Follicular Helper Cells Research Articles

Age-dependent decrease of circulating T follicular helper cells correlates with disease severity in elderly patients with COVID-19

Overwhelming evidence has shown that aging is a significant risk factor for COVID-19-related hospitalizations, death and other adverse health outcomes. Particular T cell subsets that susceptible to aging and associated with COVID-19 disease severity requires further elucidation. Our study recruited 57 elderly patients with acute COVID-19 and 27 convalescent donors. Adaptive immunity was assessed across the COVID-19 severity spectrum. Patients underwent age-dependent CD4+ T lymphopenia, preferential loss of circulating T follicular regulatory cells (cTfh) subsets including cTfh-em, cTfh-cm, cTfh1, cTfh2, cTfh17 and circulating T follicular regulatory cells (cTfr), which regulated antibody production through different pathways and correlated with COVID-19 severity, were observed. Moreover, vaccination improved cTfh-cm, cTfh2, cTfr proportion and promoted NAb production. In conclusion, the elderly had gone through age-dependent cTfh subsets deficiency, which impeded NAb production and enabled aggravation of COVID-19 to critical illness, whereas SARS-CoV-2 vaccine inoculation helped to rejuvenate cTfh, cTfr and intensify NAb responses.

Exploring the prognostic implications of cuproptosis-associated alterations in clear cell renal cell carcinoma via in vitro experiments

This study investigated the impact of novel copper ionophores on the prognosis of clear cell renal cell carcinoma (ccRCC) and the tumor microenvironment (TME). The differential expression of 10 cuproptosis and 40 TME-pathway-related genes were measured in 531 tumor samples and 71 adjacent kidney samples in The Cancer Genome Atlas database. A risk score model was constructed with LASSO cox to predict the prognosis of ccRCC patients. Forest plot and function enrichment were used to study the biological function of the key genes in depth. The study found that the risk score model accurately predicted the prognosis of ccRCC patients. Patients with high scores had higher immune responses with a higher proportion of anti-tumor lymphocytes and a lower proportion of immunosuppressive M2-like macrophages. However, the high-score group also exhibited a higher proportion of T follicular helper cells and regulatory T cells. These results suggest that cuproptosis-based therapy may be worth further investigation for the treatment of ccRCC and TME. Subsequently, by using RNAi, we established the stable depletion models of FDX1 and PDHB in ccRCC cell lines 786-O and ACHN. Through CCK8, colony formation, and Transwell assays, we observed that the knockdown of FDX1 and PDHB could significantly reduce the capabilities of proliferation and migration in ccRCC cells. In conclusion, this study illuminates the potential effectiveness of copper ionophores in the treatment of ccRCC, with higher risk scores correlating with better TME immune responses. It sets the stage for future cuproptosis-based therapy research in ccRCC and other cancers, focusing on copper’s role in TME.

Correlation of cTfh cells and memory B cells with AMR after renal transplantation

Renal transplantation is the preferred treatment option for patients with end-stage renal disease (ESRD) in a clinical setting. Antibody mediated rejection (AMR) is one of the leading causes of graft dysfunction. To address the current shortcomings in the early diagnosis and treatment of AMR in clinical practice, this article analyzes the distribution of different circulating T follicular helper (cTfh) cell subtypes and B cell subpopulations in peripheral blood and detects the cytokine levels of chemokine ligand 13 (CXCL13), interleukin-21 (IL-21), and interleukin-4 (IL-4) related to cTfh cells in peripheral blood of kidney transplant recipients. Moreover, we also explore the correlation between cTfh cells, peripheral blood memory B cells, and AMR, their value as early predictive indicators of AMR, and explore potential therapeutic targets for AMR patients. Our results indicate that the proportion of cTfh cells increased at the onset of AMR, which plays an important role in antigen-specific B-cell immune regulation. Activation of cTfh cells in AMR patients correlates with phenotypes of memory B cells and plasma blasts. cTfh cells and memory B cells have promising diagnostic efficacies and predictive values for AMR. The proportion of cTfh cells to CD4+ T cells and the proportion of memory B cells to CD19+ B cells are correlated with serum creatinine levels, indicating that cTfh cells and memory B cells may be involved in the progression of AMR. In addition, the CXCL13, IL-21, and IL-4, which were associated with cTfh cells, may be involved in the onset of AMR.

