Repertoire dynamics of autoreactive T cells in multiple sclerosis patients and healthy subjects: Epitope spreading versus clonal persistence

Abstract

Autoantigen-specific T-lymphocytes are present in patients with autoimmune disease and in normal subjects. Little is currently known about the temporal variation (dynamics) of the immune repertoire of these autoreactive T cells. We analysed the long-term variation of the immune repertoire of T cells specific for myelin basic protein (MBP) in five untreated patients with multiple sclerosis and four normal control subjects over a mean observation period of 6 years. MBP-specific CD4(+) T-cell lines were selected with purified human MBP, and their epitope specificity was mapped with overlapping synthetic peptides. Three distinct patterns of repertoire development were observed. (i) Two patients and three control subjects maintained a broad epitope response with fluctuations over time. (ii) Two patients initially showed a focused response that broadened over the course of 6 years; this finding could be described as intramolecular epitope spreading. (iii) In one patient and one control subject, a strikingly focused response, which was directed to a cluster of nested epitopes in the MBP region 83-102, persisted over time. T-cell receptor Vbeta sequence analysis allowed us to trace individual clones of MBP-specific T cells for up to 7 years in the peripheral circulation in four of the five patients and three of the four controls, suggesting that the long-term persistence of MBP-specific T-cell clones is a common 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 one of the patients by complementarity-determining region (CDR)-3 spectratyping, indicating that their frequency does not exceed 1 in 5000 T cells. The temporal characteristics of the MBP-specific T-cell repertoire described here are relevant to therapeutic strategies targeting autoantigen-specific T cells in multiple sclerosis and other autoimmune diseases.

Dichotomy of Autoreactive Th1 and Th2 Cell Responses to Desmoglein 3 in Patients with Pemphigus Vulgaris (PV) and Healthy Carriers of PV-Associated HLA Class II Alleles

“…Autoreactive T cells from the twin with systemic sclerosis and the healthy brother were able to promote the production of topisomerase-specific autoAb by B cells from the diseased twin, suggesting that lack of peripheral B cell tolerance was critical for the development of the disease. The frequencies of Dsg3-autoreactive Th cells in PV patients and Dsg3-reactive healthy individuals found in the present study are comparable to those of MBP-reactive T cells (ϳ1/5000 T cells and 1-10/10 6 PBMC, respectively) in patients with multiple sclerosis and MBP-reactive healthy donors (30,31). Moreover, autoreactive T cells specific for pyruvate dehydrogenase were detected at a frequency of 4.5-8/10 5 PBMC in the peripheral blood of patients with primary biliary cirrhosis by HLA class I tetramer staining (32).…”

Infectious diseases and autoimmunity

“…addition, longitudinal studies provided evidence for long-term persistence of individual myelin-specific Tcell clones tracked over several years in the blood of patients with multiple sclerosis [46][47][48], indicating a strong, persisting memory response and/or ongoing autoantigen exposure at least for a subset of myelinreactive T cells in multiple sclerosis. These memory responses may reflect, at least in part, persisting clonal expansions of polyspecific T cells recognizing both self and virus antigens.…”

Antigen presentation in autoimmunity and CNS inflammation: how T lymphocytes recognize the brain

“…In MS, immune reactivity in the CNS also becomes destructive. CD4 T cells are blamed for wrongly attacking CNS myelin through secretion of pro-inflammatory cytokines and activation of cytopathic factors and cytotoxic CD8 T cells [31,66,67].…”