Myelin basic protein-specific TCR/HLA-DRB5*01:01 transgenic mice support the etiologic role of DRB5*01:01 in multiple sclerosis.

Abstract

Genetic susceptibility to multiple sclerosis (MS) has been linked to the HLA-DR15 haplotype consisting of DRB1*15:01(DR2b) and DRB5*01:01(DR2a) alleles. Given almost complete linkage disequilibrium of the two alleles, recent studies suggested differential roles in susceptibility (DR2b) or protection from MS (DR2a). Our objective was to assess the potential contribution of DR2a to disease etiology in MS using a humanized model of autoimmunity. To assess the potential contribution of DR2a to disease etiology, we created DR2a humanized transgenic (Tg) mice and subsequently crossed them to Tg mice expressing TL3A6, an MS patient-derived myelin basic protein 83-99-specific TCR. In TL3A6/DR2a Tg mice, CD4 Tg T cells escape thymic and peripheral deletion and initiate spontaneous experimental autoimmune encephalomyelitis (EAE) at low rates, depending on the level of DR2a expression. The ability to induce active EAE was also increased in animals expressing higher levels of DR2a. Inflammatory infiltrates and neuronal damage were present throughout the spinal cord, consistent with a classical ascending EAE phenotype with minor involvement of the cerebellum, brainstem, and peripheral nerve roots in spontaneous, as well as actively induced, disease. These studies emphasize the pathologic contribution of the DR2a allele to the development of autoimmunity when expressed as the sole MHC class II molecule, as well as strongly argue for DR2a as a contributor to the CNS autoimmunity in MS.

• Authors: Jacqueline A Quandt, Jaebong Huh, Mirza Baig, Karen Yao, Naoko Ito, Mark Bryant, Kazuyuki Kawamura, Clemencia Pinilla, Henry F McFarland, Roland Martin, Kouichi Ito
• Journal: Journal of immunology (Baltimore, Md. : 1950) (J Immunol) Vol. 189 Issue 6 Pg. 2897-908 (Sep 15 2012) ISSN: 1550-6606 [Electronic] United States
• PMID: 22888134 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, N.I.H., Intramural, Research Support, Non-U.S. Gov't)

Chemical References

• Epitopes, T-Lymphocyte
• HLA-DRB5 Chains
• Receptors, Antigen, T-Cell
• Granulocyte-Macrophage Colony-Stimulating Factor

Topics

• Adoptive Transfer (methods)
• Animals
• CD4-Positive T-Lymphocytes (immunology, metabolism, pathology)
• Disease Models, Animal
• Epitopes, T-Lymphocyte (immunology)
• Genetic Predisposition to Disease (genetics)
• Granulocyte-Macrophage Colony-Stimulating Factor (biosynthesis)
• HLA-DRB5 Chains (biosynthesis, genetics, physiology)
• Humans
• Mice
• Mice, Knockout
• Mice, Transgenic
• Multiple Sclerosis (etiology, genetics, immunology)
• Receptors, Antigen, T-Cell (biosynthesis, immunology)
• Th1 Cells (immunology, metabolism, pathology)
• Th17 Cells (immunology, metabolism, pathology)