RACK1 enhances STAT3 stability and promotes T follicular helper cell development and function during blood-stage Plasmodium infection in mice.

CD4+ T cells are central mediators of protective immunity to blood-stage malaria, particularly for their capacity in orchestrating germinal center reaction and generating parasite-specific high-affinity antibodies. T follicular helper (Tfh) cells are predominant CD4+ effector T cell subset implicated in these processes, yet the factors and detailed mechanisms that assist Tfh cell development and function during Plasmodium infection are largely undefined. Here we provide evidence that receptor for activated C kinase 1 (RACK1), an adaptor protein of various intracellular signals, is not only important for CD4+ T cell expansion as previously implied but also plays a prominent role in Tfh cell differentiation and function during blood-stage Plasmodium yoelii 17XNL infection. Consequently, RACK1 in CD4+ T cells contributes significantly to germinal center formation, parasite-specific IgG production, and host resistance to the infection. Mechanistic exploration detects specific interaction of RACK1 with STAT3 in P. yoelii 17XNL-responsive CD4+ T cells, ablation of RACK1 leads to defective STAT3 phosphorylation, accompanied by substantially lower amount of STAT3 protein in CD4+ T cells, whereas retroviral overexpression of RACK1 or STAT3 in RACK1-deficient CD4+ T cells greatly restores STAT3 activity and Bcl-6 expression under the Tfh polarization condition. Further analyses suggest RACK1 positively regulates STAT3 stability by inhibiting the ubiquitin-proteasomal degradation process, thus promoting optimal STAT3 activity and Bcl-6 induction during Tfh cell differentiation. These findings uncover a novel mechanism by which RACK1 participates in posttranslational regulation of STAT3, Tfh cell differentiation, and subsequent development of anti-Plasmodium humoral immunity.

Nodal T follicular helper cell lymphoma with aberrant CD20 expression and monoclonal TCR, IG rearrangements secondary to Classical Hodgkin Lymphoma: a case report.

Classical Hodgkin Lymphoma (CHL) is a rare malignant neoplasm of the lymphatic system. While CHL typically responds well to conventional treatments, some cases may experience relapse to other subtypes, with the development of secondary peripheral T-cell lymphoma (PTCL) being relatively uncommon. Herein, we report a rare case of nodal T follicular helper cell lymphomas,nos (nTFHL-NOS) secondary to CHL, accompanied by aberrant CD20 expression and clonal rearrangements of T-cell receptor (TCR) and immunoglobulin (IG). A 74-year-old male, was diagnosed with CHL, leaning toward the mixed cell type, 6years ago. He received six cycles of the Adriamycin, Bleomycin, Vinblastine, Dacarbazine (ABVD) regimen, achieving complete clinical remission. The patient was admitted to our hospital due to the appearance of multiple skin nodules 66months later. Histopathological analysis revealed nTFHL-NOS, with aberrant CD20 expression and clonal rearrangements of TCR and IG. The patient underwent two cycles of chemotherapy with brentuximab vedotin and the Gemcitabine-Oxaliplatin (G-mox) regimen, resulting in a reduction of the skin lesions to 2cm × 1cm. We discuss this rare case and review related literature.

Exploring the Role of PD-1 in the Autoimmune Response: Insights into Its Implication in Systemic Lupus Erythematosus.

Despite advances in understanding systemic lupus erythematosus (SLE), many challenges remain in unraveling the precise mechanisms behind the disease's development and progression. Recent evidence has questioned the role of programmed cell death protein 1 (PD-1) in suppressing autoreactive CD4+ T cells during autoimmune responses. Research has investigated the potential impacts of PD-1 on various CD4+ T-cell subpopulations, including T follicular helper (Tfh) cells, circulating Tfh (cTfh) cells, and T peripheral helper (Tph) cells, all of which exhibit substantial PD-1 expression and are closely related to several autoimmune disorders, including SLE. This review highlights the complex role of PD-1 in autoimmunity and emphasizes the imperative for further research to elucidate its functions during autoreactive T-cell responses. Additionally, we address the potential of PD-1 and its ligands as possible therapeutic targets in SLE.

