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Objectives: Paediatric Burkitt's lymphoma (pBL) is the most common childhood non‐Hodgkin B‐cell lymphoma. Despite the encouraging survival rates for most children, treating cases with relapse/resistance to current therapies remains challenging. CD38 is a transmembrane protein highly expressed in pBL. This study investigates the effectiveness of CD38‐targeting monoclonal antibodies (mAbs), daratumumab and isatuximab, in impairing crucial cellular processes and survival pathways in pBL malignant cells. Methods: In silico analyses of patient samples, combined with in vitro experiments using the Ramos cell line, were conducted to assess the impact of daratumumab and isatuximab on cellular proliferation, apoptosis and the phosphoinositide 3‐kinase (PI3K) pathway. Results: Isatuximab was found to be more effective than daratumumab in disrupting B‐cell receptor signalling, reducing cellular proliferation and inducing apoptosis. Additionally, isatuximab caused a significant impairment of the PI3K pathway and induced metabolic reprogramming in pBL cells. The study also revealed a correlation between CD38 and MYC expression levels in pBL patient samples, suggesting CD38 involvement in key oncogenic processes. Conclusion: The study emphasises the therapeutic potential of CD38‐targeting mAbs, particularly isatuximab, in pBL. [ABSTRACT FROM AUTHOR]

Objective: Subsets of CD21−/low memory B cells (MBCs), including double‐negative (DN, CD27−IgD−) and Tbet+CD11c+ cells, are expanded in chronic inflammatory diseases. In rheumatoid arthritis (RA), CD21−/low MBCs correlate with joint destruction. However, whether this is due to the Tbet+CD11c+ subset, its function and pathogenic contribution to RA are unknown. This study aims to investigate the association between CD21−/lowTbet+CD11c+ MBCs and joint destruction as well as other clinical parameters and to elucidate their functional properties in patients with untreated RA (uRA). Methods: Clinical observations were combined with flow cytometry (n = 36) and single‐cell RNA sequencing (scRNA‐seq) and V(D)J sequencing (n = 4) of peripheral blood (PB) MBCs from patients with uRA. The transcriptome of circulating Tbet+CD11c+ MBCs was compared with scRNA‐seq data of synovial B cells. In vitro coculture of Tbet+CD11c+ B cells with T cells was used to assess costimulatory capacity. Results: CD21−/lowTbet+CD11c+ MBCs in PB correlated with bone destruction but no other clinical parameters analyzed. The Tbet+CD11c+ MBCs have undergone clonal expansion and express somatically mutated V genes. Gene expression analysis of these cells identified a unique signature of more than 150 up‐regulated genes associated with antigen presentation functions, including B cell receptor activation and clathrin‐mediated antigen internalization; regulation of actin filaments, endosomes, and lysosomes; antigen processing, loading, presentation, and costimulation; a transcriptome mirrored in their synovial tissue counterparts. In vitro, Tbet+CD11c+ B cells induced retinoic acid receptor–related orphan nuclear receptor γT expression in CD4+ T cells, thereby polarizing to Th17 cells, a T cell subset critical for osteoclastogenesis and associated with bone destruction. Conclusion: This study suggests that Tbet+CD11c+ MBCs contribute to the pathogenesis of RA by promoting bone destruction through antigen presentation, T cell activation, and Th17 polarization. [ABSTRACT FROM AUTHOR]

