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Abstract Number: 1495

Lesional Intereukin-21 Expression Correlates With Functional Germinal Center Formation and T Follicular Helper Cell Infiltration In The Salivary Glands Of Sjogren’s Syndrome

William Murray-Brown1, Cristina Croia1, Nurhan Sutcliffe2, Anwar Tappuni3, Costantino Pitzalis1 and Michele Bombardieri4, 1Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, QMUL, London, United Kingdom, 2Experimental Medicine and Rheumatology, Queen Mary University of London, London, United Kingdom, 3Department of Oral Medicine,, Institute of Dentistry, Queen Mary University of London, London, United Kingdom, 4Centre for Experimental Medicine and Rheumatology, William Harvey Research Institute, Queen Mary University of London, London, United Kingdom

Meeting: 2013 ACR/ARHP Annual Meeting

Keywords: B cells and Sjogren's syndrome

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Session Information

Title: Sjögren's Syndrome: Pathogenesis

Session Type: Abstract Submissions (ACR)

Background/Purpose: IL-21 is a pro-inflammatory cytokine that plays a key role in the activation and differentiation of B cells. 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. In SS SG, B cells are often organized as functional ectopic germinal centers (GC) and are pivotal in SS pathogenesis. 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. Here we aimed to investigate IL-21 expression in SS SG and its correlation with key regulators of GC responses and markers of B cell differentiation. Finally, we aimed to assess the relationship between IL-21, infiltrating Tfh cells and the development of functional ectopic GC.

Methods: IL-21 and IL-21R mRNA expression was assessed by Taqman PCR in 28 labial SG of patients with SS and 37 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.

Results: 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<0.0001) and Ltb (r=0.478, p<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<0.0001) and Pax5 (r=0.456, p<0.002). Finally, a subset of CD45RO/ICOS/PD1+ T cells highly resembling Tfh were observed in the presence of ectopic GC characterised by FDC networks but not in FDC- or NSCS SG.

Conclusion: 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.


Disclosure:

W. Murray-Brown,
None;

C. Croia,
None;

N. Sutcliffe,
None;

A. Tappuni,
None;

C. Pitzalis,
None;

M. Bombardieri,
None.

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ACR Meeting Abstracts - https://acrabstracts.org/abstract/lesional-intereukin-21-expression-correlates-with-functional-germinal-center-formation-and-t-follicular-helper-cell-infiltration-in-the-salivary-glands-of-sjogrens-syndrome/

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