IRF8-mutant B cell lymphoma evades immunity through a CD74-dependent deregulation of antigen processing and presentation in MHCII complexes.

The mechanism by which interferon regulatory factor 8 (IRF8) mutation contributes to lymphomagenesis is unknown. We modeled IRF8 variants in B cell lymphomas and found that they affected the expression of regulators of antigen presentation. Expression of IRF8 mutants in murine B cell lymphomas suppressed CD4, but not CD8, activation elicited by antigen presentation and downmodulated CD74 and human leukocyte antigen (HLA) DM, intracellular regulators of antigen peptide processing/loading in the major histocompatibility complex (MHC) II. Concordantly, mutant IRF8 bound less efficiently to the promoters of these genes. Mice harboring IRF8 mutant lymphomas displayed higher tumor burden and remodeling of the tumor microenvironment, typified by depletion of CD4, CD8, and natural killer cells, increase in regulatory T cells and T follicular helper cells. Deconvolution of bulk RNA sequencing data from IRF8-mutant human diffuse large B cell lymphoma (DLBCL) recapitulated part of the immune remodeling detected in mice. We concluded that IRF8 mutations contribute to DLBCL biology by facilitating immune escape.

Exploring the Mechanism of Shen Qi Gui Oral Liquid against Chemotherapy-Induced Myelosuppression in Cancer Patients Based on Network Pharmacology and Molecular Docking.

Shen Qi Gui oral liquid (SQG) may be beneficial for chemotherapyinduced myelosuppression (CIM). However, the underlying mechanism of CIM treated with SQG is still lacking. A total of 27 blood samples from cancer patients were selected to perform RNA-seq to obtain the Differentially Expressed Genes (DEGs). Then, the active components and target genes of SQG were acquired. Next, the drug targets and DEGs were intersected to obtain the intersection genes, followed by functional enrichment analysis and construction of a drug-compoundgene- disease network. Subsequently, core genes were selected. Then, immune cell infiltration, molecular docking, pharmacokinetic and toxicity prediction, and RT-qPCR were performed. A total of 1,341 DEGs, 51 active compounds, and 264 target genes were identified. Then, 30 intersection genes were acquired. Next, a drug-compound-gene-disease network was constructed, and 7 core genes were acquired. Immune infiltration analysis exhibited that only T follicular helper cells were significantly increased in the CIM group, which was significantly negatively correlated with MAPK1, MAPK14, MCL1, PTEN, and PTGS2. The luteolin, quercetin, and beta-sitosterol showed better affinity with core genes. Luteolin and quercetin, which satisfied Lipinski's rule of five, were likely absorbed by the gastrointestinal system. Toxicity predictions showed that neither luteolin nor quercetin exhibited carcinogenicity or hepatotoxicity. PTEN, PTGS2, CCL2, FOS, MCL1, MAPK1, and MAPK14 were identified as the core genes in CIM patients, which were involved in the MAPK and PI3K-Akt signaling pathways. Luteolin and quercetin may be the promising drugs against CIM.

Methylprednisolone Modulates the Tfr/Tfh ratio in EAE-Induced Neuroinflammation through the PI3K/AKT/FoxO1 and PI3K/AKT/mTOR Signalling Pathways.

