title: Association of inclusion body myositis with T cell large granular lymphocytic leukaemia.
abstract: SEE HOHLFELD AND SCHULZE-KOOPS DOI101093/BRAIN/AWW053 FOR A SCIENTIFIC COMMENTARY ON THIS ARTICLE: Inclusion body myositis and T cell large granular lymphocytic leukaemia are rare diseases involving pathogenic cytotoxic CD8+ T cells. After encountering four patients with both disorders, we prospectively screened 38 patients with inclusion body myositis for the presence of expanded large granular lymphocyte populations by standard clinical laboratory methods (flow cytometry, examination of blood smears, and T cell receptor gene rearrangements), and performed muscle immunohistochemistry for CD8, CD57, and TIA1. Most (22/38; 58%) patients with inclusion body myositis had aberrant populations of large granular lymphocytes in their blood meeting standard diagnostic criteria for T cell large granular lymphocytic leukaemia. These T cell populations were clonal in 20/20 patients and stably present on follow-up testing in 15 patients a median of 350 days later. T cell aberrant loss of CD5 or gain of expression of CD16 and CD94 were common (19/42, 45%). In comparison, 2/15 (14%) age-matched patients with dermatomyositis, polymyositis, or necrotizing myopathy, and 0/20 (0%) age-matched healthy subjects had large granular lymphocyte expansions, with none of these patients having T cell aberrant expression of CD5, CD16 or CD94. Reduced blood CD4/CD8 ratio, increased blood CD8 count, and lymphocytosis were additional biomarkers highly correlated with flow cytometry-measured large granular lymphocyte expansions. Cross-sectional data suggested more aggressive disease in patients with such expansions than without. Muscle immunohistochemistry demonstrated invasion of large granular lymphocytes into muscle in 15/15 inclusion body myositis patients but in only 1/28 patients with dermatomyositis or polymyositis. The extent of CD8+ and CD57+ cells in inclusion body myositis muscle correlated with the size of blood large granular lymphocyte populations. Myofibre-invading cells expressed CD57, a marker of persistent T cell exposure to antigen and T cell aggressiveness. In many patients with inclusion body myositis, the autoimmune T cell expansion has evolved into a neoplastic-like or overtly neoplastic disorder, perhaps contributing to its relative refractoriness to immune-directed therapies previously reported.
authors.affiliation: Brigham and Women's Hospital, Department of Neurology, Harvard Medical School, Boston, MA, USA Children's Hospital Informatics Program, Boston Children's Hospital, Boston, MA, USA.
authors.forename: Steven A
authors.initials: SA
authors.lastname: Greenberg
authors.affiliation: Brigham and Women's Hospital, Department of Neurology, Harvard Medical School, Boston, MA, USA.
authors.forename: Jack L
authors.initials: JL
authors.lastname: Pinkus
authors.affiliation: Brigham and Women's Hospital, Department of Neurology, Harvard Medical School, Boston, MA, USA.
authors.forename: Anthony A
authors.initials: AA
authors.lastname: Amato
authors.affiliation: Odense University Hospital, Department of Pathology, Odense C, Denmark.
authors.forename: Thomas
authors.initials: T
authors.lastname: Kristensen
authors.affiliation: Brigham and Women's Hospital, Department of Pathology, Harvard Medical School, Boston, MA, USA.
authors.forename: David M
authors.initials: DM
authors.lastname: Dorfman
mesh_terms: D000328:Adult; D000368:Aged; D015703:Antigens, CD / Q000097:blood / Q000378:metabolism*; D015415:Biomarkers / Q000378:metabolism; D016022:Case-Control Studies; D003430:Cross-Sectional Studies; D006801:Humans; D054066:Leukemia, Large Granular Lymphocytic / Q000150:complications* / Q000378:metabolism*; D008218:Lymphocytosis / Q000150:complications; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism; D009132:Muscles / Q000166:cytology / Q000378:metabolism; D018979:Myositis, Inclusion Body / Q000150:complications* / Q000378:metabolism*; D011446:Prospective Studies; D013601:T-Lymphocytes / Q000378:metabolism / Q000473:pathology
chemical_list: D015703:Antigens, CD; D015415:Biomarkers
keywords: T-lymphocytes; inclusion bodies; inclusion body myositis; inflammatory myopathy; neurooncology