Search

Emerging evidence indicates that memory B cells are dysfunctional in systemic lupus erythematosus (SLE). They are hyporesponsive to signalling through the B cell receptor (BCR) but retain responsiveness to Toll-like receptor (TLR) and type I interferon signalling, as well as to T cell-mediated activation via CD40–CD154. Chronic exposure to immune complexes of ribonucleoprotein (RNP)-specific autoantibodies and TLR-engaging or BCR-engaging cargo is likely to contribute to this partially anergic phenotype. TLR7 or TLR8 signalling and the resulting production of type I interferon, as well as the sustained activation by bystander T cells, fuel a positive feedforward loop in memory B cells that can evade negative selection and permit preferential expansion of anti-RNP autoantibodies. Clinical trials of autologous stem cell transplantation or of B cell-targeted monoclonal antibodies and chimeric antigen receptor (CAR) T cells have correlated replenishment of the memory B cell population with relapse of SLE. Moreover, the BCR hyporesponsiveness of memory B cells might explain the failure of non-depleting B cell-targeting approaches in SLE, including BTK inhibitors and anti-CD22 monoclonal antibodies. Thus, targeting of dysfunctional memory B cells might prove effective in SLE, while also avoiding the adverse events of broad-spectrum targeting of B cell and plasma cell subsets that are not directly involved in disease pathogenesis. BCR-independent memory B cell reactivation via TLR7 or TLR8 activation, type I interferon production, immune complex formation and T helper cell signalling is central in SLE pathogenesis. Dörner and Lipsky discuss the potential of targeting these pathways to eliminate autoreactive memory B cells and plasma cells in SLE. Key points: In systemic lupus erythematosus (SLE), memory B cells are hyporesponsive to B cell receptor (BCR) stimulation but can be activated upon engagement of Toll-like receptors (TLRs) and interaction with T cells (mainly via the CD40–CD40L axis). Both innate and adaptive immune signalling by B cells ('bridging') contribute to SLE pathology, possibly via a pathogenic positive feedforward loop. This feedforward loop is accentuated by anti-ribonucleoprotein (anti-RNP) autoantibodies sequestering RNP antigens, which, when internalized via the BCR, stimulate TLR7 and TLR8 signalling and type I interferon production. Incomplete X chromosomal inactivation of TLR7, TLR8 and CD40L might further contribute to such a positive feedforward loop, thereby potentially explaining the female sex bias in SLE. Clinical outcomes of B cell depletion in SLE, via anti-CD20 or anti-CD19 or autologous stem cell transplantation, have clearly associated relapse with memory B cell repletion, independently of the recurrence of naive B cells or autoantibodies. The safety and efficacy of CD19-targeted and BCMA-targeted chimeric antigen receptor (CAR) T cells, or bispecific T cell engagers in SLE, and their impact on tissue-resident memory B cells remain to be elucidated. BCR signalling inhibition approaches did not result in sufficient efficacy potentially owing to an incomplete impact on memory B cells. [ABSTRACT FROM AUTHOR]

Context: cholangiocarcinoma with highly heterogeneous, aggressive, and multidrug resistance has a poor prognosis. although babaodan (BBD) combined with cisplatin improved non-small cell lung cancer efficacy, its impact on overcoming resistance in cholangiocarcinoma remains unexplored. Objective: this study explored the role and mechanism of BBD on cisplatin resistance in cholangiocarcinoma cells (ccas). Materials and methods: cisplatin-resistant ccas were exposed to varying concentrations of cisplatin (25-400 μg/ml) or BBD (0.25-1.00 mg/ml) for 48 h. ic50 values, inhibition ratios, apoptosis levels, DNa damage, glutathione (GSH) levels, oxidized forms of Gsh, total Gsh content, and glutaminase relative activity were evaluated using the cell counting kit 8, flow cytometry, comet assay, and relevant assay kits. Results: BBD-reduced the cisplatin ic50 in ccas from 118.8 to 61.83 μg/ml, leading to increased inhibition rate, apoptosis, and DNa damage, and decreased expression of B-cell lymphoma-2, p-Yes-associated protein 1/ Yes-associated protein 1, solute carrier family 1 member 5, activating transcription factor 4, and eRcc excision repair 1 in a dose-dependent manner with maximum reductions of 78.97%, 51.98%, 54.03%, 56.59%, and 63.22%, respectively; bcl2-associated X and gamma histone levels were increased by 0.43-115.77% and 22.15-53.39%. the impact of YaP1 knockdown on cisplatin-resistant ccas resembled BBD. Gsh, oxidized Gsh species, total Gsh content, and glutaminase activity in cisplatin-resistant ccas with BBD treatment also decreased, while YaP1 overexpression countered BBD's effects. Discussion and conclusion: this study provides a scientific basis for BBD clinical application and provides a new direction for BBD biological mechanism research. [ABSTRACT FROM AUTHOR]

Introduction: Systemic Lupus Erythematosus, an autoimmune disease, can target various organs of the human body. Lupus nephritis (LN) is a major complication affecting almost half of all SLE patients, with classes "III and IV" being the most aggressive. The severity and prognosis of LN can be influenced by different biomarkers, some of which are used as therapeutic targets. One such target is the B-cell activating factor (BAFF), a key figure in the pathophysiology of SLE. New add-on treatments have emerged in the treatment of LN targeting BAFF as well as other pathways. Assortment of patients to suitable treatment combinations needs more precision using guiding markers. Methods: This prospective study aims to explore BAFF-expression in patients with active-proliferative LN and its possible association with the response after induction therapy. Peripheral blood mononuclear cells (PBMC) and renal tissue samples (if applicable) were collected from participants before the initiation of induction treatment. RNA was extracted, and the expression levels of BAFF-mRNA were measured using quantitative real-time polymerase chain reaction. Clinical and laboratory data, including disease activity indices and renal functions, were recorded at baseline and 6-months after the commencement of the induction treatment. Results: The study included 24 patients,14 responders and 10 non-responders. At baseline, median PBMC BAFF-mRNA expression was nearly identical in responders and non-responders. Renal BAFF-expression was found to be higher in non-responders, although non-significant (p = 0.21). Contrary to PBMC BAFF expression, renal BAFF-mRNA was negatively correlated with baseline glomerular filtration rate and with the primary endpoint of response, which was reduction of proteinuria to≥50% of baseline (p = 0.07). Conclusions: Renal BAFF expression could be a better representative of severity and therapeutic response than blood expression. We acknowledge that the use of BAFF expression as a predictive for early refractoriness to therapy in LN is not yet conclusive. [ABSTRACT FROM AUTHOR]

The article discusses a case study of a 41-year-old male with NFkB1 haploinsufficiency, a condition associated with lymphoproliferative disease (LPD). The patient exhibited chronic lymphadenopathy and impaired apoptosis, leading to resistance to cell death triggers. The study highlights the importance of understanding the mechanisms underlying LPD in NFkB1 haploinsufficient patients and suggests potential therapeutic targets for further research. The findings emphasize the need for personalized monitoring and treatment strategies for individuals with this condition. [Extracted from the article]

The article focuses on the treatment challenges and progress in understanding hidradenitis suppurativa (HS), a chronic inflammatory skin disease. Topics include the role of B cells and immune signaling in disease progression, the involvement of fibroblasts and tissue inflammation in fibrosis, and the promising future of targeted therapies based on HS's underlying pathogenesis.

B-cell activating factor belonging to the TNF family (BAFF), also known as B-lymphocyte stimulator (BLyS), plays a crucial role in B-cell development. It has multiple receptors, including BCMA, TACI, and BAFF-R, with diverse roles in different cell types. BAFF induces B-cell proliferation and immunoglobulin secretion, and acts as a survival factor for immature, naive, and activated B cells. Consequently, BAFF-deficient mice often show suppressed humoral responses, while BAFF-overexpressing mice show the higher number of mature B cells and may develop autoimmune-like manifestations and B-cell lymphoproliferative diseases. Elevated BAFF levels are also associated with various hematological malignancies, and its expression correlates with disease progression in some cases. Therefore, BAFF-targeted therapies, such as belimumab, atacicept, and tabalumab, are being explored in clinical trials for conditions like chronic lymphocytic leukemia (CLL) and multiple myeloma. Belimumab, an anti-BAFF monoclonal antibody, is being investigated in combination with rituximab/venetoclax for CLL. Atacicept, a decoy receptor for BAFF and APRIL, showed tolerability in a phase 1b trial for CLL. Tabalumab, another monoclonal antibody targeting BAFF, did not demonstrate significant efficacy in a phase 2 study for relapsed/refractory multiple myeloma. BAFF ligand-based CAR-T cells are designed to target BAFF receptors and show promise in preclinical studies, particularly for B-cell malignancies. The review emphasizes the importance of understanding the roles of BAFF and its receptors in the microenvironment of hematologic malignancies. Targeting BAFF and its receptors presents potential therapeutic avenues, and ongoing clinical trials provide valuable insights. [ABSTRACT FROM AUTHOR]

The article presents the results of a phase 3 trial comparing the effectiveness of nivolumab combined with doxorubicin, vinblastine, and dacarbazine (N+AVD) versus brentuximab vedotin with the same chemotherapy regimen (BV+AVD) for treating advanced-stage classic Hodgkin's lymphoma in adolescents and adults. The findings indicate that N+AVD significantly improves progression-free survival compared to BV+AVD.

