Radiographic axial spondyloarthritis (r-axSpA) is a chronic rheumatic disease in which innate immune cells and T cells are thought to play a major role. However, recent studies also hint at B cell involvement. Here, we performed an in-depth analysis on alterations within the B-cell compartment from r-axSpA patients.

We performed immune gene expression profiling on total peripheral blood B cells from 8 r-axSpA patients and 8 healthy controls (HCs). Next, we explored B cell subset distribution and B-cell receptor (BCR) signaling responses in circulating B cells from 28 r-axSpA patients and 15 HCs, by measuring spleen tyrosine kinase, phosphoinositide 3-kinase and extracellular signal regulated kinase 1/2 phosphorylation upon α-Ig stimulation using phosphoflow cytometry.

Immune gene expression profiling indicated an elevated pathway score for BCR signaling in total B cells from r-axSpA patients compared with HCs. Flow cytometric analysis revealed an increase in frequency of both total and double-negative 2 (DN2) B cells in r-axSpA patients compared with HCs. In r-axSpA patients, DN2 B cells displayed an isotype shift towards IgA. Remarkably, where DN2 B cells from HCs were hyporesponsive, these cells displayed significant proximal BCR signaling responses in r-axSpA patients. Enhanced BCR signaling responses were also observed in the transitional and naïve B cell population from r-axSpA patients compared with HCs. The enhanced BCR signaling responses in DN2 B cells correlated with clinical disease parameters.

In r-axSpA patients, circulating DN2 B cells are expanded and, together with transitional and naïve B cells, display significantly enhanced BCR signaling responses upon stimulation. Together, our data suggest B cell involvement in the pathogenesis of r-axSpA.

Non-infectious uveitis (NIU) is recognized as a group of autoimmune sight-threatening disorders with complex pathogenesis. This study aims to analyze the pathogenic role of B cells in NIU and evaluate the effectiveness of B cell depletion therapy in experimental autoimmune uveoretinitis (EAU) mice.

We performed high throughput transcriptome sequence on peripheral blood samples from healthy individuals (n = 6) and NIU patients (n = 12), and reanalyzed single-cell RNA transcriptome data of aqueous humor in NIU patients (n = 5). Female C57BL/6 J mice were induced the EAU model through immunization with the IRBP651-670 peptide. B cell depletion was performed via intravitreal injection of anti-CD20 antibody on day 7 and mice were executed on day 14 following antigen administration. Clinical symptoms were assessed by fundus photography and fundus fluorescein angiography. Pathological sections were analyzed using immunohistochemistry and immunofluorescence. Serum immunoglobulins and inflammatory factors were detected by ELISA.

Transcriptome sequencing and single-cell RNA analysis revealed strong B cell immune responses in both peripheral blood and aqueous humor of NIU patients. Intravitreal injection of anti-CD20 antibody partially reduces B cell numbers, suppresses T cell proliferation in CLNs, and decreases serum IgG and inflammatory cytokines level, which collectively alleviate clinical symptoms and mitigate retinal inflammation. Significant differences in BCR sequences were observed between the NIU groups and healthy controls.

B-cell depletion therapy may offer a novel strategy for the treatment of NIU and identifying specific BCR sequences provides a potential target for both therapeutic intervention and disease monitoring.

CD20 is a four-transmembrane protein expressed at the surface of B cells from late pro-B cells to memory B cells, with the exception of plasma cells. Its expression pattern makes it an attractive therapeutic target for different B cell malignancies and autoimmune diseases. Despite the clinical success of CD20-targeting antibodies, the biology of the CD20 protein is still not well understood. We investigated CD20 binding partners in the membrane of human B cells using immunoprecipitation followed by mass spectrometry analysis. We identified a molecular interaction between CD70 and CD20, and confirmed this using proximity ligation assays. CD20-CD70 spatiotemporal colocalization was validated at the plasma membrane of B cells using high-resolution microscopy. Cell surface expression of CD70 was found to be enhanced upon CD20 overexpression, suggesting a role for CD20 in stabilizing CD70 at the B cell membrane. Moreover, we observed impaired B-T cell synapse formation and defective recruitment of CD70 to the immunological synapse in the absence of CD20. Impaired synapse formation was confirmed by deleting CD20 in primary B cells, and analysis of B cells from a CD20-deficient patient. Finally, CD20-deletion resulted in diminished T cell activation and cytokine secretion. Together, this study demonstrates that CD20 interacts with CD70 at the B cell membrane, and that CD20 is required for immune synapse formation between B and T cells and consequent T cell activation.

B-cell depletion with CD20-targeted agents is commonly used for treatment of multiple sclerosis (MS), other autoimmune diseases, and certain hematologic malignancies. Initial apparent success with rituximab in MS and neuromyelitis optica spurred development of the anti-CD20 monoclonal antibody (mAb) therapies ocrelizumab, ofatumumab, and ublituximab as well as the anti-CD19 mAb inebilizumab. While each are effective at targeting and depleting B cells, structural differences translate into different mechanisms of action affecting maintenance of B-cell depletion and safety and tolerability. Although the anti-CD20 mAbs differ in degree of human versus mouse sequences as well as target CD20 epitope, these properties do not appear to substantially affect activity or tolerability. In contrast, an antibody-dependent cell-mediated cytotoxicity (ADCC) versus a complement-dependent cytotoxicity mechanism of action as well as subcutaneous versus intravenous administration may provide improved tolerability. Glycoengineering of the mAbs ublituximab and inebilizumab enhances ADCC and can overcome the reduced responses to mAb-mediated B-cell depletion associated with certain genetic polymorphisms. Other strategies for therapeutic targeting of CD20, including brain shuttle antibodies (e.g., RO7121932), bispecific antibodies, chimeric antigen receptor T-cell therapies, and antibody-drug conjugates, are in active clinical development and may be future treatment approaches in MS and other B-cell-mediated autoimmune diseases.

The cell surface proteome, or surfaceome, is the hub for cells to interact and communicate with the outside world. Many disease-associated changes are hard-wired within the surfaceome, yet approved drugs target less than 50 cell surface proteins. In the past decade, the proteomics community has made significant strides in developing new technologies tailored for studying the surfaceome in all its complexity. In this review, we first dive into the unique characteristics and functions of the surfaceome, emphasizing the necessity for specialized labeling, enrichment, and proteomic approaches. An overview of surfaceomics methods is provided, detailing techniques to measure changes in protein expression and how this leads to novel target discovery. Next, we highlight advances in proximity labeling proteomics (PLP), showcasing how various enzymatic and photoaffinity proximity labeling techniques can map protein-protein interactions and membrane protein complexes on the cell surface. We then review the role of extracellular post-translational modifications, focusing on cell surface glycosylation, proteolytic remodeling, and the secretome. Finally, we discuss methods for identifying tumor-specific peptide MHC complexes and how they have shaped therapeutic development. This emerging field of neo-protein epitopes is constantly evolving, where targets are identified at the proteome level and encompass defined disease-associated PTMs, complexes, and dysregulated cellular and tissue locations. Given the functional importance of the surfaceome for biology and therapy, we view surfaceomics as a critical piece of this quest for neo-epitope target discovery.

