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*
Department of Neurosciences, Lerner Research Institute,
Department of Neurology, Mellen Center for Multiple Sclerosis Research, and
Department of Biostatistics, Cleveland Clinic Foundation, Cleveland, OH 44195; and
§
Institute of Pathology, Case Western Reserve University, Cleveland, OH 44106
Identifying and quantifying autoaggressive responses in multiple
sclerosis (MS) has been difficult in the past due to the low frequency
of autoantigen-specific T cells, the high number of putative
determinants on the autoantigens, and the different cytokine signatures
of the autoreactive T cells. We used single-cell resolution
enzyme-linked immunospot (ELISPOT) assays to study, directly ex vivo,
proteolipid protein (PLP)-specific memory cell reactivity from MS
patients and controls. Overlapping 9-aa-long peptides, spanning the
entire PLP molecule in single amino acid steps, were used to determine
the frequency and fine specificity of PLP-specific lymphocytes as
measured by their IFN-
and IL-5 production. MS patients
(n = 22) responded to 4 times as many PLP peptides
as did healthy controls (n = 22). The epitopes
recognized in individual patients, up to 22 peptides, were scattered
throughout the PLP molecule, showing considerable heterogeneity among
MS patients. Frequency measurements showed that the number of PLP
peptide-specific IFN--producing cells averaged 11 times higher in MS
patients than in controls. PLP peptide-induced IL-5-producing T cells
occurred in very low frequencies in both MS patients and controls. This
first comprehensive assessment of the anti-PLP-Th1/Th2 response in
MS shows a greatly increased Th1 effector cell mass in MS patients.
Moreover, the highly IFN--polarized, IL-5-negative cytokine profile
of the PLP-reactive T cells suggests that these cells are committed Th1
cells. The essential absence of uncommitted Th0 cells producing both
cytokines may explain why therapeutic strategies that aim at the
induction of immune deviation show little efficacy in the established
disease.
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