Relapse after immunosuppression (IS) treatment withdrawal is frequent in patients with Autoimmune Hepatitis (AIH), and non-invasive biomarkers predictive of this risk are lacking. We assessed the frequency of circulating T cell subsets as potential biomarkers of disease activity and predictor of the risk of relapse after IS withdrawal. Serum levels of the cytokine B-cell Activating Factor (BAFF) were also investigated. Blood samples from 58 patients with active AIH, 56 AIH patients in remission, and 31 patients with NASH were analyzed. The frequency of activated CD4+ T peripheral helper (TPH) cells (CD4+CD45RA-CXCR5-PD1+CD38+) and of activated CD8+ T cells (CD8+CD45RA-PD1+CD38+) were assessed by flow cytometry. BAFF levels were determined by ELISA. Activated TPH and CD8+ T cell frequencies were significantly increased in patients with active AIH compared to remission AIH or NASH (TPH: 0.88% of total CD3+ vs. 0.42% and 0.39% respectively, p < 0.0001; CD8+ subset: 1.42% vs. 0.09% and 0.11% p < 0.0001). Among patients in remission undergoing treatment withdrawal (n = 18), those with increased frequencies of activated TPH (> 0.5% of total CD3+) and/or activated CD8+ T cells (> 0.18% total CD3+) had a higher risk of relapse (80% vs. 15% after 2 years, p = 0.0071). High BAFF serum concentration (> 213pg/ml) was also associated to a higher risk of relapse (57% vs. 11%, p = 0.0452). In conclusion, high frequency of activated TPH and of activated CD8+, as well as high levels of BAFF, before IS discontinuation, were significantly associated to a greater risk of relapse during the first two years. Thus, they represent promising biomarkers to provide personalized clinical follow-up for patients with AIH. [ABSTRACT FROM AUTHOR]

Background Telitacicept, a B lymphocyte stimulator/A proliferation-inducing ligand dual-target fusion protein, has recently been used in autoimmune diseases. We assessed the efficacy and safety of telitacicept in immunoglobulin A nephropathy (IgAN) patients. Methods This study included 42 IgAN patients who received telitacicept treatment, forming the 'whole telitacicept group'. Among them, 20 patients who had not previously received corticosteroid (CS) therapy or immunosuppressive (IS) agents were categorized as the 'newly treated telitacicept subgroup'. Additionally, 28 patients who were selected to match historical controls received conventional IS therapy (CS therapy with/without IS agents) and were classified as the 'conventional IS group'. Telitacicept was partially used in combination with conventional IS therapy, including initial CS in different doses. Various indicators were compared at 4-week intervals up to 24 weeks among the three groups. Results After 24 weeks of treatment, the 24-hour proteinuria decreased from 1.70 g [interquartile range (IQR) 1.05–2.58] to 0.21 g (IQR 0.39–0.13) (P  = .043) in the newly treated telitacicept subgroup, from 1.78 g (IQR 0.97–2.82) to 0.44 g (IQR 1.48–0.16) (P  = .001) in the conventional IS group and from 1.07 g (IQR 0.66–1.99) to 0.26 g (IQR 0.59–0.17) (P  = .028) in the whole telitacicept group. The estimated glomerular filtration rate (eGFR) increased from 76.58 ± 30.26 ml/min/1.73 m2 to 80.30 ± 26.76 ml/min/1.73 m2 (P  = .016) in the newly treated telitacicept subgroup, from 72.73 ± 33.41 ml/min/1.73 m2 to 84.08 ± 26.81 ml/min/1.73 m2 (P  = .011) in the conventional IS group and from 70.10 ± 32.88 ml/min/1.73 m2 to 71.21 ± 31.49 ml/min/1.73 m2 (P  = .065) in the whole telitacicept group. During follow-up periods, the efficacy rates of the three groups did not show statistically significant differences and no serious adverse events were observed. Conclusions Telitacicept may be a safe and effective treatment for IgAN, offering reductions in proteinuria and increases in eGFR similar to conventional IS therapy. After a 24-week follow-up, the incidence of adverse events was lower for telitacicept than for conventional IS therapy. [ABSTRACT FROM AUTHOR]

The article discusses a case study of a 1-year-old girl with diffuse alveolar hemorrhage (DAH) as the initial presentation of hypomorphic RAG1 deficiency, a combined immunodeficiency disorder. The patient experienced severe respiratory symptoms, anemia, and abnormal immune cell counts, leading to a diagnosis of leaky severe combined immunodeficiency. Treatment with corticosteroids and immunoglobulins showed improvement, but the patient later died due to acute respiratory failure. The study highlights the importance of considering RAG1 deficiency in DAH cases and expanding autoantibody testing to anti-cytokine antibodies for diagnosis. [Extracted from the article]

The document is a collection of summaries of various research studies related to HIV prevention and treatment. The studies cover a range of topics, including the use of pre-exposure prophylaxis (PrEP), the development of HIV vaccines and antibodies, and the implementation of long-acting HIV prevention methods. The studies provide valuable insights into different strategies and interventions aimed at increasing HIV testing, prevention, and treatment outcomes. [Extracted from the article]

• B-cell activating factor is essential for the modulation of immune humoral responses. • BAFF was repeatedly associated with non-psychiatric inflammatory and autoimmune conditions. • High levels of soluble BAFF characterize both acute and stabilized patients with SZ and BD and under a genetic control. • sBAFF levels are correlated with positivity of stigma of infection and of autoimmune comorbidities. • BAFF appears as a promising marker of inflammatory processes in SZ and BD. Immune dysregulation is an important aspect of schizophrenia (SZ) and bipolar disorders (BD) pathophysiology, including not only inflammatory but also autoimmune process reflective of abnormal humoral immune responses. Given that B cell-activating factor (BAFF) is an integral aspect of B lymphocyte regulation, the current study investigated BAFF in SZ and BD. 255 SZ patients, 407 BD patients and 185 healthy controls (HC) were investigated across three aspects of soluble BAFF (sBAFF) by (i) comparing sBAFF circulatory levels across SZ, BD and HC, (ii) determining potential correlations between the circulating levels of sBAFF and the genotype distribution of a functionally relevant polymorphism, namely the TNFSF13B 3′UTR insertion-deletion polymorphism (GCTGT>A), (iii) analyzing relationships between both sBAFF levels and 3′UTR insertion-deletion genotypes and disease risk, patients clinical characteristics and circulating levels of potent inflammatory molecules. In addition, in subsets of patients, we also searched for possible correlations between sBAFF levels and stigma of past infectious events as well as positivity for circulating systemic autoantibodies or those directed against central nervous system (CNS) structures. Studying blood derived serum and DNA, we observed that circulating sBAFF levels were significantly higher in SZ and BD patients, versus HC (p = 5.3*10-10 and p = 4.4*10-09). Patients experiencing acute episodes, versus stable patients, in between acute episodes, exhibited higher sBAFF levels (p = 0.017). In SZ patients, positive correlations were observed between elevated sBAFF levels and: (i) elevated positive psychotic symptoms (PANSS pos), (ii) history of childhood trauma (physical abuse), and (iii) low scores on global functioning (GAF) (p = 0.024, p = 0.024, and p = 0.041). We also found that the distribution of the BAFF Ins/Del genotypes was significantly correlated with circulating sBAFF levels in SZ and BD patients (p = 0.0004). Elevated sBAFF levels were also correlated with increased levels of pro-inflammatory markers in both SZ and BD cohorts (p < 0.001). Regarding infectious stigma, only patients seropositive, versus seronegative, for herpes simplex virus (HSV)1 immunoglobulin (Ig)G antibodies exhibited a significant association with high sBAFF levels (p = 0.013). In contrast, positivity for systemic or CNS autoantibodies was significantly associated with reduced sBAFF levels, compared to patients without autoantibodies (p = 0.0017). Overall, our findings indicate that BAFF may be a promising trans -nosographic biomarker of inflammation that is likely to offer predictive, diagnostic, and prognostic tools for the management of SZ and BD. The results therefore have practicable clinical utility given the availability of immunotherapeutic treatment options including targeted monoclonal antibodies against BAFF. [ABSTRACT FROM AUTHOR]