Diabetes foot ulcers (DFU) are the most common foot injuries leading to lower extremity amputation. Our study aimed to provide the first representative analysis highlighting the vital role of Tertiary Lymphoid Organs (TLO) inflammatory landscape in diabetic foot ulcers. The study explores mechanisms of TLO formation and the disease-specific roles of TLOs in regulating peripheral inflammatory and immune responses. Additionally, comprehensive analysis of clinical data from DFU cases, focused on TLO pathophysiology and systemic immune-inflammation landscape, is documented, aiming to identify the risk factors contributing to the development of DFUs. Our experimental results showed very significant differences were observed among the IL-17 and IFN-γ cytokine levels between the DFU vs. Control and DFU vs. NIDFU (Non-Infectious Diabetic Foot Ulcers) groups, while minimal differences were observed in IL-6 and TNF-α cytokine levels. Immunohistochemistry staining or Immunophenotyping of DFU patient-derived wound samples for TLO inflammatory stratification showed remarkable differences between DFU, NIDFU, and control groups both in CD3+ T Cells and CD20+ B cells. Overall, our study findings highlight the perspective role of TLO in DFU mechanisms and its prudent role in regulating peripheral inflammatory-immune responses. TLO study-related significant findings might be one of the important mechanisms, and its effective unveil might be a valuable treatment modality for DFU-complications.

Transcriptional profiling of peripheral blood mononuclear cells (PBMCs) is a widely explored research approach across multiple fields. Cell populations of interest are generally isolated before analysis, especially if low-frequency cell populations are desired. B cells, in particular, make up approximately 5%-10% of total PBMCs in healthy individuals, thus, isolation of B cell populations is crucial for researchers investigating B cell malignancies. The most widely used cell isolation methods include negative or positive magnetic cell sorting (MCS) and fluorescence-activated cell sorting (FACS). In contrast to negative MCS, it is widely believed that positive MCS and FACS may affect gene expression due to the direct interaction of cell selection antibodies with surface markers. To the best of our knowledge, no specific studies have examined these effects within CD19+ B cell populations. To evaluate this, we have performed RNA sequencing (RNA-seq) on B cells isolated from four healthy donors using three distinct methods: positive and negative MCS using the EasySep StemCell Technologies kits and FACS, performed using the MACSQuant Tyto sorter (Miltenyi Biotec). We report significant gene expression changes following CD19-dependent B cell isolation via either positive MCS or FACS relative to negative MCS, including a general upregulation of genes associated with immune activity and receptor signaling and downregulation of RNA processing genes. These results suggest that B cell isolation methods should be taken into consideration when designing experiments or incorporating publicly available sequencing datasets into ongoing research studies, as they may significantly impact the reliability and interpretability of the findings.

Esophageal adenocarcinoma (EAC) is a rapidly increasing malignancy with significant morbidity and mortality. The progression from gastroesophageal reflux disease (GERD) to Barrett's esophagus (BE) and ultimately to EAC is thought to be influenced by chronic inflammation and immune cell dynamics. Despite the observed correlations in observational studies, the causal relationships between immune cell phenotypes and this disease continuum remain unclear.

This study utilized a two-sample Mendelian Randomization (MR) approach to investigate the causal roles of 731 distinct immune cell phenotypes in the GERD-BE-EAC continuum. The analysis leveraged genome-wide association study (GWAS) data for immune phenotypes from a Sardinian cohort and data for GERD, BE, and EAC from the FinnGen and Open GWAS databases. A comprehensive set of MR methods, including inverse variance weighted (IVW), MR-Egger, and weighted median estimators, was employed to assess causality. Sensitivity analyses were conducted to evaluate heterogeneity and pleiotropy, ensuring the robustness of the findings.

The study revealed complex and multifaceted roles of immune cells across the GERD-BE-EAC continuum. In GERD, 34 immune phenotypes were found to be causally associated with either increased or decreased risk. Protective effects were observed in phenotypes such as Unswitched Memory B cells, while others like CD45RA- CD4+ T cells were linked to an elevated risk. In the context of BE, 28 immune phenotypes demonstrated significant causal associations, with the majority being protective, including Unswitched Memory B cells and CD62L on Granulocytes. Conversely, certain phenotypes, such as CD24 on Transitional B cells, were identified as risk factors for BE. For EAC, 34 immune phenotypes were implicated, with various B cell subsets, particularly those expressing BAFF-R and CD24, associated with an increased risk, while Switched Memory B cells and specific myeloid cell phenotypes showed protective effects.

This study provides novel insights into the complex role of immune cells in the pathogenesis of EAC, revealing a dynamic interplay where certain immune phenotypes may be protective in early stages but become risk-enhancing in later stages of disease progression. These findings highlight the potential of immune cell phenotypes to serve as biomarkers for early detection and targeted therapeutic interventions across the GERD-BE-EAC continuum. Further research is warranted to validate these findings in diverse populations and to explore the underlying mechanisms driving these immune-mediated effects.

Monoclonal antibodies are highly specific for their targets making them effective for cancer therapy. However, their large molecular weight causes slow blood clearance, often requiring weeks to be removed from circulation. This limitation affects companion nuclear imaging and antibody-based diagnostics, necessitating delayed imaging. We report the expansion of a methodology improving positron emission tomography (PET) contrast of the lymphoma biomarker CD20 at early time points after radiolabeled antibody administration. Intact radioimmunoconjugates are allowed to stay in circulation long enough to accumulate in tumors, and then, using a chemical trigger, we induced rapid clearance of the radioactivity from non-target tissues by cleaving the linker between the antibody and the radioactivity. For brevity, we refer to the this as the Tetrazine KnockOut (TKO) method which uses the transcyclooctene-tetrazine (TCO-Tz) reaction, wherein an antibody is conjugated with linker containing TCO and a radioisotope.

We optimized the TCO linker with several different radioisotopes and evaluated the ability of tetrazines to knockout radioactivity from circulating antibodies. We explored several cell types and antibodies with varying internalization rates, to characterize the parameters of TKO and tested [89Zr]Zr-DFO-TCO-rituximab in a lymphoma model with PET imaging after Tz or vehicle administration. Treatment with Tz induced > 70% cleavage of the TCO linker in vitro within 30 min. Internalizing radioimmunoconjugates exhibited similar cellular uptake with Tz compared to vehicle, whereas decreased uptake was seen with slowly internalizing antibodies. In rodents, Tz rapidly liberated the radioactivity from the antibody, cleared from the blood, and accumulated in the bladder. TKO resulted in > 50% decreased radioactivity in non-target organs following Tz injection. No decrease in tumor uptake was observed when rate of antibody internalization is higher in a lymphoma model, and the target-to-background ratio increased by > twofold in comparison with Tz nontreated groups at 24 h.

