Iranian Journal of Immunology最新文献

Background: Glucose deprivation in T lymphocytes can trigger compensatory metabolic pathways, potentially contributing to T-cell exhaustion. Additionally, it may induce the unfolded protein response (UPR), ultimately resulting in endoplasmic reticulum (ER) stress.

Objective: To examine the transcriptional profiles of endoplasmic reticulum (ER) stress markers and T-cell exhaustion indicators in CD8+ T lymphocytes isolated from B-ALL patients.

Methods: Peripheral blood samples were collected from 22 untreated B-ALL patients and 22 healthy controls. Magnetic Activated Cell Sorting (MACS) was used to isolate CD8+ T lymphocytes. The relative gene expression was then assessed using qRT-PCR with primers specific to XBP1, CHOP, GLUT1, and T-bet.

Results: The ER stress response was significantly activated in CD8+ T lymphocytes from B-ALL patients, as evidenced by significant increase in both XBP1 and CHOP transcript levels, relative to normal donors. Although GLUT1 mRNA expression was significantly higher than in control groups, T-bet expression showed no significant difference between the two groups.

Conclusion: Collectively, our gene expression data suggest ER stress activation in CD8+ T lymphocytes from B-ALL patients. These findings warrant further investigation into ER stress-related signaling pathways and their potential role in promoting T-cell exhaustion in B-ALL.

The balance between follicular helper T cells (Tfh) and follicular regulatory T cells (Tfr) is crucial for maintaining immune tolerance. Tfh cells are key in producing autoantibodies by providing essential help to germinal center (GC) B cells, while Tfr cells prevent autoimmune inflammatory processes by controling Tfh responses. However, the signals that regulate Tfh and Tfr cells are largely unknown. Due to dysregulated Tfr/Tfh balance and autoantibody production, regulatory B cells (Bregs) have emerged as a key checkpoint in the GC response. Bregs are B cells with immunosuppressive capabilities. Significant advancements have been made in understanding the roles of Bregs, particularly their capacity to produce cytokines with anti-inflammatory properties and regulate Th17, Th1, and regulatory T cells (Tregs) in the context of autoimmune conditions. Bregs also play a pivotal role in shaping the development, regulation, and localization of Tfh and Tfr cells within the immune environment. Consequently, gaining mechanistic knowledge about the interactions between Tfh-Bregs and Tfr-Bregs has the potential to establish homeostasis and suppress the development of autoantibodies in a various disorders. Within the context of autoimmune disorders, this article provides a concise summary of the dysregulation of Tfh/Tfr, highlighting the critical role of Bregs in regulating this balance. The previously unrecognized interplay between Bregs and Tfh/Tfr cells will serve as an essential basis for the comprehension and management of autoimmune illnesses. It also promises to offer invaluable knowledge of the biological mechanisms of autoantibody synthesis.

Background: COVID-19 (2019) clearly demonstrates an imbalanced immune response. Variations in the function and subtypes of dendritic cells (DCs) may have effects on immune responses in COVID-19 patients and contribute to immunopathology.

Objective: To assess the phenotype and frequency of Plasmacytoid dendritic cells (pDCs), Conventional DCs (cDCs), and double-positive DCs in COVID-19 patients admitted to the ICU and non-ICU compared to the healthy control group.

Methods: The study included 10 healthy individuals and 25 COVID-19 patients. In the second week of their illness, Peripheral blood mononuclear cells (PBMCs) were isolated from the patients and labeled with targeted antibodies for HLA-DR, CD123, and CD11c. The samples were then analyzed using flow cytometry. The COVID-19 patients were divided into two ICU and non-ICU groups and were closely monitored throughout the study.

Results: In comparison to healthy controls, COVID-19 patients exhibited a significantly lower pDCs ratio (P=0.04). Patients were categorized into two groups: (A) the ICU group (n=11; 44%) and (B) the non-ICU group (n=14; 56%). The frequency of pDC was significantly lower in ICU patients than in non-ICU patients (P<0.01). Although not statistically significant, ICU patients had a lower frequency of cDCs and double positive DCs compared to non-ICU patients. Additionally, a significant association between the age of COVID-19 patients and cDC levels was observed (p=0.049).

