title: Autoimmune manifestations in aged mice arise from early-life immune dysregulation.
abstract: Autoantibodies can be present years to decades before the onset of disease manifestations in autoimmunity. This finding suggests that the initial autoimmune trigger involves a peripheral lymphoid component, which ultimately drives disease pathology in local tissues later in life. We show that Sjögren's syndrome manifestations that develop in aged NOD.H-2h4 mice were driven by and dependent on peripheral dysregulation that arose in early life. Specifically, elimination of spontaneous germinal centers in spleens of young NOD.H-2h4 mice by transient blockade of CD40 ligand (CD40L) or splenectomy abolished Sjögren's pathology of aged mice. Strikingly, a single injection of anti-CD40L at 4 weeks of age prevented tertiary follicle neogenesis and greatly blunted the formation of key autoantibodies implicated in glandular pathology, including anti-muscarinic receptor antibodies. Microarray profiling of the salivary gland characterized the expression pattern of genes that increased with disease progression and showed that early anti-CD40L greatly repressed B cell function while having a broader effect on multiple biological pathways, including interleukin-12 and interferon signaling. A single prophylactic treatment with anti-CD40L also inhibited the development of autoimmune thyroiditis and diabetes in NOD.H-2h4 and nonobese diabetic mice, respectively, supporting a key role for CD40L in the pathophysiology of several autoimmune models. These results strongly suggest that early peripheral immune dysregulation gives rise to autoimmune manifestations later in life, and for diseases predated by autoantibodies, early prophylactic intervention with biologics may prove efficacious.
authors: Respiratory, Inflammation, and Autoimmunity Group, MedImmune LLC, Gaithersburg, MD 20878, USA.
authors: Tamer I
authors: TI
authors: Mahmoud
authors: Respiratory, Inflammation, and Autoimmunity Group, MedImmune LLC, Gaithersburg, MD 20878, USA.
authors: Jingya
authors: J
authors: Wang
authors: Respiratory, Inflammation, and Autoimmunity Group, MedImmune LLC, Gaithersburg, MD 20878, USA.
authors: Jodi L
authors: JL
authors: Karnell
authors: The Jackson Laboratory, Bar Harbor, ME 04609, USA.
authors: Qiming
authors: Q
authors: Wang
authors: Respiratory, Inflammation, and Autoimmunity Group, MedImmune LLC, Gaithersburg, MD 20878, USA.
authors: Shu
authors: S
authors: Wang
authors: Respiratory, Inflammation, and Autoimmunity Group, MedImmune LLC, Gaithersburg, MD 20878, USA.
authors: Brian
authors: B
authors: Naiman
authors: Respiratory, Inflammation, and Autoimmunity Group, MedImmune LLC, Gaithersburg, MD 20878, USA.
authors: Phillip
authors: P
authors: Gross
authors: Translational Sciences-Pharmacogenomics, MedImmune LLC, Gaithersburg, MD 20878, USA.
authors: Philip Z
authors: PZ
authors: Brohawn
authors: Translational Sciences-Pharmacogenomics, MedImmune LLC, Gaithersburg, MD 20878, USA.
authors: Chris
authors: C
authors: Morehouse
authors: Translational Sciences-Pharmacogenomics, MedImmune LLC, Gaithersburg, MD 20878, USA.
authors: Jordan
authors: J
authors: Aoyama
authors: Departments of Pathology and Pediatrics, University of Florida, Gainesville, FL 32610, USA.
authors: Clive
authors: C
authors: Wasserfall
authors: Respiratory, Inflammation, and Autoimmunity Group, MedImmune LLC, Gaithersburg, MD 20878, USA.
authors: Laura
authors: L
authors: Carter
authors: Departments of Pathology and Pediatrics, University of Florida, Gainesville, FL 32610, USA.
authors: Mark A
authors: MA
authors: Atkinson
authors: The Jackson Laboratory, Bar Harbor, ME 04609, USA.
authors: David V
authors: DV
authors: Serreze
authors: Department of Medicine, University of Missouri, Columbia, MO 65212, USA.
authors: Helen
authors: H
authors: Braley-Mullen
authors: Respiratory, Inflammation, and Autoimmunity Group, MedImmune LLC, Gaithersburg, MD 20878, USA.
authors: Tomas
authors: T
authors: Mustelin
authors: Respiratory, Inflammation, and Autoimmunity Group, MedImmune LLC, Gaithersburg, MD 20878, USA.
authors: Roland
authors: R
authors: Kolbeck
authors: Respiratory, Inflammation, and Autoimmunity Group, MedImmune LLC, Gaithersburg, MD 20878, USA.
authors: Ronald
authors: R
authors: Herbst
authors: Respiratory, Inflammation, and Autoimmunity Group, MedImmune LLC, Gaithersburg, MD 20878, USA. ettingerc@medimmune.com.
authors: Rachel
authors: R
authors: Ettinger
mesh_terms: D000375:Aging; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D001323:Autoantibodies / Q000276:immunology; D015551:Autoimmunity; D001854:Bone Marrow Cells / Q000378:metabolism; D019013:CD40 Antigens / Q000235:genetics / Q000378:metabolism*; D023201:CD40 Ligand / Q000037:antagonists & inhibitors / Q000276:immunology; D016207:Cytokines / Q000378:metabolism; D003921:Diabetes Mellitus, Experimental / Q000235:genetics / Q000276:immunology; D004195:Disease Models, Animal; D005260:Female; D007107:Immune System / Q000473:pathology*; D008024:Ligands; D008214:Lymphocytes / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D012469:Salivary Glands / Q000378:metabolism; D012859:Sjogren's Syndrome / Q000235:genetics / Q000276:immunology; D013154:Spleen / Q000378:metabolism; D013967:Thyroiditis, Autoimmune / Q000235:genetics / Q000276:immunology
chemical_list: D000911:Antibodies, Monoclonal; D001323:Autoantibodies; D019013:CD40 Antigens; D016207:Cytokines; D008024:Ligands; D023201:CD40 Ligand