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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
  1. W. Murray-Brown1,2,
  2. C. Croia1,
  3. N. Sutcliffe2,
  4. A. Tappuni2,
  5. S. Vartoukian2,
  6. F. Fortune2,
  7. C. Pitzalis3,
  8. M. Bombardieri1
  1. 1Experimental Medicine and Rheumatology, Queen Mary University of London
  2. 2Department of Oral Medicine, Institute of Dentistry, Queen Mary University of London
  3. 3Queen Mary University of London, London, United Kingdom

Abstract

Background IL-21 is a pro-inflammatory cytokine that plays a key role in the activation and differentiation of B cells1. 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 dysfunction2. In SS SG, B cells are organized as functional ectopic germinal centers (GC) and are pivotal in SS pathogenesis3. 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 switching4.

Objectives 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.

Methods 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.

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 invariably observed in the presence of ectopic GC characterised by FDC networks but not in FDC- or NSCS SG.

Conclusions 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.

References

  1. Mehta, D. S., et al., (2004). Immunological Reviews

  2. Christodoulou, M. I., et al., (2010). Journal of Autoimmunity

  3. Barone, F., et al., (2005). Arthritis and Rheumatism

  4. Crotty, S. (2011). Annual Review of Immunology

References

Disclosure of Interest None Declared

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