Cytotoxic T cells go awry in inclusion body myositis

This scientific commentary refers to ‘Association of inclusion body myositis with T cell large granular lymphocytic leukaemia’, by Greenberg et al. (doi:10.1093/brain/aww024) Inclusion body myositis (IBM) is the most prevalent acquired myopathy in adults beyond the age of 50. The disease is relentlessly progressive and largely resistant to immunosuppressive therapy (reviewed by Hohlfeld, 2011). In IBM, and less frequently also in polymyositis, non-necrotic muscle fibres are focally surrounded and invaded by CD8+ cytotoxic T cells (CTL) (Fig. 1) (Engel and Arahata, 1986). The CTLs show immunohistological features of activation and form close contacts with muscle fibres. The muscle fibres that are attacked express major histocompatibility complex (MHC) class I molecules on their surface, and are therefore capable of presenting MHC class I-bound peptides to CD8+ T cells (Fig. 1). It is thus assumed that the muscle-invading CTLs recognize an unknown antigen (or antigens) on muscle fibres. This is further supported by the observation that CTLs tend to orient their cytotoxic granules towards the contacting muscle fibre, providing tell-tale evidence that an immunological synapse has formed between the CTL and its target cell (Goebels et al. , 1996). Furthermore, the muscle-infiltrating CTLs are clonally expanded, and identical clones of CTLs may be detected in muscle and blood for prolonged periods of time, providing evidence for chronic antigen-driven proliferation of the CTLs (Hohlfeld, 2011). In this issue of Brain , Greenberg and co-workers report that ∼50% of patients with IBM harbour clonally expanded populations of …