Sept 02, 2002
By Karla Gale
Results of a study by an international team of researchers may explain T cell receptor cross-reactivity in multiple sclerosis (MS), and why the disease is associated with the HLA DR2 haplotype.
According to a paper in Nature Immunology for September 3, two distinct major histocompatability complex (MHC) class II alleles become structurally equivalent when complexed with an Epstein-Barr virus peptide in one case and with myelin basic protein in the other.
Multiple sclerosis, like other autoimmune diseases, is associated with certain major histocompatability complex (MHC) class II alleles, Dr. E. Yvonne Jones, of Oxford University in the UK, told Reuters Health. "The MHC association strongly suggests that T cells that recognize antigens presented by the disease-associated MHC molecules are involved in the disease process," she noted.
Dr. Jones and her colleagues found that a T cell clone derived from a patient with relapsing-remitting MS recognized both a myelin basic protein epitope and an Epstein-Barr virus DNA polymerase peptide. They now report that this T cell receptor cross-reactivity is restricted by two different DR2 molecules. One is DRB1*1501, which forms complexes with myelin basic protein. The other, DRB5*0101, binds to an Epstein-Barr virus DNA polymerase peptide.
The investigators compared the crystalline structure of the two MHC protein-peptide complexes. They found that the two complexes "have highly similar TCR contact surfaces with four identical TCR-peptide contacts." Even though the two peptide sequences are dissimilar, the researchers explain, they bear four identical side chain conformations when complexed.
As Dr. Jones elaborated, the two MHC class II molecules display antigens from myelin proteins and EBV proteins "in such a similar way that the T cell cannot tell the difference... The T cells may therefore continue to attack healthy tissue in the nervous system after first starting to attack viral infection," she added.
Dr. Jones and her colleagues write, "This system thus provides a distinct example where functional MHC-based molecular mimicry corresponds to true structural mimicry." They note that this is the first time such a phenomenon has been demonstrated for interactions of the cellular immune response.
Dr. Jones emphasized that the findings "do not demonstrate that EBV is associated with MS." However, it does "provide an explanation for how T cells can be misled to attack both" foreign protein and self-antigens.
Nature Immunol 2002. http://dx.doi.org/10.1038/ni835
© 2002 Reuters Ltd