Background studies on B cell-mediated autoimmune diseases highlight the relevance of the B Lymphocyte Stimulator (BLyS) and A Proliferation-Inducing Ligand (APRIL), but emerging evidence points to an interaction with cell lineages other than B subsets. Although disturbances in the B cell compartment underlie the early stages of rheumatoid arthritis (RA), this phenomenon is poorly understood.
Objectives to investigate the cellular populations responsible of BLyS expression and their association with the soluble forms of BLyS, APRIL and its receptor TACI (Transmembrane Activator and CALM Interactor) in early RA and to evaluate the changes in these parameters upon TNFα-blockade.
Methods membrane BLyS (mBLyS) expression was assessed on B cells, monocytes (MØ), myeloid (mDC) and plasmacytoid (pDC) dendritic cells and neutrophils (NØ) by flow cytometry in fresh blood samples from 37 RA patients [DAS28 score (mean±SD): 4.84±1.44, disease duration (mean (range)): 1.26 (0–11) years, 23 (62.1%) RF+, 19 (51.3%) ACPA+, 19 untreated] and 31 healthy controls (HC). A subgroup of 13 biologic-naïve RA patients was prospectively followed for three months upon TNFα-blockade. Serum levels of soluble BLyS (sBLyS), APRIL (sAPRIL) and TACI (sTACI) were quantified by immunoassays.
Results mBLyS expression was increased on B cells (p=0.002), MØ (p<0.001), mDC (p<0.001) and NØ (p=0.014) in RA patients. Higher sBLyS (p=0.018) and sAPRIL (p<0.001) serum levels were found in RA, whereas those of sTACI were not different compared to HC (p=0.460). Serum sAPRIL levels paralleled those of sTACI (r=0.325, p=0.040), and mBLyS expression on B cells (r=0.463, p=0.009), MØ (r=0.521, p=0.003), mDC (r=0.438, p=0.014) and NØ (r=0.509, p=0.009) in HC but not in RA patients. Serum levels of sTACI were negatively associated with DAS28 score (r=-0.272, p=0.006) in RA. However, sAPRIL was associated with mBLyS expression on mDC in patients with longer disease duration (>3 months) (r=0.779, p<0.001), but not in those recruited at onset (r=0.245, p=0.361). In the whole RA group, TNFα serum levels were found to be correlated with sAPRIL (r=0.499, p<0.001) and sBLyS (r=0.362, p=0.013). Similarly, IFNα and sAPRIL were positively associated (r=0.423, p<0.001). TNFα-blockade was associated with decreasing mBLyS expression on B cells, MØ, mDC and NØ (all p<0.050) and a slight increase in sTACI (p=0.064). Higher levels of mBLyS on MØ and mDC at baseline were associated with a poor clinical response upon TNFα-blockade (n=8; p=0.006 and p=0.010 compared to HC, respectively).
Conclusions a role for B cell-activating factors in the pathogenesis of early RA is supported. B cells and myeloid populations (MØ, mDC and NØ) can account for the BLyS overexpression in RA, although important differences arise in their involvement. TNFα and IFNα are related to sBLyS and sAPRIL levels. An increased production of the soluble forms of BLyS and APRIL in addition to a less efficient feedback from their decoy receptors may delineate its detrimental effect.
Disclosure of Interest None declared
Statistics from Altmetric.com
If you wish to reuse any or all of this article please use the link below which will take you to the Copyright Clearance Center’s RightsLink service. You will be able to get a quick price and instant permission to reuse the content in many different ways.