{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n DEFB103B, which encodes human β‐defensin 3 (hBD3), is a multifunctional cationic antimicrobial peptide produced primarily by epithelial cells. Its potent, salt‐insensitive microbicidal activity extends to a broad spectrum of pathogens—including multiresistant Staphylococcus aureus, various Gram‐positive organisms, and certain fungi—mediated in part by binding to lipid II and disrupting cell wall biosynthesis to induce localized lesions."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "1", "end_ref": "3"}]}, {"type": "t", "text": ""}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Structural studies reveal that although hBD3 forms a dimer with a high positive surface charge essential for its antimicrobial properties, the integrity of its disulfide bridges is not requisite for killing microbes but is critical for receptor binding events that underlie its chemotactic functions."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "4"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n In addition to direct pathogen killing, hBD3 functions as an immunomodulator. It is induced by epithelial cell stimulation from bacterial confrontations and commensal organisms, and it activates innate immune signaling via Toll‐like receptor (TLR) pathways—such as TLR1/2—to promote the upregulation of costimulatory molecules on antigen‐presenting cells."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "6"}]}, {"type": "t", "text": " Furthermore, hBD3 can modulate cytokine responses through attenuation of NF‐κB signaling in macrophages"}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": "and interfere with chemokine receptor activity by promoting CXCR4 internalization, thereby acting as an endogenous antagonist for its ligand stromal‐derived factor 1 (SDF‐1)."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "9"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n hBD3 also contributes to epithelial barrier integrity. For example, it enhances tight-junction formation in keratinocytes through a CCR6-dependent pathway that involves activation of Rac1 and other downstream signaling molecules."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": " Conversely, a failure to mobilize hBD3 to the cell surface—observed in atopic dermatitis where Th2 cytokines (IL-4, IL-13) predominate—compromises the rapid killing of skin pathogens, highlighting its critical role in cutaneous host defense."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "11"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Moreover, certain pathogens (e.g., Helicobacter pylori) can subvert host defenses by interfering with IFN-γ–mediated signaling pathways, thereby dampening hBD3 expression and facilitating microbial persistence."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "12"}]}, {"type": "t", "text": "\n "}]}, {"type": "t", "text": "\n "}, {"type": "p", "children": [{"type": "t", "text": "\n Collectively, these findings underscore the dual role of DEFB103B/hBD3 in direct antimicrobial defense and in the orchestration of innate and adaptive immune responses, as well as in maintaining epithelial barrier function.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "J Harder, J Bartels, E Christophers, et al. 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