Conclusion: SARS-CoV-2 can evade attacks from the immune response by reducing the number of DCs and suppressing their function of DCs, ultimately resulting in weakened development of both innate and adaptive immunity.

Background: Previous research has identified several potential biomarkers associated with pathological ‎tumor (pT) staging in prostate cancer (PCa) patients. Among these biomarkers, CX3CR1 is ‎notable for its connection to the immune microenvironment.‎.

Objective‎: To further investigate the significance of CX3CR1 as a key biomarker for predicting pT ‎staging and PCa progression.‎.

Methods‎: Prostate cancer tissue samples were analyzed using quantitative reverse transcription ‎polymerase chain reaction (qRT-PCR) and immunohistochemical staining. The diagnostic ‎performance of CX3CR1 was evaluated using receiver operating characteristic (ROC) curves, ‎while Kaplan-Meier survival analysis was conducted to determine overall survival (OS) rates.‎.

Results: A significant decrease in CX3CR1 expression was observed in PCa tissues compared to ‎adjacent normal tissues, with the lowest levels detected in pT3 tumors. CX3CR1 expression ‎showed a negative correlation with preoperative prostate-specific antigen (PSA) levels, lymph ‎node staging (N stage), Gleason score, and overall survival (OS). Additionally, CX3CR1 levels ‎were associated with the polarization of infiltrating CD4+ T cells in PCa patients.‎.

Conclusion‎: CX3CR1, as a biomarker associated with pT staging, plays a role in predicting PCa prognosis, ‎potentially by modulating the immune microenvironment.‎.

Background: Radiotherapy destroys tumor cells primarily through direct DNA damage by high-energy particles or indirect DNA damage by free radicals. High-dose radiotherapy (HDR) destroys tumor cells while also damaging normal cells and may potentially cause immunosuppression. The effect of low-dose radiotherapy (LDR) on the tumor microenvironment (TME) may differ from those of HDR.

Objective: To determine if combining low-dose radiotherapy with immune checkpoint inhibitors results in synergistic effects.

Methods: We established a mouse model for lung cancer and categorized mice into 4 cohorts: NC (negative control) cohort, LDR cohort, anti-CTLA-4 cohort, and LDR+anti-CTLA-4 cohort. Changes in tumor volume were observed in each group, with particular attention given to the variations in immune cells and cytokines within the mouse tumors following LDR.

Results: The mice in the LDR+anti-CTLA-4 group exhibited the slowest growth in tumor volume, and low-dose radiotherapy tended to inhibit tumor growth. The proportion of infiltrating CD8+T cells increased and the proportion of infiltrating Treg cells decreased in the tumor after LDR. The levels of interferon (IFN) and the chemokines CXCL9, CXCL10 and CXCL11 were increased after low-dose radiotherapy.

Conclusion: LDR has the ability to alter the immune microenvironment of tumors by promoting the production of IFN. Additionally, when combined with anti-CTLA-4, whole-body LDR can effectively suppress tumor growth in mice. The finding is of potential clinical significance and deserves further exploration.

Background: Circular RNAs are involved in the tumorigenesis of various tumors, including Non-small cell lung cancer (NSCLC).

Objective: To investigate the expression of circ_0001006 in patients with NSCLC and its role in tumorigenesis and immune escape.

Methods: A total of 115 patients with NSCLC were enrolled in the study. The expression of circ_0001006 and PD-L1 mRNA were detected using RT-qPCR. Cell proliferation activity, cell migration and invasion abilities were measured using the CCK-8 assay and Transwell chambers assay. Coculture of NSCLC cells with CD8 cytotoxic T cells was conducted to measure the levels of INF-γ, TNF-α, IL-2, and lactate dehydrogenase release in culture supernatants. Bioinformatic analysis was used to predict the target relevance among circ_0001006, miR-320a, and PD-L1.

