Immunological Investigations最新文献

Autoimmune diseases (AIDs) constitute a group of disorders where the immune system mistakenly attacks the body's tissues. The pathogenesis of AIDs involve a breakdown in immune tolerance, culminating in an immune response that targets autoantigens. In adaptive immunity, secondary rearrangement of T cell receptors (TCRs) and B cell receptors (BCRs) involves sequential V(D)J recombination events during lymphocyte development. Imperfect receptor editing during this process can generate autoreactive clones, thereby contributing to the pathogenesis of AIDs. Emerging evidence implicates secondary V(D)J recombination in TCR and BCR genes as a pathogenic driver in multiple AIDs. The detection of secondary rearrangements, along with targeted therapeutic interventions (e.g. anti-CD40L, IL6), offers novel avenues for the early prediction and diagnosis of these diseases. This article provides a comprehensive overview of the current research on the role of TCR/BCR secondary rearrangements in AIDs, elucidating their mechanisms of action to enhance our understanding of the pathogenesis, diagnosis, and treatment of autoimmune disorders.

Background: Tetrahydrobiopterin (BH₄) maintains nitric oxide synthase (NOS) coupling. However, its therapeutic potential in non-alcoholic fatty liver disease (NAFLD) remains unexplored.

Methods: Male C57BL/6J mice were subjected to a high-fat diet (HFD) for 16 weeks to establish NAFLD, with oral administration of sapropterin (10 mg/kg/day) initiated at week 5.

Results: Sapropterin treatment significantly elevated both systemic and hepatic BH₄ concentrations and ameliorated HFD-induced dyslipidemia, as evidenced by reductions in circulating total cholesterol, triglycerides, and low-density lipoprotein cholesterol. Hepatocellular injury markers (ALT, AST) were also markedly decreased. Histopathological examination revealed substantial improvements in hepatic steatosis, ballooning degeneration, and macrovesicular lipid accumulation, with the NAFLD activity score reduced by 63.1% and hepatic lipid content by over 60%. Molecular analyses demonstrated that sapropterin suppressed lipogenic gene expression (Fasn, Cd36) and enhanced transcription of Ppara, promoting lipid catabolism. Concurrently, hepatic fibrotic burden was significantly reduced, accompanied by downregulation of Tgfb1 and diminished TGF-β protein expression. Anti-inflammatory effects were evidenced by decreased hepatic IL-6 and IL-1β levels and a 131.5% increase in IL-10. Additionally, sapropterin facilitated macrophage polarization toward an anti-inflammatory M2 phenotype (Cd206, Arg1), while suppressing pro-inflammatory M1 markers (Cd86).

Conclusion: These findings indicated that sapropterin improvedNAFLD by regulatinglipid metabolism, inflammation, and fibrosis.

Background: Hepatitis B virus (HBV) modulates immune epigenetic landscape. Therefore, we investigated immune epigenetic landscape in HBsAg seroconverters and non-seroconverters.

Methods: Sixteen rHBV patients including seroconverters (SC, n = 7) and non-seroconverters (NSC, n = 9) at baseline and week 24 were recruited. Age matched naïve chronic hepatitis B patients (nCHBV, n = 7) and healthy controls (HC, n = 6) were also included. PBMCs and plasma were subjected to genome-methylation, gene-expression, immunophenotyping, functionality, and cytokines analysis using Reduced Representation Bisulfite Sequencing (RRBS), qRT-PCR, flow-cytometry, and cytokine-bead-array.

Results:  In rHBV patients, as compared to nCHBV, there is significant hypomethylation (p < .05) of epigenetic remodellers and immune and metabolic genes like KDM2B, NCOR2 and GATA6, TGF-β, IL-6, IRF8, RPTOR, HK3, specifically at CpG islands. At baseline, HBsAg SC had hypomethylation of KDM2B, COX19, IRF8, TLR5, and hypermethylation of LAG3 compare to NSC. By week-24, SC demonstrated hypomethylation of IL17RA, IFN-γ, TGF-β, STAT5B (p < .05) and correlated with increased plasma IL-6 (p = .009) and decreased LAG3 (p = .01). At baseline and 24 weeks, SC depicted differentiation of HBV-specific CD8+, Tfh, and Th1/17 cells.

Conclusion: This study identifies hypomethylation of immune genes suggesting enhanced immune response and viral clearance in SC. Conversely, nCHBV and NSC consistently exhibited hypomethylation of LAG3 and TOX, contributing to immune exhaustion.

Background: Psoriasis is a chronic autoimmune condition characterized by recurrent episodes of skin inflammation. Despite progress in treatment, managing flare-ups of psoriasis remains a significant hurdle once the therapy is halted. This review aims to unravel the enigma of relapse by examining the interactions between epigenetics, metabolic reprogramming, and inflammatory memory.

