Lack of restriction of T cell receptor beta variable gene usage in cerebrospinal fluid lymphocytes in acute optic neuritis

Objectives-There have been many studies reporting restricted patterns of T cell receptor usage in established multiple sclerosis and these have led to clinical trials of immunomodulation directed at deleting clonal T cell pop ulations. The present study aims to test the hypothesis that highly restric ted T cell populations are also present in the CSF in the earliest clinical stages of acute demyelinating disease of the CNS. Methods-T cell receptor V beta (TCRBV) gene expression was studied in CSF a nd blood in nine patients with acute optic neuritis within 7 days of onset of symptoms, six patients with an acute relapse of multiple sclerosis, and 13 control subjects. RNA was extracted and cDNA synthesised from unstimulat ed CSF and blood lymphocytes, and TCRBV gene segments were amplified from t he cDNA by polymerase chain reaction (PCR) using 21 family specific primers . PCR products were separated by polyacrylamide gel electrophoresis and det ected via a labelled oligonucleotide probe. A semiquantitative analysis of band intensity was performed by laser densitometry. Results-TCRBV mRNA was detected in the CSF of eight of nine patients with o ptic neuritis, six of six patients with multiple sclerosis, and five of 13 controls, and was closely correlated with the presence of oligoclonal IgG. Usage of a single TCRBV family was demonstrated in two of nine patients wit h optic neuritis and two of six patients with multiple sclerosis. The numbe r of TCRBV families expressed in the other patients ranged between 5 and 15 (optic neuritis) and 4 and 17 (multiple sclerosis). Conclusions-There is a relative lack of restriction of TCRBV usage by CSF l ymphocytes in the very earliest stages (<7 days) of acute optic neuritis. T his may imply either that multiple sclerosis is not a monoclonal disease ev en at onset, or that the autoimmune response has widened before the disease becomes clinically evident. This may have important consequences for the d esign of immune therapies in multiple sclerosis. Further studies are requir ed to determine whether the CSF T cell repertoire at presentation has progn ostic importance. Longitudinal studies are required to follow the CSF T cel l repertoire from the time of presentation and to determine whether it may have prognostic significance.