Quandt JA, Huh J, Baig M, Yao K, Ito N, Bryant M, Kawamura K, Pinilla C, McFarland HF, Martin R, Ito K. Myelin Basic Protein-Specific TCR/HLA-DRB5*01:01 Transgenic Mice Support the Etiologic Role of DRB5*01:01 in Multiple Sclerosis. J Immunol. 2012 Aug 10. [Epub ahead of print]
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 aetiology in MS using a humanized model of autoimmunity. To assess the potential contribution of DR2a to disease aetiology, 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.
Each gene is inherited from mum or dad but rather than there being an equal chance of the variant from one parent being inherited, some blocks of genes are inherited together. This because there is no recombination hotspot that allows the DNA from the other parents chromosome, Therefore they are inherited in blocks which is linkage disequilibrium. There are some genes in the major histocompatibility complex that are inherited together. DR2 variants are associated with susceptibility to MS. In some studies DR2b variants are more likely to be associated with MS whereas others DR2a may not be. In this study they looked at one that may be associated with protection and found that if they expressed the human DR2a variant and then made all the T cells to recognise myelin basic protein in the context of DR2a and low an behold they got disease. This is a self-fulfilling prophecy and if animals are loaded with T cells that react to a single protein at some stage it will get autoimmune disease. Does it tell you that this occurs in human, well no but shows it is a possibility.