthermore, we highlighted several aminoacidic interactions between TCR alpha, TCR beta, CD3 gamma delta, and CD3 epsilon.In silico structural analyses suggest that trout TCR alpha beta complex would fit similarly to that described for mammals. Herein, we explore the implications of the modeled trout complex and the leukocyte phenotypes, mainly associated with different regulation mechanisms of trout TCR alpha beta/CD3 subunits gene expression or may be due to differences in the assembly process of the complex in the RER. However, further studies will be needed to study deeper the mechanisms involved.
      原文链接:
    • NSTL
    • Elsevier

    The role of endoplasmic reticulum stress in the MHC class I antigen presentation pathway of dendritic cells

    Manoury, BenedicteMaisonneuve, LuciePodsypanina, Katrina
    5页
    查看更多>>摘要：Dendritic cells (DCs) have the unique capacity to link innate to adaptive immunity. While most cells that express major histocompatibility (MHC) molecules are able to present antigens to activated T cells, DCs possess the means for presenting antigens to naive T cells, and, as such, are able to instruct T cells to initiate immune response. There are two cascades of events necessary for DCs to start their instructive function. First, DCs enzymatically process proteins to make T cells recognize an antigen as unique peptide-MHC complexes. Second, DCs provide secretory cytokines and co-stimulatory functions for T cells to respond to this antigen. Thus, the compartments for protein degradation and for protein synthesis are central to DC function. The endoplasmic reticulum (ER), a vast network of membranes and vesicles, connects these compartments and helps modulate DC-specific performance, such as antigen capture and presentation. However, while the health of ER appears relevant for DC function, the intersection between ER stress and antigen presentation remains to be explored.
      原文链接:
    • NSTL
    • Elsevier

    Absolute reduction in peripheral regulatory T cells in patients with Graves' disease and post-treatment recovery

    Liu, Hai-YanShi, Zhi-YongFan, DiZhang, Sheng-Xiao...
    9页
    查看更多>>摘要：Objective: Graves' disease (GD) is one of the most common autoimmune conditions, but the mechanisms un-derlying the associated induction of autoimmunity are not known. We explored the role of peripheral lympho-cyte subpopulations in disease pathogenesis. Methods: In total, 32 patients and 40 age-and sex-matched healthy controls were recruited in this study. Pe-ripheral levels of T, B, NK, CD4(+) T, CD8(+) T, Th1, Th2, Th17, and Treg cells were measured using flow cytometry. For all patients, we compared all lymphocyte subpopulations between GD patients and healthy controls. Changes in patient lymphocyte subsets were compared before and after treatment. Results: The absolute numbers of circulating Th17 cells (0.45 +/- 1.16, p > 0.05) between GD patients and healthy controls were not significantly different. However, the percentage of Th17 cells was significantly increased (0.25 +/- 0.11, p < 0.05). The absolute numbers and percentages of circulating Tregs in GD patients were significantly decreased compared with those in healthy participants (11.61 +/- 2.75, p < 0.05). There was a significant difference in Treg absolute numbers between the untreated and drug-treated groups. Furthermore, we found that the Treg percentage in untreated patients (mean=4.78) was not significantly different from that in the drug-treated group (mean=4.81). In addition, circulating Treg absolute numbers in GD patients with exophthalmos were significantly lower than those in GD patients without exophthalmos (9.96 +/- 4.16, p < 0.05). A similar trend was observed in GD patients with weight loss (11.97 +/- 3.28, p < 0.05). Conclusion: GD pathogenesis was associated with a lower Treg population and an increased Th17/Treg ratio (T helper cell 17/ regulatory T cells). Th17 cells in this study were not related to the disease. Furthermore, anti-thyroid drug therapy improved immune-mediated system disorders. Finally, we found lower absolute numbers of circulating Tregs in GD patients with certain positive signs, such as exophthalmos and/or weight loss. Thus, immune changes are correlated with partial clinical manifestations.
      原文链接:
    • NSTL
    • Elsevier

    Natural killer cell dysfunction in cancer and new strategies to utilize NK cell potential for cancer immunotherapy

    Li, FanZhang, WanzeZhao, Zhenghua
    13页
    查看更多>>摘要：The continuous, in-depth exploration of the occurrence and development of cancer has shown that immune cell dysfunction is closely associated with tumor progression and poor clinical prognosis. The inhibition of the effector functions of immune cells by numerous immunosuppressive factors in the tumor microenvironment (TME) promotes the progression and metastasis of malignant tumors. Natural killer (NK) cells are the main effector cells in the anti-tumor innate immune system. Dysfunctional NK cells, characterized as weakened proliferation capacity and reduced production of effector cytokines, have limited ability to kill malignant cells and inhibit tumor progression. The reversal of the dysfunctional state of NK cells and enhancement of their effector functions is a promising strategy that could improve the effectiveness of cancer immunotherapy. In order to fully use of the cytotoxic effects of NK cells and revitalize the anti-tumor potential of NK cells in tumor patients, it is necessary to learn more about the characteristics of NK cell dysfunction in TME. This will provide valuable information for the development of personalized strategies to restore anti-tumor immunity. Here, we reviewed the characteristics of dysfunctional NK cells in the TME and latest progress in research, and discussed promising immunotherapy strategies that could utilize NK cell potential for cancer immunotherapy.
      原文链接:
    • NSTL
    • Elsevier