Methylprednisolone (MP) is a potent glucocorticoid that can effectively inhibit immune system inflammation and brain tissue damage in Multiple sclerosis (MS) patients. T follicular helper (Tfh) cells are a subpopulation of activated CD4 + T cells, while T follicular regulatory (Tfr) cells, a novel subset of Treg cells, possess specialized abilities to suppress the Tfh-GC response and inhibit antibody production. Dysregulation of either Tfh or Tfr cells has been implicated in the pathogenesis of MS. However, the molecular mechanism underlying the anti-inflammatory effects of MP therapy on experimental autoimmune encephalomyelitis (EAE), a representative model for MS, remains unclear. This study aimed to investigate the effects of MP treatment on EAE and elucidate the possible underlying molecular mechanisms involed. We evaluated the effects of MP on disease progression, CNS inflammatory cell infiltration and myelination, microglia and astrocyte activation, as well as Tfr/Tfh ratio and related molecules/inflammatory factors in EAE mice. Additionally, Western blotting was used to assess the expression of proteins associated with the PI3K/AKT pathway. Our findings demonstrated that MP treatment ameliorated clinical symptoms, inflammatory cell infiltration, and myelination. Furthermore, it reduced microglial and astrocytic activation. MP may increase the number of Tfr cells and the levels of cytokine TGF-β1, while reducing the number of Tfh cells and the levels of cytokine IL-21, as well as regulate the imbalanced Tfr/Tfh ratio in EAE mice. The PI3K/AKT/FoxO1 and PI3K/AKT/mTOR pathways were found to be involved in EAE development. However, MP treatment inhibited their activation. MP reduced neuroinflammation in EAE by regulating the balance between Tfr/Tfh cells via inhibition of the PI3K/AKT/FoxO1 and PI3K/AKT/mTOR signalling pathways.

TNFSF9 Is Associated with Favorable Tumor Immune Microenvironment in Patients with Renal Cell Carcinoma Who Are Treated with the Combination Therapy of Nivolumab and Ipilimumab.

Combination therapy of nivolumab and ipilimumab (NIVO + IPI) for metastatic renal cell carcinoma (mRCC) has shown efficacy, but approximately 20% of patients experience disease progression in the early stages of treatment. No useful biomarkers have been reported to date. Therefore, it is desirable to identify biomarkers to predict treatment responses in advance. We examined the tumor microenvironment (TME)-related gene expression in mRCC patients treated with NIVO + IPI, between the response and non-response groups, using tumor tissues, before administering NIVO + IPI. In TME-related genes, TNFSF9 expression was identified as a candidate for the predictive biomarker. Its expression discriminated between the response and non-response groups with 88.89% sensitivity and 87.50% specificity (AUC = 0.9444). We further analyzed the roles of TNFSF9 in TME using bioinformatics from The Cancer Genome Atlas (TCGA) cohort. An adaptive immune response was activated in the TNFSF9-high-expression tumors. Indeed, T follicular helper cells, plasma B cells, and tumor-infiltrating CD8+ T cells were increased in the tumors, which indicates the promotion of humoral immunity due to enhanced T-B interactions. However, as the number of regulatory T cells (Treg) increased in the tumors, the percentage of dysfunctional T cells also increased. This suggests that not only PD-1 but also CTLA-4 inhibition may have suppressed Treg activation and improved the therapeutic effect in the TNFSF9 high-expression tumors. Therefore, TNFSF9 may predict the therapeutic efficacy of NIVO + IPI for mRCC and allow more appropriate patient selection.

IL-12 drives the differentiation of human T follicular regulatory cells.

T follicular regulatory (Tfr) cells can counteract the B cell helper activity of T follicular helper (Tfh) cells and hinder the production of antibodies against self-antigens or allergens. A mechanistic understanding of the cytokines initiating the differentiation of human regulatory T (Treg) cells into Tfr cells is still missing. Herein, we report that low doses of the pro-Tfh cytokine interleukin-12 (IL-12) drive the induction of a Tfr cell program on activated human Treg cells while also preserving their regulatory function. Mechanistically, we found that IL-12 led to STAT4 (signal transducer and activator of transcription 4) phosphorylation and binding to IL-12-driven follicular signature genes. Patients with inborn errors of immunity in the IL12RB1 gene presented with a strong decrease in circulating Tfr cells and produced higher levels of anti-actin autoantibodies in vivo. Overall, this study unveils IL-12 as an inducer of Tfr cell differentiation in vivo and provides an approach for the in vitro generation of human Tfr-like cells.

