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Does a shift in the T-cell receptor repertoire precede the onset of MS?

From the Discipline of Laboratory Medicine (T. Cowan and Dr. Haegert), Faculty of Medicine, Memorial University of Newfoundland, St. John’s, Newfoundland; Dalhousie MS Research Unit (Dr. Murray), Dalhousie University, Halifax, Nova Scotia; Division of Community Health (Dr. Gadag), Faculty of Medicine, Memorial University of Newfoundland, St. John’s, Newfoundland; and the Multiple Sclerosis Clinic (Dr. O’Connor), St. Michael’s Hospital, University of Toronto, Ontario, Canada.

Address correspondence and reprint requests to Dr. D.G. Haegert, Discipline of Laboratory Medicine, Faculty of Medicine, Memorial University of Newfoundland, St. John’s, NF, A1B 3V6, Canada.

BACKGROUND: Utz et al., in a study of identical twins discordant for MS, showed that antigen-stimulated T cells from the MS twins have a major shift in their T-cell receptor (TCR) repertoires when compared with the healthy twins. We hypothesized that a shift in the TCR repertoire precedes the onset of MS and tested this hypothesis by studying unstimulated naïve T cells because the TCR repertoires of these cells are largely unaffected by disease.

OBJECTIVE: To investigate whether unstimulated naïve T cells from MS patients have a detectable shift in their TCR repertoires.

METHODS: We analyzed the TCR J beta (TCRBJ) repertoires of naïve T cells from identical twin pairs discordant for MS, healthy identical twin pairs, healthy unrelated pairs, and unrelated MS patient pairs. The correlation coefficient (r value) was used as a measure of similarity of TCRBJ repertoires in each pair of individuals. Fisher’s z transformation was then used to test for the significance of the difference between the r values from different pairs.

RESULTS: The TCRBJ repertoires of the discordant MS twin pairs were significantly different from those of the healthy identical twin pairs, whereas MS patient pairs had TCRBJ repertoires similar to those of the healthy unrelated pairs formed from healthy twin pairs and discordant MS twin pairs.

CONCLUSIONS: MS patients have a major shift in their naïve T-cell TCRBJ repertoires compared with healthy individuals, implying that this shift precedes the disease onset. This shift could represent the nongenetic factor that explains MS discordance in genetically identical individuals.

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