The TKO approach potentiates early imaging of rituximab radioimmunoconjugates and has translational potential for lymphoma imaging.

The relationship between Polycystic ovary syndrome (PCOS) and immune dysregulation, along with metabolic disturbances, remains unclear. This study used Mendelian Randomization (MR) to investigate causal relationships between immune cells, PCOS, and possible metabolite mediators.

We explored the genetic-level relationship between immune cells and PCOS, focusing on metabolites as potential mediators. Data from genome-wide association studies (GWAS) included 731 immune cell types (n=3757), 1400 plasma metabolites (n=8299), and PCOS cases (n=797) versus controls (n=140,558). Bidirectional MR analysis examined immune-PCOS relationships, while two-step MR and mediation analysis identified metabolites as potential mediators. The inverse variance-weighted (IVW) method was used for primary causal assessment, with sensitivity analysis validating results.

We identified a total of 33 immune cells that were associated with increased or decreased risk of PCOS (P < 0.05), and these immune cells were also associated with alterations in certain metabolite levels (P < 0.05). Among them, 12 immune cells were found to influence the occurrence of PCOS through the mediation of 17 metabolites. Notably, the effects of Myeloid DC %DC, NKT AC, CD20 on CD20- CD38-, CD25 on memory B cell, and HLA DR on CD33dim HLA DR+ CD11b+ were mediated by multiple metabolites on PCOS development. Similarly, histidine betaine (hercynine) levels and alpha-ketoglutarate to ornithine ratio mediated the association of more than one immune cell with PCOS.

This study highlights 12 immune cells impacting PCOS through 17 metabolites, advancing the understanding of immune mechanisms in PCOS risk and suggesting potential therapeutic approaches targeting immune modulation.

Background: Aortic stenosis is the most prevalent valvular heart disease in high-income population, and there are currently no medical therapies to slow the disease progression. Given that gut microbiota influences the immune system, lipid metabolism, and inflammation, there may be a potential link between gut microbiota and AS. Aims: We aimed to examine the causal effects of gut microbiota on AS and to investigate the mediating roles of inflammatory proteins, blood metabolites, and immune cells. Methods: Bidirectional Mendelian randomization analysis was performed to assess the causal relationships between gut microbiota, inflammatory proteins, blood metabolites, immune cells, and AS. Two-step Mendelian randomization was utilized to explore direct and indirect effects. The data were derived from genome-wide association study summary statistics available in public databases. Results: The study identified nine gut microbial features (six microbial taxa and three pathways), four inflammatory proteins, 91 blood metabolites, and four immune cell traits associated with AS. However, no significant mediating roles were found for inflammatory proteins, blood metabolites, and immune cells in the causal pathway between gut microbiota and AS. Conclusion: This study revealed novel causal associations between gut microbial features, inflammatory proteins, blood metabolites, and immune cell traits with AS. These findings offer new insights into the pathophysiology of AS and provide potential targets for therapeutic approaches.

B cell-directed CAR T cell therapy has fundamentally changed the treatment of haematological malignancies, and its scope of application is rapidly expanding to include other diseases such as solid tumours or autoimmune disorders. Therapy-refractoriness remains an important challenge in various inflammatory and non-inflammatory disorders of the CNS. The reasons for therapy failure are diverse and include the limited access current therapies have to the CNS, as well as enormous inter- and intra-individual disease heterogeneity. The tissue-penetrating properties of CAR T cells make them a promising option for overcoming this problem and tackling pathologies directly within the CNS. First application of B cell-directed CAR T cells in neuromyelitis optica spectrum disorder and multiple sclerosis patients has recently revealed promising outcomes, expanding the potential of CAR T cell therapy to encompass CNS diseases. Additionally, the optimization of CAR T cells for the therapy of gliomas is a growing field. As a further prospect, preclinical data reveal the potential benefits of CAR T cell therapy in the treatment of primary neurodegenerative diseases such as Alzheimer's disease. Considering the biotechnological optimizations in the field of T cell engineering, such as extension to target different antigens or variation of the modified T cell subtype, new and promising fields of CAR T cell application are rapidly opening up. These innovations offer the potential to address the complex pathophysiological properties of CNS diseases. To use CAR T cell therapy optimally to treat CNS diseases in the future while minimizing therapy risks, further mechanistic research and prospective controlled trials are needed to assess seriously the disease and patient-specific risk-benefit ratio.

The atypical expression of immune phenotypes in lymphoma is often associated with a poor prognosis and presents diagnostic challenges. The present study reports on a rare extranodal NK/T cell lymphoma. In addition to typical morphology and immunohistochemical characteristics, these tumors strongly express CD20 and CD30 and partially express CD15, which is associated with aggressive clinical behavior. Differential diagnosis should be cautiously approached in extranodal NK/T cell lymphoma because the abovementioned markers are typically expressed in B cell lymphoma or Hodgkin's lymphoma. In addition to rigorous histological and comprehensive immunohistochemical staining, whole-body imaging and molecular testing can assist with diagnosis. In the present case, the patient died of multiple organ failure shortly after diagnosis. Lymphoma exhibits an atypical immunophenotype, thus emphasizing the importance of a thorough analysis of the interrelations among clinical, imaging and pathological features.

Cancer remains a formidable global health challenge requiring the continued exploration of innovative therapeutic approaches. While traditional treatment strategies including surgery, chemotherapy, and radiation therapy have had some success, primarily in early-stage disease, the quest for more targeted, personalized, safer, and effective therapies remains an ongoing pursuit. Over the past decade, significant advances in the field of tumor immunology have dramatically shifted a focus towards immunotherapy, although the ability to harness and coopt the immune system to treat cancer is still just beginning to be realized. One important area that has yet to be fully explored is the complement system, an integral part of innate immunity that has gathered attention recently as a source of potential targets for anti-cancer therapy. The complement system has a complex and context dependent role in cancer biology in that it not only contributes to immune surveillance but also may promote tumor progression. Complement regulators, including CD46, CD55, CD59, and complement factor H, exercise defined control over complement activation, and have also been acknowledged for their role in the tumor microenvironment. This review explores the intricate role of complement regulators in cancer development and progression, examining their potential as therapeutic targets, current strategies, challenges, and the evolving landscape of clinical research.

