Molecular mimicry and antigen-specific T cell responses in multiple sclerosis and chronic CNS Lyme disease.
The concept of molecular mimicry provides and elegant framework as to how cross-reactivity between antigens from a foreign agent with self proteins may trigger autoimmune diseases. While it was previously thought that sequence and structural homology between foreign and self proteins or the sharing of T cell receptor (TCR) and MHC-binding motifs are required for molecular mimicry to occur, we have shown that even completely unrelated peptide sequences may lead to cross-recognition by T cells. The use of synthetic combinatorial peptide libraries in the positional scanning format (PS-SCL) together with novel biometric prediction approaches has allowed us to describe the recognition profiles of individual autoreactive T cell clones (TCC) with unprecedented accuracy. Through studies of myelin-specific TCC as well as clones from the nervous system of patients suffering from chronic central nervous (CNS) Lyme disease it has become clear that at least some T cells are more degenerate than previously anticipated. These data will not only help us to redefine what constitutes specific T cell recognition, but also allow us to study in more detail the biological role of molecular mimicry. A recent clinical trial with an altered peptide ligand (APL) of one of the candidate myelin basic protein (MBP) epitopes in MS (amino acids 83-99) has shown that such a modified MBP peptide may not only have therapeutic efficacy, but also bears the potential to exacerbate disease. Thus, we provide firm evidence that the basic principles of cross-recognition and their pathogenetic significance are relevant in MS.
Martin
R
R
Neuroimmunology Branch, NINDS, NIH Building, 10 Room 5B-16, 10 Center DR MSC 1400, Bethesda, MD, 20892-1400, USA. martinr@ninds.nih.gov
Gran
B
B
Zhao
Y
Y
Markovic-Plese
S
S
Bielekova
B
B
Marques
A
A
Sung
M H
MH
Hemmer
B
B
Simon
R
R
McFarland
H F
HF
Pinilla
C
C
D000595:Amino Acid Sequence; D000818:Animals; D001324:Autoantigens / Q000276:immunology; D002908:Chronic Disease; D003429:Cross Reactions; D006801:Humans; D008193:Lyme Disease / Q000276:immunology*; D008213:Lymphocyte Activation; D018716:Molecular Mimicry / Q000276:immunology*; D008969:Molecular Sequence Data; D009103:Multiple Sclerosis / Q000276:immunology*; D013601:T-Lymphocytes / Q000276:immunology*
D001324:Autoantigens