Shared blood and muscle CD8+ T-cell expansions in inclusion body myositis.
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).
Dimitri
Dalia
D
Service de médecine interne 1, Hôpital Pitié-Salpêtrière, Paris, France.
Benveniste
Olivier
O
Dubourg
Odile
O
Maisonobe
Thierry
T
Eymard
Bruno
B
Amoura
Zahir
Z
Jean
Laetitia
L
Tiev
Kiet
K
Piette
Jean-Charles
JC
Klatzmann
David
D
Herson
Serge
S
Boyer
Olivier
O
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
D022801:Complementarity Determining Regions; D007376:Interleukin-2