Multiple sclerosis (MS) is a chronic, and potentially disabling, inflammatory disease of the central nervous system (CNS). MS is generally characterized by recurrent, and self-limited, episodes of neurological dysfunction, which occur unpredictably and often result in multifocal tissue injury within the CNS. Currently, women are affected two to three times as often as men although this may not have been the case during earlier Time-Periods. The pathogenesis of MS is known to involve both critical genetic and environmental mechanisms. Nevertheless, in addition to these two mechanisms, disease-pathogenesis also involves a "truly" random event. Indeed, it is this random mechanism, which is responsible for the currently-observed (and increasing) excess of women among patients with MS. This review summarizes the current state of knowledge regarding the pathogenesis of MS (includong its epidemiology, pathology, and genetics) and considers the therapeutic implications that these pathogenetic mechanisms have both for our currently available therapies as well as for the possible therapeutic approaches to the management of this potentially disabling condition in the future.

Prior research has indicated a link between seborrheic dermatitis (SD) and dysregulated immune responses; however, the causal linkage between this association and certain immune cell features has yet to be thoroughly clarified. This study seeks to examine the potential causal influence of immune cell characteristics on the pathogenesis of seborrheic dermatitis (SD) and to evaluate if these characteristics can function as biomarkers for early diagnosis and therapy. Data mining was performed using the Genome-Wide Association Study (GWAS) Catalog database to select 731 immune cell features for exposure variables and seborrheic dermatitis for the outcome variable in a forward Mendelian Randomization (MR) study. In a reverse MR analysis, seborrheic dermatitis was designated as the exposure factor, while the significant immune cell traits recognized by a forward MR analysis were used as outcome factors to exclude potential reverse causality. Five MR analyses were carried out by utilizing methods such as inverse variance weighting (IVW). Additionally, false discovery rate (FDR) correction, heterogeneity testing, level-dependent pleiotropy analysis, and sensitivity analysis were conducted. This study identified 11 immune traits causally associated with seborrheic dermatitis (SD). Specifically, five immune phenotypes were found to have been linking to a lower risk of SD: CD24on transitional, CD28 - DN(CD4 - CD8-)%T cell, CD45RA - CD28 - CD8br AC, Resting Treg%CD4, SSC - A on NKT. Conversely, six immunized traits have been shown with a greater risk of SD: CD127 - CD8br AC, CD20on CD24 + CD27+, CD27on IgD - CD38br, CD27on unsw mem, CD28 + DN(CD4 - CD8-)%T cell, HLA DR on CD33br HLA DR + CD14dim. The sensitivity analysis showed an absence of heterogeneity and level-dependent pleiotropy.This study demonstrates that specific immune cell traits not only correlate with SD but also provide valuable mechanistic insights into its pathogenesis. These immune traits also hold promise as biomarkers for early diagnosis, risk stratification, and personalized therapy. In addition, the findings provide new insights into immune mechanisms, highlighting the potential of targeted immunotherapies in SD treatment.

Conflict reports exist on the impact of pyrethroid insecticides on immune function and the probable underlying mechanisms.

This study evaluated the effect of an extensively used pyrethroid insecticide, fenpropathrin (FTN) (15 mg/kg b.wt), on the innate and humoral immune components, blood cells, splenic oxidative status, and mRNA expression of CD3, CD20, CD56, CD8, CD4, IL-6, TNF-α, and Caspase3 in a 60-day trial in rats. Besides, the possible defensive effect of curcumin-loaded chitosan nanoparticle (CML-CNP) (50 mg/kg b.wt) was evaluated.

FTN exposure resulted in hypochromic normocytic anemia, thrombocytosis, leukocytosis, and lymphopenia. Besides, a significant reduction in IgG, not IgM, but increased C3 serum levels was evident in the FTN-exposed rats. Moreover, their splenic tissues displayed a substantial increase in the ROS, MDA, IL-6, and IL-1β content, altered splenic histology, and reduced GPX, GSH, and GSH/GSSG. Furthermore, a substantial upregulation of mRNA expression of splenic CD20, CD56, CD8, CD4, CD3, IL-6, and TNF-α, but downregulation of CD8 was detected in FTN-exposed rats. FTN exposure significantly upregulated splenic Caspase-3 and increased its immunohistochemical expression, along with elevated TNF-α immunoexpression. However, the alterations in immune function, splenic antioxidant status, blood cell populations, and immune-related gene expression were notably restored in the FTN + CML-CNP-treated group.

The findings of this study highlighted the immunosuppressive effects of FTN and suggested the involvement of many CD cell markers as a potential underlying mechanism. Additionally, the results demonstrated the effectiveness of CML-CNP in mitigating pollutant-induced immune disorders.

Cancer-related fatigue (CRF) is a prominent cancer-related complication occurring in Prostate cancer (PCa) patients, profoundly affecting prognosis. The lack of diagnostic criteria and biomarkers hampers the management of CRF.

The CRF-related data and PCa single-cell data were retrieved from the GEO database and clinical data was downloaded from the TCGA database. The univariate logistic/Cox regression analysis were used to construct the prediction models. The predictive value of models was analyzed using the ROC curve and Kaplan-Meier survival. The hub genes were screened by an intersection analysis of DEGs. The mice model of PCa and PCa-related fatigue were established, and fatigue-like behaviors of mice were detected. The expression of selected hub genes was validated by RT-PCR and IHC analysis.

The diagnosis and risk models showed great predictive value both in the training and validation dataset. Five genes (Baiap2l2, Cacng4, Sytl2, Sec31b and Ms4a1) that enriched the CXCL signaling were identified as hub genes. Among all hub genes, the MS4A1 expression is the most significant in PCa-related fatigue mice.

We identified MS4A1 as a promising biomarker for the diagnosis of PCa-related fatigue. Our findings would lay a foundation for revealing the pathogenesis and developing therapies for PCa-related fatigue.

Waterhouse-Friderichsen Syndrome (WFS) is a rare but life-threatening condition characterized by massive adrenal hemorrhage. WFS represents one of the features of the Overwhelming Post-Splenectomy Infection, which occurs any time after spleen removal and is recognized as the most serious complication in asplenic patients. We report a fatal case of WFS resulting from Streptococcus pneumoniae infection in a vaccinated and splenectomized patient. D.R., a 62-year-old man who had been splenectomized 20 years earlier following a traffic accident and had undergone Streptococcus Pneumoniae vaccination, had an acute febrile episode with chills at home, followed by vomiting. He died suddenly within 12 h of presentation. A multidisciplinary approach was adopted to resolve the case. Autopsy, histological, immunohistochemical, microbiological and toxicological examinations were performed. At autopsy, both adrenal glands presented increased volume and diffuse intraparenchimal hemorrhage. Postmortem bacteriological cultures of blood, cerebrospinal fluid and pericardial fluid showed S. pneumoniae, while serologic and molecular characterization demonstrated that the serotype responsible was serotype 23B, which was not included in the vaccination which D.R. underwent. Accordingly, the cause of death of D.R. was attributed to acute adrenal insufficiency due to Waterhouse-Friderichsen syndrome caused by Serotype 23B Streptococcus pneumoniae infection. In splenectomized patients with fever, accompanied by other nonspecific symptoms, the diagnosis of WFS should be considered, even if the subjects received the recommended vaccinations. The postmortem diagnosis of WFS requires a multidisciplinary approach, including macroscopic examination, histological analysis, and microbiologic investigations, so it is necessary to collect appropriate postmortem biological specimens for microbiological investigation.

