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Myelin Basic Protein-Specific TCR/HLA-DRB5*01:01 Transgenic Mice Support the Etiologic Role of DRB5*01:01 in Multiple Sclerosis

Jacqueline A. Quandt, Jaebong Huh, Mirza Baig, Karen Yao, Naoko Ito, Mark Bryant, Kazuyuki Kawamura, Clemencia Pinilla, Henry F. McFarland, Roland Martin and Kouichi Ito
J Immunol August 10, 2012, 1103087; DOI: https://doi.org/10.4049/jimmunol.1103087
Jacqueline A. Quandt
*Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892;
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Jaebong Huh
*Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892;
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Mirza Baig
*Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892;
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Karen Yao
*Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892;
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Naoko Ito
†Department of Neurology, University of Medicine and Dentistry of New Jersey, Piscataway, NJ 08854;
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Mark Bryant
‡Division of Veterinary Resources, Office of Research Services, National Institutes of Health, Bethesda, MD 20892; and
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Kazuyuki Kawamura
*Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892;
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Clemencia Pinilla
§Torrey Pines Institute for Molecular Studies, San Diego, CA 92121
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Henry F. McFarland
*Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892;
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Roland Martin
*Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892;
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Kouichi Ito
*Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892;
†Department of Neurology, University of Medicine and Dentistry of New Jersey, Piscataway, NJ 08854;
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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.

Footnotes

  • This work was supported by the National Institutes of Health intramural program and in part by National Institutes of Health Grant R21 AI067474 (to K.I.), with additional support from the Multiple Sclerosis National Research Institute. J.A.Q. was supported by fellowships from the Multiple Sclerosis Society of Canada and the National Multiple Sclerosis Society.

  • The online version of this article contains supplemental material.

  • Received January 9, 2012.
  • Accepted July 16, 2012.
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The Journal of Immunology: 208 (11)
The Journal of Immunology
Vol. 208, Issue 11
1 Jun 2022
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Myelin Basic Protein-Specific TCR/HLA-DRB5*01:01 Transgenic Mice Support the Etiologic Role of DRB5*01:01 in Multiple Sclerosis
Jacqueline A. Quandt, Jaebong Huh, Mirza Baig, Karen Yao, Naoko Ito, Mark Bryant, Kazuyuki Kawamura, Clemencia Pinilla, Henry F. McFarland, Roland Martin, Kouichi Ito
The Journal of Immunology August 10, 2012, 1103087; DOI: 10.4049/jimmunol.1103087

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Myelin Basic Protein-Specific TCR/HLA-DRB5*01:01 Transgenic Mice Support the Etiologic Role of DRB5*01:01 in Multiple Sclerosis
Jacqueline A. Quandt, Jaebong Huh, Mirza Baig, Karen Yao, Naoko Ito, Mark Bryant, Kazuyuki Kawamura, Clemencia Pinilla, Henry F. McFarland, Roland Martin, Kouichi Ito
The Journal of Immunology August 10, 2012, 1103087; DOI: 10.4049/jimmunol.1103087
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