title: B-lymphocytes expressing an Ig specificity recognizing the pancreatic ß-cell autoantigen peripherin are potent contributors to type 1 diabetes development in NOD mice.
abstract: While the autoimmune destruction of pancreatic ß-cells underlying type 1 diabetes (1D) development is ultimately mediated by T-cells in NOD mice and also likely humans, B-lymphocytes play an additional key pathogenic role. It appears expression of plasma membrane bound immunoglobulin (Ig) molecules that efficiently capture ß-cell antigens allows autoreactive B-lymphocytes bypassing normal tolerance induction processes to be the subset of antigen presenting cells most efficiently activating diabetogenic T-cells. NOD mice transgenically expressing Ig molecules recognizing antigens that are (insulin) or not (hen egg lysozyme; HEL) expressed by ß-cells have proven useful in dissecting the developmental basis of diabetogenic B-lymphocytes. However, these transgenic Ig specificities were originally selected for their ability to recognize insulin or HEL as foreign, rather than autoantigens. Thus, we generated and characterized NOD mice transgenically expressing an Ig molecule representative of a large proportion of naturally occurring islet-infiltrating B-lymphocytes in NOD mice recognizing the neuronal antigen peripherin. Transgenic peripherin autoreactive B-lymphocytes infiltrate NOD pancreatic islets, acquire an activated proliferative phenotype, and potently support accelerated T1D development. These results support the concept of neuronal autoimmunity as a pathogenic feature of T1D, and targeting such responses could ultimately provide an effective disease intervention approach.
authors.affiliation: The Jackson Laboratory, Bar Harbor, Maine, USA Department of Animal and Poultry Sciences, Virginia Tech, Blacksburg, Virginia, USA.
authors.forename: Caroline M
authors.initials: CM
authors.lastname: Leeth
authors.affiliation: The Jackson Laboratory, Bar Harbor, Maine, USA.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Racine
authors.affiliation: The Jackson Laboratory, Bar Harbor, Maine, USA.
authors.forename: Harold D
authors.initials: HD
authors.lastname: Chapman
authors.affiliation: Immunology Unit, Department of Experimental Medicine, Faculty of Medicine, University of Lleida & IRBLleida, Lleida, Spain.
authors.forename: Berta
authors.initials: B
authors.lastname: Arpa
authors.affiliation: Immunology Unit, Department of Experimental Medicine, Faculty of Medicine, University of Lleida & IRBLleida, Lleida, Spain.
authors.forename: Jorge
authors.initials: J
authors.lastname: Carrillo
authors.affiliation: Immunology Unit, Department of Experimental Medicine, Faculty of Medicine, University of Lleida & IRBLleida, Lleida, Spain.
authors.forename: Jorge
authors.initials: J
authors.lastname: Carrascal
authors.affiliation: The Jackson Laboratory, Bar Harbor, Maine, USA.
authors.forename: Qiming
authors.initials: Q
authors.lastname: Wang
authors.affiliation: The Jackson Laboratory, Bar Harbor, Maine, USA.
authors.forename: Jeremy
authors.initials: J
authors.lastname: Ratiu
authors.forename: Leire
authors.initials: L
authors.lastname: Egia-Mendikute
authors.forename: Estela
authors.initials: E
authors.lastname: Rosell-Mases
authors.affiliation: Department of Physiology and Immunology, Faculty of Biology, University of Barcelona, Spain.
authors.forename: Thomas
authors.initials: T
authors.lastname: Stratmann
authors.affiliation: Immunology Unit, Department of Experimental Medicine, Faculty of Medicine, University of Lleida & IRBLleida, Lleida, Spain dave.serreze@jax.org joan.verdaguer@mex.udl.cat.
authors.forename: Joan
authors.initials: J
authors.lastname: Verdaguer
authors.affiliation: The Jackson Laboratory, Bar Harbor, Maine, USA dave.serreze@jax.org joan.verdaguer@mex.udl.cat.
authors.forename: David V
authors.initials: DV
authors.lastname: Serreze