Dysautonomia, a parasympathetic-sympathetic imbalance, has clinical and public health consequences. Colon neoplasm is linked to dysautonomia through a complex interplay between the two conditions. In this prospective cohort study, we evaluated 18 patients divided into three groups: six patients with both colon cancer and dysautonomia, six patients with colon cancer without dysautonomia, and six patients with dysautonomia only (control group). Dysautonomia was defined by the presence of orthostatic hypotension, a non-increased or dropped heart rate, and various autonomic symptoms. During abdominal surgery, tissue samples from the celiac ganglion were collected and analyzed using immunohistochemistry (IHC). Our findings revealed a significant correlation between IHC marker expression in colon cancer and dysautonomia (control) (r = 0.927, P = 0.008). ANOVA results confirmed that the model was significant and that the dysautonomia group (control) had a significant effect on the independent variables (colon cancer or colon cancer + dysautonomia). The study proposes that a shared immunological mechanism underlies both dysautonomia and colon cancer, suggesting that the immune system plays a crucial role in the development or progression of these two conditions.

The domain of cancer treatment has persistently been confronted with significant challenges, including those associated with recurrence and drug resistance. The complement system, which serves as the foundation of the innate immune system, exhibits intricate and nuanced dual characteristics in the evolution of tumors. On the one hand, the complement system has the capacity to directly inhibit cancer cell proliferation via specific pathways, thereby exerting a beneficial anti-tumor effect. Conversely, the complement system can also facilitate the establishment of an immune escape barrier for cancer cells through non-complement-mediated mechanisms, thereby protecting them from eradication. Concurrently, the complement system can also be implicated in the emergence of drug resistance through a multitude of complex mechanisms, directly or indirectly reducing the efficacy of therapeutic interventions and facilitating the progression of cancer. This paper analyses the role of the complement system in tumors and reviews recent research advances in the mechanisms of tumor immune tolerance and drug resistance.

B-cell depleting therapy (BCDT) has revolutionised the treatment of B-cell malignancies and autoimmune diseases by targeting specific B-cell surface antigens, receptors, ligands, and signalling pathways. This narrative review explores the mechanisms, applications, and complications of BCDT, focusing on the therapeutic advancements since the introduction of rituximab in 1997. Various monoclonal antibodies and kinase inhibitors are examined for their roles in depleting B cells through antibody-dependent and independent mechanisms. The off-target effects, such as hypogammaglobulinemia, infections, and cytokine release syndrome, are discussed, emphasising the need for immunologists to identify and help manage these complications. The increasing prevalence of BCDT has necessitated the involvement of clinical immunologists in addressing treatment-associated immunological abnormalities, including persistent hypogammaglobulinemia and neutropenia. We highlight the importance of considering underlying inborn errors of immunity (IEI) in patients presenting with these complications. Furthermore, we discuss the impact of BCDT on other immune cell populations and the challenges in predicting and managing long-term immunological sequelae. The potential for novel BCDT agents targeting the BAFF/APRIL-TACI/BCMA axis and B-cell receptor signalling pathways to treat autoimmune disorders is also explored, underscoring the rapidly evolving landscape of B-cell targeted therapies.

Periapical lesions (PLs) are common inflammatory diseases primarily caused by microbial infections within root canals. These infections trigger complex immune responses in periapical tissues, with B lymphocytes playing dual roles: defending against pathogens while also contributing to tissue damage. This highlights the crucial role of B cells in the immunological processes of PLs.

A comprehensive review of the literature on B cells in PLs was conducted using PubMed, Web of Science, Scopus, and ScienceDirect databases.

The review included 120 studies that examined the distribution and subtypes of B cells, their dual functions in PLs, and the potential applications of B-cell-related therapies in treating apical periodontitis.

This review enhances our understanding of the complex immune mechanisms in PLs and aids in the development of new therapeutic approaches from a B-cell perspective.

Mycobacterium bovis (M. bovis) causes bovine tuberculosis (bTB). The challenges in controlling and eradicating this zoonotic disease are compounded by our incomplete understanding of the host immune response. In this study, we used high-throughput bulk RNA sequencing (RNA-seq) to characterise the response profiles of γδ T cells to antigenic stimulation using purified protein derivate from M. bovis (PPDb). γδ T cells are a subgroup of T cells that bridge innate and adaptive immunity and have known anti-mycobacterial response mechanisms. These cells are usually classified based on the expression of a pathogen-recognition receptor, Workshop Cluster 1 (WC1), into two main subsets: WC1.1+ and WC1.2+. Previous studies have identified a preferential transcriptomic response in WC1.1+ cells during natural bTB infection, suggesting a subset-specific response to mycobacterial antigens. This follow on study tested the hypothesis that a subset specific response would also be apparent from γδ T cells from infected cattle after repeat stimulation. Peripheral blood was collected from Holstein-Friesian cattle naturally infected with M. bovis, confirmed by a single intradermal comparative tuberculin test (SICTT) and IFN-γ ELISA and stimulated with 10 μg/ml PPDb for 6 hours. After whole blood stimulation, WC1.1+ and WC1.2+ γδ T cell subsets were isolated using magnetic cell sorting (n = 5 per group). High-quality RNA was extracted from each purified lymphocyte subset (WC1.1+ and WC1.2+) to generate transcriptomes using bulk RNA sequencing, resulting in 20 RNA-seq libraries. Transcriptomic analysis revealed 111 differentially expressed genes (DEGs) common to both WC1.1+ and WC1.2+ γδ T cell compartments, including upregulation of IL1A, IL1B, IL6, IL17A, IL17F, and IFNG genes (FDR-Padj. < 0.1). Interestingly, the WC1.2+ cells showed upregulation of IL10, CCL22, and GZMA (log2FC ≥ 1.5, and FDR-Padj. < 0.1). In conclusion, while WC1.1+ and WC1.2+ γδ T cells exhibit a conserved inflammatory response to PPDb, differences in anti-inflammatory and antimicrobial gene expression between these cell subsets provide new insights into their effector functions in response to mycobacterial antigens.