This document provides a concise summary of the management and treatment of immunoglobulin A nephropathy (IgAN), a common kidney disease. It highlights the importance of early detection, referral to a nephrologist, and initiation of appropriate treatment. The article discusses various treatment options, including corticosteroids and emerging therapies, and emphasizes the role of general practitioners in optimizing standard care and monitoring treatment response. The ultimate goal is to delay the progression of kidney disease, and collaboration between general practitioners and nephrologists is expected to strengthen as new therapies emerge. [Extracted from the article]

The "multi‐hit theory/4‐hit theory" pathogenesis hypothesis is widely accepted and IgA nephropathy (IgAN) is understood to be a disease originating from Hit 1, galactose deficient IgA1 (GdIgA1). The chronic repetitive activation of the complement pathway (alternative and lectin pathways) and the subsequent inflammation results in progressive glomerular damage that spills over into increased intraglomerular pressure and other hemodynamic changes, increased urinary protein, glomerulosclerosis, and tubulointerstitial fibrosis. The basic pathophysiology of this disease is the progression of a mixture of such acute and chronic pathologies. Currently, a number of new drugs has emerged as promising agents, such as complement regulators, endothelin receptor antagonists, and SGLT2 inhibitors, which are associated with each pathological step after glomerular deposition of GdIgA1/immune complexes. On the other hand, the molecular mechanisms of GdIgA1 production are gradually being elucidated, and the development of several novel therapeutic agents targeting the responsible B cells and their international clinical trials are progressing. These agents that inhibit or control the production of the Hit1, GdIgA1, are highly expected as essential therapies for this disease. The large body of clinical and basic research findings to date strongly suggest that nephritogenic GdIgA1 is a polymeric IgA1 of mucosal origin. In addition, the B cells involved in its nephritogenic GdIgA1 production are mainly differentiated mature B cells such as plasma cells, which may migrate to the bone marrow as well as the mucosa. The innate immune system in the mucosa, especially Toll‐like receptors (TLRs), is thought to be involved in their production. Among TLRs, TLT9 and TLR7, which recognize bacterial and viral unmethylated DNA and RNA, have been reported to be involved. The mucosal activation of these TLRs is associated with the production of APRIL (A Proliferation Inducing Ligand) and BAFF (B cell activating factor), which are TNF superfamily cytokines involved in B cell maturation, survival, and IgA class switching, and may also be involved in the production of nephritogenic GdIgA1. It is still inconclusive whether APRIL or BAFF is more closely involved in the production of nephritogenic GdIgA1. Phenotypes in transgenic animal models suggest BAFF involvement, however, a genome wide association study (GWAS) analysis of human IgAN has identified APRIL, not BAFF, as a candidate gene. Based on the above background, several international clinical trials are underway for drugs such as TLR regulators (hydroxychloroquine), anti‐APRIL drugs, anti‐BAFF drugs, APRIL/BAFF receptor (TACI) binding inhibitors, and cytoreductive drugs (proteasome inhibitors, anti‐CD38 antibodies) to inhibit nephritogenic GdIgA1 production in responsible B cells. This session will provide an overview of the responsible B cells, their GdIgA1 production mechanism, and ongoing drugs. [ABSTRACT FROM AUTHOR]

The challenge of disease relapsed/refractory (R/R) remains a therapeutic hurdle in chimeric antigen receptor (CAR) T‐cell therapy, especially for hematological diseases, with chronic lymphocytic leukemia (CLL) being particularly resistant to CD19 CAR T cells. Currently, there is no approved CAR T‐cell therapy for CLL patients. In this study, we aimed to address this unmet medical need by choosing the B‐cell activating factor receptor (BAFF‐R) as a promising target for CAR design against CLL. BAFF‐R is essential for B‐cell survival and is consistently expressed on CLL tumors. Our research discovered that BAFF‐R CAR T‐cell therapy exerted the cytotoxic effects on both CLL cell lines and primary B cells derived from CLL patients. In addition, the CAR T cells exhibited cytotoxicity against CD19‐knockout CLL cells that are resistant to CD19 CAR T therapy. Furthermore, we were able to generate BAFF‐R CAR T cells from small blood samples collected from CLL patients and then demonstrated the cytotoxic effects of these patient‐derived CAR T cells against autologous tumor cells. Given these promising results, BAFF‐R CAR T‐cell therapy has the potential to meet the long‐standing need for an effective treatment on CLL patients. [ABSTRACT FROM AUTHOR]

Background: Despite being a major global cause of mortality, the exact underlying mechanisms of cardiovascular diseases (CVDs) remain uncertain. This study aimed to elucidate the possible pathological connection between circulating activated immune cell types and the advancement of CVD. Methods: A two-sample Mendelian randomization analysis was performed on publicly available genetic databases to examine the potential causal relationships among 731 immune phenotypes and CVD risks. The study focused on four distinct immune signatures: relative cell counts (RC), absolute cell counts (AC), morphological parameters (MP), and median fluorescence intensities (MFI). A sensitivity analysis was performed to assess the findings' consistency, robustness, and potential pleiotropic effects. Results: Significant associations between CVD and various immunophenotypes were observed in this study. Specifically, two phenotypes exhibited protective effects against CVD. The odds ratio (OR) for activated and secretory CD4+ regulatory T-cells (Tregs) was 0.757 [95% confidence interval (CI): 0.628–0.913; p = 0.004], whereas that for B-cell activating factor receptor on IgD−CD38+ memory B-cells was 0.654 (95% CI: 0.468–0.915; p = 0.013). Conversely, three major immunophenotypes were linked to heightened risks of CVD: CD80 on myeloid dendritic cells (OR: 1.181; 95% CI: 1.015–1.376; p = 0.032), the proportion of CD28+ CD45RA+ CD8+ T-cells in total T-cell population (OR: 1.064; 95% CI: 1.002–1.128; p = 0.041), and the proportion of CD28−CD45RA+ CD8+ T-cells in total T-cell population (OR: 1.005; 95% CI: 1.000–1.011; p = 0.045). Conclusion: This study underscores significant correlations between specific immune phenotypes and the risks associated with CVD onset, thus providing valuable perspectives for forthcoming clinical inquiries. [ABSTRACT FROM AUTHOR]

Impact: Immune dysregulation is thought to contribute to chronic lymphocytic leukemia (CLL) risk, but biological mechanisms are unclear. We discovered that increased serum levels of B-cell activating factor (BAFF), an important regulator of B-cell maturation, were associated with a decreased risk of CLL, even >10 years after blood draw. Our findings suggest that BAFF could be a useful biomarker to assess risk among individuals at high risk, such as those with monoclonal b-cell lymphocytosis. [ABSTRACT FROM AUTHOR]

This article explores the use of visual representations to aid patients in making decisions about kidney transplantation. The authors argue that personalized visualizations of risks, outcomes, waiting times, and dialysis risks could help patients make more informed decisions about accepting a kidney from a specific donor or remaining on dialysis. The article suggests that these visual representations could improve patient outcomes by facilitating better decision-making. [Extracted from the article]

Background and purpose: This study aimed to investigate the clinical efficacy and safety of telitacicept in patients with generalized myasthenia gravis (gMG) who tested positive for acetylcholine receptor antibodies or muscle‐specific kinase antibodies and were receiving standard‐of‐care therapy. Methods: Patients meeting the eligibility criteria were randomly assigned to receive telitacicept subcutaneously once a week for 24 weeks in addition to standard‐of‐care treatment. The primary efficacy endpoint was the mean change in the quantitative myasthenia gravis (QMG) score from baseline to week 24. Secondary efficacy endpoints included mean change in QMG score from baseline to week 12 and gMG clinical absolute score from baseline to week 24. Additionally, safety, tolerability and pharmacodynamics were assessed. Results: Twenty‐nine of the 41 patients screened were randomly selected and enrolled. The mean (± standard deviation [SD]) reduction in QMG score from baseline to week 24 was 7.7 (± 5.34) and 9.6 (± 4.29) in the 160 mg and 240 mg groups, respectively. At week 12, mean reductions in QMG scores for these two groups were 5.8 (± 5.85) and 9.5 (± 5.03), respectively, indicating rapid clinical improvement. Safety analysis revealed no adverse events leading to discontinuation or mortalities. All patients showed consistent reductions in serum immunoglobulin (Ig) A, IgG and IgM levels throughout the study. Conclusion: Telitacicept demonstrated safety, good tolerability and reduced clinical severity throughout the study period. Further validation of the clinical efficacy of telitacicept in gMG will be conducted in an upcoming phase 3 clinical trial. [ABSTRACT FROM AUTHOR]

