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Related Experiment Videos

A humanized model for multiple sclerosis using HLA-DR2 and a human T-cell receptor.

L S Madsen1, E C Andersson, L Jansson

  • 1Department of Clinical Immunology, The Royal Danish School of Pharmacy,Copenhagen, Denmark.

Nature Genetics
|December 28, 1999
PubMed
Summary

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Multiple sclerosis (MS) susceptibility is linked to HLA-DR2 genes. This study shows HLA-DR2 can cause MS-like disease in mice by presenting myelin basic protein to T cells.

Area of Science:

  • Neuroimmunology
  • Genetics of autoimmune diseases
  • Molecular immunology

Background:

  • Multiple sclerosis (MS) is a chronic neurologic disease with suspected autoimmune origins.
  • Genetic factors, particularly human histocompatibility leukocyte antigens (HLA) class II genes, are implicated in MS susceptibility.
  • Previous studies faced challenges in pinpointing specific MS susceptibility genes within the MHC class II region due to linkage disequilibrium.

Purpose of the Study:

  • To investigate the role of HLA-DR2 in MS pathogenesis.
  • To determine if HLA-DR2 can present MS-relevant autoantigens to T cells and induce disease.
  • To model MS-like disease in a genetically engineered mouse system.

Main Methods:

  • Generation of transgenic mice expressing human HLA-DR2, a specific T-cell receptor (TCR), and CD4 coreceptor.

Related Experiment Videos

  • Induction of experimental autoimmune encephalomyelitis (EAE) using myelin basic protein (MBP) peptide and adjuvant.
  • Analysis of spontaneous disease development in TCR and HLA-DR2 double-transgenic mice, including Rag2-deficient models.

    • Main Results:

    • Transgenic mice developed CNS inflammation, demyelination, and MS-like clinical symptoms after MBP peptide administration.
    • A subset of mice (4%) spontaneously developed MS-like disease.
    • Increased spontaneous disease incidence in Rag2-deficient double-transgenic mice confirmed the necessity and sufficiency of T cells for disease development.

    Conclusions:

    • The human HLA-DR2 molecule can present an MBP self-peptide to T cells, mediating both induced and spontaneous MS-like disease.
    • This study provides strong evidence for HLA-DR2's role in the autoimmune pathogenesis of multiple sclerosis.
    • The findings highlight the potential of targeting HLA-DR2-mediated T-cell responses in MS therapy.