Background Disturbance of the balance in the immune system plays a major role in rheumatoid arthritis (RA). Programmed Death 1 (PD-1) expressed by activated T cells and its ligand (PD-L2) expressed by antigen presenting cells, are involved in negative regulation of T cell receptor induced activation 1. Both PD-1 and PD-L2 exist in soluble forms (sPD-1 and sPD-L2). Soluble PD-1 is up-regulated in RA2, but sPD-L2 has to our knowledge not been investigated.
Objectives To investigate sPD-1 and sPD-L2 in early RA patients and their association with disease.
Methods In a longitudinal set of steroid- and DMARD-naïve RA patients (n=76, <3 months’ disease) who initiated treatment with methotrexate (MTX) or MTX and adalimumab, we measured plasma levels of sPD-L2 and sPD-1 by ELISA, at baseline (0 month) and after 3 and 12 months. To remove un-specific binding, plasma samples were saturated with mouse, bovine and human IgG. We examined for correlations (Spearman’s rho) with disease parameters (DAS28, doctors VAS, HAQ, CRP), anti-CCP and IgM-RF. Data are expressed as median values (IQR).
Results Plasma levels of sPD-L2 were 3.88ng/ml (2.8-5.2) at baseline, had increased 78% after 3 months, and stayed high at 12 months (6.44ng/ml (5.5-8.1)), (both p<0.05). In contrast, plasma levels of sPD-1 showed no significant changes. Addition of adalimumab to MTX had no influence on sPD-1 or sPD-L2 plasma levels.
Baseline sPD-1 and sPD-L2 plasma levels were associated with the presence of anti-CCP antibodies (rho=0.4 and 0.3, respectively, both p<0.05) and IgM-RF (rho=0.64, p<0.0001 and rho=0.4 p<0.05). Interestingly, sPD-L2 relative to sPD-1 (sPD-L2/sPD-1) showed inverse correlation with anti-CCP and IgM-RF (all rho= -0.40, p<0.05). Changes in plasma levels of sPD-L2 (0-12 months) and sPD-1 correlated with disease parameters.
Conclusions Plasma levels of sPD-L2 and sPD-1 in RA are unaffected by addition of adalimumab to MTX treatment. The association between plasma levels of sPD-L2 and disease parameters suggests that sPD-L2 plays a vital role in disease progression. Also considering the close correlations with anti-CCP and IgM-RF, sPD-1 and sPD-L2 are possible new indicators of disease activity and progression. Because PD-1 is closely connected to the regulation of follicular T cells, our findings support the involvement of these T cells in the early phase of RA.
Messal, N., Serriari, N.-E., Pastor, S., Nunès, J. A. & Olive, D. PD-L2 is expressed on activated human T cells and regulates their function. Molecular Immunology 48, 2214–2219 (2011).
Wan, B. et al. Aberrant regulation of synovial T cell activation by soluble costimulatory molecules in rheumatoid arthritis. J. Immunol. 177, 8844–8850 (2006).
Disclosure of Interest None Declared