Myasthenia gravis (MG) is a typical autoimmune disease of the nervous system. It is characterized by skeletal muscle weakness and fatigue due to impaired neuromuscular junction transmission mediated by IgG autoantibodies. Muscle-specific receptor tyrosine kinase-associated MG (MuSK-MG), a rare and severe subtype of MG, is distinguished by the presence of anti-MuSK antibodies; it responds poorly to traditional therapies. Recent research on MuSK-MG treatment has focused on specific targeted therapies. Since B cells play a critical pathogenic role in producing autoantibodies and inflammatory mediators, they are often considered the preferred target for treating MuSK-MG. Currently, various B cell-targeted drugs have been developed to treat MuSK-MG; they have shown good therapeutic effects. This review explores the evolving landscape of B cell-targeted therapies in MuSK-MG, focusing on their mechanisms, efficacy, and safety, and the current limitations associated with their use. We discuss current B cell-targeted therapies aimed at depleting or modulating B cells via both direct and indirect approaches. Furthermore, we focus on novel and promising strategies such as Chimeric Autoantibody Receptor T cell therapy, which explicitly targets MuSK-specific B cells without compromising general humoral immunity. Finally, this review provides an outlook on the potential benefits and limitations of B cell-targeted therapy in developing new therapies for MuSK-MG. We conclude by discussing future research efforts needed to optimize these therapies, expand treatment options, and improve long-term outcomes in MuSK-MG management.

Antibody-based and cell-based novel immunotherapies, such as bispecific T-cell engagers (BiTE), antibody-drug conjugates, or chimeric antigen receptor (CAR) T cells are currently standard treatment options for patients with relapsed or refractory (R/R) B-cell precursor acute lymphoblastic leukemia (ALL). To date, CD20-targeting monoclonal antibodies and the CD19-targeting BiTE's blinatumomab have been established elements of frontline therapy, either in patients with CD20+ ALL or in patients with measurable disease (MRD) following conventional chemotherapy. Recently, blinatumomab has also demonstrated a survival benefit in patients with MRD-negative ALL. Based on the observed high response rates and improved survival outcomes in patients with R/R ALL, antibody-based immunotherapies are being prospectively studied in the upfront setting, particularly in older adult patients, where even age-adapted conventional chemotherapies are still associated with significant rates of early death, treatment-related toxicity, and poor prognosis. In these approaches, conventional chemotherapy has been replaced or reduced and supplemented by immunotherapeutic agents, resulting in promising outcomes that form the basis for evaluating and defining new treatment standards.

Philadelphia chromosome-positive acute lymphoblastic leukemia (PH + ALL) is the most common cytogenetic abnormality of B-ALL in adults and is associated with poor prognosis. Previously, the only curative treatment option in PH + ALL was allogeneic hematopoietic stem cell transplantation (Allo-HSCT). Since 2000, targeted therapy combined with chemotherapy, represented by the tyrosine kinase inhibitor Imatinib, has become the first-line treatment for PH + ALL. Currently, the remission rate and survival rate of Imatinib are superior to those of simple chemotherapy, and it can also improve the efficacy of transplantation. More recently, some innovative immune-targeted therapy greatly improved the prognosis of PH + ALL, such as Blinatumomab and Inotuzumab Ozogamicin. For patients with ABL1 mutations and those who have relapsed or are refractory to other treatments, targeted oral small molecule drugs, monoclonal antibodies, Bispecific T cell Engagers (BiTE), and chimeric antigen receptor (CAR) T cells immunotherapy are emerging as potential treatment options. These new therapeutic interventions are changing the treatment landscape for PH + ALL. In summary, this review discusses the current advancements in targeted therapeutic agents shift in the treatment strategy of PH + ALL towards using more tolerable chemotherapy-free induction and consolidation regimens confers better disease outcomes and might obviate the need for HSCT.

Elderly patients with lymphoproliferative diseases (LPD) are vulnerable to severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection. Here, we retrospectively described the clinical features and outcomes of the first time infection of Omicron SARS-CoV-2 in 364 elderly patients with lymphoma enrolled in Jiangsu Cooperative Lymphoma Group (JCLG) between November 2022 and April 2023 in China. Median age was 69 years (range 60-92). 54.4% (198/364) of patients were confirmed as severe and critical COVID-19 infection. In univariable analysis, Age > 70 years (OR 1.88, p = 0.003), with multiple comorbidities (OR 1.41, p = 0.005), aggressive lymphoma (OR 2.33, p < 0.001), active disease (progressive or relapsed/refractory, OR 2.02, p < 0.001), and active anti-lymphoma therapy (OR 1.90, p < 0.001) were associated with severe COVID-19. Multiple (three or more) lines of previous anti-lymphoma therapy (OR 3.84, p = 0.021) remained an adverse factor for severe COVID-19 in multivariable analysis. Moreover, CD20 antibody (Rituximab or Obinutuzumab)-based treatments within the last 6 months was associated with severe COVID-19 in the entire cohort (OR 3.42, p < 0.001). Continuous BTK inhibitors might be protective effect on the outcome of COVID-19 infection (OR 0.44, p = 0.043) in the indolent lymphoma cohort. Overall, 7.7% (28/364) of the patients ceased, multiple lines of previous anti-lymphoma therapy (OR 3.46, p = 0.016) remained an adverse factor for mortality.

Human T cells expressing CD20 play an important role in the defense against virus and cancer and are central in the pathogenesis of both malignancies and various autoimmune disorders. Therapeutic modulation of CD20+ T cells and the CD20 expression level is therefore of significant interest. In rodents, CD20 on T cells is likely the product of an active transfer of CD20 from a donor B cell interacting with a recipient T cell in a process termed trogocytosis. Whether the same applies to human CD20+ T cells is highly debated. Investigating this dispute showed that human CD20- T cells could achieve CD20 along with a series of other B-cell markers from B cells through trogocytosis. However, none of these B-cell markers were co-expressed with CD20 on human CD20+ T cells in blood or inflamed CSF, implying that additional mechanisms may be involved in the development of human CD20+ T cells. In support of this, we identified true naïve CD20+ T cells, measured endogenous production of CD20, and observed that CD20 could be inherited to daughter cells, contradicting that all human CD20+ T cells are a product of trogocytosis.

FoxO transcription factors (FoxO1, FoxO3a, FoxO4, FoxO6) are a highly evolutionary conserved subfamily of the 'forkhead' box proteins. They have traditionally been considered tumor suppressors, but FoxO1 also exhibits oncogenic properties. The complex nature of FoxO1 is illustrated by its various roles in B cell development and differentiation, immunoglobulin gene rearrangement and cell-surface B cell receptor (BCR) structure, DNA damage control, cell cycle regulation, and germinal center reaction. FoxO1 is tightly regulated at a transcriptional (STAT3, HEB, EBF, FoxOs) and post-transcriptional level (Akt, AMPK, CDK2, GSK3, IKKs, JNK, MAPK/Erk, SGK1, miRNA). In B cell malignancies, recurrent FoxO1 activating mutations (S22/T24) and aberrant nuclear export and activity have been described, underscoring the potential of its therapeutic inhibition. Here, we review FoxO1's roles across B cell and myeloid malignancies, namely acute lymphoblastic leukemia (ALL), acute myeloid leukemia (AML), chronic lymphocytic leukemia (CLL), follicular lymphoma (FL), diffuse large B cell lymphoma (DLBCL), mantle cell lymphoma (MCL), Burkitt lymphoma (BL), Hodgkin lymphoma (HL), and multiple myeloma (MM). We also discuss preclinical evidence for FoxO1 targeting by currently available inhibitors (AS1708727, AS1842856, cpd10).

