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BACKGROUND: Research has suggested significant correlations among ageing, immune microenvironment, inflammation and tumours. However, the relationships among ageing, immune microenvironment, cystitis and bladder urothelial carcinoma (BLCA) in the bladder have rarely been reported.
METHODS: Bladder single-cell and transcriptomic data from young and old mice were used for immune landscape analysis. Transcriptome, single-cell and The Cancer Genome Atlas Program datasets of BLCA and interstitial cystitis/bladder pain syndrome (IC/BPS) were used to analyse immune cell infiltration and molecular expression. Bladder tissues from mice, IC/BPS and BLCA were collected to validate the results.
RESULTS: Eight types of immune cells (macrophages, B-cells, dendritic cells, T-cells, monocytes, natural killer cells, γδ T-cells and ILC2) were identified in the bladder of mice. Aged mice bladder tissues had a significantly higher number of T-cells, γδ T-cells, ILC2 and B-cells than those in the young group (P < 0.05). Three types of T-cells (NK T-cells, γδ T-cells and naïve T-cells) and three types of B-cells (follicular B-cells, plasma and memory B-cells) were identified in aged mice bladder. Chemokine receptor 7 (CCR7) is highly expressed in aged bladder, IC/BPS and BLCA (P < 0.05). CCR7 is likely to be involved in T- and B-cell infiltration in aged bladder, IC/BPS and BLCA. Interestingly, the high CCR7 expression on BLCA cell membranes was a prognostic protective factor.
CONCLUSIONS: In this study, we characterised the expression profiles of immune cells in bladder tissues of aged and young mice and demonstrated that CCR7-mediated T- and B-cell filtration contributes to the development of bladder ageing, IC/BPS and BLCA.

BACKGROUND: Bushen Formula (BSF) is the effective traditional Chinese medicine (TCM) for chronic hepatitis B (CHB) according to our previous researches. However, the special effectiveness of BSF treating CHB patients in different stages and the immunoregulatory mechanisms remain to be explored.
OBJECTIVE: To compare the therapeutic effects of BSF in both treatment-naive patients and Peg-IFN-α-treated patients, and explore the potential mechanism of immunomodulation.
METHODS: Ultra-high performance liquid chromatography-quadrupole electrostatic field-orbital trap high resolution mass spectrometry and the TCMSP database were used to determine the main components of BSF. Two hundred and sixty-six patients were enrolled in the retrospective study, and they were divided into the treatment group (T-Group, BSF plus Peg-IFN-α) and the control group (C-Group, Peg-IFN-α monotherapy). Within each group, patients were further grouped into subgroups, namely T1/C1 groups (treatment-naive patients, T1 = 34, C1 = 94) and T2/C2 groups (Peg-IFN-α-treated patients, T2 = 56, C2 = 82). Serum HBV markers, serum HBV DNA levels, serum ALT/AST and TCM symptoms were obtained from the record. Bioinformatics analysis was employed to obtain the potential immunoregulatory mechanisms of BSF treating CHB patients. Among patients in T2 and C2 group, peripheral mononuclear cells from 36 patients were used to analyze the characteristics of peripheral follicular helper T (Tfh) cells and B-cell subtypes by flow cytometry. Preparation of BSF-containing serum in rats. In vitro, the co-culture system of CXCR5+ cells and HepG2.2.15 cells was built to investigate the immunoregulatory effects of BSF.
RESULTS: A total of 14 main active compounds were detected in BSF, which were deemed critical for the treatment of CHB. Our findings indicated that the T2-Group exhibited the higher percentage of HBsAg decline ≥ 1-log10 IU/ml and rate of HBeAg seroclearance compared to the C2-Group (35.7% vs. 15.9%, P = 0.033; 33.9% vs. 11.0%, P = 0.002). Additionally, the T2-Group demonstrated the higher percentage of HBsAg decline ≥ 1-log10 IU/ml and rate of HBeAg seroclearance compared to the T1-Group (35.7% vs. 14.7%, P = 0.031; 33.9% vs. 2.9%, P = 0.000). The total effective rate based on TCM clinical syndrome in T1-Group and T2-Group were significantly greater than those in C1-Group and C2-Group (85.3% vs. 61.7%, P = 0.012; 89.1% vs. 63.4%, P = 0.000). Bioinformatics analysis indicated that the immunoregulatory mechanisms of BSF treating CHB patients were mainly linked to the growth and stimulation of B-cell, T-cell differentiation, and the signaling pathway of the B-cell receptor. Furthermore, the frequencies of Tfh cells and its IL-21 level, and the IL-21R expressed by B-cell were all increased after BSF treatment. Additionally, in the co-culture system of CXCR5+ cells and HepG2.2.15 cells, HBsAg and HBeAg levels were decreased after BSF-containing serum treatment，as well as the up-regulating of Tfh cell frequencies and down-regulating of B-cell frequencies.
CONCLUSIONS: BSF have the higher percentage of HBsAg decline and HBeAg seroclearance in Peg-IFN-α-treated patients compared with treatment-naive patients. The potential immunoregulatory mechanism may correlate with promoting the interaction between Tfh cells and B-cell through IL-21/IL-21R signaling pathway.

