Potential Contribution of DR2a to Multiple Sclerosis

Our objective was to assess the potential contribution of DR2a to disease etiology in MS using a humanized model of autoimmunity.

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

  1. Jacqueline A. Quandt *1,
  2. Jaebong Huh *,
  3. Mirza Baig *,
  4. Karen Yao *,
  5. Naoko Ito ,
  6. Mark Bryant ,
  7. Kazuyuki Kawamura *,
  8. Clemencia Pinilla §,
  9. Henry F. McFarland *,
  10. Roland Martin *23 and
  11. Kouichi Ito *3

+ Author Affiliations

  1. * Neuroimmunology Branch, National Institute of Neurological Disorders and Stroke, National Institutes of Health, Bethesda, MD 20892;
  2. † Department of Neurology, University of Medicine and Dentistry of New Jersey, Piscataway, NJ 08854;
  3. ‡ Division of Veterinary Resources, Office of Research Services, National Institutes of Health, Bethesda, MD 20892; and
  4. § Torrey Pines Institute for Molecular Studies, San Diego, CA 92121

+ Author Notes

  1. Address correspondence and reprint requests to Prof. Jacqueline A. Quandt or Prof. Kouichi Ito, Department of Pathology and Laboratory Medicine, University of British Columbia, G227-2211 Wesbrook Mall, Vancouver, British Columbia V6T 2B5, Canada (J.A.Q.) or Department of Neurology, Robert Wood Johnson Medical School, University of Medicine and Dentistry of New Jersey, SPH/RWJMS Building, Room 184, 683 Hoes Lane, Piscataway, NJ 08854 (K.I.). E-mail addresses: jquandt@pathology.ubc.ca (J.A.Q.) or itoko@umdnj.edu (K.I.)
  1. ↵3 R.M. and K.I. contributed equally to this work.

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

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