title: Inducible tertiary lymphoid structures, autoimmunity, and exocrine dysfunction in a novel model of salivary gland inflammation in C57BL/6 mice.
abstract: Salivary glands in patients with Sjögren's syndrome (SS) develop ectopic lymphoid structures (ELS) characterized by B/T cell compartmentalization, the formation of high endothelial venules, follicular dendritic cell networks, functional B cell activation with expression of activation-induced cytidine deaminase, as well as local differentiation of autoreactive plasma cells. The mechanisms that trigger ELS formation, autoimmunity, and exocrine dysfunction in SS are largely unknown. In this article, we present a novel model of inducible ectopic lymphoid tissue formation, breach of humoral self-tolerance, and salivary hypofunction after delivery of a replication-deficient adenovirus-5 in submandibular glands of C57BL/6 mice through retrograde excretory duct cannulation. In this model, inflammation rapidly and consistently evolves from diffuse infiltration toward the development of SS-like periductal lymphoid aggregates within 2 wk from AdV delivery. These infiltrates progressively acquire ELS features and support functional GL7(+)/activation-induced cytidine deaminase(+) germinal centers. Formation of ELS is preceded by ectopic expression of lymphoid chemokines CXCL13, CCL19, and lymphotoxin-β, and is associated with development of anti-nuclear Abs in up to 75% of mice. Finally, reduction in salivary flow was observed over 3 wk post-AdV infection, consistent with exocrine gland dysfunction as a consequence of the inflammatory response. This novel model has the potential to unravel the cellular and molecular mechanisms that regulate ELS formation and their role in exocrine dysfunction and autoimmunity in SS.
authors.affiliation: Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Queen Mary University of London, London EC1M 6BQ, United Kingdom. bombardieri@qmul.ac.uk
authors.forename: Michele
authors.initials: M
authors.lastname: Bombardieri
authors.forename: Francesca
authors.initials: F
authors.lastname: Barone
authors.forename: Davide
authors.initials: D
authors.lastname: Lucchesi
authors.forename: Saba
authors.initials: S
authors.lastname: Nayar
authors.forename: Wim B
authors.initials: WB
authors.lastname: van den Berg
authors.forename: Gordon
authors.initials: G
authors.lastname: Proctor
authors.forename: Christopher D
authors.initials: CD
authors.lastname: Buckley
authors.forename: Costantino
authors.initials: C
authors.lastname: Pitzalis
mesh_terms: D000818:Animals; D001327:Autoimmune Diseases / Q000276:immunology* / Q000473:pathology* / Q000503:physiopathology; D004195:Disease Models, Animal; D005088:Exocrine Glands / Q000276:immunology / Q000473:pathology / Q000503:physiopathology*; D008221:Lymphoid Tissue / Q000276:immunology* / Q000473:pathology* / Q000503:physiopathology; D051379:Mice; D008810:Mice, Inbred C57BL; D017434:Protein Structure, Tertiary; D012793:Sialadenitis / Q000276:immunology / Q000473:pathology* / Q000503:physiopathology