{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\nTNFSF13—also known as APRIL—is a multifunctional cytokine of the tumor necrosis factor superfamily that plays a pivotal role in B‐cell biology. It promotes immunoglobulin class switch recombination and plasma cell differentiation by engaging with its receptors (primarily TACI and BCMA), even in the absence of classical CD40–CD40L interactions. In this way, APRIL bridges innate and adaptive immune responses by enhancing T cell–independent antibody isotype switching (e.g., to IgG, IgA, or IgE) and by providing survival signals crucial for the long‐term maintenance of antibody‐secreting cells. Moreover, during certain viral infections such as by Epstein–Barr virus, APRIL induction contributes to aberrant class switching that may predispose to autoimmunity."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "6"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nIn the context of B‐cell malignancies and related disorders, APRIL acts as a potent survival and growth factor. It is frequently overexpressed by tumor cells and elements of the tumor microenvironment in conditions such as multiple myeloma, chronic lymphocytic leukemia, non‐Hodgkin’s lymphoma, and diffuse large B‐cell lymphoma. Engagement of APRIL with its receptors activates intracellular cascades—including NF‑κB, PI3K/AKT, and MAPK pathways—that result in the upregulation of antiapoptotic proteins and the maintenance of malignant cell survival. Elevated APRIL expression or serum levels often correlate with disease aggressiveness and poorer clinical outcomes, highlighting its potential as both a prognostic biomarker and a therapeutic target."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "7", "end_ref": "19"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nAt the molecular level, APRIL’s biological activity is determined by its mode of receptor engagement and the requirement for oligomerization. APRIL interacts with TACI and BCMA through defined regions within its TNF homology domain, while a distinct basic amino acid motif enables binding to cell surface heparan sulfate proteoglycans. Such interactions facilitate both the clustering and stabilization of APRIL, which is essential for potent receptor signaling. Moreover, APRIL can form heterotrimeric complexes with its homolog BLyS, thereby broadening its functional repertoire and fine‐tuning B cell activation and survival pathways."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "20"}, {"type": "fg_f", "ref": "18"}, {"type": "fg_f", "ref": "21"}]}, {"type": "t", "text": "\n\n"}, {"type": "p", "children": [{"type": "t", "text": "\nBeyond its direct effects on B lymphocytes, APRIL modulates a broader immune microenvironment. It is produced not only by B cells but also by various stromal and myeloid cell types—including neutrophils, osteoclasts, and bone marrow precursors—to maintain plasma cell niches and regulate local immune responses. Dysregulated APRIL expression is associated with several autoimmune and inflammatory diseases (such as rheumatoid arthritis, Sjögren’s syndrome, IgA nephropathy, and ANCA‑associated vasculitis) and is implicated in the immunosuppressive tumor microenvironment by enhancing regulatory T‐cell and B‐cell functions. These multifaceted roles underscore APRIL’s importance as both an immune modulator and a candidate for targeted therapeutic interventions."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "23", "end_ref": "31"}]}, {"type": "t", "text": ""}]}]}]}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Jens V Stein, Marta López-Fraga, Fernando A Elustondo, et al. 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