This article discusses the role of B cells in autoimmune kidney diseases and presents new B cell-targeting therapies used in their treatment. B cells are involved in autoimmune diseases as precursors of cells producing pathogenic autoantibodies and also play a role in presenting antigens to T lymphocytes and perpetrating inflammation. The article explores B cell-depleting therapies, such as anti-CD20 monoclonal antibodies, and B cell-modulating therapies that target molecules involved in B cell homeostasis. The efficacy of these therapies varies across diseases and patients, and further research is needed to determine their place in the management of autoimmune kidney diseases. [Extracted from the article]

Background: To explore the impact of ARGs on the prognosis of NSCLC, and its correlation with clinicopathological parameters and immune microenvironment. Preliminary research on the biological functions of CEBPA in NSCLC. Methods: Using consensus clustering analysis to identify molecular subtypes of ARGs in NSCLC patients; employing LASSO regression and multivariate Cox analysis to select 7 prognostic risk genes and construct a prognostic risk model; validating independent prognostic factors of NSCLC using forest plot analysis; analyzing immune microenvironment correlations using ESTIMATE and ssGSEA; assessing correlations between prognostic risk genes via qPCR and Western blot in NSCLC; measuring mRNA and protein expression levels of knocked down and overexpressed CEBPA in NSCLC using CCK-8 and EdU assays; evaluating the effects of knocked down and overexpressed CEBPA on cell proliferation using Transwell experiments; examining the correlation of CEBPA with T cells and B cells using mIHC analysis. Results: Consensus clustering analysis identified three molecular subtypes, suggesting significant differential expression of these ARGs in NSCLC prognosis and clinical pathological parameters. There was significant differential expression between the two risk groups in the prognostic risk model, with P < 0.001. The risk score of the prognostic risk model was also P < 0.001. CEBPA exhibited higher mRNA and protein expression levels in NSCLC cell lines. Knockdown of CEBPA significantly reduced mRNA and protein expression levels of CEBPB, YWHAZ, ABL1, and CDK1 in H1650 and A549 cells. siRNA-mediated knockdown of CEBPA markedly inhibited proliferation, migration, and invasion of NSCLC cells, whereas overexpression of CEBPA showed the opposite trend. mIHC results indicated a significant increase in CD3 + CD4+, CD3 + CD8+, and CD20 + cell counts in the high CEBPA expression group. Conclusions: The risk score of the prognostic risk model can serve as an independent prognostic factor, guiding the diagnosis and treatment of NSCLC. CEBPA may serve as a potential tumor biomarker and immune target, facilitating further exploration of the biological functions and immunological relevance in NSCLC. [ABSTRACT FROM AUTHOR]

Introduction Diabetic peripheral neuropathy (DPN) impacts patient quality of life. In such patients, increased expression of mer tyrosine kinase (MerTK) has been demonstrated; however, its mechanism of action remains unclear. In this study, type 2 diabetes mellitus (T2DM) and DPN models were established in Sprague Dawley rats via low-dose streptozotocin and a high-fat diet and the mode of action of MerTK was examined. Methods MerTK-specific inhibitors were administered by gavage once daily for 2 weeks. Sciatic nerve conduction velocity and nerve structure were measured. The levels of MerTK, nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB), tumor necrosis factor-alpha (TNF-α), interleukin-1 beta (IL-1β), and relevant biochemical indexes were detected. Results The study revealed upregulation of MerTK expression in T2DM and more so in DPN groups. Inhibiting MerTK led to reduced nerve conduction velocity and further deterioration of sciatic nerve structure, as evidenced by structural morphology. Concurrently, serum levels of total cholesterol, glycated hemoglobin, and triglyceride significantly increased. Moreover, levels of NF-κB increased in both serum and nerve tissue, alongside a significant rise in TNF-α and IL-1β expressions. MerTK could bind to the inhibitor of kappa B kinase beta (Ikbkb) in Schwann cells, establishing Ikbkb as a precursor to NF-κB activation. Discussion Inhibition of MerTK exacerbates neuropathy, indicating its protective role in DPN by suppressing the NF-κB pathway, highlighting a potential new target for its diagnosis and treatment. [ABSTRACT FROM AUTHOR]

There is a reciprocal relationship between extracellular matrix (ECM) remodelling and inflammation that could be operating in the progression of severe COVID-19. To explore the immune-driven ECM remodelling in COVID-19, we in this explorative study analysed these interactions in hospitalised COVID-19 patients. RNA sequencing and flow analysis were performed on peripheral blood mononuclear cells. Inflammatory mediators in plasma were measured by ELISA and MSD, and clinical information from hospitalised COVID-19 patients (N=15) at admission was included in the analysis. Further, we reanalysed two publicly available datasets: (1) lung tissue RNA-sequencing dataset (N=5) and (2) proteomics dataset from PBCM. ECM remodelling pathways were enriched in PBMC from COVID-19 patients compared to healthy controls. Patients treated at the intensive care unit (ICU) expressed distinct ECM remodelling gene profiles compared to patients in the hospital ward. Several markers were strongly correlated to immune cell subsets, and the dysregulation in the ICU patients was positively associated with plasma levels of inflammatory cytokines and negatively associated with B-cell activating factors. Finally, our analysis of publicly accessible datasets revealed (i) an augmented ECM remodelling signature in inflamed lung tissue compared to non-inflamed tissue and (ii) proteomics analysis of PBMC from severe COVID-19 patients demonstrated an up-regulation in an ECM remodelling pathway. Our results may suggest the presence of an interaction between ECM remodelling, inflammation, and immune cells, potentially initiating or perpetuating pulmonary pathology in severe COVID-19. [ABSTRACT FROM AUTHOR]

Background: The immune system plays an important role in the development and treatment of thyroid cancer(THCA).However, the correlation between immune cells and THCA has not been systematically studied. Methods: This study used a two-sample Mendelian randomization (MR) study to determine the causal relationship between immune cell characteristics and THCA. Based on a large sample of publicly available genetic data, we explored the causal relationship between 731 immune cell characteristics and THCA risk. The 731 immunophenotypes were divided into 7 groups, including B cell panel(n=190), cDC panel(n=64), Maturation stages of T cell panel(n=79), Monocyte panel(n=43), Myeloid cell panel(n=64), TBNK panel(n=124), and Treg panel(n=167). The sensitivity of the results was analyzed, and heterogeneity and horizontal pleiotropy were excluded. Results: After FDR correction, the effect of immunophenotype on THCA was not statistically significant. It is worth mentioning, however, that there are some unadjusted low P-values phenotypes. The odds ratio (OR) of CD62L on monocyte on THCA risk was estimated to be 0.953 (95% CI=0.930~0.976, P=1.005×10−4), and which was estimated to be 0.975(95% CI=0.961–0.989, P=7.984×10−4) for Resting Treg%CD4 on THCA risk. Furthermore, THCA was associated with a reduced risk of 5  immunophenotype: CD25 on CD39+ CD4 on Treg (OR=0.871, 95% CI=0.812~0.935, P=1.274×10−4), activated Treg AC (OR=0.884, 95% CI=0.820~0.953, P=0.001), activated & resting Treg % CD4 Treg (OR=0.872, 95%CI=0.811~0.937, P=2.109×10−4), CD28- CD25++ CD8br AC(OR=0.867, 95% CI=0.809~0.930, P=6.09×10−5), CD28-CD127-CD25++CD8brAC(OR=0.875, 95%CI=0.814~0.942, P=3.619×10−4). THCA was associated with an increased risk of Secreting Treg % CD4 Treg (OR=1.143, 95% CI=1.064~1.229, P=2.779×10−4) and CD19 on IgD+ CD24+ (OR=1.118, 95% CI=1.041~1.120, P=0.002). Conclusions: These findings suggest the causal associations between immune cells and THCA by genetic means. Our results may have the potential to provide guidance for future clinical research. [ABSTRACT FROM AUTHOR]