P-389 Miscarriage in recurrent pregnancy loss (RPL) patients is associated with decreased peripheral T follicular helper cells and double-positive T cells

Abstract Study question Is there a relation between certain T cell subpopulations in the peripheral blood and the reproductive outcome in patients with recurrent pregnancy loss (RPL)? Summary answer We found that miscarriage in RPL patients is associated with low quantities of peripheral T follicular helper cells (TFH) and double-positive T cells (DPT). What is known already Previous studies showed that, the quantity of certain types of immune cells, such as natural killer cells and B cells has been associated with recurrent miscarriages. It is also well known that the first trimester is characterized by inflammation profile, required for successful implantation and specific Th1/Th2-type immune microenvironment. Follicular T helper cells and rare T-cells populations such as double-positive and double-negative T cells also have an important effect on the post-implantation processes. However, the effect of these specific immune cell types and their relative quantities in relation to the reproduction outcome is not fully understood. Study design, size, duration This observational study was performed from November 2022 to September 2023. Blood samples were collected from 65 pregnant RPL women (≥2 gestational losses) aged 28-49 years during the first trimester, at 8-10 weeks of pregnancy. Patients were followed up and divided into two groups according to their reproductive outcome: live birth or miscarriage. The exclusion criteria were history of recent inflammatory, autoimmune or oncological diseases, recent antibiotic treatment, and endometrial pathologies. Participants/materials, setting, methods The percentage of eight peripheral T cell subpopulations were measured by flow cytometry: T helpers (CD3+CD4+CD8-), T killers (CD3+CD4-CD8+), double-positive T cells (DPT) (CD3+CD4+CD8+), double-negative T cells (CD3+CD4-CD8-), T follicular helper cells (TFH) (CD3+CD4+CD8-CD185+), T helper type 1 (TH1) (CD4+CD183+CD196-CD194-), type 2 (TH2) (CD4+CD183-CD194+CD196-), and type 17 (TH17) (CD4+CD183-CD194+CD196+) cells. Study groups were compared by Student’s t-test using SPSS v.21 (IBM Corp., Armonk, NY, USA). Main results and the role of chance Among the studied RPL patients, 41 women gave live birth and 24 patients had a miscarriage after the blood sample. The mean percentage and standard deviation in the of the studied T cell subpopulations was: T helpers (49.86%±14.07%), T killers (39.49%±11.50%), DPT (2.96%±1.12%), DNT (5.61%±4.76%), TFH (8.09%±3.03%), TH1 (20.86%±8.81%), TH2 (6.22%±3.68%), and TH17 (3.93%±2.37%).The performed Student’s t-test revealed significant difference only in the percentage of TFH and DPT cells between the two studied patient groups. The percentages of TFH cells and DPT cells were significantly lower in patient group with miscarriage compared to the patient group with live birth (8.07% vs. 13.35%, p = 0.04, and 1.07% vs. 2.44%, p = 0.02, respectively). Limitations, reasons for caution The study was limited in sample size. It would be beneficial future studies to include more subsets of T cells, such as TH9, TH22, and T reg. Wider implications of the findings Low percentage of peripheral TFH and DPT cells in RPL patients could be considered as an indication for potential risk of miscarriage. Routine measurement of these immune biomarkers from the peripheral blood might be beneficial for an adequate assessment and treatment of patients with previous pregnancy losses. Trial registration number not applicable

P-390 The percentage of regulatory T cells is associated with T follicular helper cell quantity in the peripheral blood of pregnant women

