AB0142 IMMUNOREGULATORY ROLES OF β2INTEGRINS IN RHEUMATOID ARTHRITIS

Abstract

Background: Evidence is mounting that β2 integrins, adhesion receptors that exist in a continuum between ‘inactive’ and ‘active’, facilitate not only inflammation but are also important in immune regulation. Elucidating their role on dendritic cells (DCs) is hereby of special interest due to the pivotal role DCs play in immune activation and tolerance. Previous research suggests that β2 integrin-mediated immunoregulation is prominent in murine DCs1, but a similar role in human cells has yet to be characterised. Objectives: We hypothesised that altered β2 integrin expression, activation or function in DCs may contribute to the immune dysregulation prevalent in autoimmune disorders such as Rheumatoid Arthritis (RA). To this end, we aimed to characterise β2 integrin expression and activation in antigen-presenting cell (APC) populations from people with RA compared to healthy controls. Methods: Using flow cytometry, we can detect both total and activated β2 integrin subunits (CD11a, CD11b, CD18) on different APC populations present in human blood and synovial fluid. Results: Based on our results so far, we found CD11b expression to be equivalent in APC populations between patients with RA and healthy controls. However, expression of both the total and active forms of CD11a was reduced across several APC populations in RA patients compared to healthy controls, with cDC2s (CD1c+) showing the most striking reduction. Interestingly, we found that cDC2s from matched RA synovial fluid samples express even lower levels of CD11a than blood cDC2s. Previous studies show that cDC2s are the DC population predominant in the RA joint, characterised by an increased capacity to attract T cells to the site of inflammation and activate self-reactive T cells2. As CD11a is described to have largely pro-inflammatory effects by contributing to immune cell contacts and recruitment to inflammatory sites, this could suggest that contrary to our initial hypothesis, cells downregulate CD11a as a means of limiting the aberrant inflammation present in the disease. Furthermore, cDC2s from RA patients in remission express lower levels of active CD11a compared to those from patients with high disease activity. Upon stimulation of cDC2s with PMA, cells from patients with active disease decrease their activation of CD11a, while neither healthy controls nor patients in remission show any change in CD11a activation. This might suggest that CD11a activation is differentially regulated in patients with active disease, while remission signifies a return to a state of normal CD11a regulation on cDC2s. In additional work on exploring monocyte-derived DCs (MO-DCs) as a potential therapeutic for RA, we did not detect a reduction in CD11a expression in activated MO-DCs, suggesting that the effect may be specific to settings of chronic inflammation that cannot be easily modelled in vitro. Conclusion: Further interrogation of our integrin expression data, including disease stratification, together with functional studies on RA patient cDC2s compared to MO-DCs, is currently under way to fully investigate the role of this immunoregulatory pathway in autoimmune disorders. In doing so, we will explore β2 integrin subunits and signalling pathways as potential therapeutic targets in RA.