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

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.
• 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.