THU0045 Expansion of activated cxcr5+icos+ tfh cells and plasmablasts induced by seasonal influenza vaccine is impaired in anti-il-6r treated rheumatoid arthritis patients
Authors: V.C. Romao, A. Agua-Doce, J. Polido-Pereira, R. Barros, I.P. Lopes, M.I. Seixas, M.J. Saavedra, E. Sacadura-Leite, H. Rebelo-de-Andrade, J.E. Fonseca, L. Graca
Journal: Annals of the Rheumatic Diseases (2018)

<h3>Background</h3> T follicular helper (Tfh) cells are essential for the generation of high affinity neutralising antibodies elicited following vaccination and are involved in the pathogenesis of rheumatoid arthritis (RA). Interleukin (IL)−6 has been shown to be critical for Tfh differentiation in mice, while its importance in humans has been less clear, given the lack of adequate <i>in vivo</i> assessment. <h3>Objectives</h3> To investigate the importance of IL-6 for the <i>in vivo</i> differentiation of human Tfh cells, taking advantage of influenza vaccination in patients under anti-IL-6R therapy. <h3>Methods</h3> Blood was collected before, 7 and 28 days after vaccination from established RA patients treated with tocilizumab (TCZ, IL-6R blocker), methotrexate (MTX) ±other DMARDs and age- and sex-matched healthy donors (HD). We analysed the frequency of Tfh (CD3<sup>+</sup>CD4<sup>+</sup>CD25<sup>-</sup>Foxp3<sup>-</sup>CXCR5<sup>+</sup>CD45RO<sup>+</sup>), T follicular regulatory (Tfr, CD3<sup>+</sup>CD4<sup>+</sup>CD25<sup>+</sup>Foxp3<sup>+</sup>CXCR5<sup>+</sup>) and B cell populations at each time point. We used non-parametric tests, deemed significant at p&lt;0.05. <h3>Results</h3> We included 137 participants (42 TCZ, 42 MTX, 53 HD) with similar age and gender distribution. Patients from the TCZ group had more active and severe disease. At baseline, patients treated with TCZ had higher frequency of Tfh and Tfh-Th2-like cells (CXCR3<sup>-</sup>CCR6<sup>-</sup>) and lower frequency of Tfr-Th1-like (CXCR3<sup>+</sup>CCR6<sup>-</sup>) and B cells. Following influenza vaccination, the overall blood Tfh and Tfr populations remained unchanged in all groups. However, as previously reported, there were marked changes in specific subsets at day 7 of HD following vaccination. We found a marked expansion of activated CXCR5<sup>+</sup>ICOS<sup>+</sup> Tfh cells at day 7, in HD and MTX-treated patients, but this was impaired in the TCZ group (figure 1). The increase in activated CXCR5<sup>+</sup>ICOS<sup>+</sup> Tfh cells was mainly due to a Tfh-Th1-like subpopulation, greatly increased in HD and MTX-treated patients (figure 1). Of note, CXCR5<sup>+</sup>ICOS<sup>+</sup> Tfh-Th17-like cells also accumulated in HD but not in RA patients. The proliferative capacity of CXCR5<sup>+</sup>ICOS<sup>+</sup> Tfh cells seemed to be partially impaired in patients under IL-6R blockade, that displayed marked reduction of Ki67<sup>+</sup>CD38<sup>+</sup> proliferative cells within that compartment (figure 1). Anti-IL-6R treatment also impaired expansion of CD19<sup>+</sup>IgD<sup>-</sup> CD27<sup>+</sup>CD38<sup>hi</sup> plasmablasts following vaccination, when compared with both MTX and HD groups (figure 1). Changes in CXCR5<sup>+</sup>ICOS<sup>+</sup> Tfh and plasmablasts were significantly correlated in all groups. <h3>Conclusions</h3> Anti-IL-6R treatment limits proliferative ability of activated CXCR5<sup>+</sup>ICOS<sup>+</sup> Tfh cells, blocking their emergence as well as plasmablast accumulation following influenza vaccination. Our data suggest that IL-6 is crucial for optimal <i>in vivo</i> generation of activated Tfh cells in humans. <h3>Disclosure of Interest</h3> None declared