Progressive Development of Ectopic Lymphoid Structures as Mediators of Autoimmunity in a Sjögren’s Disease Mice Model 2309026

Abstract

Abstract Introduction Ectopic lymphoid structures (ELS) are dynamic immune assemblies that acquire phenotypic and functional features of secondary lymphoid organs (SLO). They develop and persist in inflammatory conditions such as Sjögren’s Disease (SjD), a chronic autoimmune disease characterized by lymphocytic infiltration of lacrimal (LG) and salivary (SG) gland. The presence of ELS in patient SG biopsies is linked to poor prognosis but less is known about ELS formation in the LG in SjD in human disease or murine models. Methods Development of ELS was studied in LG from male NOR mice, the diabetes free sub-strain of the NOD (n = 6 LG from 6 mice/group) at early (8 weeks), intermediate (16 weeks) and established (24 weeks) disease. ELS were identified based on immunofluorescence labeling of B/T cells, and the presence of follicular dendritic cells (FDC) and high endothelial venules (HEV). Gene expression of essential markers associated with the initiation and development of ELS were explored as well as those involved in glandular health in terms of secretory function and apoptosis. Results ELS were identified by identification of regions with distinct segregation of B and T cell zones and further validated by demonstrating the presence of HEV, the FDC network, GL7+ germinal center B cells, and the presence of IgG-producing plasma cells. Analysis of gene expression showed significant early upregulation of Ltb, Glycam1, Cxcl13, Cxcr5, Ccl19 and Ccr7 (P-value< 0.05) while other markers of ELS were elevated later in disease (Acida and Il21) (P-value< 0.05). In parallel, compromised glandular epithelial health was indicated by increased gene expression of FasL (P-value< 0.05), suggestive of apoptosis, and decreased expression of Gpx4 (P-value< 0.05), suggestive of ferroptosis, in intermediate disease. Conclusion Male NOR mice spontaneously develop ELS in LG with features of SLO. These structures may function as key local drivers of autoimmunity and autoantibody production. Funding Source NIH grant RO1 EY026635, NIH RO1 EY011386, P30EY029220 to the Department of Ophthalmology at USC Keck School of Medicine. Topic Categories Basic Autoimmunity (BA)