Summary: Memory B cells (MBCs) are an essential part of our immunological memory. They respond fast upon re-encountering pathogens and can differentiate into plasma cells that secrete protective antibodies. The focus of this review is on MBCs that lack, or express low levels of, CD21, hereafter referred to as CD21–/low. These cells are expanded in peripheral blood with age and during chronic inflammatory conditions such as viral infections, malaria, common variable immunodeficiency, and autoimmune diseases. CD21–/low MBCs have gained significant attention; they produce disease-specific antibodies/autoantibodies and associate with key disease manifestations in some conditions. These cells can be divided into subsets based on classical B-cell and other markers, e.g. CD11c, FcRL4, and Tbet which, over the years, have become hallmarks to identify these cells. This has resulted in different names including age-associated, autoimmune-associated, atypical, tissue-like, tissue-resident, tissue-restricted, exhausted, or simply CD21–/low B cells. It is however unclear whether the expanded 'CD21–/low' cells in one condition are equivalent to those in another, whether they express an identical gene signature and whether they have a similar function. Here, we will discuss these issues with the goal to understand whether the CD21–/low B cells are comparable in different conditions. CD21-/low memory B cells are expanded with age in healthy individuals and in patients with viral infections and autoimmune conditions and are associated with pathogen-specific antibodies as well as key disease manifestations. Depending on condition, CD21-/low memory B cells have been termed age-associated, autoimmune-associated, atypical, tissue-like, tissue-resident, tissue-restricted, exhausted or simply CD21-/low B cells. CD21-/low memory B cells are often CD27-IgD-CD11c+ and in some conditions they express Tbet, in others FcRL4 and in yet others both. [ABSTRACT FROM AUTHOR]

Objective: Subsets of CD21 -/low memory B cells (MBCs), including double-negative (DN, CD27 - IgD - ) and Tbet + CD11c + cells, are expanded in chronic inflammatory diseases. In rheumatoid arthritis (RA), CD21 -/low MBCs correlate with joint destruction. However, whether this is due to the Tbet + CD11c + subset, its function and pathogenic contribution to RA are unknown. This study aims to investigate the association between CD21 -/low Tbet + CD11c + MBCs and joint destruction as well as other clinical parameters and to elucidate their functional properties in patients with untreated RA (uRA)., Methods: Clinical observations were combined with flow cytometry (n = 36) and single-cell RNA sequencing (scRNA-seq) and V(D)J sequencing (n = 4) of peripheral blood (PB) MBCs from patients with uRA. The transcriptome of circulating Tbet + CD11c + MBCs was compared with scRNA-seq data of synovial B cells. In vitro coculture of Tbet + CD11c + B cells with T cells was used to assess costimulatory capacity., Results: CD21 -/low Tbet + CD11c + MBCs in PB correlated with bone destruction but no other clinical parameters analyzed. The Tbet + CD11c + MBCs have undergone clonal expansion and express somatically mutated V genes. Gene expression analysis of these cells identified a unique signature of more than 150 up-regulated genes associated with antigen presentation functions, including B cell receptor activation and clathrin-mediated antigen internalization; regulation of actin filaments, endosomes, and lysosomes; antigen processing, loading, presentation, and costimulation; a transcriptome mirrored in their synovial tissue counterparts. In vitro, Tbet + CD11c + B cells induced retinoic acid receptor-related orphan nuclear receptor γT expression in CD4 + T cells, thereby polarizing to Th17 cells, a T cell subset critical for osteoclastogenesis and associated with bone destruction., Conclusion: This study suggests that Tbet + CD11c + MBCs contribute to the pathogenesis of RA by promoting bone destruction through antigen presentation, T cell activation, and Th17 polarization., (© 2024 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.)

Background: Neurological disorders can present with a vast array of visual disturbances. The constellation of symptoms and findings in this patient prompted workup for unusual causes of both stroke and neurodegenerative disorder., Case Presentation: A woman in her sixties presented with visual disturbances, followed by weakness in her right arm and aphasia three days later. Her close acquaintances had suspected progressive cognitive decline during the previous year. CT and MRI showed an occluded left posterior cerebral artery with a subacute occipito-temporal infarction. The finding of extensive white matter lesions and segmental arterial vasoconstriction necessitated further workup of vasculitis and hereditary small vessel disease, which were ruled out. The stroke aetiology was considered to be atherosclerotic intracranial large vessel disease. FDG-PET scan revealed decreased metabolism in the left hemisphere, and cerebrospinal biomarkers had slightly decreased beta-amyloid. The findings were suggestive of early Alzheimer's disease or primary progressive aphasia, but currently inconclusive., Interpretation: Based on clinical-anatomical correlation, the patient's visual disturbances, in this case right hemianopsia and object agnosia, were solely related to the stroke and not to a neurodegenerative disorder. Knowledge and interpretation of visual agnosias can in many cases be clinically valuable.