TDP-43 dependent cryptic exon derived neoepitopes as a novel diagnostic biomarker in muscle biopsies of inclusion body myositis patients
NEUROMUSCULAR DISORDERS(2023)
摘要
Inclusion body myositis (IBM) is an idiopathic inflammatory myopathy with muscle pathology characterized by primary endomysial inflammation, rimmed vacuoles, and mislocalization of TDP-43. The loss of TDP-43-mediated splicing repression in myonuclei generates cryptic exons in IBM confirmed by both reverse transcription polymerase chain reaction and in situ hybridization. In most cases, cryptic exons are out-of-frame and degraded via nonsense-mediated decay. Utilizing a novel antibody recognizing cryptic peptide Hepatoma-Derived Growth Factor-Like protein 2 (HDGFL2), immunohistochemical analysis of muscle biopsies from 119 IBM patients revealed cryptic HDGFL2 in the myonuclei in 81 patients (68%). In contrast, cryptic HDGFL2 immunoreactivity was absent in 195 muscle biopsies from a variety of disease controls, except in one patient with Valosin-containing protein disease. Combining cryptic HDGFL2 immunoreactivity with the presence of rimmed vacuoles, the sensitivity for a diagnosis of IBM increased to 82% and specificity remained 99%. Notably, cryptic HDGFL2 transcripts and proteins were detected in both normal and abnormal appearing muscle fibers in IBM as judged by the hematoxylin and eosin stain, suggesting the loss of TDP-43 splicing repression may occur in an early phase of the disease, preceding the appearance of rimmed vacuoles and protein aggregates in a myofiber. These results support the view that loss of TDP-43 occurs in skeletal muscle of IBM patients and suggest that immunostaining for the presence of the cryptic peptide HDGFL2 could be a potential early diagnostic marker for IBM patients. Inclusion body myositis (IBM) is an idiopathic inflammatory myopathy with muscle pathology characterized by primary endomysial inflammation, rimmed vacuoles, and mislocalization of TDP-43. The loss of TDP-43-mediated splicing repression in myonuclei generates cryptic exons in IBM confirmed by both reverse transcription polymerase chain reaction and in situ hybridization. In most cases, cryptic exons are out-of-frame and degraded via nonsense-mediated decay. Utilizing a novel antibody recognizing cryptic peptide Hepatoma-Derived Growth Factor-Like protein 2 (HDGFL2), immunohistochemical analysis of muscle biopsies from 119 IBM patients revealed cryptic HDGFL2 in the myonuclei in 81 patients (68%). In contrast, cryptic HDGFL2 immunoreactivity was absent in 195 muscle biopsies from a variety of disease controls, except in one patient with Valosin-containing protein disease. Combining cryptic HDGFL2 immunoreactivity with the presence of rimmed vacuoles, the sensitivity for a diagnosis of IBM increased to 82% and specificity remained 99%. Notably, cryptic HDGFL2 transcripts and proteins were detected in both normal and abnormal appearing muscle fibers in IBM as judged by the hematoxylin and eosin stain, suggesting the loss of TDP-43 splicing repression may occur in an early phase of the disease, preceding the appearance of rimmed vacuoles and protein aggregates in a myofiber. These results support the view that loss of TDP-43 occurs in skeletal muscle of IBM patients and suggest that immunostaining for the presence of the cryptic peptide HDGFL2 could be a potential early diagnostic marker for IBM patients.
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关键词
inclusion body myositis patients,muscle biopsies,novel diagnostic biomarker,neoepitopes
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