Background: The advent of first- and second-generation BCR/ABL1 tyrosine kinase inhibitors (TKIs), such as imatinib and dasatinib, has markedly improved the clinical outcomes of patients with philadelphia chromosome-positive acute lymphoblastic leukemia (Ph+-ALL). However, due to acquired drug resistance, most Ph+-ALL patients experience relapse. Thus, third-generation BCR/ABL1 TKIs, including ponatinib and olverembatinib, have been developed with the aim of overcoming drug resistance. Case report: A 79-year-old woman presented with intermittent fever and fatigue for 4 days. After comprehensive cytogenetic examination, the patient was diagnosed with Ph+-B-ALL. Starting on 22 September 2021, a combined regimen of flumatinib and vincristine/prednisone (VP) was administered for seven cycles, followed by flumatinib maintenance therapy. The patient remained in first complete molecular remission (1st CMR) for 19 months. On 12 March 2023, she again complained of fatigue and loss of appetite for nearly a month. A comprehensive examination showed Ph+-B-ALL relapse with additional E255V mutation, although T315I mutation was negative. In view of her frail physical condition, she received olverembatinib monotherapy and achieved second CMR (second CMR). No severe toxicities were recorded except for mild fatigue. At present, she has been in second CMR for over 6 months. Conclusion: For elderly patients with relapsed Ph+-ALL, olverembatinib monotherapy may offer a novel option with a good safety profile, suggesting the feasibility of a chemo-free regimen.

The epitope is the site where antigens and antibodies interact and is vital to understanding the immune system. Experimental identification of linear B-cell epitopes (BCEs) is expensive, is labor-consuming, and has a low throughput. Although a few computational methods have been proposed to address this challenge, there is still a long way to go for practical applications. We proposed a deep learning method called DeepLBCEPred for predicting linear BCEs, which consists of bi-directional long short-term memory (Bi-LSTM), feed-forward attention, and multi-scale convolutional neural networks (CNNs). We extensively tested the performance of DeepLBCEPred through cross-validation and independent tests on training and two testing datasets. The empirical results showed that the DeepLBCEPred obtained state-of-the-art performance. We also investigated the contribution of different deep learning elements to recognize linear BCEs. In addition, we have developed a user-friendly web application for linear BCEs prediction, which is freely available for all scientific researchers at: http://www.biolscience.cn/DeepLBCEPred/.

Plasmablastic lymphoma (PBL) is a rare form of lymphoma in people. PBL originates from plasmablasts and usually presents with swelling/mass in the mouth/neck. A 7-year-old Mongrel dog was presented for a large oral and neck mass. Cytology and histopathology were suggestive of a round cell tumor that was suspected to be lymphoma. An immunohistochemical (IHC) stain panel showed positive for CD18, thus supporting the diagnosis of round cell tumor, but negative for T- and B-cell lymphomas, CD3, CD20, and PAX-5. Other markers including cytokeratin AE1/3 (for epithelial cell origin), CD31 (for endothelial cells), SOX10 (for melanoma), IBa-1 (for histiocytic sarcoma), and CD117 (for mast cell tumor) were all negative. MUM-1 (for plasma cell differentiation) was strongly positive and CD79a (B cell and plasma cells) was also scantly positive. Based on the histopathology and immunohistochemistry results in combination with the clinical presentation, a suspected diagnosis of PBL was made. As per available literature, this is perhaps the first highly suspected case of PBL in a dog.

OBJECTIVE: CRLF2 alterations are associated with B-cell precursor acute lymphoblastic leukemia (BCP-ALL). This study aimed to explore the clinical, biological, and outcome features of pediatric BCP-ALL with CRLF2 abnormalities.
METHODS: This study enrolled 630 childhood BCP-ALLs treated on CCLG-ALL 2008 or 2018 protocol. P2RY8-CRLF2 was determined by Sanger sequencing and CRLF2 expression was evaluated by qRT-PCR. The correlation between clinical, biological features and outcomes with P2RY8-CRLF2 or CRLF2 over-expression were analyzed.
RESULTS: P2RY8-CRLF2 and CRLF2 over-expression were found in 3.33% and 5.71% respectively. P2RY8-CRLF2 was associated with male, higher frequency of CD7 expression, high WBC and MRD before consolidation. CRLF2 over-expression showed ETV6-RUNX1- , higher frequency of CD22, CD34, CD66c, CD86 expression, hyperdiploidy and high MRD at early treatment. The lower overall survival (OS) was found in patients with P2RY8-CRLF2 and confined only in IR group. Furthermore, adverse event-free survival and OS of P2RY8-CRLF2 were discovered comparing to those without known fusions or treated on CCLG-ALL 2008 protocol. However, P2RY8-CRLF2 was not confirmed as independent prognostic factors and no prognostic impact of CRLF2 over-expression was found.
CONCLUSIONS: These findings indicate P2RY8-CRLF2 identifies a subset of patients with specific features and adverse outcomes that could be improved by risk-directed treatment.