Abstract Study question Is there a relationship between the percentage of peripheral regulatory T cells (Treg) and other T cell subtypes in the first trimester of pregnancy? Summary answer The percentage of Treg cells showed a significant positive correlation with the quantity of T follicular helper cells (TFH). What is known already Regulatory T cells (Treg) play an essential role in the process of embryo implantation and maintenance of normal pregnancy. The quantity of these cells in the peripheral blood expands during the first trimester of pregnancy. Several studies report the importance of Treg in the control of the inflammatory process and in the pathophysiology of common adverse pregnancy outcomes. However, there is a scarce data about the quantitative relation between Treg and other important T sub-types during pregnancy. Study design, size, duration This is an observational study of 93 women, 28 to 53 years of age (mean 38 years), who had a blood sample during the first trimester (at 8-10 weeks of pregnancy). The study was conducted between November 2022 and October 2023. The exclusion criteria were history of recent inflammatory or infection disorders, recent antibiotic treatment, autoimmune diseases, oncological diseases, moderate or severe endometriosis, and endometrial polyps. Written informed consent was obtained from each participant. Participants/materials, setting, methods SIx peripheral T cell subtypes were measured by flow cytometry: T helpers % (CD3+CD4+CD8-/CD3+), T killers % (CD3+CD4-CD8+/CD3+), double-positive T cells % (CD3+CD4+CD8+/CD3+), double-negative T cells % (CD3+CD4-CD8-/ CD3+), T follicular helper cells % (CD3+CD4+CD8-CD185+/CD4+), T reg cells (CD4+CD8-CD25+CD127−/CD4+). Spearman’s correlation test was performed with all studied T cell subtypes in SPSS 21 package program. Main results and the role of chance The median percentage (range) of the studied T cell subtypes was: T helpers (51.7%, 12.1%÷91.45%), T killers (39.0%, 4.1%÷72.5%), DPT cells (1.2%, 0÷8.75), DNT cells (8.4%, 1.9%÷46.2%), Treg cells (4.6%, 1.9%÷12.7%), TFH cells (7.6%, 1.4%÷42.6%). To examine the association between the percentage of Treg cells and the other T cell subtypes, the Spearman’s Rho Correlation coefficient for non-paramentric data was used. No correlation was found between the quantity of Treg and T helpers, T killers, Total T cells, double-positive T cells (p > 0.05). In contrast, the percentage of Treg showed a significant positive correlation with the percentage of TFH (R = 0.36; p = 0.01), and a significant negative correlation with double-negative T cells (R= - 0.29; p = 0.04). Limitations, reasons for caution The main limitation of the study is that it was carried out only in a limited period of time during the pregnancy. Thus, it would be beneficial to compare the percentage of Treg cells with other T cell sub-types in the second and third trimester of pregnancy. Wider implications of the findings Our study demonstrated that Treg cells have stronger association with TFH cells than with other T cell subtypes. The strength of this quantitative relationship might be important for the normal progress of pregnancy, and it remains subject of further studies. Trial registration number not applicable

Immunomodulatory Effects of Yu-Ping-Feng Formula on Primary Sjögren's Syndrome: Interrogating the T Cell Response.

Ethnopharmacological treatments have shown beneficial effects in the clinical practice of autoimmune disorders. However, the underlying mechanism of immunomodulatory effects remains challenging, given the complicate composition of herbal medicines. Here, we developed an immunological approach to interrogate the T helper cell response. Through data mining we hypothesized that Chinese medicine formula, Yu-Ping-Feng (YPF) might be a promising candidate for treating primary Sjögren's syndrome (pSS), a common autoimmune disease manifested by exocrine gland dysfunction. We took advantage of a mouse model of experimental Sjögren's syndrome (ESS) that we previously established for YPF formula treatment. YPF therapy ameliorated the ESS pathology in mice with active disease, showing improved salivary function and decreased serum levels of autoantibodies. Phenotypic analysis suggested that both effector T and B cells were significantly suppressed. Using co-culture assay and adoptive transfer models, we demonstrated that YPF formula directly restrained effector/memory T cell expansion and differentiation into Th17 and T follicular helper (Tfh) cells, the key subsets in ESS pathogenesis. Importantly, we recruited 20 pSS patients and conducted a pilot study of 8-week therapy of YPF formula. YPF treatment effectively improved fatigue symptoms, exocrine gland functions and reduced serum IgG/IgA levels, while effector T and B cell subsets were significantly decreased. There was a trend of reduction on disease activity, but not statistically significant. Together, our findings suggested a novel approach to assess the immunomodulatory effects of YPF formula, which may be favorable for patients with autoimmune disorders.

