The current work aimed to provide a comprehensive single-cell landscape of lupus nephritis (LN) kidneys, including immune and non-immune cells, identify disease-associated cell populations and ...unravel their participation within the kidney microenvironment.
Single-cell RNA and T cell receptor sequencing were performed on renal biopsy tissues from 40 patients with LN and 6 healthy donors as controls. Matched peripheral blood samples from seven LN patients were also sequenced. Multiplex immunohistochemical analysis was performed on an independent cohort of 60 patients and validated using flow cytometric characterisation of human kidney tissues and in vitro assays.
We uncovered a notable enrichment of CD163
dendritic cells (DC3s) in LN kidneys, which exhibited a positive correlation with the severity of LN. In contrast to their counterparts in blood, DC3s in LN kidney displayed activated and highly proinflammatory phenotype. DC3s showed strong interactions with CD4
T cells, contributing to intrarenal T cell clonal expansion, activation of CD4
effector T cell and polarisation towards Th1/Th17. Injured proximal tubular epithelial cells (iPTECs) may orchestrate DC3 activation, adhesion and recruitment within the LN kidneys. In cultures, blood DC3s treated with iPTECs acquired distinct capabilities to polarise Th1/Th17 cells. Remarkably, the enumeration of kidney DC3s might be a potential biomarker for induction treatment response in LN patients.
The intricate interplay involving DC3s, T cells and tubular epithelial cells within kidneys may substantially contribute to LN pathogenesis. The enumeration of renal DC3 holds potential as a valuable stratification feature for guiding LN patient treatment decisions in clinical practice.
To improve the energy dissipation capacity of rubber isolation bearings, it is important to find a new rubber material with good applicability and high damping properties. Two types of blends were ...prepared using nitrile rubber (NBR), brominated butyl rubber (BIIR) and ethylene-vinyl acetate copolymer (EVA): NBR/BIIR and NBR/BIIR/EVA. The vulcanization, mechanical and damping properties of the blends were analyzed. The results show that both blends exhibit excellent vulcanization plateaus and mechanical properties. For NBR/BIIR, as the BIIR content increases, the complementary effects of NBR and BIIR afforded by blending are enhanced. Two damping peaks appeared in the tanδ-T curve and shifted toward lower and higher temperatures, respectively, which clearly widened the effective damping temperature range. However, the damping value in the valley of the tanδ-T curve was as low as 0.39. For NBR/BIIR/EVA, the addition of EVA greatly increased damping in the valley of the tanδ-T curve to approximately 0.54. EVA was observed to be the optimal polymer for improving the compatibility of the NBR/BIIR blend. Moreover, hot air thermal aging tests showed that both blends demonstrated good stability.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Circular RNAs (circRNAs) is a newly discovered non-coding RNA that can be used as biomarkers in clinical blood samples. This study aims to screen differentially expressed circular RNAs in PBMCs of ...patients with rheumatoid arthritis (RA) to determine new biomarkers for the diagnosis of RA.
The differentially expressed circRNAs in peripheral blood mononuclear cells (PBMCs) of 4 RA patients and 4 healthy participants were screened and analyzed by gene microarray technology. We then validated some of the differentially expressed circRNAs in PBMCs of 20 RA patients, 10 systemic lupus erythematosus (SLE) patients and 20 healthy participants using reverse transcription-quantitative polymerase chain reaction amplification (RT-qPCR). Spearman correlation test was performed to analyze the correlation between differentially expressed circRNAs and clinical variables in RA patients. Receiver operating characteristic (ROC) curves were calculated to evaluate the diagnostic value of circRNAs.
Differential analysis obtained 149 circRNAs with significant up-regulated expression and 250 circRNAs with significant down-regulated expression, which predicted the miRNA targets and binding sites. Compared with SLE and health control group, hsa_circ_101328 was found to be a common gene with differential expression of RA. Besides, correlation analysis revealed significant correlation between hsa_circ_101328 and positive CRP. ROC curve analysis showed that hsa_circ_101328 has the potential of RA diagnosis.
We identified some dysregulated circRNAs in PBMCs from RA patients, and hsa_circ_101328 may be a novel and effective biomarker for early diagnosis of RA.
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IZUM, KILJ, NUK, PILJ, PNG, SAZU, UL, UM, UPUK
Substantial evidence indicates that immune activation at stroma can be rerouted in a tumor-promoting direction. CD69 is an immunoregulatory molecule expressed by early-activated leukocytes at sites ...of chronic inflammation, and CD69(+) T cells have been found to promote human tumor progression. In this study, we showed that, upon encountering autologous CD69(+) T cells, tumor macrophages (MΦs) acquired the ability to produce much greater amounts of IDO protein in cancer nests. The T cells isolated from the hepatocellular carcinoma tissues expressed significantly more CD69 molecules than did those on paired circulating and nontumor-infiltrating T cells; these tumor-derived CD69(+) T cells could induce considerable IDO in monocytes. Interestingly, the tumor-associated monocytes/MΦs isolated from hepatocellular carcinoma tissues or generated by in vitro culture effectively activated circulating T cells to express CD69. IL-12 derived from tumor MΦs was required for early T cell activation and subsequent IDO expression. Moreover, we found that conditioned medium from IDO(+) MΦs effectively suppressed T cell responses in vitro, an effect that could be reversed by adding extrinsic IDO substrate tryptophan or by pretreating MΦs with an IDO inhibitor 1-methyl-DL-tryptophan. These data revealed a fine-tuned collaborative action between different types of immune cells to counteract T cell responses in tumor microenvironment. Such an active induction of immune tolerance should be considered for the rational design of effective immune-based anticancer therapies.
