title: Shared blood and muscle CD8+ T-cell expansions in inclusion body myositis.
abstract: Inclusion body myositis (IBM) is the most frequent inflammatory myopathy over the age of fifty. Pathological findings suggest that two processes may contribute to IBM pathogenesis: a primary degenerative process affecting muscle fibre and/or an autoimmune process mediated by major histocompatibility complex (MHC) class-I-restricted cytotoxic CD8+ T cells. Previous studies have demonstrated that muscle-infiltrating CD8+ T cells in IBM display restricted expression of T-cell receptor (TCR)-BV families or evidenced oligoclonal T-cell expansions. This study was performed to investigate whether blood T cells similarly exhibit clonal expansions due to the recirculation of muscle-infiltrating T cells in the periphery. For this, we studied the T-cell repertoire of 17 IBM patients by complementarity-determining-region (CDR) 3 length distribution (immunoscope) analysis of TCR-B transcripts. Mean age was 68 years (range 53-88) and mean duration of the disease was 6.5 years (2-20). Oligoclonal T-cell expansions were observed in the blood of IBM patients. The quantitative average perturbation D index was significantly increased in IBM patients [D = 13.7% +/- 1.2%, mean +/- standard error of measurement (SEM)] as compared with 17 age-matched controls suffering from connective tissue diseases not associated with T-cell repertoire perturbation, that is, dermatomyositis (DM) and systemic sclerosis (9.3 +/- 0.6%, P < 0.005). Nevertheless, there was no correlation between the level of blood perturbation and muscle inflammation. Sorting experiments showed that these perturbations were due to oligoclonal expansions of CD8+ T cells. In the three IBM patients analysed, we could relate the blood expansions to T-cell clones also found in muscle. The clonally expanded blood T cells dramatically responded to interleukin-2 (IL-2) in vitro, suggesting that they had been primed in vivo, presumably in response to yet unknown muscle auto-antigens. Together, our results indicate that clonally expanded muscle-infiltrating CD8+ T cells re-circulate in the blood and support the concept of a CD8+ T-cell-mediated autoimmune component in IBM, similarly to what is observed in polymyositis (PM).
authors.affiliation: Service de médecine interne 1, Hôpital Pitié-Salpêtrière, Paris, France.
authors.forename: Dalia
authors.initials: D
authors.lastname: Dimitri
authors.forename: Olivier
authors.initials: O
authors.lastname: Benveniste
authors.forename: Odile
authors.initials: O
authors.lastname: Dubourg
authors.forename: Thierry
authors.initials: T
authors.lastname: Maisonobe
authors.forename: Bruno
authors.initials: B
authors.lastname: Eymard
authors.forename: Zahir
authors.initials: Z
authors.lastname: Amoura
authors.forename: Laetitia
authors.initials: L
authors.lastname: Jean
authors.forename: Kiet
authors.initials: K
authors.lastname: Tiev
authors.forename: Jean-Charles
authors.initials: JC
authors.lastname: Piette
authors.forename: David
authors.initials: D
authors.lastname: Klatzmann
authors.forename: Serge
authors.initials: S
authors.lastname: Herson
authors.forename: Olivier
authors.initials: O
authors.lastname: Boyer
mesh_terms: D000368:Aged; D000369:Aged, 80 and over; D001327:Autoimmune Diseases / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D002465:Cell Movement / Q000276:immunology; D002478:Cells, Cultured; D022801:Complementarity Determining Regions / Q000032:analysis; D005260:Female; D006801:Humans; D007376:Interleukin-2 / Q000276:immunology; D008213:Lymphocyte Activation / Q000276:immunology; D008297:Male; D008875:Middle Aged; D018482:Muscle, Skeletal / Q000276:immunology*; D018979:Myositis, Inclusion Body / Q000276:immunology* / Q000473:pathology; D012720:Severity of Illness Index; D016176:T-Lymphocyte Subsets / Q000276:immunology
chemical_list: D022801:Complementarity Determining Regions; D007376:Interleukin-2