Epitope spread has been proposed as a possible mechanism for diversifi
cation of the autoimmune T-cell response during disease. Specifically,
it offers a plausible mechanism for the previously obscure cyclical n
ature of autoimmune demyelination whereby the sequence of attack, quie
scence and reactivation may recur over a long period of time. However,
we were concerned that previous studies of epitope spread have not ne
cessarily shown it to be well correlated with disease severity or rela
pse. Furthermore, we had studied two transgenic models of exacerbated
experimental allergic encephalomyelitis (EAE) in which no indication o
f spread away from the initial disease-inducing peptide could be obser
ved. We conducted a systematic, longitudinal study in SJL mice to look
for determinant spread during relapsing and remitting EAE, correlatin
g epitope recognition and cytokine production with disease severity. W
hen T cells from spleen, lymph node and central nervous system (CNS) w
ere analysed, little or no determinant spread was found. The best immu
nological correlate of relapse was the reappearance after remission of
CNS-infiltrating T cells mounting a strong proliferative and interfer
on (IFN)-gamma response to the original disease-inducing epitope. Our
data do not support a general role for determinant spread in EAE relap
se. Rather, they indicate the importance of a focused proliferative an
d IFN-gamma response to the disease-inducing peptide.