title: Enhanced anti-serpin antibody activity inhibits autoimmune inflammation in type 1 diabetes.
abstract: Intracellular (clade B) OVA-serpin protease inhibitors play an important role in tissue homeostasis by protecting cells from death in response to hypo-osmotic stress, heat shock, and other stimuli. It is not known whether these serpins influence immunological tolerance and the risk for autoimmune diseases. We found that a fraction of young autoimmune diabetes-prone NOD mice had elevated levels of autoantibodies against a member of clade B family known as serpinB13. High levels of anti-serpinB13 Abs were accompanied by low levels of anti-insulin autoantibodies, reduced numbers of islet-associated T cells, and delayed onset of diabetes. Exposure to anti-serpinB13 mAb alone also decreased islet inflammation, and coadministration of this reagent and a suboptimal dose of anti-CD3 mAb accelerated recovery from diabetes. In a fashion similar to that discovered in the NOD model, a deficiency in humoral activity against serpinB13 was associated with early onset of human type 1 diabetes. These findings suggest that, in addition to limiting exposure to proteases within the cell, clade B serpins help to maintain homeostasis by inducing protective humoral immunity.
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Rochester, Rochester, NY 14642, USA. jan_czyzyk@urmc.rochester.edu
authors.forename: Jan
authors.initials: J
authors.lastname: Czyzyk
authors.forename: Octavian
authors.initials: O
authors.lastname: Henegariu
authors.forename: Paula
authors.initials: P
authors.lastname: Preston-Hurlburt
authors.forename: Raman
authors.initials: R
authors.lastname: Baldzizhar
authors.forename: Christine
authors.initials: C
authors.lastname: Fedorchuk
authors.forename: Enric
authors.initials: E
authors.lastname: Esplugues
authors.forename: Kim
authors.initials: K
authors.lastname: Bottomly
authors.forename: Frans K
authors.initials: FK
authors.lastname: Gorus
authors.forename: Kevan
authors.initials: K
authors.lastname: Herold
authors.forename: Richard A
authors.initials: RA
authors.lastname: Flavell
mesh_terms: D000293:Adolescent; D000818:Animals; D001323:Autoantibodies / Q000276:immunology*; D001324:Autoantigens / Q000276:immunology*; D015153:Blotting, Western; D002648:Child; D002675:Child, Preschool; D003922:Diabetes Mellitus, Type 1 / Q000276:immunology*; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008810:Mice, Inbred C57BL; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D015843:Serpins / Q000276:immunology*; D014162:Transfection; D055815:Young Adult
chemical_list: D001323:Autoantibodies; D001324:Autoantigens; D015843:Serpins