Mucosa-associated lymphoid tissue (MALT) lymphoma is a B-cell tumour that develops over many decades in the stomachs of individuals with chronic Helicobacter pylori infection. We developed a new mouse model of human gastric MALT lymphoma in which mice with a myeloid-specific deletion of the innate immune molecule, Nlrc5, develop precursor B-cell lesions to MALT lymphoma at only 3 months post-Helicobacter infection versus 9-24 months in existing models. The gastric B-cell lesions in the Nlrc5 knockout mice had the histopathological features of the human disease, notably lymphoepithelial-like lesions, centrocyte-like cells, and were infiltrated by dendritic cells (DCs), macrophages, and T-cells (CD4+ , CD8+ and Foxp3+ ). Mouse and human gastric tissues contained immune cells expressing immune checkpoint receptor programmed death 1 (PD-1) and its ligand PD-L1, indicating an immunosuppressive tissue microenvironment. We next determined whether CD40L, overexpressed in a range of B-cell malignancies, may be a potential drug target for the treatment of gastric MALT lymphoma. Importantly, we showed that the administration of anti-CD40L antibody either coincident with or after establishment of Helicobacter infection prevented gastric B-cell lesions in mice, when compared with the control antibody treatment. Mice administered the CD40L antibody also had significantly reduced numbers of gastric DCs, CD8+ and Foxp3+ T-cells, as well as decreased gastric expression of B-cell lymphoma genes. These findings validate the potential of CD40L as a therapeutic target in the treatment of human gastric B-cell MALT lymphoma. © 2023 The Authors. The Journal of Pathology published by John Wiley & Sons Ltd on behalf of The Pathological Society of Great Britain and Ireland.

Monkeypox virus is an infectious agent that causes fever, Pneumonitis encephalitis, rash, lymphadenopathy and bacterial infection. The current outbreak of monkeypox has reawakened the global health concern. In the current situation of increasing viral infection, no vaccine or drug is available for monkeypox. Thus, there is an urgent need for viable vaccine development to prevent viral transmission by boosting human immunity. Herein, using immunoinformatics approaches, a multi-epitope vaccine was constructed for the Monkeypox virus. In this connection, B-Cell and T-cell epitopes were identified and joined with the help of adjutants and linkers. The vaccine construct was selected based on promising vaccine candidates and immunogenic potential. Further epitopes were selected based on antigenicity score, non-allergenicity and good immunological properties. Molecular docking reveals strong interactions between TLR-9 and the predicted vaccine construct. Finally, molecular dynamics simulations were performed to evaluate the stability and compactness of the constructed vaccine. The MD simulation results demonstrated the significant stability of the polypeptide vaccine construct. The predicted vaccine represented good stability, expression, immunostimulatory capabilities and significant solubility. Design vaccine was verified as efficient in different computer-based immune response investigations. Additionally, the constructed vaccine also represents a good population coverage in computer base analysis.Communicated by Ramaswamy H. Sarma.

Type 1 diabetes (T1D) is one of the T cells mediated autoimmune diseases, although B cells also play an important role in the development. Both T cell and B cell targeted immunotherapies exhibited efficacies in preventing and reversing the T1D. Current study was performed to investigate the protective effects of anti-CD20/CD3 bi-specific antibody (bsAb) in combination with adenovirus mediated mouse insulin-like growth factor 1 (Adv-mIGF-1) gene on T1D in non-obese diabetes (NOD) mice. To simultaneously restore the proportion of Th cells and block the interaction of B cells as well as mediate T cell populations, the NOD model mice were randomly assigned to four groups received the saline, anti-CD20/CD3 bsAb and Adv-mIGF-1 gene alone or combination, respectively. After 16-consecutive weeks intervention, the ELISA, RT-PCR, western blot and histopathological analysis were performed to assess the pancreatic tissues and serum samples to evaluate the treatment effects. Chronic treatment of combination therapy improved T1D morbidity by improving the compartment and function of the CD4+Foxp3+ Tregs, reversing the secretion of insulin, controlling the blood glucose levels (BGLs) and alleviating insulitis as well as cell apoptosis in the NOD model mice. Moreover, current combination therapy also accelerated the proliferation and differentiation of pancreatic β cells via suppressing the apoptosis-related factors, including caspase-3, caspase-8 and Fas, and activating the Bcl-2-related anti-apoptotic pathway. Furthermore, the cytokeratin-19 (CK-19) and pancreatic duodenal homoplasmic box-1 (PDX-1), as two important stem cell markers of pancreas were both significantly improved by treatment of combination therapy. On conclusions, chronic treatment of anti-CD20/CD3 bsAb in combination with Adv-mIGF-1 gene exerts synergistic protection on T1D in the NOD mice.