Aetiopathogenesis
Stepwise changes in the murine salivary gland immune response during virally-induced ectopic lymphoid structure formation
R. Coleby1, D. Lucchesi2, E. Pontarini3, C. Pitzalis4, M. Bombardieri5
- Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Queen Mary University of London, UK.
- Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Queen Mary University of London, UK.
- Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Queen Mary University of London, UK.
- Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Queen Mary University of London, UK.
- Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Queen Mary University of London, UK. m.bombardieri@qmul.ac.uk
CER14883
2021 Vol.39, N°6 ,Suppl.133
PI 0039, PF 0048
Aetiopathogenesis
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PMID: 34596023 [PubMed]
Received: 11/06/2021
Accepted : 30/08/2021
In Press: 30/09/2021
Published: 15/12/2021
Abstract
OBJECTIVES:
Sjögren’s syndrome (SS) is a chronic autoimmune disease characterised by lymphocytic infiltration into the salivary glands (SG) and, in a subset of patients, formation of ectopic lymphoid structures (ELS) in the glands. However, the mechanisms of how ELS form ectopically are not fully elucidated. Here we used a viral inducible murine model of ELS formation in the SG to elucidate the key immunological steps regulating the formation of ELS in the SG.
METHODS:
We have utilised an inducible murine model of sialadenitis whereby retrograde cannulation of the submandibular SG with a replication-deficient adenovirus 5 leads to the formation of ELS. Flow cytometry, immunofluorescence and gene expression was performed on the SGs at regular time points after cannulation to follow the organisation of ELS.
RESULTS:
Innate immune cells (neutrophils, eosinophils and monocytes) rapidly infiltrated the SG by 3 days post cannulation (dpc) whereby monocytes started to differentiate into resident macrophages. Myeloid dendritic cells accumulated inside leukocytic aggregates whereas macrophages were excluded from the developing ELS. Meanwhile, CD11b+ cells upregulated Il18, Cxcl13, Ltb, April and other lymphoid genes stimulating the influx of T cells by 12 days and B cells shortly after. Infiltration of T-follicular helper (Tfh) cells correlated with an increase in GL7+ germinal centre B cells, which peaked at 19 dpc.
CONCLUSIONS:
Immune cell infiltration in virally-infected murine SG follows a highly reproducible step-wise process whereby early innate immune cells reshape the SG myeloid compartment leading to upregulation of genes involved in the ectopic lymphoid neogenesis process. This in turns leads to T and B cell recruitment, differentiation and activation, culminating in the organization of ELS and localised germinal centres responses.