Systemic lupus erythematosus (SLE) is a complex autoimmune disease characterized by persistent activation of immune cells and overproduction of autoantibodies. The accumulation of senescent T and B cells has been observed in SLE and other immune‐mediated diseases. However, the exact mechanistic pathways contributing to this process in SLE remain incompletely understood. In this study, we found that in SLE patients: (1) the frequency of CD4+CD57+ senescent T cells was significantly elevated and positively correlated with disease activity; (2) the expression levels of B‐lymphoma‐2 (BCL‐2) family and interferon‐induced genes (ISGs) were significantly upregulated; and (3) in vitro, the cytokine IL‐15 stimulation increased the frequency of senescent CD4+ T cells and upregulated the expression of BCL‐2 family and ISGs. Further, treatment with ABT‐263 (a senolytic BCL‐2 inhibitor) in MRL/lpr mice resulted in decreased: (1) frequency of CD4+CD44hiCD62L−PD‐1+CD153+ senescent CD4+ T cells; (2) frequency of CD19+CD11c+T‐bet+ age‐related B cells; (3) level of serum antinuclear antibody; (4) proteinuria; (5) frequency of Tfh cells; and (6) renal histopathological abnormalities. Collectively, these results indicated a dominant role for CD4+CD57+ senescent CD4+ T cells in the pathogenesis of SLE and senolytic BCL‐2 inhibitor ABT‐263 may be the potential treatment in ameliorating lupus phenotypes. [ABSTRACT FROM AUTHOR]

Myasthenia gravis (MG) is an antibody-mediated autoimmune disease with a prevalence of 150-250 cases per million individuals. Autoantibodies include long-lived antibodies against the acetylcholine receptor (AChR), mainly of the IgG1 subclass, and IgG4, produced almost exclusively by short-lived plasmablasts, which are prevalent in muscle-specific tyrosine kinase (MuSK) myasthenia gravis. Numerous investigations have demonstrated that MG patients receiving conventional medication today still do not possess satisfactory symptom control, indicating a substantial disease burden. Subsequently, based on the type of the autoantibody and the pathogenesis, we synthesized the published material to date and reached a conclusion regarding the literature related to personalized targeted therapy for MG. Novel agents for AChR MG have shown their efficacy in clinical research, such as complement inhibitors, FcRn receptor antagonists, and B-cell activating factor (BAFF) inhibitors. Rituximab, a representative drug of anti-CD20 therapy, has demonstrated benefits in treatment of MuSK MG patients. Due to the existence of low-affinity antibodies or unidentified antibodies that are inaccessible by existing methods, the treatment for seronegative MG remains complicated; thus, special testing and therapy considerations are necessary. It may be advantageous to initiate the application of novel biologicals at an early stage of the disease. Currently, therapies can also be combined and individualized according to different types of antibodies. With such a wide range of drugs, how to tailor treatment strategies to patients with various conditions and find the most suitable solution for each MG profile are our necessary and urgent aims. [ABSTRACT FROM AUTHOR]

Background: Primary mediastinal B-cell lymphoma (PMBL) and classical Hodgkin lymphoma (cHL) are distinct hematological malignancies of B-cell origin that share many biological, molecular, and clinical characteristics. In particular, the JAK/STAT signaling pathway is a driver of tumor development due to multiple recurrent mutations, particularly in STAT6. Furthermore, the XPO1 gene that encodes exportin 1 (XPO1) shows a frequent point mutation (E571K) resulting in an altered export of hundreds of cargo proteins, which may impact the success of future therapies in PMBL and cHL. Therefore, targeted therapies have been envisioned for these signaling pathways and mutations. Methods: To identify novel molecular targets that could overcome the treatment resistance that occurs in PMBL and cHL patients, we have explored the efficacy of a first-in-class HSP110 inhibitor (iHSP110-33) alone and in combination with selinexor, a XPO1 specific inhibitor, both in vitro and in vivo. Results: We show that iHSP110-33 decreased the survival of several PMBL and cHL cell lines and the size of tumor xenografts. We demonstrate that HSP110 is a cargo of XPO1wt as well as of XPO1E571K. Using immunoprecipitation, proximity ligation, thermophoresis and kinase assays, we showed that HSP110 directly interacts with STAT6 and favors its phosphorylation. The combination of iHSP110-33 and selinexor induces a synergistic reduction of STAT6 phosphorylation and of lymphoma cell growth in vitro and in vivo. In biopsies from PMBL patients, we show a correlation between HSP110 and STAT6 phosphorylation levels. Conclusions: These findings suggest that HSP110 could be proposed as a novel target in PMBL and cHL therapy. [ABSTRACT FROM AUTHOR]

Chronic kidney disease (CKD) is an emerging cause for morbidity and mortality worldwide. Acute kidney injury (AKI) can transition to CKD and finally to end-stage renal disease (ESRD). Targeted treatment is still unavailable. NF-κB signaling is associated with CKD and activated by B cell activating factor (BAFF) via BAFF-R binding. In turn, renal tubular epithelial cells (TECs) are critical for the progression of fibrosis and producing BAFF. Therefore, the direct involvement of the BAFF/BAFF-R system to the pathogenesis of CKD is conceivable. We performed non-accelerated nephrotoxic serum nephritis (NTN) as the CKD model in BAFF KO (B6.129S2-Tnfsf13btm1Msc/J), BAFF-R KO (B6(Cg)-Tnfrsf13ctm1Mass/J) and wildtype (C57BL/6J) mice to analyze the BAFF/BAFF-R system in anti-glomerular basement membrane (GBM) disease using high throughput RNA sequencing. We found that BAFF signaling is directly involved in the upregulation of collagen III as BAFF ko mice showed a reduced expression. However, these effects were not mediated via BAFF-R. We identified several upregulated genes that could explain the effects of BAFF in chronic kidney injury such as Txnip, Gpx3, Igfbp7, Ccn2, Kap, Umod and Ren1. Thus, we conclude that targeted treatment with anti-BAFF drugs such as belimumab may reduce chronic kidney damage. Furthermore, upregulated genes may be useful prognostic CKD biomarkers. [ABSTRACT FROM AUTHOR]

Background: Refractory generalized myasthenia gravis (GMG) remains a substantial therapeutic challenge. Telitacicept, a recombinant human B-lymphocyte stimulator receptor-antibody fusion protein, holds promise for interrupting the immunopathology of this condition. Objectives: This study retrospectively assessed the effectiveness and safety of telitacicept in patients with refractory GMG. Design: A single-center retrospective study. Methods: Patients with refractory GMG receiving telitacicept (160 mg/week or biweekly) from January to September in 2023 were included. We assessed effectiveness using Myasthenia Gravis Foundation of America post-intervention status (MGFA-PIS), myasthenia gravis treatment status and intensity (MGSTI), quantitative myasthenia gravis (QMG), and MG-activity of daily living (ADL) scores, alongside reductions in prednisone dosage at 3- and 6-month intervals. Safety profiles were also evaluated. Results: Sixteen patients with MGFA class II–V refractory GMG were included, with eight females and eight males. All patients were followed up for at least 3 months, and 11 patients reached 6 months follow-up. At the 3-month evaluation, 75% (12/16) demonstrated clinical improvement with MGFA-PIS. One patient achieved pharmacological remission, two attained minimal manifestation status, and nine showed functional improvement; three remained unchanged, and one deteriorated. By the 6-month visit, 90.1% (10/11) sustained significant symptomatic improvement. MGSTI scores and prednisone dosages significantly reduced at both follow-ups (p < 0.05). MG-ADL and QMG scores showed marked improvement at 6 months (p < 0.05). The treatment was well tolerated, with no severe adverse events such as allergy or infection reported. Conclusion: Our exploratory investigation suggests that telitacicept is a feasible and well-tolerated add-on therapy for refractory GMG, offering valuable clinical evidence for this novel treatment option. [ABSTRACT FROM AUTHOR]

Neuropsychiatric systemic lupus erythematosus (NPSLE) is a form of SLE associated with severe NP syndromes causing mortality and morbidity. Respecting the fundamental of BAFF in NPSLE pathophysiology, we investigated its clinical value. Totally 105 NPSLE and 101 SLE cases without NPSLE (non-NPSLE, control) were included. Serum BAFF/TNF-α/IL-6/IL-10 levels were measured using ELISA kits. T lymphocytes were detected by flow cytometry. The independent influencing factors for NPSLE, and the auxiliary diagnostic efficacy and the ability of BAFF levels to predict adverse prognosis of NPSLE patients were analyzed by multiple factor logistic regression, and ROC curve and survival curve. In NPSLE patients, serum BAFF level was increased and positively correlated with SLEDAI-2k, serum proinflammatory cytokines, while negatively correlated with CD4+T/CD8+T cells, and anti-inflammatory cytokine. High serum BAFF protein level was associated with a higher risk of developing NPSLE. The AUC of serum BAFF > 301.7 assisting in NPSLE diagnosis was 0.8196. Furthermore, high levels of serum BAFF were associated with a higher risk of adverse outcomes in NPSLE patients. Serum BAFF level in NPSLE patients was correlated with lymphocytes and high serum BAFF protein level could assist in diagnosis and to predict adverse outcomes in NPSLE patients. [ABSTRACT FROM AUTHOR]