    Kupffer cells depletion alters cytokine expression and delays liver regeneration after Radio-frequency-assisted Liver Partition with Portal Vein Ligation

    Zhang, WeikangZhu, XiwenTang, YongLi, Jinzheng...
    7页
    查看更多>>摘要：Radio-frequency-assisted Liver Partition with Portal Vein Ligation (RALPP) induces comparable hypertrophy of the liver remnant compared to Associating Liver Partition and Portal vein ligation for Staged hepatectomy (ALPPS) in humans. However, whether it is significantly improved compared to ALPPS is unclear, and the underlying mechanisms of liver regeneration after RALPP need to further investigate. The present study was to develop an animal model mimicking RALPP and explore mechanisms of liver regeneration. The mice in RALPP group received liver radiofrequency ablation and 90% portal vein ligation (PVL), followed by resection of the targeted liver within two days after the first surgery. The mice in ALPPS group underwent 90% PVL combined with parenchyma transection. Controls received liver radiofrequency ablation (RAF group) or PVL (PVL group) or small left lateral lobe (LLL group) resection alone. Liver regeneration was assessed by liver weight and proliferation-associated molecules. The role of Kupffer cells (KCs) in liver regeneration was investigated after RALPP. The results showed that RALPP induced comparable liver regeneration compared to ALPPS, but with less liver injury and mortality in mice. RALPP led to over-expression of TNF-alpha and IL-6 in the circulating plasma compared with PVL. KCs infiltrating in liver tissues was a characteristic of mice in the RALPP group. KCs depletion markedly depressed cytokine expression and delayed liver regeneration after RALPP. These results suggested that RALPP in mice induced accelerated liver regeneration similar to ALPPS, but safer than ALPPS. KCs depletion altered cytokine expression and delayed liver regeneration after RALPP.
      原文链接:
    • NSTL
    • Elsevier

    Comprehensive analysis of TAMs marker genes in glioma for predicting prognosis and immunotherapy response

    Zhao, ZijunWang, ZairanWu, YueLiao, Dongmei...
    18页
    查看更多>>摘要：Glioma is one of the most frequent types of primary tumors in central nervous system. Previous studies deomostrated that tumor-associated macrophages (TAMs) and their marker genes were significantly associated with immunologic suppression and immune escape of cancer. However, the molecular mechanism between glioma and TAM marker genes is still rarely reported. In this research, we performed a comprehensive analysis of the prognostic prediction value of TAM marker genes in multiple glioma cohorts. Further investigation indicated that the increased expression of TAM marker genes resulted in the immune suppressive microenvironment in glioma through regulating tumor-infiltrating immune cells and Cancer-Immunity Cycle. To better forecast the survival of glioma patients, we then developed gene risk models in four glioma datasets (CGGA, TCGA, Rembrandt and Gravendeel). Univariate and multivariate Cox analysis exhibited the good survival prediction ability and prognostic discrimination ability of our models. The results of immunotherapy prediction indicated that glioma patients with low risk were more likely to benefit from ICB (immune checkpoint blockade) treatment. Altogether, our research provided a comprehensive analysis of TAM marker genes and explored their value for predicting prognosis and immunotherapy response in glioma.
      原文链接:
    • NSTL
    • Elsevier

    In silico and in vivo approaches to recombinant multi-epitope immunogen of GroEL provides efficient cross protection against S. Typhimurium, S. flexneri, and S. dysenteriae

    Ardestani, HassanNazarian, ShahramHajizadeh, AbbasSadeghi, Davoud...
    10页
    查看更多>>摘要：Objectives: Stress or Heat Shock Proteins (HSPs) have been included in various operations like protein folding, autophagy, and apoptosis. HSP families recognize as protective antigens in a wide range of bacteria because they have been conserved through evolution. Due to their homology as well as antigenicity they are competent for applying in cross-protection against bacterial diseases. Methods: In the present study, bioinformatics approaches utilized to design epitope-based construction of Hsp60 (or GroEL) protein. In this regard, potential B-cell and T-cell epitopes except for allergenic sequences were selected by immunoinformatic tools. The structural and functional aspects of the DNA, RNA, and protein levels were assessed by bioinformatics software. Following in silico investigations, recombinant GroEL multi-epitope of Salmonella typhi was expressed, purified, and validated. Mouse groups were immunized with recombinant protein and humoral immune response was measured by enzyme linked immunosorbent assay (ELISA). Animal challenge against Salmonella Typhimurium, Shigella flexneri, and Shigella dysenteriae was evaluated. Results: recombinant protein expression and purification with 14.3 kilodaltons (kDa) was confirmed by SDS-PAGE and western blotting. After animal administration, the immunoglobulins evaluated increase after each immunization. Immunized antisera exhibited 80%, 40%, and 40% protection against the lethal dose infection by S. Typhimurium, S. flexneri, and S. dysenteriae respectively. Passive immunization conferred 50%, 30%, and 30% protection in mice against S. Typhimurium, S. flexneri and S. dysentery respectively. In addition, bacterial organ load had exhibited a significant decrease in colony forming unit (CFU) in the liver and spleen of the immunized mice compared to the control. Conclusion: Our study demonstrates the efficacy of S. Typhi recombinant GroEL multi-epitope to consider as a universal immunogen candidate versus multiple bacterial pathogens.
      原文链接:
    • NSTL
    • Elsevier