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A functional and structural basis for TCR cross-reactivity in multiple sclerosis.
Heather L E Lang1, Helle Jacobsen, Shinji Ikemizu
1Nuffield Department of Clinical Medicine, John Radcliffe Hospital, Headington, Oxford OX3 9DU, UK.
Nature Immunology
|September 24, 2002
Summary
Multiple sclerosis (MS) risk may involve multiple HLA genes working together. Structural analysis reveals molecular mimicry between HLA molecules, explaining genetic associations in diseases.
Area of Science:
- Immunogenetics
- Molecular mimicry
- Autoimmune diseases
Background:
- Human leukocyte antigen (HLA) class II alleles DRB1*1501, DRB5*0101, and DQB1*0602 are strongly linked to multiple sclerosis (MS) risk.
- Linkage disequilibrium complicates identifying the primary MS susceptibility gene within this complex.
Purpose of the Study:
- To investigate the combined role of DRB1 and DRB5 loci in MS susceptibility.
- To explore the structural basis of molecular mimicry in HLA-associated diseases.
Main Methods:
- Analysis of T cell receptor (TCR) recognition of myelin basic protein (MBP) and Epstein-Barr virus (EBV) peptides presented by HLA molecules.
- Crystal structure determination of the DRB5*0101-EBV peptide complex.
Main Results:
- A TCR from an MS patient recognized both a DRB1*1501-restricted MBP peptide and a DRB5*0101-restricted EBV peptide.
- Structural analysis showed significant similarity between the DRB5*0101-EBV and DRB1*1501-MBP peptide complexes at the TCR recognition surface.
- This provides structural evidence for molecular mimicry mediated by HLA molecules.
Conclusions:
- The DRB1 and DRB5 loci may jointly contribute to MS susceptibility.
- Structural similarities between peptide-HLA complexes offer a molecular explanation for mimicry and the strong association of HLA class II with autoimmune diseases.