Session Type: Abstract Submissions (ACR)
CXCL13 is central in the formation of lymphoid follicles in secondary and tertiary lymphoid tissue. It attracts CXCR5-expressing B cells and follicular helper T cells (TFH). CXCL13 has previously been associated with disease in RA. We examined the role of CXCL13 and CXCR5 in early rheumatoid arthritis (eRA) and in a murine collagen induced arthritis (CIA) model.
CXCL13 was measured by ELISA in plasma from 76 treatment naïve eRA patients (disease < 3 month), at baseline and after 6 months of treatment. Treatment was methotrexate (MTX) (n=39) or MTX + Adalimumab (ADA) (n=37). Clinical disease was assessed by: DAS28, VAS, CRP, no. of swollen joints (SJ28+40), SDAI, IgM-RF and ACPA. Healthy volunteers (HV) (n=38) were age and gender matched with eRA patients. Negative selected CD14+ cells from healthy blood donor buffy coats were cultured with GM-CSF (100 ng/ml) and IL-4 (40 ng/ml) to acquire monocyte derived dendritic cells (Mo-DC). At day 6 Mo-DC were stimulated with: LPS, CD40L, IL-21, TGFb, PD-1, CXCL13, OX40, TNFa, IL-22, LIGHT etc. Up regulation of CXCL13 and CXCR5 mRNA was evaluated by PCR with GAPDH as reference. CIA was induced in DBA/1 mice. Arthritis was scored according to the Mean Arthritis Score (MAS). Adoptive transfer was done with CXCR5+/- splenocytes from CIA mice to healthy DBA/1 mice, boosted with incomplete Freunds adjuvant. Mice were sacrificed at day 48, and paws embedded in paraffin were stained. Statistical correlations were assessed by Spearman’s rho. Data are expressed as median (IQR).
Treatment reduced CXCL13 plasma levels by 30% (baseline: 149.3 pg/ml (74.8 pg/ml – 245.0 pg/ml vs. 6 months: 48.1 pg/ml (26.9 pg/ml – 93.0 pg/ml), p<0.001). At 6 months CXCL13 levels were similar to levels observed in HV (50.3 pg/ml (29.2 pg/ml - 92.7 pg/ml), p=0.99). Patients in the MTX group had 50% reduction in plasma CXCL13 compared with ADA (p=0.015). We observed correlation with baseline CXCL13 and disease parameters in both groups (VAS, SDAI and SJ28+40 (all r=0.3-0.4, all p<0.05)). CXCL13 mRNA expression in Mo-DC was only up regulated by TNFa, LIGHT and IL-22, whereas CXCR5 also was up regulated by PD-1 and CXCL13. Adoptive transfer of CXCR5+ splenocytes from CIA mice resulted in a more severe inflammation and cartilage destruction, compared with CXCR5- and total splenocytes. Adoptive transfer of similar cell types from healthy mice did not result in arthritis development in the recipient mice.
CXCL13 plasma levels were significantly elevated in eRA patients and decreased to levels comparable with HV within 6 months of treatment. Treatment with ADA resulted in a more prominent decrease in CXCL13 levels, supporting a close connection between TNF a inhibition and CXCL13 production, also supported by CXCL13 up regulation by TNFa. CXCL13 serves as a prominent marker of joint involvement, evaluated by the close association with number of swollen joints and the VAS score. The high degree of joint inflammation and destruction in mice receiving CXCR5+ cells, points to a memory development within this cellular subset, and considering the upregulation of CXCR5 by TNFa and CXCL13 the importance of these two chemokines in joint involvement is supported.
M. L. Hetland,
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ACR Meeting Abstracts - https://acrabstracts.org/abstract/cxcl13-is-a-marker-of-joint-involvement-in-early-rheumatoid-arthritis/