Results: The circ_0001006 and PD-L1 mRNA levels were elevated in NSCLC tissues and cells. Patients with high levels of circ_0001006 had a shorter overall survival rate. Inhibiting circ_0001006 reduced the proliferation, migration, and invasion of NSCLC cells, while increasing PD-L1 partially counteracting the inhibitory effects of si-circ_0001006. The co-culture system of NSCLC and CD8+ T cell was found to reduce the viability of activated CD8+ T cell when circ_0001006 is present. Knocking down circ_0001006 in co-culture cells led to an increase in the expression of INF-γ, TNF-α, and IL-2. The ability of si-circ_0001006 to enhance the activation of CD8+ T cells was diminished when PD-L1 was overexpressed.

Conclusion: circ_0001006 may serve as a potential prognostic predictor and therapeutic target for NSCLC. Additionally, it offers insight into a novel regulatory mechanism of circ_0001006.

Background: Earlier studies have highlighted the involvement of miRNA146a in tumor suppression indicating its potential to inhibit the progression of diffuse large B-cell lymphoma (DLBCL).

Objective: To identify programmed death-ligand 1 (PD-L1) as a candidate for further research, as it plays a key role in regulating immune checkpoints in cancer and is associated with the involvement of miRNA146a in immune regulation and the response to inflammation.

Methods: The expression of miR-146a and PD-L1 in DLBCL cells was detected using qPCR analysis. Subsequently, DLBCL cells (OCI-Ly-3 and OCI-Ly-7) were treated with either the miR-146a mimic or a blank plasmid. To assess immune evasion, DLBCL cells were cocultured with peripheral blood mononuclear cells, CD8+ T cells, or cytokine-induced killer cells. Furthermore, the target gene of miR-146a was predicted and validated.

Results: Compared to the normal B-cell line (NCB), the level of miR-146a was significantly lower in DLBCL cells. Additionally, overexpression of miR-146a significantly reduced DLBCL viability, invasion, and immune evasion while simultaneously promoting apoptosis. Our findings also confirmed that miR-146a targeted PD-L1. Finally, the upregulation of PD-L1 notably reversed the tumor suppressive effects of miR-146a on DLBCL.

Conclusion: Our study indicates that miR-146a inhibits the progression of DLBCL by enhancing antitumor immunity through the targeting of PD-L1. The therapeutic potential of this miRNA in lymphoma is highly desirable.

Background: Severe combined immunodeficiency (SCID) is the most severe form of inborn errors of immunity (IEIs) and typically leads to death within the first year of life. Combined immunodeficiencies (CID) are immune disorders that are less severe than SCID and are characterized by qualitative or quantitative defects in T and B cells.

Objective: To explore the clinical, laboratory, and genetic diagnostic approaches for patients diagnosed with SCID and CID.

Methods: In this retrospective single-center study, we evaluated 54 patients diagnosed with SCID and CID between 2006 and 2019.

Results: The male to female ratio was 30:24 and the rate of consanguinity was 77.8%. Among the patients, 23 were diagnosed with SCID and 31 diagnosed with CID. The most common phenotype in the SCID group was T-B-NK+ while in the CID group it was MHC class II deficiency. The median age at symptom onset for SCID and CID were 1 month and 5 months, respectively, while the median age at diagnosis was 4 months for SCID and 11 months for CID. The age at diagnosis of SCID and the age at diagnosis of symptoms were earlier than CID (p<0.05). Lymphopenia was present in 90.9% of patients with SCID and 51.6% of patients with CID (p<0.05). HSCT was performed in 10 out of 23 (43.4%) SCID patients and 10 out of 31 (32.2%) CID patients (total of 20 out of 54, 37%). The survival rates of SCID and CID patients who underwent HSCT were 80% and 70%, respectively.

