HLA-DR4-IE chimeric class II transgenic, murine class II-deficient mice are susceptible to experimental allergic encephalomyelitis

Kouichi Ito, Hong Jin Bian, Margarita Molina, Jihong Han, Jeanne Magram, Elizabeth Saar, Charles Belunis, David R. Bolin, Reynaldo Arceo, Robert Campbell, Fiorenza Falcioni, Damir Vidović, Juergen Hammer, Zoltan A. Nagy

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To investigate the development of HLA-DR-associated autoimmune diseases, we generated transgenic (Tg) mice with HLA-DRA-IEα and HLA-DRB1*0401-IEβ chimeric genes. The transgene-encoded proteins consisted of antigen-binding domains from HLA-DRA and HLA-DRB1*0401 molecules and the remaining domains from the IE9(d)-α and IE(d)-β chains. The chimeric molecules showed the same antigen-binding specificity as HLA-DRB1*0401 molecules, and were functional in presenting antigens to T cells. The Tg mice were backcrossed to MHC class II-deficient (IAβ, IEα-) mice to eliminate any effect of endogenous MHC class II genes on the development of autoimmune diseases. As expected, IAαβ or IEαβ molecules were not expressed in Tg mice. Moreover, cell-surface expression of endogenous IEβ associated with HLA-DRA-IEα was not detectable in several Tg mouse lines by flow cytometric analysis. The HLA-DRA-IEα/HLA-DRB1*0401-IEβ molecules rescued the development of CD4+ T cells in MHC class II-deficient mice, but T cells expressing Vβ5, Vβ11, and Vβ12 were specifically deleted. Tg mice were immunized with peptides, myelin basic protein (MBP) 87-106 and proteolipid protein (PLP) 175-192, that are considered to be immunodominant epitopes in HLA-DR4 individuals. PLP175-192 provoked a strong proliferative response of lymph node T cells from Tg mice, and caused inflammatory lesions in white matter of the CNS and symptoms of experimental allergic encephalomyelitis (EAE). Immunization with MBP87-106 elicited a very weak proliferative T cell response and caused mild EAE. Non- Tg mice immunized with either PLP175-192 or MBP87-106 did not develop EAE. These results demonstrated that a human MHC class II binding site alone can confer susceptibility to an experimentally induced murine autoimmune disease.

Original languageEnglish (US)
Pages (from-to)2635-2644
Number of pages10
JournalJournal of Experimental Medicine
Issue number6
StatePublished - Jun 1 1996


All Science Journal Classification (ASJC) codes

  • Immunology and Allergy
  • Immunology

Cite this

Ito, K., Bian, H. J., Molina, M., Han, J., Magram, J., Saar, E., Belunis, C., Bolin, D. R., Arceo, R., Campbell, R., Falcioni, F., Vidović, D., Hammer, J., & Nagy, Z. A. (1996). HLA-DR4-IE chimeric class II transgenic, murine class II-deficient mice are susceptible to experimental allergic encephalomyelitis. Journal of Experimental Medicine, 183(6), 2635-2644. https://doi.org/10.1084/jem.183.6.2635