Methods and results: Skin-resident memory T cells and keratinocytes with a history of inflammation play crucial roles in the metabolic and epigenetic alterations observed during relapse. This review explores epigenetic factors involved in the recurrence of psoriasis, such as histone alterations, chromatin restructuring, and non-coding RNAs. Furthermore, we explored environmental influences, metabolic reprogramming, and genetic predispositions that influence the persistence and recurrence of psoriasis. We also outline the function of the gut-brain-skin axis in this scenario. Finally, we discuss pharmacological strategies for managing psoriasis relapse, including targeted biologics.

Conclusion: This review provides a comprehensive summary on the intricate epigenetic, molecular, metabolic and environmental cues that exacerbate or facilitate psoriasis relapse. In summary, it also provides an enticing update on the therapeutics currently employed to treat psoriasis relapse.

Objective: Systemic lupus erythematosus (SLE) is a chronic inflammatory autoimmune disorder. This study aims to investigate the association between UBQLN family genes and the systemic lupus erythematosus (SLE).

Methods: In the present study, plasma levels of UBQLN family genes were evaluated in 113 SLE patients and 115 healthy controls. The relative mRNA expression levels of UBQLN family genes in peripheral blood lymphocytes were quantified using qRT-PCR. Additionally, UBQLN protein levels in serum were measured using enzyme-linked immunosorbent assay (ELISA). The diagnostic potential of UBQLN family genes was evaluated by calculating the area under the receiver operating characteristic (ROC) curve. Correlation analysis was conducted using Pearson and Spearman methods, while logistic regression was employed for one-way analysis.

Results: The mRNA expression levels of UBQLN4 and UBQLN2 SLE patients were significantly lower than those in the control group (both p < .05). Moreover, the combined diagnostic performance of UBQLN4 and UBQLN2 surpassed that of each gene alone, with a combined AUC of 0.697. The protein expression levels of UBQLN1, UBQLN2, and UBQLN4 were also significantly reduced in SLE patients compared to controls (all p < .05).

Conclusion: These findings suggest that UBQLN family genes in peripheral blood lymphocytes may play a role in the pathogenesis of SLE and hold promise as biomarkers for the diagnosis and treatment of the disease.

Background: Posterior subcapsular cataract (PSC) substantially impacts visual function, and prior studies have suggested that inflammatory cytokines may have a role in its development. We aimed to analyze inflammatory cytokine concentrations in the aqueous humor by cataract type and severity, specifically comparing them in relation to the presence of PSC, and to identify risk factors for PSC.

Methods: We prospectively recruited patients undergoing routine cataract surgery. PSC presence was documented via slit-lamp examination and anterior segment photography during cataract diagnosis. Aqueous humor samples were collected prior to surgery and analyzed using quantitative multiplexed antibody assays to measure the concentrations of 10 inflammatory cytokines (interferon-α [IFN-α], IFN-γ, interleukin [IL]-1α, IL-1β, IL-2, IL-4, IL-5, IL-6, IL-10, and tumor necrosis factor-α). Cytokine concentrations were compared according to PSC status.

Results: Overall,80 eyes of 80 patients were included, 45 with and 35 without PSC. Compared with those in the non-PSC group, patients with PSC showed significantly higher aqueous humor concentrations of IFN-γ (2.764 vs. 2.301 pg/mL, p = .013). No significant correlation was observed between PSC status and the aqueous humor concentrations of other examined inflammatory cytokines.

Conclusion: IFN-γ expression tended to be higher in eyes with PSC than in those without PSC, suggesting a possible role in PSC pathophysiology.

Background: The aim of the present study was to assess the therapeutic effects of ADSC-Exos for SS-induced skin injury.

Methods: A mouse model of SS was constructed and Exos from ADSCs (Exos) and hypoxia-pretreated ADSCs (HExos) were isolated. The therapeutic effects of Exos were identified using an enzyme-linked immunosorbent assay, immunohistochemistry, and immunofluorescence. High-throughput sequencing (HTS) was employed to identify differentially expressed genes between ADSC-Exos and ADSC-HExos. The results showed that treatment with ADSC-Exos, especially ADSC-HExos, inhibited SS-induced expression of inflammatory factors, ferroptosis, and deposition of reactive oxygen species.

Results: The results of HTS and polymerase chain reaction analysis revealed that GLRX2 plays an important role in protected effects of ADSC-HExo against SS-induced skin injury. In vitro analysis usingHaCaT cells confirmed that GLRX2 inhibited lipopolysaccharide-induced skin injury by inhibiting ferroptosis, as confirmed with the ferroptosis inhibitorFerrostatin-1. GLRX2 upregulation increased the therapeutic effects of ADSC-Exos against skin injury of SS mice.

Conclusion: Moreover,ADSC-HExos effectively promoted collagen I expression, suggesting that ADSC-HExos attenuated primary SS-induced skin injury via GLRX2 delivery and ferroptosis suppression.

