Session Title: Sjögren's Syndrome - Pathogenesis
Session Type: Abstract Submissions (ACR)
Background/Purpose: Primary Sjögren’s syndrome (pSS) is an autoimmune rheumatic disease mainly affecting the salivary and lacrimal glands causing xerostomia and keratoconjunctivitis sicca. Focal mononuclear cell inflammation in the form of germinal center-like structures (GC) is found in the minor salivary glands of 20-25 % of patients. We have previously shown that GC+ pSS patients presented with elevated serum levels of IL-1RA, IL-4, IL-17 and MCP compared to GC- patients. In this follow-up study, we aimed to assess the genetic variations in GC+ and GC- pSS patients.
Methods: In a Swedish-Norwegian pSS cohort (n=540), GC+ (n=76) and GC- (n=244) patients were identified. 1536 single-nucleotide polymorphisms (SNPs) were analysed in whole blood DNA by the Illumina GoldenGate assay (Illumina Inc.). Minor allele frequencies in GC+ and GC- patients were compared using Fisher’s exact test and associations were considered significant when p<0.001 and suggestive when p<0.01. Statistical analysis were performed using the PLINK software.
Results: In this case-only analysis of 320 pSS patients with known GC status, we identified two SNPs in Eotaxin associated with GC+ patients with OR 0.45 and 0.41. Furthermore, we found suggestive associations with BANK-1, ICA-1, IL-17, PRKCL1, CARD-8, Bcl-2, TANK, IKBKE, AID and APRIL. We also detected weak associations (p<0.05) with SNPs in the BLK, STAT1, STAT4, SSA1, SSB, IL15RA, IL-6 and TNF-a genes. Serum eotaxin (CCL11) has previously been identified as a key discriminator between GC+ and GC- pSS patients. The formation of GCs depends on B cell stimulation by helper T cells via the CD40-CD40L system, which also contribute to the expression of activation induced deaminase (AID). Genetic variations in CD40L and AID suggest that GC+ patients may be genetically predisposed for ectopic GC formation. B lymphoid kinase (BLK) has a role in the development and activation of marginal zone B cells present in the GC formations, and Bcl-2 is an anti-apoptotic protein which gene is implicated in a number of cancers and autoimmunity. CARD-8, IKBKE and TANK are regulators of the NF-κB pathway, a pathway with a well-established role in secondary lymphoid organ development.
Conclusion: Taken together, our findings suggest that genetic variations may help explain why ectopic GC-like structures are present in some pSS patients but not all
T. R. Reksten,
M. V. Jonsson,
« Back to 2012 ACR/ARHP Annual Meeting
ACR Meeting Abstracts - https://acrabstracts.org/abstract/genetic-associations-to-germinal-centre-formation-in-primary-sjogrens-syndrome/