title: Infectious Th1 and Th2 autoimmunity in diabetes-prone mice.
abstract: In the non-obese diabetic (NOD) mouse, a Th1-biased autoimmune response arises spontaneously against glutamic acid decarboxylase, concurrent with the onset of insulitis. Subsequently, Th1-type autoreactivity spreads intra- and intermolecularly to other beta-cell autoantigens (beta CAAs), suggesting that a spontaneous Th1 cascade underlies disease progression. Induction of Th2 immunity to a single beta CAA results in the spreading of Th2-type T-cell and humoral responses to other beta CAAs in an infectious manner. Thus, both Th1 and Th2 autoimmunity can evolve in amplificatory cascades defined by site-specific, but not antigen-specific, positive feedback circuits. Despite the continued presence of Th1 autoimmunity, the induction of Th2 spreading is associated with active tolerance to beta CAAs and reduced disease incidence. With disease progression there is an attenuation of beta CAA-inducible Th2 spreading, presumably because of a reduced availability of uncommitted beta CAA-reactive precursor T cells. We discuss the implications of these findings for the rational design of antigen-based immunotherapeutics.
authors.affiliation: Department of Molecular and Medical Pharmacology, University of California, Los Angeles 90095-1735, USA.
authors.forename: J
authors.initials: J
authors.lastname: Tian
authors.forename: A P
authors.initials: AP
authors.lastname: Olcott
authors.forename: L R
authors.initials: LR
authors.lastname: Hanssen
authors.forename: D
authors.initials: D
authors.lastname: Zekzer
authors.forename: B
authors.initials: B
authors.lastname: Middleton
authors.forename: D L
authors.initials: DL
authors.lastname: Kaufman
mesh_terms: D000818:Animals; D015551:Autoimmunity; D003924:Diabetes Mellitus, Type 2 / Q000276:immunology* / Q000628:therapy; D018604:Epitope Mapping; D007108:Immune Tolerance; D007515:Islets of Langerhans / Q000276:immunology; D051379:Mice; D016688:Mice, Inbred NOD; D018417:Th1 Cells / Q000276:immunology*; D018418:Th2 Cells / Q000276:immunology*