This study aims to investigate the diagnostic potential of IL-2 for PDAC and develop a method to improve the dendritic cell (DC) based vaccine against PDAC. The gene expression data and clinical characteristics information for 178 patients with PDAC were obtained from The Cancer Genome Atlas (TCGA). DCs were isolated from Human peripheral blood mononuclear cells (PBMCs) and were cultured in 4 different conditions. DCs were pulsed by tumor cell lysates or KRAS G12D1 − 23 peptide, and then used to activate T cells. The mixture of DCs and T cells were administered to xenograft mouse model through the tail vein. The infiltration of DCs and T cells were detected by immunohistochemistry. The generation of KRAS G12D mutation specific cytotoxic T cells was determined by in vitro killing assay. We observed that PDAC patients with higher IL-2 mRNA levels exhibited improved overall survival and increased infiltration of CD8 + T cells, NK cells, naïve B cells, and resting myeloid DCs in the tumor microenvironment. IL-2 alone did not enhance DC proliferation, antigen uptake, or apoptosis inhibition unless co-cultured with PBMCs. DCs co-cultured with PBMCs in IL-2-containing medium demonstrated the strongest tumor repression effect in vitro and in vivo. Compared to DCs obtained through the traditional method (cultured in medium containing GM-CSF and IL-4), DCs cultured with PBMCs, and IL-2 exhibited increased tumor infiltration capacity, potentially facilitating sustained T cell immunity. DCs cultured in the PBMCs-IL-2 condition could promote the generation of cytotoxic T cells targeting tumor cells carrying KRAS G12D mutation. [ABSTRACT FROM AUTHOR]

This document provides summaries of various research studies on different medical conditions related to kidney diseases. The studies cover a wide range of topics, including the safety and effectiveness of certain treatments, genetic associations, diagnostic methods, and management strategies. These summaries offer valuable insights into potential therapeutic targets, diagnostic tools, and treatment options for kidney diseases. Library patrons conducting research on kidney-related topics will find these summaries helpful in their studies. [Extracted from the article]

This document presents the findings of a study on the outcomes of patients with acute kidney injury (AKI) who received kidney replacement therapy (KRT) in an intensive care unit (ICU). The study found that among all patients, the mortality rate was 42.3%, with 33% experiencing renal recovery and 7.4% starting chronic hemodialysis (HD). In the AKI group, the majority of patients received sustained low-efficiency dialysis (SLED), while a smaller percentage received continuous venovenous hemodiafiltration (cvvHDF) or intermittent hemodialysis (HD). The study concludes that their ICU's multidisciplinary approach, including critical care nephrology specialists, has resulted in a significant amount of experience with SLED and comparable outcomes to centers that primarily use continuous KRTs. [Extracted from the article]

This document contains several abstracts related to kidney diseases and research. The first abstract discusses the presence of renal progenitor cells (RPCs) as a potential biomarker for renal injury in various diseases. The second abstract focuses on a new treatment option for Autosomal Dominant Polycystic Kidney Disease (ADPKD) using small molecule activation of long form PDE4 enzymes. The third abstract explores the investigation of genetic and environmental modifiers of ADPKD through a specific PKD2 variant. The fourth abstract examines the effects of low-salt and high-salt diets on kidney immune cells and endothelial cells. The final abstract discusses the relationship between KIR-HLA-I genetic mismatch and the development of antibody-mediated rejection and microvascular inflammation after renal transplantation. [Extracted from the article]

Background: Rapid progressive interstitial lung disease (RP-ILD) is the leading cause of anti-melanoma differentiation associated protein 5 antibody positive dermatomyositis (anti-MDA5+DM) related death. Elevated serum B-cell activating factor (BAFF) levels have been implicated in connective tissue diseases associated ILD. Here, we evaluate whether BAFF could be a prognostic biomarker for predicting RP-ILD in anti-MDA5+DM patients. Methods: Serums were collected from 39 patients with anti-MDA5+DM (20 with RP-ILD and 19 with non-RP-ILD), 20 antisynthase syndrome (ASS) patients and 20 healthy controls (HC). BAFF concentration was measured by an enzyme-linked immunosorbent assay. Results: Serum BAFF level was higher in anti-MDA5+DM patients than those in ASS patients and HC (3882.32 ± 1880.09 vs. 2540.89 ± 1403.04 and 2486.28 ± 767.97 pg/mL, p = 0.0056 and 0.0038, respectively). Within anti-MDA5+DM groups, RP-ILD patients exhibited higher BAFF concentration than non-RP-ILD group (4549.78 ± 1839.97 vs. 3297.28 ± 1794.69 pg/mL, p = 0.04). The BAFF concentration was positively correlated with levels of C-reactive protein (CRP), dehydrogenase (LDH) and cytokeratin (CK) in anti-MDA5+DM patients (r = 0.350, p = 0.035; r = 0.393, p = 0.016; r = 0.518, p = 0.001; respectively). The best cut-off value of BAFF concentration was 2971.5 pg/mL by ROC curve (AUC area = 0.690, p = 0.045) and BAFF > 2971.5 pg/mL was an independent risk factor for RP-ILD using multivariate analysis (OR = 9.389, 95% CI = 1.609—54.769; p = 0.013). Conclusions: Serum BAFF could be a useful prognostic biomarker for early detecting RP-ILD risk in anti-MDA5+DM patients. [ABSTRACT FROM AUTHOR]

Cell and antibody therapies directed against surface molecules on B cells, e.g., CD19-targeting chimeric antigen receptor T cells (CD19 CAR-T), are now standard for patients with chemorefractory B cell acute lymphoblastic leukemias and other B cell malignancies. However, early relapse rates remain high. In this issue of the JCI, Aminov, Giricz, and colleagues revealed that leukemia cells resisting CD19-targeted therapy had reduced CD19 but also low CD22 expression and were sensitive to Bruton's tyrosine kinase and/or MEK inhibition. Overall, their observations support the evolution of resistance following a Lamarckian model: the oncotherapy directly elicits adaptive, resistance-conferring reconfigurations, which are then inherited by daughter cells as epigenetic changes. The findings prompt reflection also on the broader role of epigenetics in decoupling of replication from lineage differentiation activation by the B cell lineage master transcription factor hub. Such oncogenesis and resistance mechanisms, being predictable and epigenetic, offer practical opportunities for intervention, potentially noncross-resistant and safe vis-à-vis present cytotoxic and CAR-T treatments. [ABSTRACT FROM AUTHOR]

Worldwide, gastrointestinal (GI) cancer is recognized as one of the leading malignancies diagnosed in both genders, with mortality largely attributed to metastatic dissemination. It has been identified that in GI cancer, a variety of signaling pathways and key molecules are modified, leading to the emergence of an immunotolerance phenotype. Such modifications are pivotal in the malignancy's evasion of immune detection. Thus, a thorough analysis of the pathways and molecules contributing to GI cancer's immunotolerance is vital for advancing our comprehension and propelling the creation of efficacious pharmacological treatments. In response to this necessity, our review illuminates a selection of groundbreaking cellular signaling pathways associated with immunotolerance in GI cancer, including the Phosphoinositide 3-kinases/Akt, Janus kinase/Signal Transducer and Activator of Transcription 3, Nuclear Factor kappa-light-chain-enhancer of activated B cells, Transforming Growth Factor-beta/Smad, Notch, Programmed Death-1/Programmed Death-Ligand 1, and Wingless and INT-1/beta-catenin-Interleukin 10. Additionally, we examine an array of pertinent molecules like Indoleamine-pyrrole 2,3-dioxygenase, Human Leukocyte Antigen G/E, Glycoprotein A Repetitions Predominant, Clever-1, Interferon regulatory factor 8/Osteopontin, T-cell immunoglobulin and mucin-domain containing-3, Carcinoembryonic antigenrelated cell adhesion molecule 1, Cell division control protein 42 homolog, and caspases-1 and -12. [ABSTRACT FROM AUTHOR]

