MULTIPLE-SCLEROSIS - COMPARISON OF THE HUMAN T-CELL RESPONSE TO S100-BETA AND MYELIN BASIC-PROTEIN REVEALS PARALLELS TO RAT EXPERIMENTAL AUTOIMMUNE PANENCEPHALITIS

The adoptive transfer of autoreactive S100 beta-specific T cells induc es experimental autoimmune panencephalomyelitis and uveoretinitis in t he Lewis rat, mimicking the distribution of lesions seen in a subset o f patients with multiple sclerosis. We studied the frequency and funct ional properties of the human T-cell response to S100 beta In eight pa tients (two relapsing-remitting multiple sclerosis, one chronic-progre ssive multiple sclerosis, two with multiple sclerosis and uveitis, two neuromyelitis optica, one panuveitis) and in seven healthy individual s, using bovine S100 beta for T-cell stimulation. Both in patients and controls, the frequency of S100 beta-specific T-cell responses was ha lf of that obtained for myelin basic protein (MBP), and only 10% of th at obtained using purified protein derivative (PPD). The stimulation i ndices obtained in response to S100 beta were also less than half thos e obtained with either MBP or PPD. However, four long-term S100 beta-s pecific T-cell lines were established and studied in more detail. The four T-cell lines all exhibited a CD4+, CD8-, T-cell receptor alpha be ta+ surface phenotype and secreted tumour necrosis factor-alpha, inter feron-gamma interleukin-10 and interleukin-4 upon antigenic stimulatio n, but they were heterogeneous with respect to T-cell receptor usage; two T-cell lines expressed V beta 2, one V beta 6.7 and one V beta 13. Antigen-specificity was confirmed using bovine S100 beta beta and alp ha beta-isoforms, as well as a recombinant rat S100 beta preparation. The response to S100 beta was shown to be HLA(human leukocyte antigen- ) DR-restricted for two of the S100 beta-specific T-cell lines. Human S100 beta-specific T-cell lines were cytotoxic, although to a lesser e xtent than MBP-specific T-cell lines derived fr om the same donors. Th e phenotypic and functional properties of human S100 beta-specific T-c ell lines raise the possibility that these T cells are pathogenic, as they are in the mt. The low frequency and proliferative index of S100 beta-specific, as opposed to MBP-specific T-cell responses suggests th at the T-cell response to this widely expressed calcium-binding protei n is under more efficient regulatory control.