Advertisement
Research Article Free access | 10.1172/JCI167
Department of Immunology, Mayo Clinic, Rochester, Minnesota 55905, USA.
Find articles by Drescher, K. in: JCI | PubMed | Google Scholar
Department of Immunology, Mayo Clinic, Rochester, Minnesota 55905, USA.
Find articles by Nguyen, L. in: JCI | PubMed | Google Scholar
Department of Immunology, Mayo Clinic, Rochester, Minnesota 55905, USA.
Find articles by Taneja, V. in: JCI | PubMed | Google Scholar
Department of Immunology, Mayo Clinic, Rochester, Minnesota 55905, USA.
Find articles by Coenen, M. in: JCI | PubMed | Google Scholar
Department of Immunology, Mayo Clinic, Rochester, Minnesota 55905, USA.
Find articles by Leibowitz, J. in: JCI | PubMed | Google Scholar
Department of Immunology, Mayo Clinic, Rochester, Minnesota 55905, USA.
Find articles by Strauss, G. in: JCI | PubMed | Google Scholar
Department of Immunology, Mayo Clinic, Rochester, Minnesota 55905, USA.
Find articles by Hammerling, G. in: JCI | PubMed | Google Scholar
Department of Immunology, Mayo Clinic, Rochester, Minnesota 55905, USA.
Find articles by David, C. in: JCI | PubMed | Google Scholar
Department of Immunology, Mayo Clinic, Rochester, Minnesota 55905, USA.
Find articles by Rodriguez, M. in: JCI | PubMed | Google Scholar
Published April 15, 1998 - More info
The role of various MHC genes in determining the progression of multiple sclerosis (MS) remains controversial. The HLA-DR3 gene has been associated with benign relapsing MS in some genetic epidemiologic studies, but with disease progression in others. We induced demyelination in highly susceptible B10.M and B10.Q mice expressing the DR3 (HLA-DRB1*0301) transgene to determine directly the effects of a human transgene by infecting them with Theiler's murine encephalomyelitis virus (TMEV). DR3+ mice experienced a dramatic reduction in the extent and severity of demyelination compared with DR3- littermate controls, whereas anti-TMEV antibody titers, delayed-type hypersensitivity responses, and levels of infectious virus, virus antigen, and virus RNA were similar in both groups. To address a possible mechanism of how the human transgene is reducing virus-induced demyelination, we analyzed cytokine expression in the lesions and also determined whether B10.M mice can respond to peptides derived from the DR3 molecule. Intense staining for IFN-gamma and IL-4, T helper (TH) 1 and TH2 cytokines, respectively, was found in the lesions of TMEV-infected DR3- mice but not in the DR3+ transgenic mice at day 21 after infection. DR3 peptides elicited strong proliferative responses in B10.M mice but not in B10.M (DR3+) mice. These experiments are the first to demonstrate that a human class II DR gene can alter the severity of demyelination in an animal model of MS without influencing viral load. These experiments are consistent with a mechanism by which DR3 reduces demyelination by altering the cytokine expression in the lesions, possibly by deleting T cells involved in virus-induced pathology.