title: Compromised central tolerance of ICA69 induces multiple organ autoimmunity.
abstract: For reasons not fully understood, patients with an organ-specific autoimmune disease have increased risks of developing autoimmune responses against other organs/tissues. We identified ICA69, a known β-cell autoantigen in Type 1 diabetes, as a potential common target in multi-organ autoimmunity. NOD mice immunized with ICA69 polypeptides exhibited exacerbated inflammation not only in the islets, but also in the salivary glands. To further investigate ICA69 autoimmunity, two genetically modified mouse lines were generated to modulate thymic ICA69 expression: the heterozygous ICA69(del/wt) line and the thymic medullary epithelial cell-specific deletion Aire-ΔICA69 line. Suboptimal central negative selection of ICA69-reactive T-cells was observed in both lines. Aire-ΔICA69 mice spontaneously developed coincident autoimmune responses to the pancreas, the salivary glands, the thyroid, and the stomach. Our findings establish a direct link between compromised thymic ICA69 expression and autoimmunity against multiple ICA69-expressing organs, and identify a potential novel mechanism for the development of multi-organ autoimmune diseases.
authors.affiliation: Division of Immunogenetics, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Yong
authors.initials: Y
authors.lastname: Fan
authors.affiliation: Division of Immunogenetics, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Giulio
authors.initials: G
authors.lastname: Gualtierotti
authors.affiliation: Division of Immunogenetics, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Asako
authors.initials: A
authors.lastname: Tajima
authors.affiliation: Division of Immunogenetics, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Maria
authors.initials: M
authors.lastname: Grupillo
authors.affiliation: Division of Immunogenetics, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Antonina
authors.initials: A
authors.lastname: Coppola
authors.affiliation: Division of Immunogenetics, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: He
authors.affiliation: Division of Immunogenetics, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Suzanne
authors.initials: S
authors.lastname: Bertera
authors.affiliation: Division of Immunogenetics, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: Gregory
authors.initials: G
authors.lastname: Owens
authors.affiliation: Department of Medicine, University of Michigan Medical School, Ann Arbor, MI, USA.
authors.forename: Massimo
authors.initials: M
authors.lastname: Pietropaolo
authors.affiliation: Division of Immunogenetics, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA.
authors.forename: William A
authors.initials: WA
authors.lastname: Rudert
authors.affiliation: Division of Immunogenetics, Department of Pediatrics, University of Pittsburgh School of Medicine, Pittsburgh, PA, USA. Electronic address: MTrucco1@wpahs.org.
authors.forename: Massimo
authors.initials: M
authors.lastname: Trucco
mesh_terms: D000818:Animals; D001324:Autoantigens / Q000235:genetics / Q000276:immunology*; D001327:Autoimmune Diseases / Q000235:genetics / Q000276:immunology* / Q000473:pathology; D005786:Gene Expression Regulation / Q000235:genetics / Q000276:immunology; D007108:Immune Tolerance; D007249:Inflammation / Q000235:genetics / Q000276:immunology / Q000473:pathology; D007515:Islets of Langerhans / Q000276:immunology / Q000473:pathology; D051379:Mice; D016688:Mice, Inbred NOD; D008822:Mice, Transgenic; D012469:Salivary Glands / Q000276:immunology / Q000473:pathology; D013270:Stomach / Q000276:immunology / Q000473:pathology; D013950:Thymus Gland / Q000276:immunology / Q000473:pathology; D013961:Thyroid Gland / Q000276:immunology / Q000473:pathology
chemical_list: D001324:Autoantigens; C490184:Ica1 protein, mouse
keywords: Autoimmune diabetes; Autoimmune polyendocrine syndrome; Autoimmune thyroiditis; ICA69; Primary Sjogren's syndrome; Thymus
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