Background: Periodontitis (PD) is a chronic inflammatory disease characterized by alveolar bone loss, primarily driven by excessive osteoclast differentiation and activation. Exosomes derived from M2 macrophages have been implicated in the pathological progression of various diseases, including PD. Pyruvate kinase (PK)M2, a key metabolic enzyme, promotes inflammation in periodontal disease through enhanced production of pro-inflammatory cytokines. This study investigated whether M2 macrophage-derived exosomes regulate osteoclast differentiation and contribute to PD progression.

Methods: Exosomes were isolated from M2-polarized RAW264.7 cells. Osteoclast differentiation was induced in M2-polarized RAW264.7 cells through treatment with receptor activator of nuclear factor kappa-B ligand (RANKL). Reverse transcription quantitative PCR (RT-qPCR) was used to analyze mRNA levels of osteoclast differentiation-related genes. Enzyme-linked immunosorbent assay (ELISA) quantified inflammatory cytokine production. Co-immunoprecipitation assays were performed to detect the interaction between PKM2 and hypoxia-inducible factor-1α (HIF-1α). To inhibit or activate PKM2 activity, RAW 264.7 cells were treated with Shikonin or TEPP46.

Results: Exosomes were successfully extracted from RAW264.7 cells. M2-derived exosomes significantly suppressed RANKL-induced osteoclast differentiation and inflammatory responses. Furthermore, these exosomes modulated the PKM2/HIF-1α signaling axis. Shikonin treatment inhibited RANKL-induced osteoclastogenesis and inflammation, whereas TEPP46 treatment enhanced these processes.

Conclusion: The M2 polarization of RAW264.7-derived exosomes inhibits osteoclast differentiation and inflammation through the PKM2/HIF-1α pathway, providing potential insights into the molecular mechanisms underlying PD pathogenesis.

Introduction: Preeclampsia (PE) is a specific pregnancy syndrome characterized by a systemic inflammatory response that may be dependent on the presence of danger molecules called damage-associated molecular patterns (DAMPs). High mobility group Box 1 (HMGB1) is a DAMP that shows possible interaction with haptoglobin and can be removed from circulation by the CD163 receptor.

Objective: This study aimed to evaluate the involvement of haptoglobin, HMGB1, and CD163 receptor in the systemic inflammatory response in pregnant women with PE.

Methods: Monocytes obtained from preeclamptic and normotensive (NT) pregnant women were evaluated for surface TLR4, RAGE, CD64, and CD163 receptors, as well as intracellular haptoglobin and HMGB1 expression by flow cytometry.

Results: Plasma levels of haptoglobin, HMGB1, and hemeoxygenase-1, as well as pro- and anti-inflammatory cytokines, were determined by the ELISA. Compared with NT group expression of TLR4, CD64, and RAGE receptors and intracellular HMGB1 and haptoglobin by monocytes was higher in women with PE, whereas extracellular CD163 expression was reduced in this group. Plasma concentrations of HMGB1, TNF-α, IL-1β, and IL-6 were higher in preeclamptic women, whereas the levels of haptoglobin, hemeoxygenase-1, and IL-10 were significantly lower.

Conclusion: The elevated concentration of inflammatory cytokines and higher expression of TLR4, CD64, and RAGE receptors demonstrated that monocytes from PE women are polarized to the M1-like profile. Furthermore, the CD163 internalization and the absence of a high haptoglobin monocyte subset, along with decreased levels of haptoglobin, IL-10, and hemeoxygenase-1 in the PE group, indicates a deficiency in mechanisms that could regulate the intense inflammatory process associated with PE.

Introduction: Colon cancer is a highly heterogeneous malignancy with significant global incidence and mortality. The tumor microenvironment (TME) plays a pivotal role in disease progression and treatment response. Among key components of the TME are tumor-infiltrating lymphocytes (TILs), particularly regulatory T cells (Tregs) and effector T cells, whose balance influences cancer outcomes.

Methods: This review analyzes recent findings regarding the role of Treg cells in colon cancer progression by evaluating preclinical and clinical studies that explore immune cell composition, function, and modulation within the TME.

Results: Treg cells demonstrate a dual role in colon cancer. While they suppress effective anti-tumor immune responses, facilitating immune evasion, they may also mitigate chronic inflammation, which contributes to carcinogenesis. High intratumoral Treg levels are correlated with poor prognosis, reduced immunotherapy efficacy, and lower overall survival. Strategies to deplete or reprogram Tregs, such as immune checkpoint inhibition, modulation of T cell plasticity, and selective targeting, have shown promise in enhancing anti-tumor immunity.

Discussion: Complete depletion of Tregs risks inducing autoimmune toxicity. Therefore, a precise understanding of Treg cell subsets and functions is essential. This review highlights the importance of developing targeted immunotherapeutic strategies that modulate Treg activity while preserving immune homeostasis in colon cancer treatment.