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Anti-Mi2 autoantibodies target PHD fingers of SP140L and TIF1γ, while anti-TIF1γ autoantibodies primarily bind TIF1γ outside the PHD region.

I. Pinal-Fernández,J. Musai,M. Casal-Domínguez,K. Pak,M. Kaplan,B. Warner,L. Rider,Rohit Aggarwal,C. Oddis,S. Moghadam-Kia,G. Garrabou,A. Selva-O’Callaghan,J. Milisenda,J. A. Chiorini,Andrew L. Mammen,P. Burbelo

Published 2025 in Rheumatology

ABSTRACT

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.

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