Repertoire dynamics of autoreactive T cells in multiple sclerosis patientsand healthy subjects - Epitope spreading versus clonal persistence

Autoantigen-specific T-lymphocytes are present in patients with autoimmune disease and in normal subjects. Little is currently known about the tempora l variation (dynamics) of the immune repertoire of these autoreactive T cel ls, We analysed the long-term variation of the immune repertoire of T cells specific for myelin basic protein (MBP) in five untreated patients with mu ltiple sclerosis and four normal control subjects over a mean observation p eriod of 6 years, MBP-specific CD4(+) T-cell lines were selected with purif ied human MBP, and their epitope specificity was mapped with overlapping sy nthetic peptides, Three distinct patterns of repertoire development were ob served, (i) Two patients and three control subjects maintained a broad epit ope response with fluctuations over time, (ii) Two patients initially showe d a focused response that broadened over the course of 6 years; this findin g could be described as intramolecular epitope spreading, (iii) In one pati ent and one control subject, a strikingly focused response, which was direc ted to a cluster of nested epitopes in the MBP region 83-102, persisted ove r time, T-cell receptor V beta sequence analysis allowed us to trace indivi dual clones of MBP-specific T cells for up to 7 years in the peripheral cir culation in four of the five patients and three of the four controls, sugge sting that the long-term persistence of MBP-specific T-cell clones is a com mon feature of the T-cell repertoire not unique to multiple sclerosis, The persisting MBP-specific T-cell clones were not detectable in the blood of o ne of the patients by complementarity-determining region (CDR)-3 spectratyp ing, indicating that their frequency does not exceed 1 in 5000 T cells, The temporal characteristics of the MBP-specific T-cell repertoire described h ere are relevant to therapeutic strategies targeting autoantigen-specific T cells in multiple sclerosis and other autoimmune diseases.