{"type": "root", "children": [{"type": "p", "children": [{"type": "t", "text": "\n A2ML1 is an alpha‐2‐macroglobulin–like protease inhibitor that plays multifaceted roles in epithelial biology and disease. In the epidermis, A2ML1 is expressed predominantly by granular keratinocytes and is secreted into the extracellular space, where it inhibits a broad spectrum of proteases (for example, chymotrypsin, kallikrein‐related proteases) to regulate desquamation and tissue homeostasis (see."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "1"}]}, {"type": "t", "text": " Moreover, through binding to receptors such as LRP1, A2ML1 may control the bioavailability of proteases, further influencing epidermal differentiation and barrier integrity. In addition, A2ML1 is recognized as an autoantigen in paraneoplastic pemphigus, where autoantibodies against it disrupt normal inhibitor function and contribute to loss of cell adhesion and blistering in affected mucocutaneous tissues (see."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "3"}]}, {"type": "t", "text": " Genetic studies have identified rare A2ML1 variants in patients with otitis media, suggesting that altered function or expression of A2ML1 may impair keratinocyte differentiation in the middle ear and modify the local microbiome, thereby increasing susceptibility to chronic middle ear inflammation (see."}, {"type": "fg", "children": [{"type": "fg_fs", "start_ref": "5", "end_ref": "7"}]}, {"type": "t", "text": " Rare missense mutations in A2ML1 have also been reported in individuals with Noonan syndrome–like features; however, in such cases the causative role of A2ML1 remains uncertain due to observations of variant transmission from unaffected parents and the frequent presence of additional mutations (see."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "8"}]}, {"type": "t", "text": " Altered A2ML1 expression may furthermore have prognostic utility in other settings, such as lung squamous cell carcinoma and inflammatory conditions like digital dermatitis in cattle, underscoring its broader involvement in processes that regulate extracellular proteolysis and tissue integrity (see."}, {"type": "fg", "children": [{"type": "fg_f", "ref": "10"}]}, {"type": "t", "text": " Collectively, these findings portray A2ML1 as a multifunctional extracellular inhibitor that not only governs normal epithelial differentiation and desquamation through its protease inhibitory activity but also serves as a target of autoimmunity and a genetic determinant in inflammatory and developmental disorders.\n "}]}, {"type": "rg", "children": [{"type": "r", "ref": 1, "children": [{"type": "t", "text": "Marie-Florence Galliano, Eve Toulza, Hélène Gallinaro, et al. 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