A humanized model of experimental autoimmune uveitis in HLA class II transgenic mice.
Experimental autoimmune uveitis (EAU) is a disease of the neural retina induced by immunization with retinal antigens, such as interphotoreceptor retinoid-binding protein (IRBP) and arrestin (retinal soluble antigen, S-Ag). EAU serves as a model for human autoimmune uveitic diseases associated with major histocompatibility complex (HLA) genes, in which patients exhibit immunological responses to retinal antigens. Here we report the development of a humanized EAU model in HLA transgenic (TG) mice. HLA-DR3, -DR4, -DQ6, and -DQ8 TG mice were susceptible to IRBP-induced EAU. Importantly, HLA-DR3 TG mice developed severe EAU with S-Ag, to which wild-type mice are highly resistant. Lymphocyte proliferation was blocked by anti-HLA antibodies, confirming that antigen is functionally presented by the human MHC molecules. Disease could be transferred by immune cells with a Th1-like cytokine profile. Antigen-specific T cell repertoire, as manifested by responses to overlapping peptides derived from S-Ag or IRBP, differed from that of wild-type mice. Interestingly, DR3 TG mice, but not wild-type mice, recognized an immunodominant S-Ag epitope between residues 291 and 310 that overlaps with a region of S-Ag recognized by uveitis patients. Thus, EAU in HLA TG mice offers a new model of uveitis that should represent human disease more faithfully than currently existing models.
Pennesi
Giuseppina
G
Laboratory of Immunology, National Eye Institute/NIH, 10 Center Drive, Bethesda, MD 20892, USA.
Mattapallil
Mary J
MJ
Sun
Shu-Hui
SH
Avichezer
Dody
D
Silver
Phyllis B
PB
Karabekian
Zaruhi
Z
David
Chella S
CS
Hargrave
Paul A
PA
McDowell
J Hugh
JH
Smith
W Clay
WC
Wiggert
Barbara
B
Donoso
Larry A
LA
Chan
Chi-Chao
CC
Caspi
Rachel R
RR
D000595:Amino Acid Sequence; D000818:Animals; D017951:Antigen Presentation; D019393:Arrestin / Q000276:immunology; D001327:Autoimmune Diseases / Q000209:etiology*; D004195:Disease Models, Animal; D018984:Epitopes, T-Lymphocyte; D005136:Eye Proteins; D015803:HLA-DR3 Antigen / Q000502:physiology; D000949:Histocompatibility Antigens Class II / Q000502:physiology*; D006801:Humans; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D012177:Retinol-Binding Proteins / Q000276:immunology; D014605:Uveitis / Q000209:etiology*; D000099214:Retinol-Binding Proteins, Interstitial
D019393:Arrestin; D018984:Epitopes, T-Lymphocyte; D005136:Eye Proteins; D015803:HLA-DR3 Antigen; D000949:Histocompatibility Antigens Class II; D012177:Retinol-Binding Proteins; D000099214:Retinol-Binding Proteins, Interstitial