Autoantibody production in hepatitis B e antigen transgenic mice elicited with a self T-cell peptide and inhibited with nonself peptides.
Studies in hepatitis B e antigen (HBeAg)-expressing transgenic mice indicate that self tolerance to two T-cell determinants on the same transgenic self molecule can differ markedly. The dominant T-cell site on HBeAg is tolerogenic, whereas a proportion of T cells recognizing a second T-cell site evade tolerance induction, persist in the periphery, and can be activated in vivo by a single injection of a 12-residue T-cell self peptide. The self-reactive T cells mediate in vivo autoantibody production sufficient to neutralize detection of the autoantigen in serum. Furthermore, autoantibody production can be inhibited by nonself peptides that compete with the self peptide for binding to major histocompatibility complex molecules. This model illustrates that T cells specific for an immunogenic T-cell site on a nonsequestered autoantigen can escape tolerance induction and, more importantly, can mediate autoreactivity in vivo. Furthermore, these results suggest that synthetic T-cell sites may be useful as immunotherapeutic agents for the purpose of circumventing nonresponse to HBeAg during persistent hepatitis B virus infection.
Milich
D R
DR
Department of Molecular Biology, Scripps Clinic and Research Foundation, La Jolla, CA 92037.
McLachlan
A
A
Raney
A K
AK
Houghten
R
R
Thornton
G B
GB
Maruyama
T
T
Hughes
J L
JL
Jones
J E
JE
D000595:Amino Acid Sequence; D000818:Animals; D001323:Autoantibodies / Q000096:biosynthesis*; D001324:Autoantigens / Q000276:immunology*; D001667:Binding, Competitive; D015870:Gene Expression; D006513:Hepatitis B e Antigens / Q000235:genetics / Q000276:immunology*; D006649:Histocompatibility Antigens / Q000378:metabolism; D007108:Immune Tolerance; D007114:Immunization; D051379:Mice; D008822:Mice, Transgenic; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000276:immunology; D013601:T-Lymphocytes / Q000276:immunology*; D006377:T-Lymphocytes, Helper-Inducer / Q000276:immunology
D001323:Autoantibodies; D001324:Autoantigens; D006513:Hepatitis B e Antigens; D006649:Histocompatibility Antigens; D010446:Peptide Fragments