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Brain Advance Access originally published online on February 25, 2004
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Brain, Vol. 127, No. 5, 981-995, 2004
© 2004 Guarantors of Brain
doi: 10.1093/brain/awh119

Blood T-cell receptor ß chain transcriptome in multiple sclerosis. Characterization of the T cells with altered CDR3 length distribution

David-Axel Laplaud1,2, Catherine Ruiz1, Sandrine Wiertlewski2, Sophie Brouard1, Laureline Berthelot1, Marina Guillet3, Benoît Melchior1, Nicolas Degauque1, Gilles Edan4, Philippe Brachet1, Philippe Damier1,2 and Jean-Paul Soulillou1

1 Institut National de la Santé et de la Recherche Médicale (INSERM) Unité 437: ‘Immunointervention dans les Allo- et Xénotransplantations’, Institut de Transplantation et de Recherche en Transplantation (ITERT), CHU Hôtel Dieu, 30 Bd Jean Monnet, 2 Clinique Neurologique and Centre d’Investigation Clinique, Hôpital G. et R. Laennec, Bd J. Monod, 3 TcLand S.A., 30 Bd Jean Monnet, 44093 Nantes Cedex and 4 Service de Neurologie, Hôpital Pontchaillou, 35000, Rennes, France

Correspondence to: Jean-Paul Soulillou, INSERM U437, 30 Bd Jean-Monnet, 44093 Nantes Cedex 01, France E-mail: jps{at}nantes.inserm.fr

Multiple sclerosis is an inflammatory demyelinating disease of the CNS associated with T cells autoreactive for myelin components. In this study, we analysed the T-cell receptor (TCR) usage of the variable ß (Vß) chain transcriptome in the blood of multiple sclerosis patients at various stages of the disease using a global and quantitative comparison of the complementarity-determining region 3 length distribution (CDR3-LD) of transcripts of the 26 Vß genes. We investigated 35 patients: 12 with a high risk of multiple sclerosis, 10 with clinically definite multiple sclerosis, 13 with a relapsing–remitting worsening and active multiple sclerosis and 13 healthy individuals. Cells bearing the TCR transcripts with altered CDR3-LD were sorted and studied for CD4 or CD8 phenotype, cytokine transcript accumulation and response to human myelin basic protein (MBP). We show that patients from all the groups have a significantly skewed blood T-cell repertoire. Vß transcriptome patterns were more altered in patients from the clinically definite multiple sclerosis group and the worsening and active multiple sclerosis group than in the high risk group. The T cells sorted from Vß families with altered CDR3-LD concerned both CD4 and CD8 T cells, with a more pronounced skewing in the CD8 compartment. These cells displayed a significantly increased level of interferon-{gamma}, interleukin-2 and tumour necrosis factor-{alpha} transcripts compared with their counterparts from the healthy individual group. Furthermore, using interferon-{gamma} enzyme-linked immunospot (ELISPOT) assays, T cells from four out of seven altered Vß families tested from multiple sclerosis patients responded to human MBP, whereas no response was observed with human albumin or with altered Vß families from healthy individuals. Our data support the concept of an early autoimmune component in the disease and emphasize the possible involvement of CD8-positive T cells in multiple sclerosis.

Key Words: CD4/CD8; CDR3; cytokines; multiple sclerosis; T cells; Vß genes

Abbreviations: APC= antigen-presenting cell; CDMS = clinically definite multiple sclerosis; CDR3 = complementarity-determining region 3; CDR3-LD = complementarity-determining region 3 length distribution; ELISPOT = enzyme-linked immunospot; HI = healthy individuals; HLA = histocompatibility leukocyte antigen; HPRT = hypoxanthine phosphorylribosyl transferase; HRMS = high risk of multiple sclerosis; IFN-{gamma} = interferon-{gamma}; IL = interleukin; MBP = myelin basic protein; PBL = peripheral blood lymphocyte; PBMC = peripheral blood mononuclear cell;TCR = T-cell receptor; TNF-{alpha} = tumour necrosis factor-{alpha}; Vß = variable ß; WMS = worsening multiple sclerosis

Received October 1, 2003. Revised December 10, 2003. Accepted December 14, 2003.


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