Hemophagocytic lymphohistiocytosis (HLH) is a rapidly progressing, life-threatening syndrome characterized by excessive immune activation, often presenting as a complex cytokine storm. This hyperactive immune response can lead to multi-organ failure and systemic damage, resulting in an extremely short survival period if left untreated. Over the past decades, although HLH has garnered increasing attention from researchers, there have been few advancements in its treatment. The cytokine storm plays a crucial role in the treatment of HLH. Investigating the detailed mechanisms behind cytokine storms offers insights into targeted therapeutic approaches, potentially aiding in early intervention and improving the clinical outcome of HLH patients. To date, there is only one targeted therapy, emapalumab targeting interferon-γ, that has gained approval for primary HLH. This review aims to summarize the current treatment advances, emerging targeted therapeutics and underlying mechanisms of HLH, highlighting its newly discovered targets potentially involved in cytokine storms, which are expected to drive the development of novel treatments and offer fresh perspectives for future studies. Besides, multi-targeted combination therapy may be essential for disease control, but further trials are required to determine the optimal treatment mode for HLH.

Chronic lymphocytic leukemia (CLL) is one of the most common types of leukemia in adult patients. The landscape of CLL therapy has changed in the last decades with the introduction of antibody-based therapies and novel targeted agents resulting in improved outcomes.

This article describes the use of monoclonal antibodies, bispecific antibodies and antibody-drug conjugates in the treatment of relapsed and refractory CLL. The mechanism of action and clinical applications and safety of antibody-based therapies, both as monotherapy and in combination with other drugs, are discussed. A literature search was performed using PubMed, Web of Science, and Google Scholar for articles published in English. Additional relevant publications were obtained by reviewing the references from the chosen articles.

Antibody-based therapeutic strategies have drastically changed the treatment of CLL, as they have introduced the concept of boosting immune responses against tumor cells. While immunotherapy is generally effective, some treatment failure can occur due to antigen loss, mutation, or down-regulation, and this remains the main obstacle to cure. The development of novel antibody therapies, including their combinations with targeted drugs and bispecific antibodies, might help to reduce toxicity and improve efficacy.

Philadelphia chromosome-positive B-cell precursor acute lymphoblastic leukemia (Ph+ BCP-ALL) is a high-risk subtype of acute lymphoblastic leukemia characterized by the presence of the BCR::ABL1 fusion gene. Tyrosine kinase inhibitors (TKI) combined with chemotherapy are established as the first-line treatment. Additionally, rituximab, an anti-CD20 monoclonal antibody is administered to adult BCP-ALL patients with ≥20% CD20+ blasts. In this study, we observed a marked prevalence of CD20 expression in patients diagnosed with Ph+ BCP-ALL, indicating a potential widespread clinical application of rituximab in combination with TKI. Consequently, we examined the influence of TKI on the antitumor effectiveness of anti-CD20 monoclonal antibodies by evaluating levels of CD20 on the cell surface and conducting in vitro functional assays. All tested TKI were found to uniformly downregulate CD20 on leukemic cells, diminishing the efficacy of rituximab-mediated complement- dependent cytotoxicity. Interestingly, these TKI displayed varied effects on natural killer (NK) cell-mediated antibody- dependent cytotoxicity and macrophage phagocytic function. While asciminib demonstrated no inhibition of effector cell functions, dasatinib notably suppressed the anti-CD20-monoclonal antibody-mediated NK cell cytotoxicity and macrophage phagocytosis of BCP-ALL cells. Dasatinib and ponatinib also decreased NK cell degranulation in vitro. Importantly, oral administration of dasatinib, but not asciminib, compromised NK cell activity in patients' blood, as determined by an ex vivo degranulation assay. Our results indicate that asciminib might be preferred over other TKI for combination therapy with anti-CD20 monoclonal antibodies.

Recent studies have confirmed that B cell-related genes CD20 and FCRL5 may be involved in the pathogenesis of autoimmune thyroid diseases (AITDs). However, there is a lack of comprehensive genetic susceptibility studies on this subject.

The purpose of this study was to investigate the relationship of CD20 and FCRL5 gene polymorphisms with AITD susceptibility.

A total of 1740 subjects were recruited from the Chinese Han population. They consisted of 1007 patients with AITD and 633 healthy controls. Multiplex polymerase chain reaction (PCR) combined with high-throughput sequencing was used to genotype four screened single nucleotide polymorphisms (SNPs). The four SNPs were rs7126354 of CD20 and rs6667109, rs6692977 and rs3811035 of FCRL5.

The minor allele frequency of rs7126354 was significantly lower in patients with AITD and Hashimoto's thyroiditis (HT) than in healthy controls (P = 0.031; P = 0.017). The minor allele frequency of rs6667109 was significantly higher in the Graves' disease (GD) subgroup than in the healthy control group (P = 0.029). In the Log-additive model, rs6667109 in the GD group also showed an increased risk of onset disease.

This study presents robust evidence of a genetic association of CD20 and FCRL5 with AITDs. The C allele of CD20 rs7126354 is a protective factor for HT susceptibility. The A allele of FCRL5 rs6667109 is a risk factor for the susceptibility to GD.

Systemic sclerosis (SSc) is a severe autoimmune disease characterized by vasculopathy, fibrosis, and dysregulated immunity, with hallmark autoantibodies targeting nuclear antigens such as centromere protein (ACA) and topoisomerase I (ATA). These autoantibodies are highly prevalent and disease-specific, rarely coexisting, thus serving as crucial biomarkers for SSc diagnosis. Despite their diagnostic value, their roles in SSc pathogenesis remain unclear. This review summarizes current literature on ACA and ATA in SSc, comparing them to autoantibodies in other rheumatic diseases to elucidate their potential pathogenic roles. Similarities are drawn with anti-citrullinated protein antibodies (ACPA) in rheumatoid arthritis, particularly regarding disease specificity and minimal pathogenic impact of antigen binding. In addition, differences between ANA and ACPA in therapeutic responses and Fab glycosylation patterns are reviewed. While ACA and ATA are valuable for disease stratification and monitoring activity, understanding their origins and the associated B cell responses is critical for advancing therapeutic strategies for SSc.