Protection from environmental enteric dysfunction and growth improvement in malnourished newborns by amplification of secretory IgA

Environmental enteric dysfunction (EED) is a condition associated with malnutrition that can progress to malabsorption and villous atrophy. Severe EED results in linear growth stunting, slowed neurocognitive development, and unresponsiveness to oral vaccines. Prenatal exposure to malnutrition and breast feeding by malnourished mothers replicates EED. Pups are characterized by deprivation of secretory IgA (SIgA) and altered development of the gut immune system and microbiota. Extracellular ATP (eATP) released by microbiota limits T follicular helper (Tfh) cell activity and SIgA generation in Peyer's patches (PPs). Administration of a live biotherapeutic releasing the ATP-degrading enzyme apyrase to malnourished pups restores SIgA levels and ameliorates stunted growth. SIgA is instrumental in improving the growth and intestinal immune competence of mice while they are continuously fed a malnourished diet. The analysis of microbiota composition suggests that amplification of endogenous SIgA may exert a dominant function in correcting malnourishment dysbiosis and its consequences on host organisms, irrespective of the actual microbial ecology.

Disulfidptosis-related Protein RPN1 may be a Novel Anti-osteoporosis Target of Kaempferol.

Osteoporosis (OP) is an age-related skeletal disease. Kaempferol can regulate bone mesenchymal stem cells (BMSCs) osteogenesis to improve OP, but its mechanism related to disulfidptosis, a newly discovered cell death mechanism, remains unclear. The study aimed to investigate the biological function and immune mechanism of disulfidptosis- related ribophorin I (RPN1) in OP and to experimentally confirm that RPN1 is the target for the treatment of OP with kaempferol. Differential expression analysis was conducted on disulfide-related genes extracted from the GSE56815 and GSE7158 datasets. Four machine learning algorithms identified disease signature genes, with RPN1 identified as a significant risk factor for OP through the nomogram. Validation of RPN1 differential expression in OP patients was performed using the GSE56116 dataset. The impact of RPN1 on immune alterations and biological processes was explored. Predictive ceRNA regulatory networks associated with RPN1 were generated via miRanda, miRDB, and TargetScan databases. Molecular docking estimated the binding model between kaempferol and RPN1. The targeting mechanism of kaempferol on RPN1 was confirmed through pathological HE staining and immunohistochemistry in ovariectomized (OVX) rats. RPN1 was abnormally overexpressed in the OP cohort, associated with TNF signaling, hematopoietic cell lineage, and NF-kappa B pathway. Immune infiltration analysis showed a positive correlation between RPN1 expression and CD8+ T cells and resting NK cells, while a negative correlation with CD4+ naive T cells, macrophage M1, T cell gamma delta, T cell follicular helper cells, activated mast cells, NK cells, and dendritic cells, was found. Four miRNAs and 17 lncRNAs associated with RPN1 were identified. Kaempferol exhibited high binding affinity (-7.2 kcal/mol) and good stability towards the RPN1. The experimental results verified that kaempferol could improve bone microstructure destruction and reverse the abnormally high expression of RPN1 in the femur of ovariectomized rats. RPN1 may be a new diagnostic biomarker in patients with OP, and may serve as a new target for kaempferol to improve OP.

Reciprocal regulation of T follicular helper cells and dendritic cells drives colitis development.

The immunological mechanisms underlying chronic colitis are poorly understood. T follicular helper (TFH) cells are critical in helping B cells during germinal center reactions. In a T cell transfer colitis model, a lymphoid structure composed of mature dendritic cells (DCs) and TFH cells was found within T cell zones of colonic lymphoid follicles. TFH cells were required for mature DC accumulation, the formation of DC-T cell clusters and colitis development. Moreover, DCs promoted TFH cell differentiation, contributing to colitis development. A lineage-tracing analysis showed that, following migration to the lamina propria, TFH cells transdifferentiated into long-lived pathogenic TH1 cells, promoting colitis development. Our findings have therefore demonstrated the reciprocal regulation of TFH cells and DCs in colonic lymphoid follicles, which is critical in chronic colitis pathogenesis.

CDK1 Acts as a Prognostic Biomarker Associated with Immune Infiltration in Pan-Cancer, Especially in Gastrointestinal Tumors.

