Rheumatology (Oxford, England) · 2025
Anti-Mi2 autoantibodies target PHD fingers of SP140L and TIF1γ, while anti-TIF1γ autoantibodies primarily bind TIF1γ outside the PHD region.
СтатьяResearch Support, N.I.H., IntramuralНазвание и аннотация: Перевод в очереди
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Pinal-Fernandez Iago, Musai Jon, Casal-Dominguez Maria, Pak Katherine, Kaplan Mariana, Warner Blake M, Rider Lisa G, Aggarwal Rohit, Oddis Chester V, Moghadam-Kia Siamak, Garrabou Gloria, Selva-O'Callaghan Albert, Milisenda Jose C, Chiorini John A, Mammen Andrew L, Burbelo Peter D
Аннотация
OBJECTIVES: Plant homeodomain (PHD) fingers are present in many chromatin-binding proteins. We recently discovered that anti-Mi2 autoantibodies recognize PHD fingers in Mi2 and AIRE. The purpose of this study was to characterize anti-Mi2 autoantibody recognition of PHD fingers in SP140L and TIF1γ as well as to explore recognition of TIF1γ by both anti-TIF1γ and anti-Mi2 autoantibodies.
METHODS: Luciferase immunoprecipitation system (LIPS) assays were performed to detect autoantibodies against full-length and protein fragments of SP140L and TIF1γ in serum samples from myositis patients, disease controls and healthy controls.
RESULTS: Anti-Mi2 autoantibodies recognized SP140L. When a 49 amino acid fragment of the PHD finger of SP140L was used as the target, the specificity for selectively detecting anti-Mi2 autoantibodies increased. Additionally, anti-Mi2 autoantibodies weakly bound TIF1γ compared with anti-TIF1γ autoantibodies. Excluding the TIF1γ PHD finger from the TIF1γ target autoantigen eliminated cross-reactivity with anti-Mi2 autoantibodies, confirming that anti-Mi2 autoantibodies specifically target the PHD finger of TIF1γ. Switching two amino acids in the TIF1γ PHD finger to resemble those in AIRE markedly enhanced anti-Mi2 autoantibody immunoreactivity. Anti-TIF1γ autoantibodies primarily recognized the N-terminal fragment outside of the PHD finger, indicating this region contains the immunodominant epitopes.
CONCLUSIONS: Anti-Mi2 autoantibodies recognize the PHD fingers of SP140L and TIF1γ. TIF1γ is recognized by two different myositis-specific autoantibodies: anti-Mi2 autoantibodies bind the C-terminal PHD domain and anti-TIF1γ autoantibodies predominantly bind the N-terminal region. Removing the PHD finger from the anti-TIF1γ target autoantigen can improve the specificity of anti-TIF1γ autoantibody assays by reducing cross-reactivity with anti-Mi2 autoantibodies.
METHODS: Luciferase immunoprecipitation system (LIPS) assays were performed to detect autoantibodies against full-length and protein fragments of SP140L and TIF1γ in serum samples from myositis patients, disease controls and healthy controls.
RESULTS: Anti-Mi2 autoantibodies recognized SP140L. When a 49 amino acid fragment of the PHD finger of SP140L was used as the target, the specificity for selectively detecting anti-Mi2 autoantibodies increased. Additionally, anti-Mi2 autoantibodies weakly bound TIF1γ compared with anti-TIF1γ autoantibodies. Excluding the TIF1γ PHD finger from the TIF1γ target autoantigen eliminated cross-reactivity with anti-Mi2 autoantibodies, confirming that anti-Mi2 autoantibodies specifically target the PHD finger of TIF1γ. Switching two amino acids in the TIF1γ PHD finger to resemble those in AIRE markedly enhanced anti-Mi2 autoantibody immunoreactivity. Anti-TIF1γ autoantibodies primarily recognized the N-terminal fragment outside of the PHD finger, indicating this region contains the immunodominant epitopes.
CONCLUSIONS: Anti-Mi2 autoantibodies recognize the PHD fingers of SP140L and TIF1γ. TIF1γ is recognized by two different myositis-specific autoantibodies: anti-Mi2 autoantibodies bind the C-terminal PHD domain and anti-TIF1γ autoantibodies predominantly bind the N-terminal region. Removing the PHD finger from the anti-TIF1γ target autoantigen can improve the specificity of anti-TIF1γ autoantibody assays by reducing cross-reactivity with anti-Mi2 autoantibodies.