Ofatumumab (OFA) and ocrelizumab (OCRE) are two anti-CD20 monoclonal antibodies approved for the treatment of relapsing forms of multiple sclerosis due to their ability to deplete B lymphocytes. The aim of this study was to investigate the impact of these anti-hCD20 antibodies on B lymphocyte subsets in the circulation and in primary and secondary lymphoid organs in an immune system humanized mouse model (immunocompromised Rag2-/-Il2rg-/-CD47-/-) engrafted with human CD34+ hematopoietic stem cells. Three months after humanization, mice, which present adaptive immune cells only of human origin, were treated with OFA (0.3 mg/Kg; day 1, 3 and 5), or OCRE (10 mg/kg; day 1) or saline. Seven days after the last injection a robust (>90 %) decrease of circulating human CD20+ B lymphocytes was observed in both OFA- and OCRE-treated mice. A partial replenishment of B lymphocytes was detectable in blood 36 days from the last injection in OFA-treated mice, while no B lymphocytes could be detected in OCRE-treated mice up to 65 days post injection. Bone marrow profiling showed that during hCD20+ B cell depletion and replenishment, OCRE-treated mice preserved only preB-I cells in the bone marrow, while the bone marrow of OFA-treated mice presented both preB-I as well as preB-II cells, with the latter subset being the one closest to differentiate into immature B cells. These data together with changes in B cell distribution in other tissues suggest that ofatumumab preserve BM niches, critical for B lymphocyte replenishment, limiting potential side effects of the treatment associated with the increased risk of infection.

Myasthenia gravis (MG) is a chronic autoimmune neuromuscular disorder characterized by muscle weakness and fatigue. The disease is primarily caused by antibodies targeting acetylcholine receptors (AChR) and muscle-specific kinase (MuSK) proteins at the neuromuscular junction. Traditional treatments for MG, such as acetylcholinesterase inhibitors, corticosteroids, and immunosuppressants, have shown efficacy but are often associated with significant long-term side effects and variable patient response rates. Notably, approximately 15% of patients exhibit inadequate responses to these standard therapies. Recent advancements in molecular therapies, including monoclonal antibodies, B cell-depleting agents, complement inhibitors, Fc receptor antagonists, and chimeric antigen receptor (CAR) T cell-based therapies, have introduced promising alternatives for MG treatment. These novel therapeutic approaches offer potential improvements in targeting specific immune pathways involved in MG pathogenesis. This review highlights the progress and challenges in developing and implementing these molecular therapies. It discusses their mechanisms, efficacy, and the potential for personalized medicine in managing MG. The integration of new molecular therapies into clinical practice could significantly transform the treatment landscape of MG, offering more effective and tailored therapeutic options for patients who do not respond adequately to traditional treatments. These innovations underscore the importance of ongoing research and clinical trials to optimize therapeutic strategies and improve the quality of life for individuals with MG.

Cognitive decline is a frequent complaint in healthy controls and neurological patients, regardless of the underlying pathology. Whilst cognitive impairment can be easily diagnosed in the more advanced stages of neurodegenerative diseases, early detection can be challenging. This is mainly the consequence of the incomplete understanding of the underlying pathophysiological mechanisms. In addition, currently available neurological treatments do not specifically target cognitive decline, since other motor and non-motor symptoms, such as bradykinesia, tremor, autonomic disturbances and depression, are of greater relevance from a therapeutic perspective. In this context, prospective studies must address a number of issues, including the risk factors associated with cognitive deficits in neurodegenerative diseases. The present review aims to offer a novel perspective on the association between Epstein-Barr virus infection and cognitive decline found in patients with neurodegenerative disorders. Specifically, relevant epidemiological studies and clinical trials explaining this connection were reviewed, focusing on the most frequent neurodegenerative disorders. They are namely Alzheimer's disease, Parkinson's disease and multiple sclerosis. Despite their limitations, possible underlying pathophysiological mechanisms that explain the impact of Epstein-Barr virus infection on cognitive decline are expected to offer novel study directions on this clinically relevant topic.

Diffuse large B-cell lymphoma (DLBCL) is a malignancy of immense biological and clinical heterogeneity. Based on the transcriptomic or genomic approach, several different classification schemes have evolved over the years to subdivide DLBCL into clinically (prognostically) relevant subsets, but each leaves unclassified samples. Herein, we outline the DLBCL tumor biology behind the actual and potential drug targets and address the challenges and drawbacks coupled with their (potential) use. Therapeutic modalities are discussed, including small-molecule inhibitors, naked antibodies, antibody-drug conjugates, chimeric antigen receptors, bispecific antibodies and T-cell engagers, and immune checkpoint inhibitors. Candidate drugs explored in ongoing clinical trials are coupled with diverse toxicity issues and refractoriness to drugs. According to the literature on DLBCL, the promise for new therapeutic targets lies in epigenetic alterations, B-cell receptor and NF-κB pathways. Herein, we present putative targets hiding in lipid pathways, ferroptosis, and the gut microbiome that could be used in addition to immuno-chemotherapy to improve the general health status of DLBCL patients, thus increasing the chance of being cured. It may be time to devote more effort to exploring DLBCL metabolism to discover novel druggable targets. We also performed a bibliometric and knowledge-map analysis of the literature on DLBCL published from 2014-2023.

BTK inhibitor therapy induces peripheral blood lymphocytosis in chronic lymphocytic leukemia (CLL) lasting for several months. It remains unclear whether non-genetic adaptation mechanisms exist, allowing CLL cells' survival during BTK inhibitor-induced lymphocytosis and/or playing a role in therapy resistance. We show that in approximately 70 % of CLL cases, ibrutinib treatment in vivo increases Akt activity above pre-therapy levels within several weeks, leading to compensatory CLL cell survival and a more prominent lymphocytosis on therapy. Ibrutinib-induced Akt phosphorylation (pAktS473) is caused by the upregulation of FoxO1 transcription factor, which induces expression of Rictor, an assembly protein for mTORC2 protein complex that directly phosphorylates Akt at serine 473 (S473). Knock-out or inhibition of FoxO1 or Rictor led to a dramatic decrease in Akt phosphorylation and growth disadvantage for malignant B cells in the presence of ibrutinib (or PI3K inhibitor idelalisib) in vitro and in vivo. FoxO1/Rictor/pAktS473 axis represents an early non-genetic adaptation to BCR inhibitor therapy not requiring PI3Kδ or BTK kinase activity. We further demonstrate that FoxO1 can be targeted therapeutically, and its inhibition induces CLL cells' apoptosis alone or in combination with BTK inhibitors (ibrutinib, acalabrutinib, pirtobrutinib) and blocks their proliferation triggered by T-cell factors (CD40L, IL-4, and IL-21).