Autoimmunity / Molecular Mimicry

Edited by: Karen Young Kreeger K.W. Wucherpfennig, J.L. Strominger, "Molecular mimicry in T cell-mediated autoimmunity: Viral peptides activate human T cell clones specific for myelin basic protein," Cell, 80:695-705, 1995. (Cited in more than 90 publications as of March 1997) IMMUNE IMPERSONATIONS: Kai Wucherpfennig’s work with T-cell clones may explain why some autoimmune diseases are related to microbial infections. Comments by Kai Wucherpfennig, Dana-Farber Cancer Institute, Harvard Medical School. Many autoimmune diseases are related to microbial infections, a phenomenon that has puzzled scientists for years. One of the theories explaining how pathogens induce an immune reaction is called molecular mimicry. According to this theory, a viral or bacterial peptide is similar enough to a human peptide to cause an autoimmune reaction. When Kai Wucherpfennig, now an assistant professor at the Dana-Farber Cancer Institute and Harvard Medical School, came to work in the lab of molecular biologist Jack Strominger at Harvard, he wanted to learn how the major histocompatibility complex molecule associated with multiple sclerosis (MS) might be involved in the disease. "Susceptibility to multiple sclerosis is associated with HLA- DR2, a molecular genetic marker," Wucherpfennig explains. "HLA-DR2 may be involved in MS by presenting particular peptides to T cells. We examined HLA-DR2 binding of a myelin basic protein peptide, since cells specific for myelin basic protein induce central nervous system inflammation in animal models of MS." Wucherpfennig and Strominger determined which residues of the myelin basic protein (MBP) peptide were required for HLA-DR2 binding and for T-cell recognition of the HLA-DR2-bound MBP peptide. "Once we performed this structure-function analysis, it occurred to us that this data could be used to identify microbial peptides that stimulate MBP-specific T-cell clones," Wucherpfennig recalls. "We found eight peptides- seven viral and one bacterial-that stimulated T-cell clones from MS patients." The observation that a T-cell receptor from an individual T- cell clone can recognize distinct but structurally related peptides from a self-antigen and from pathogens has important ramifications for understanding autoimmune diseases, the authors conclude. In addition to this summation, Wucherpfennig cites several other important observations from the paper. "Stimulation of autoreactive T cells by microbial peptides is possible because HLA-DR2 can bind a large variety of different peptides. The microbial sequences can be quite distinct from the sequence of the self-peptide because the peptide positions that are buried in the HLA-DR2 binding site can be exchanged by many structurally related amino acids. Only the peptide surface that is contacted by the T-cell receptor has to be similar to the self-peptide." Wucherpfennig notes several reasons for the paper's frequent citation. First, it is the first report to demonstrate that a single T-cell receptor can recognize a set of peptides with diverse peptide sequences. "Previously it was thought that a single T-cell receptor could only recognize a single well-defined sequence," he explains. "Secondly, it provided a structural basis for understanding cross-reactivity between microbial antigens and self-proteins. The third reason is that the T-cell clones were isolated from MS patients, so the results may be relevant to understanding human disease." In upcoming studies, Wucherpfennig plans to use transgenic mice that express one of the human T-cell receptors specific for myelin basic protein to test if microbial peptides will cause disease. "We're trying to establish an animal model that is relevant for the human condition," he remarks. The articles listed here, all approximately two years old, have received a substantially greater number of citations than others of the same type and vintage, according to data from the Science Citation Index" of the Institute for Scientific Information, Philadelphia. Why have these research reports become such standouts? In conversations with The Scientist, the authors attempt to provide an answer.

Autoimmunity / Molecular Mimicry

The Scientist Staff

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