Conclusion: Consanguineous marriage, sibling death and family members with similar characteristics should be investigated for early diagnosis. Further investigations should be performed in the presence of lymphopenia. With the increasing number of genetic diagnosis facilities and HSCT centers, the survival rate of patients is expected to rise.

Background: Gastroesophageal reflux disease (GERD) is a prevalent clinical condition that affects millions ‎of individuals worldwide.‎.

Objective‎: To assess the level of soluble HLA-E (sHLA-E) as a biomarker in the diagnosis and ‎immunopathogenesis of GERD patients.‎.

Methods‎: The case-control prospective study included 40 GERD patients who were consulted at the ‎Gastroenterology Unit of Al-Kindy Teaching Hospital, as along with 40 healthy control ‎subjects. The study period extended from January 2023 to May 2024. Blood was drawn from ‎both groups and serum was separated to assesss HLA-E using a sandwich enzyme-linked ‎immunosorbent assay (ELISA) kit.‎.

Results: There was a statistically significant difference in sHLA-E levels between GERD patients and ‎healthy controls (p = 0.021). The median sHLA-E level was significantly higher in GERD ‎patients (0.370 ng/mL) compared to controls (0.148 ng/mL). A receiver operating characteristic ‎‎(ROC) curve was generated to evaluate the diagnostic performance of soluble HLA-E (sHLA-E) ‎in predicting GERD. The area under the ROC curve (AUC) was calculated to assess the ‎discriminatory ability of sHLA-E, with a value of 0.649 (95% CI: 0.534-0.752, p = 0.021). The ‎optimal cutoff value for sHLA-E was determined to be ≤0.65 ng/mL, with a sensitivity of ‎‎85.1%, specificity of 27.3%, positive predictive value of 65.9%, negative predictive value of ‎‎69.4%, and accuracy of 35.0%.‎.

Conclusion‎: The study provides evidence of an association between elevated sHLA-E levels and GERD. It ‎also suggests that sHLA-E has a moderate discriminatory ability as a biomarker in predicting ‎GERD.‎.

Background: Studies have demonstrated that transmembrane tumor necrosis factor-α (tmTNF-α) plays an anti-inflammatory role. tmTNF-α has a dual function, acting as both a signaling ligand and a receptor that transmits reverse signaling to cells expressing tmTNF-α. However, the role and mechanisms of tmTNF-α reverse signaling in sepsis are not fully understood.

Objective‎: To explore the potential role and mechanisms of tmTNF-α reverse signaling in lipopolysaccharide (LPS)-induced inflammation.

Methods‎: The expression levels of tmTNF-α and TNF-α mRNA were evaluated using flow cytometry and real-time PCR, respectively. We employed the anti-TNF-α drug infliximab to stimulate tmTNF-α reverse signaling and measured interleukin-6 (IL-6) and monocyte chemoattractant protein (MCP)-1 production through real-time PCR and ELISA in THP-1-derived macrophages. The location of p65 was determined through immunofluorescence assay. The phosphorylation and acetylation of p65, as well as the expression levels of MCP-induced protein 1 (MCPIP1) and Sirtuin 1 (SIRT1), were evaluated using western blotting.

Results: Our findings revealed that tmTNF-α reverse signaling reduced the expression of IL-6 and MCP-1 triggered by LPS. tmTNF-α reverse signaling inhibited the nuclear translocation of p65, suppressed p65 phosphorylation and acetylation, and upregulated the expression of negative regulatory molecules MCPIP1 and SIRT1 in the LPS/ toll-like receptor 4 (TLR4) signaling pathway.

Conclusion‎: This study demonstrates that tmTNF-α reverse signaling plays a negative regulatory role in inflammation triggered by LPS by inhibiting the TLR4/ nuclear factor kappa B (NF-κB) signaling pathway. This study helps to further understand the function of tmTNF-α reverse signaling and offers new therapeutic possibilities for sepsis and other inflammatory disease conditions.