Sepsis is a systemic inflammatory response to a severe, life-threatening infection with organ dysfunction. Although there is no effective treatment for this fatal illness, a deeper understanding of the pathophysiological basis of sepsis and its underlying mechanisms could lead to the development of new treatment approaches. Here, we demonstrate that the selective Bruton's tyrosine kinase (Btk) inhibitor acalabrutinib augments survival rates in a lipopolysaccharide (LPS)-induced septic model. Our in vitro and in vivo findings both indicate that acalabrutinib reduces IL-6 production specifically in marginal zone B (MZ B) cells rather than in macrophages. Furthermore, Btk-deficient MZ B cells exhibited suppressed LPS-induced IL-6 production in vitro. Nuclear factor-kappa B (NF-κB) signaling, which is the downstream signaling cascade of Toll-like receptor 4 (TLR4), was also severely attenuated in Btk-deficient MZ B cells. These findings suggest that Btk blockade may prevent sepsis by inhibiting IL-6 production in MZ B cells. In addition, although Btk inhibition may adversely affect B cell maturation and humoral immunity, antibody responses were not impaired when acalabrutinib was administered for a short period after immunization with T-cell-independent (TI) and T-cell-dependent (TD) antigens. In contrast, long-term administration of acalabrutinib slightly impaired humoral immunity. Therefore, these findings suggest that Btk inhibitors may be a potential option for alleviating endotoxic shock without compromising humoral immunity and emphasize the importance of maintaining a delicate balance between immunomodulation and inflammation suppression. [ABSTRACT FROM AUTHOR]

Background: High expression of the glycosyltransferase UGT2B17 represents an independent adverse prognostic marker in chronic lymphocytic leukemia (CLL). It also constitutes a predictive marker for therapeutic response and a drug resistance mechanism. The key determinants driving expression of the UGT2B17 gene in normal and leukemic B-cells remain undefined. The UGT2B17 transcriptome is complex and is comprised of at least 10 alternative transcripts, identified by previous RNA-sequencing of liver and intestine. We hypothesized that the transcriptional program regulating UGT2B17 in B-lymphocytes is distinct from the canonical expression previously characterized in the liver. Results: RNA-sequencing and genomics data revealed a specific genomic landscape at the UGT2B17 locus in normal and leukemic B-cells. RNA-sequencing and quantitative PCR data indicated that the UGT2B17 enzyme is solely encoded by alternative transcripts expressed in CLL patient cells and not by the canonical transcript widely expressed in the liver and intestine. Chromatin accessible regions (ATAC-Seq) in CLL cells mapped with alternative promoters and non-coding exons, which may be derived from endogenous retrotransposon elements. By luciferase reporter assays, we identified key cis-regulatory STAT3, RELA and interferon regulatory factor (IRF) binding sequences driving the expression of UGT2B17 in lymphoblastoid and leukemic B-cells. Electrophoretic mobility shift assays and pharmacological inhibition demonstrated key roles for the CLL prosurvival transcription factors STAT3 and NF-κB in the leukemic expression of UGT2B17. Conclusions: UGT2B17 expression in B-CLL is driven by key regulators of CLL progression. Our data suggest that a NF-κB/STAT3/IRF/UGT2B17 axis may represent a novel B-cell pathway promoting disease progression and drug resistance. [ABSTRACT FROM AUTHOR]

Chronic rejection, closely related to the activation of B cells and donor-specific antibody (DSA) production, has unsatisfactory therapeutic outcomes. B lymphocyte stimulator (BLyS) is a major regulatory factor that controls the activation and differentiation of B cells. However, it remains unclear whether BLyS blockade can regulate B and plasma cells in the transplantation setting and affect chronic rejection. Here, we investigated the efficacy of the BLyS inhibitors belimumab and telitacicept in controlling B-cell response and preventing chronic rejection. The effects of belimumab and telitacicept on B-cell activation, differentiation, and antibody production in vitro were determined. A chronic rejection model in mouse was established by allogeneic cardiac transplantation with CTLA4-Ig treatment. Allograft survival, histology, DSA levels, and B-cell responses were analyzed to evaluate the chronic rejection-preventive effects of belimumab and telitacicept. In vitro experiments confirmed that belimumab and telitacicept inhibited B-cell activation and differentiation and reduced antibody production. In vivo experiments indicated that they significantly prolonged allograft survival, attenuated chronic rejection through significant suppression of myocardial ischemic necrosis and interstitial fibrosis, and reduced DSA-IgG levels, C4d deposition, and inflammatory cell infiltration. Furthermore, the frequencies of B cells, plasma cells, and IgG-producing cells in the recipients' spleen, lymph nodes, bone marrow, and blood were decreased after BLyS inhibitors treatment. This study demonstrated that belimumab and telitacicept inhibit B-cell responses and antibody production and alleviate chronic transplant rejection. Therefore, BLyS inhibitors are expected to be used for the prevention of chronic rejection in clinical practice. [ABSTRACT FROM AUTHOR]

Background: Systemic lupus erythematosus (SLE)–associated hepatitis ("lupus hepatitis") was one of the most frequent causes of liver function abnormalities in patients with SLE. Lupus hepatitis (LH) is commonly treated with conventional treatment, including non-steroidal anti-inflammatory drugs, corticosteroids, and immunomodulators. However, in refractory cases, other treatment options may be required. Methodology: We report the case of a patient with lupus hepatitis refractory to both conventional therapy and belimumab who was successfully treated with telitacicept, a new dual B lymphocyte stimulator (BLyS)/APRIL (a proliferation-inducing ligand) inhibitor.Literature review was performed on PubMed search forum. Result: The specific search term was "telitacicept", 23 papers were searched, among them 10 case reports/series articles reporting telitacicept treatment were elected.Apart from our literature reporting the effectiveness of telitacicept in treating LH, there is no report on it in treating LH. Conclusion: This case suggests that telitacicept should be an effective and safe treatment for LH refractory, even to those who failed to belimumab based on the standard treatment, and can reduce the dosage of glucocorticoids.However, further investigations, particularly prospective randomized controlled trials, are warranted to verify our findings and ensure patient safety. [ABSTRACT FROM AUTHOR]

Programmed cell death protein 1 (PD-1) axis blockade has become the mainstay in the treatment of recurrent and/or metastatic (R/M) head and neck squamous cell cancer (HNSCC). Programmed death-ligand 1 (PD-L1) is the only approved biomarker for patient selection; however, response rate is limited even among high expressors. Our primary objective was to investigate the association of immune cell-related biomarkers in the tumor and tumor microenvironment with PD-1 checkpoint inhibitors' outcomes in patients with R/M HNSCC. NCT03652142 was a prospective study in nivolumab-treated platinum-refractory R/M HNSCC, aiming to evaluate biomarkers of response to treatment. Tumor biopsies and blood samples were collected from 60 patients at baseline, post-treatment, and at progression. Immune cells in the tumor and stromal compartments were quantified by immunofluorescence using a five-protein panel (CD3, CD8, CD20, FoxP3, cytokeratin). Tertiary lymphoid structures (TLSs), PD-L1 expression, and peripheral blood immune cell composition were also evaluated for associations with outcome. Our findings were validated by gene set enrichment analysis (GSEA) messenger RNA in situ expression data from the same patients, for B-cell- and TLS-associated genes. High pre-treatment density of stromal B cells was associated with prolonged progression-free survival (PFS) (P = 0.011). This result was validated by GSEA, as stromal enrichment with B-cell-associated genes showed association with response to nivolumab. PD-L1 positivity combined with high B-cell counts in stroma defined a subgroup with significantly longer PFS and overall survival (P = 0.013 and P = 0.0028, respectively). Increased B cells in pre-treatment HNSCC biopsy samples correlate with prolonged benefit from PD-1-based immunotherapy and could further enhance the predictive value of PD-L1 expression. • PD-1/PD-L1 axis inhibitors have become the standard of care for R/M HNSCC. • Low response rates dictate the need to identify resistance mechanisms and develop biomarkers for patient selection. • The associations of immune cell density with treatment outcomes were investigated in nivolumab-treated R/M HNSCC cases. • Increased B-cell infiltration led to prolonged PFS and improved PD-L1-based patient selection. • The synchronous assessment of B-cell infiltration and PD-L1 expression could guide therapeutic decisions in R/M HNSCC. [ABSTRACT FROM AUTHOR]