Cyclin-dependent kinase 1 (CDK1) regulates the cell cycle and is highly expressed in most tumors. CDK1 expression has been associated with poor disease prognosis. This study aimed to identify the prognostic value of CDK1 in pan-cancer and investigate the association between CDK1 expression and immune cell infiltration. CDK1 expression and its correlation with prognosis in pan-cancer were analyzed using online databases. Immune infiltration was assessed by ESTIMATE and CIBERSORT algorithms. We then evaluated the relationship between CDK1 expression and tumor mutational burden (TMB), microsatellite instability (MSI), or tumor-infiltrating immune cells. In addition, we performed the co-expression analysis of immune-related genes and GO analysis with CDK1 expression in pan-cancer. Finally, we compared the CDK1 expression profile with the immune-related genes in 30 pairs of clinical gastrointestinal tumor samples. Our analysis demonstrated overexpression of CDK1 in most tumor tissues, especially in gastrointestinal tumors. The high expression of CDK1 was associated with poor overall survival, disease-specific survival, disease-free interval, and progression-free interval in kidney renal papillary cell carcinoma (KIRP), liver hepatocellular carcinoma (LIHC), lung adenocarcinoma (LUAD), pancreatic adenocarcinoma (PAAD), prostate adenocarcinoma (PRAD), and sarcoma (SARC). Besides, CDK1 expression was significantly associated with TMB in 22 cancer types and MSI in 8 cancer types as well as greater frequencies of MSI-high (MSI-H) status and high tumor mutational burden (TMB-H) in uterine corpus endometrial carcinoma (UCEC), stomach adenocarcinoma (STAD), sarcoma (SARC), rectum adenocarcinoma (READ), mesothelioma (MESO), head and neck squamous cell carcinoma (HNSC), and colon adenocarcinoma (COAD). In addition, CDK1 expression correlated with immune cell infiltrating levels, such as M0, M1, or M2 macrophages, memory CD4 T cells, T follicular helper cells, and naive B cells. Our data showed that CDK1 was remarkably correlated with 47 immune-related and immune checkpoint genes in many cancer types. Furthermore, CDK1 was up-regulated in gastrointestinal tumor samples, especially in gastric cancer and intestinal cancer. CDK1 was positively correlated with IDO1 in gastric cancer and PD-1 in intestinal cancer. Taken together, our data demonstrated the roles of CDK1 in oncogenesis and metastasis in pan-cancer. Thus, CDK1 is a potential prognostic biomarker and a target for tumor immunotherapy.

A combination of 5-azacytidine and nivolumab is a potentially effective rescue therapy in relapsed/refractory AITL.

Angioimmunoblastic T-cell lymphoma (AITL) is a peripheral T-cell lymphoma characterized by a T follicular helper cell phenotype expressing PD-1 (programmed cell death-1). AITL exhibits a poor response to conventional chemotherapy, with a median 5-year overall survival of 44% and a progression-free survival of 32%. Relapse is common, resulting in a median overall survival of 6 months. Recurrent mutations are detected in genes regulating DNA methylation, including TET2, DNMT3A, and IDH2 variants, along with the prevalent RHOA G17V mutation. In this context, patients treated with the hypomethylating agent 5-azacytidine achieved overall response and complete response rates of 75% and 41%, respectively. We hypothesized that targeted therapies combining anti-PD-1 checkpoint blockers with hypomethylating agents could be efficient in AITL patients and less toxic than standard chemotherapy. Here, we report the efficacy of a regimen combining 5-azacytidine and nivolumab in nine relapsed or refractory AITL patients. This regimen was well-tolerated, especially in elderly patients. The overall response rate was 78%, including four partial responses (44%) and three complete responses (33%). Allogeneic hematopoietic stem cell transplantation was performed in two patients who reached complete response. These preliminary favorable results may serve as a basis for further investigation in prospective studies.

Inhibition of receptor interacting protein kinase-1 (RIPK1) in the treatment of murine lupus

ObjectiveSystemic lupus erythematosus (SLE) is a type of autoimmune disease that involves multiple organs involved as well as cytokine dysregulation. The treatment of SLE is still challenging due to the...