{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n Follicular dendritic cell‐secreted protein (FDC‐SP) is a small secreted peptide first identified in human tonsils where it is produced by activated follicular dendritic cells and preferentially localized within germinal centers."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " In this setting, FDC‐SP binds selectively to activated B cells and modulates their responses, suggesting a role as an immunomodulatory mediator."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": " In vivo studies in transgenic mice indicate that FDC‐SP can alter antigen‐specific immunoglobulin isotype production and suppress germinal center responses, further supporting its immunoregulatory function."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "2"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Beyond lymphoid tissues, FDC‐SP is expressed in oral tissues. Its detection in the periodontal ligament and junctional epithelium implicates it in the regulation and homeostasis of oral connective tissue."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "4", "end_ref": "7"}]}, {"type": "t", "text": " In these tissues, overexpression of FDC‐SP has been shown to inhibit osteogenic differentiation and mineralization by periodontal ligament cells, thereby stabilizing a fibroblastic phenotype that is essential for periodontal regeneration."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "7"}]}, {"type": "t", "text": " FDC‐SP expression in oral epithelia is also subject to regulation by pro‐inflammatory cytokines (e.g., TNF‐α and IL‐1β) and bacterial challenges, indicating its participation in the local inflammatory response."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "8", "end_ref": "10"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Moreover, studies in mucosal immunity have revealed that decreased FDC‐SP expression correlates with enhanced immunoglobulin A (IgA) production in the tonsils of patients with IgA nephropathy, and pharmacological modulation (e.g., by Triptolide) that increases FDC‐SP levels results in lowered IgA synthesis."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": " In addition, forensic investigations have identified FDC‐SP as a body fluid–specific marker for saliva."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "13"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Finally, evolutionary analyses place FDC‐SP within the secretory calcium‐binding phosphoprotein gene cluster and suggest that the Ca–insensitive casein gene evolved directly from FDC‐SP, highlighting its relevance as a progenitor among calcium‐binding proteins."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "14"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n \n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these findings establish FDC‐SP as a multifunctional protein with roles in immune regulation, particularly in modulating B cell responses and IgA production, as well as in maintaining periodontal ligament homeostasis by inhibiting osteogenic differentiation. Its regulated expression in response to inflammatory signals and bacterial products further underscores its significance in both normal physiology and disease, while its diagnostic potential is supported by its utility as a saliva‐specific marker.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Aaron J Marshall, Quijiang Du, Kevin E Draves, et al. 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