Association of inclusion body myositis with T cell large granular lymphocytic leukaemia
Open Access
- 26 February 2016
- journal article
- research article
- Published by Oxford University Press (OUP) in Brain
- Vol. 139 (5), 1348-1360
- https://doi.org/10.1093/brain/aww024
Abstract
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.Keywords
This publication has 52 references indexed in Scilit:
- STAT3 mutations unify the pathogenesis of chronic lymphoproliferative disorders of NK cells and T-cell large granular lymphocyte leukemiaBlood, 2012
- Post-thymic regulation of CD5 levels in human memory T cells is inversely associated with the strength of responsiveness to interleukin-15Human Immunology, 2011
- CD8+ CD28− and CD8+ CD57+ T cells and their role in health and diseaseImmunology, 2011
- Autoantibodies against a 43 KDa Muscle Protein in Inclusion Body MyositisPLOS ONE, 2011
- How I treat LGL leukemiaBlood, 2011
- Analysis of a French cohort of patients with large granular lymphocyte leukemia: a report on 229 casesHaematologica, 2010
- Molecular profiling of LGL leukemia reveals role of sphingolipid signaling in survival of cytotoxic lymphocytesBlood, 2008
- T cell receptor profiling in muscle and blood lymphocytes in sporadic inclusion body myositisNeurology, 2007
- Reprogramming of CTLs into natural killer–like cells in celiac diseaseThe Journal of Experimental Medicine, 2006
- T-Cell Large Granular Lymphocyte Leukemias Have Multiple Phenotypic Abnormalities Involving Pan–T-Cell Antigens and Receptors for MHC MoleculesAmerican Journal of Clinical Pathology, 2005