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A6.2 Inducible Tertiary Lymphoid Structures and Autoimmunity in a Novel model of Sialoadenitis in Wild-Type Mice
  1. D Lucchesi1,
  2. M Bombardieri1,
  3. F Barone2,
  4. S Nayar2,
  5. G Proctor3,
  6. CD Buckley2,
  7. C Pitzalis1
  1. 1William Harvey Research Institute, Experimental Medicine and Rheumatology, London, UK
  2. 2University of Birmingham, Rheumatology Research Group, Birmingham, UK
  3. 3King’s College, Oral Medicine and Pathology, London, UK

Abstract

Introduction Salivary glands of patients with Sjögren’s syndrome (SS) develop ectopic lymphoid structures (ELS) characterised by B/T cell compartmentalisation, the formation of high endothelial venules (HEV), follicular dendritic cell networks (FDCs), functional B cell activation with expression of activation-induced cytidine deaminase (AID) as well as local differentiation of autoreactive plasma cells. The mechanisms triggering ELS formation, autoimmunity and exocrine dysfunction in SS are largely unknown. Here we present a novel model of inducible ectopic lymphoid tissue formation, breach of humoral self-tolerance and salivary hypofunction following delivery of a replication-deficient adenovirus-5 (AdV5) in submandibular glands of C57BL/6 mice through retrograde excretory duct cannulation.

Materials and Methods Luciferase- or LacZ-encoding Ad5 were delivered in C57BL/6 mice salivary glands (SG) through retrograde cannulation. SGs were collected at various time-points 1, 2 and 3 weeks post-cannulation (pc) and frozen sections were graded for infiltration and stained for T/B cell segregation, FDCs and HEV markers. Submandibular salivary flow was induced by pilocarpine stimulation and the amount of saliva measured. Expression of TLS-related genes was investigated by TaqMan-PCR. Anti-viral antibodies and autoantibodies were detected by IF and western blot.

Results In this model, inflammation rapidly and consistently evolves from diffuse infiltration towards the development of SS-like periductal lymphoid aggregates within 2 weeks from AdV delivery. These infiltrates progressively acquire ELS features and support functional GL7+/AID+ germinal centres. Formation of ELS is preceded by ectopic expression of lymphoid chemokines CXCL13, CCL21 and CCL19 as well as lymphotoxin-β and is associated with development of anti-nuclear antibodies in 75% of the mice. Finally, reduction in salivary flow was observed over 3 weeks post AdV infection consistent with exocrine gland dysfunction as a consequence of the inflammatory response.

Conclusions This novel model has the potential to unravel the cellular and molecular mechanisms regulating ELS formation and their role in exocrine dysfunction and autoimmunity in SS.

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