OP0080 Lesional IL-21 Expression Correlates with Functional Germinal Center Formation and T Follicular Helper Cell Infiltration in the Salivary Glands of Sjögren’s Syndrome
Authors: W. Murray-Brown, C. Croia, N. Sutcliffe, A. Tappuni, S. Vartoukian, F. Fortune, C. Pitzalis, M. Bombardieri
Journal: Annals of the Rheumatic Diseases (2013)

<h3>Background</h3> IL-21 is a pro-inflammatory cytokine that plays a key role in the activation and differentiation of B cells<sup>1</sup>. B cells infiltrate the salivary glands (SG) of Sjögren’s syndrome (SS), an autoimmune disease characterized by immune infiltration in the lacrimal and salivary glands leading to exocrine dysfunction<sup>2</sup>. In SS SG, B cells are organized as functional ectopic germinal centers (GC) and are pivotal in SS pathogenesis<sup>3</sup>. Follicular helper T cells (Tfh) abundantly express IL-21 and contribute to GC B cell affinity maturation via induction of AID, somatic hypermutation and class switching<sup>4</sup>. <h3>Objectives</h3> We aimed to investigate IL-21 mRNA expression in SS SG, to correlate expression with markers of inflammation such as CXCL13, Ltb, BAFF as well as markers of B cell differentiation AID, Pax5 and Blimp1, and then to assess the relationship of IL-21 and Tfh cells with the development of functional ectopic GC. <h3>Methods</h3> IL-21 and IL-21R mRNA expression was assessed by Taqman PCR in 22 labial SG of patients with SS and 17 with non-specific chronic sialadenitis (NSCS). Expression levels were correlated with genes regulating ectopic GC formation such as CXCL13 and Ltb and B cell function such as BAFF, AID, Pax5 and Blimp1. In addition, GC formation in the SG was assessed by IHC for B/T cell segregation and follicular dendritic cell (FDC) networks. Finally, Tfh cells infiltration in the SG was assessed by IF for CD3/CD45RO/ICOS and PD1. <h3>Results</h3> SG of SS patients displayed higher expression of IL-21 and IL-21R mRNA compared to NSCS (mean fold increase±SEM 38±12 vs 5±4, p=0.02 for IL-21 and 59±13 vs 12±2, p=0.01). In SS, IL-21 mRNA strictly correlated with the levels of CXCL13 (Spearman’s r=0.697, p&lt;0.0001) and Ltb (r=0.478, p&lt;0.001) which were closely associated with the formation of CD21L+ ectopic GC. Furthermore, IL-21 expression was associated with functional B cell activation as shown by its correlation with AID (r=0.540, p&lt;0.0001) and Pax5 (r=0.456, p&lt;0.002). Finally, a subset of CD45RO/ICOS/PD1+ T cells highly resembling Tfh were invariably observed in the presence of ectopic GC characterised by FDC networks but not in FDC- or NSCS SG. <h3>Conclusions</h3> Here we show that IL-21 expression is significantly increased in the SG of SS patients and strongly correlates with ectopic GC formation, functional B cell activation and accumulation of Tfh. These data strongly implicate IL-21 and Tfh cells in the development and maintenance of functional ectopic GC in the SG and could represent novel therapeutic targets in SS. <h3>References</h3> Mehta, D. S., <i>et al.</i>, (2004). <i>Immunological Reviews</i> Christodoulou, M. I., <i>et al.,</i> (2010)<i>. Journal of Autoimmunity</i> Barone, F., <i>et al.,</i> (2005)<i>. Arthritis and Rheumatism</i> Crotty, S. (2011)<i>. Annual Review of Immunology</i> <h3>Disclosure of Interest</h3> None Declared