Introduction: Lacticaseibacillus rhamnosus AFY06 (LR-AFY06) is a microorganism isolated from naturally fermented yogurt in Xinjiang, China. Methods: In this study, we investigated the effects and mechanisms of LR-AFY06 in a mouse model of inflammation-associated colon cancer. The mouse model was established by azoxymethane/dextran sulfate sodium (AOM/DSS) induction. The tumor number in intestinal tissues was counted, and the histopathological analysis was performed on colon tissues. Enzyme-linked immunosorbent assay and real-time quantitative polymerase chain reaction were performed to measure relevant protein levels in colon tissues. Results: LR-AFY06 treatment alleviated weight loss, increased organ index, reduced intestinal tumor incidence, improved histopathological damage, decreased the levels of inflammatory cytokines such as interleukin-6 (IL-6), interleukin-1 beta (IL-1b), tumor necrosis factor alpha (TNF-a), nuclear factor kB (NF-kB), and inducible nitric oxide synthase (iNOS) in the serum and colon tissue, downregulated the mRNA expression of inhibitor of NF-kB beta (IkBb), p65, p50, p52, B-cell lymphoma-2 (Bcl-2), and B-cell lymphoma-extra large (Bcl-xL) in colon tissues, and increased the mRNA expression of Bid and caspase-8. The high concentration of LR-AFY06 exerted a better effect than the low concentration; however, the effect was slightly inferior to that of aspirin. Moreover, LR-AFY06 mitigated the intestinal inflammatory process and inhibited intestinal tumor development by regulating the NF-kB and apoptosis pathways. Discussion: The present study indicates the regulatory potential of LR-AFY06 in inflammation-associated colorectal cancer in mice, providing a valuable basis for further research. [ABSTRACT FROM AUTHOR]

Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease associated with B‐cell hyperactivity. Telitacicept is a transmembrane activator, calcium modulator, and cyclophilin ligand interactor‐Fc fusion protein, which can neutralize both B‐cell lymphocyte stimulator and a proliferation‐inducing ligand. Patients with active SLE who received telitacicept were prospectively followed at month 1, 3, 6, 9, and 12 after telitacicept initiation. Thirty‐seven participants were involved and followed for 6.00 [3.00, 6.00] months. SRI‐4 rate at month 6 was 44.7%. The median dosage of prednisone was decreased by 43.8% (from 10 to 5.62 mg/d) at month 6. The anti‐dsDNA level was significantly decreased, while complement levels were significantly increased at month 6 from baseline. Continuously significant reductions in serum immunoglobin (Ig)G IgA, and IgM levels were also observed. Patients experienced significant decreases in the numbers of total and naive B cells, whereas memory B cells and T cell populations did not change. The number of NK cells was significantly increased during the follow‐up. At month 6, 58.3% (14 out of 24) patients experienced improved fatigue accessed by FACIT–Fatigue score exceeding the minimum clinically important difference of 4. Most adverse events were mild, but one each case of severe hypogammaglobulinemia, psychosis with suicidal behavior, and B‐cell lymphoma were occurred. In our first prospective real‐world study, telitacicept treatment led to a significant clinical and laboratory improvement of disease activity, as well as fatigue amelioration in patients with SLE. Safety profile was favorable overall, but more studies are greatly needed. [ABSTRACT FROM AUTHOR]

Dyslipidemias involving high concentrations of low-density lipoproteins (LDLs) increase the risk of developing triple-negative breast cancer (TNBC), wherein cholesterol metabolism and protein translation initiation mechanisms have been linked with chemoresistance. Doxorubicin (Dox) treatment, a member of the anthracycline family, represents a typical therapeutic strategy; however, chemoresistance remains a significant challenge. Exosomes (Exs) secreted by tumoral cells have been implicated in cell communication pathways and chemoresistance mechanisms; the content of exosomes is an outcome of cellular cholesterol metabolism. We previously induced Dox resistance in TNBC cell models, characterizing a variant denominated as variant B cells. Our results suggest that LDL internalization in parental and chemoresistant variant B cells is associated with increased cell proliferation, migration, invasion, and spheroid growth. We identified the role of eIF4F translation initiation factor and the down-regulation of tumor suppressor gene PDCD4, an inhibitor of eIF4A, in chemoresistant variant B cells. In addition, the exomes secreted by variant B cells were characterized by the protein content, electronic microscopy, and cell internalization assays. Critically, exosomes purified from LDL-treated variant B cell promoted cell proliferation, migration, and an increment in lactate concentration. Our results suggest that an autocrine phenomenon induced by exosomes in chemoresistant cells may induce modifications on signaling mechanisms of the p53/Mdm2 axis and activation of p70 ribosomal protein kinase S6. Moreover, the specific down-regulated profile of chaperones Hsp90 and Hsp70 secretion inside the exosomes of the chemoresistant variant could be associated with this phenomenon. Therefore, autocrine activation mediated by exosomes and the effect of LDL internalization may influence changes in exosome chaperone content and modulate proliferative signaling pathways, increasing the aggressiveness of MDA-MB-231 chemoresistant cells. [ABSTRACT FROM AUTHOR]

Innate and adaptive immunity play different roles in the pathogenesis of chronic obstructive pulmonary disease (COPD). However, previous studies on the relationship between immune cells and COPD reported inconsistent results. The causal connection between 731 immune cells and COPD was established using a two-sample Mendelian randomization (MR) analysis through publicly accessible genetic data. The heterogeneity and horizontal pleiotropism of the findings were confirmed using sensitivity analysis. In the B-cell panel, B-cell activating factor receptor (BAFF-R) on CD20− and CD20 on IgD−CD38bright (OR (95% CI): 0.93 (0.88, 0.99) and 0.97 (0.95, 0.98), respectively) were discovered to be protective. In the cDC panel, CD62L− plasmacytoid DC AC, CD80 on monocytes and CD11c on myeloid DCs (OR (95% CI): 0.94 (0.92, 0.97), 0.97 (0.94, 0.99) and (0.97 (0.95, 0.98), respectively) exerted protective effects. However, unswitched memory AC (OR (95%CI): 1.08 (1.01,1.15)) and CD 19 on IgD− CD 27− (OR (95%CI): 1.06 (1.02,1.10)) were hazardous in the B-cell panel. However, among the 731 immune cell phenotypes, no causal relationship was found for COPD on immune cells. This study found a potential causal relationship between immune cells in COPD, ruling out reverse causation. This study provides new avenues for studying the mechanisms of COPD. [ABSTRACT FROM AUTHOR]

This article explores the pathogenesis of IgA nephropathy (IgAN), a kidney disease characterized by abnormal production of immunoglobulin A (IgA). The source and triggers for the production of pathogenic IgA in IgAN are still unknown. The article discusses the structure and function of IgA, highlighting the differences between mucosal and circulatory IgA. It suggests that the pathogenic IgA in IgAN may originate from the mucosal immune system, specifically from cells in the mucosal associated lymphoid tissue or the bone marrow. However, emerging data also suggest that IgA-producing cells from the mucosal compartment may migrate to other locations in the body. Further research is needed to fully understand the nature and source of pathogenic IgA in IgAN. [Extracted from the article]

This article discusses the use of combined rituximab and belimumab therapy to treat recalcitrant epidermolysis bullosa aquisita (EBA) associated with systemic lupus erythematosus (SLE). EBA is a rare blistering disorder caused by antibodies that bind to type VII collagen, resulting in blister formation. The two patients in the study had severe skin fragility and laryngopharyngeal ulceration, and previous treatments had failed to control the disease. Treatment with rituximab and belimumab resulted in complete B-cell depletion and a decrease in anti-collagen VII antibody titres, leading to a dramatic improvement in cutaneous lesions. The authors suggest that this combined therapy may be a safe and effective treatment for recalcitrant EBA and other immunobullous disorders. [Extracted from the article]

Primary Sjögren's disease is primarily driven by B-cell activation and is associated with a high risk of developing non-Hodgkin's lymphoma (NHL). Over the last few decades, microRNA-155 (miR-155) has arisen as a key regulator of B-cells. Nevertheless, its role in primary Sjögren's disease remains elusive. Thus, the purpose of this study was (i) to explore miR-155, B-cell activating factor (BAFF)-receptor (BAFF-R), and Interleukin 6 receptor (IL-6R) expression in the labial salivary glands (LSG) of patients with primary Sjögren's disease, aiming to identify potential B-cell activation biomarkers related to NHL development. Twenty-four patients with primary Sjögren's disease, and with available tissue blocks from a LSG biopsy performed at diagnosis, were enrolled. Among them, five patients developed B-cell NHL during follow-up (7.3 ± 3.1 years). A comparison group of 20 individuals with sicca disease was included. Clinical and laboratory parameters were recorded and the LSG biopsies were evaluated to assess local inflammation in terms of miR-155/BAFF-R and IL-6R expression. Stratifying the primary Sjögren's disease cohort according to lymphomagenesis, miR-155 was upregulated in primary Sjögren's disease patients who experienced NHL, more so than those who did not experience NHL. Moreover, miR-155 expression correlated with the focus score (FS), as well as BAFF-R and IL-6R expression, which were increased in primary Sjögren's disease patients and in turn related to neoplastic evolution. In conclusion, epigenetic modulation may play a crucial role in the aberrant activation of B-cells in primary Sjögren's disease, profoundly impacting the risk of NHL development. [ABSTRACT FROM AUTHOR]