Macrophages (Mφ) in most solid tumors exhibit a distinct immunosuppressive phenotype, but the mechanisms that allow tumor microenvironments to “educate” Mφ are incompletely understood. Here, we ...report that culture supernatants (TSNs) from several types of tumor cell lines can drive monocytes to become immunosuppressive Mφ. Kinetic experiments revealed that soon after exposure to these TSNs, monocytes began to provoke transient proinflammatory responses and then became refractory to subsequent stimulation. Other TSNs that failed to cause such temporary preactivation did not alter Mφ polarization. Consistent with these results, we observed that the monocytes/Mφ in different areas of human tumor samples exhibited distinct activation patterns. Moreover, we found that hyaluronan fragments constitute a common factor produced by various tumors to induce the formation of immunosuppressive Mφ, and also that upregulation of hyaluronan synthase-2 in tumor cells is correlated with the ability of the cells to cause Mφ dysfunction. These results indicate that soluble factors derived from tumor cells, including hyaluronan fragments, co-opt the normal development of Mφ to dynamically educate the recruited blood monocytes in different niches of a tumor. The malignant cells can thereby avoid initiation of potentially dangerous Mφ functions and create favorable conditions for tumor progression.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
Emerging studies have focused on ways to treat cancers by modulating T cell activation. However, whether B cell receptor signaling in the tumor microenvironment (TME) can be harnessed for ...immunotherapy is unclear. Here, we report that an Asia-specific variant of human IgG1 containing a Gly396 to Arg396 substitution (hIgG1-G396R) conferred improved survival of patients with colorectal cancer (CRC). Mice with knockin of the murine functional homolog mIgG2c-G400R recapitulated the alleviated tumorigenesis and progression in murine colon carcinoma models. Immune profiling of the TME revealed broad mobilizations of IgG1+ plasma cells, CD8+ T cells, CD103+ DCs, and active tertiary lymphoid structure formation, suggesting an effective antitumor microenvironment in hIgG1-G396R CRC patients. Mechanistically, this variant potentiated tumor-associated antigen-specific (TAA-specific) plasma cell differentiation and thus antibody production. These elevated TAA-specific IgG2c antibodies in turn efficiently boosted the antibody-dependent tumor cell phagocytosis and TAA presentation to effector CD8+ T cells. Notably, adoptive transfer of TAA-specific class-switched memory B cells harboring this variant exhibited therapeutic efficacy in murine tumor models, indicating their clinical potential. All these results prompted a prospective investigation of hIgG1-G396R in patients with CRC as a biomarker for clinical prognosis and demonstrated that manipulating the functionality of IgG1+ memory B cells in tumors could improve immunotherapy outcomes.
The data collected by ATIC, CREAM and PAMELA all display remarkable cosmic ray nuclei spectrum hardening above the magnetic rigidity ∼240 GV. One natural speculation is that the primary electron ...spectrum also gets hardened (possibly at ∼80 GV) and the hardening partly accounts for the electron/positron total spectrum excess discovered by ATIC, HESS and Fermi-LAT. If it is the case, the increasing behavior of the subsequent positron-to-electron ratio will get flattened and the spectrum hardening should be taken into account in the joint fit of the electron/positron data otherwise the inferred parameters will be biased. Our joint fits of the latest AMS-02 positron fraction data together with the PAMELA/Fermi-LAT electron/positron spectrum data suggest that the primary electron spectrum hardening is needed in most though not all modelings. The bounds on dark matter models have also been investigated. In the presence of spectrum hardening of primary electrons, the amount of dark-matter-originated electron/positron pairs needed in the modeling is smaller. Even with such a modification, the annihilation channel χχ→μ+μ− has been tightly constrained by the Fermi-LAT Galactic diffuse emission data. The decay channel χ→μ+μ− is found to be viable.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
The reinvigoration of anti-tumor T cells in response to immune checkpoint blockade (ICB) therapy is well established. Whether and how ICB therapy manipulates antibody-mediated immune response in ...cancer environments, however, remains elusive. Using tandem mass spectrometric analysis of modification of immunoglobulin G (IgG) from hepatoma tissues, we identified a role of ICB therapy in catalyzing IgG sialylation in the Fc region. Effector T cells triggered sialylation of IgG via an interferon (IFN)-γ-ST6Gal-I-dependent pathway. DC-SIGN+ macrophages represented the main target cells of sialylated IgG. Upon interacting with sialylated IgG, DC-SIGN stimulated Raf-1-elicited elevation of ATF3, which inactivated cGAS-STING pathway and eliminated subsequent type-I-IFN-triggered antitumorigenic immunity. Although enhanced IgG sialylation in tumors predicted improved therapeutic outcomes for patients receiving ICB therapy, impeding IgG sialylation augmented antitumorigenic T cell immunity after ICB therapy. Thus, targeting antibody-based negative feedback action of ICB therapy has potential for improving efficacy of cancer immunotherapies.
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•ICB therapy catalyzes IgG sialylation in HCC that predicts an improved outcome•Effector T cells trigger sialylated IgG via IFN-γ-ST6Gal-I-dependent pathways•Sialylated IgG binding to DC-SIGN abrogates macrophage type I IFN production•Impeding IgG sialylation enhances antitumorigenic T cell immunity during ICB therapy
Although immune checkpoint blockade (ICB) influence on T cells is well known, its impact on antibodies is less understood. Wu et al. show how ICB-elicited sialylation of IgG suppresses DC-SIGN-expressing macrophages in human hepatocellular carcinoma. Impeding IgG sialylation augments macrophage IFN-I responses and antitumorigenic T cell immunity during immunotherapy.
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GEOZS, IJS, IMTLJ, KILJ, KISLJ, NLZOH, NUK, OILJ, PNG, SAZU, SBCE, SBJE, UILJ, UL, UM, UPCLJ, UPUK, ZAGLJ, ZRSKP
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