Myelin protein expression in lymphoid tissues: implications for peripheral tolerance.

During chronic relapsing experimental autoimmune encephalomyelitis (EAE), T lymphocytes specific for myelin protein epitopes are stimulated in vivo. When epitopes are unique from the disease-initiating myelin protein epitope, this phenomenon has been termed "epitope spreading". These T-lymphocyte responses have been detected primarily in lymph node and spleen during the relapsing phase of disease. If myelin proteins are sequestered behind the blood brain barrier, a fundamental question arises: where does the in vivo stimulation of T lymphocytes occur during relapsing EAE? While it has been thought that epitope spreading may occur within the central nervous system (CNS), here we present data supporting a novel hypothesis. Epitope spreading during EAE may not occur within the CNS, but rather within lymphoid tissues. Both myelin basic protein (MBP) and proteolipid protein (PLP) are expressed at the RNA and protein level in lymph node, thymus and spleen of SJL mice with relapsing EAE. This myelin protein expression occurs within T lymphocytes, B lymphocytes and macrophages. Further, T-lymphocyte lines from SJL mice specific for the immunodominant and subdominant epitopes of MBP and PLP can recognize endogenous protein within cells derived from lymphoid tissues. Thus, immunologically relevant myelin proteins are endogenously produced and presented within lymphoid tissues. The hypothesis that epitope spreading occurs within lymphoid tissues would explain how myelin protein-specific T lymphocytes become activated outside the CNS to allow their passage through the blood brain barrier to form new CNS lesions during relapses.