Role of CD1d in the regulation of tumour-propagating cells in multiple myeloma (360G-Wellcome-097744_Z_11_Z)

The pathogenic role of B cells in autoimmunity is well established, both through maturation into plasma cells and also in antigen presentation to T cells. Antineutrophil cytoplasmic antibody (ANCA) associated vasculitis (AAV) is a multisystem disorder associated with significant morbidity and mortality. A subset of B cells capable of inhibiting inflammatory responses and inducing immune tolerance has been termed regulatory B cells (Bregs). Recent reports have shown functional deficiency of Bregs in patients with systemic lupus erythematosus (SLE), and in one recent study, patients with AAV in remission have been found to have increased numbers of B regs. This project aims to identify the role of Bregs in AAV and assess their therapeutic potential. I hypothesise that Bregs are deficient in patients with active AAV, may increase in proportion in disease remission, and could be amenable to ex vivo expansion for possible therapeutic use Using flow cytometry, the proportion of Bregs in patients with active AAV will be compared with those in remission, and with healthy controls. Breg function will be assessed by measurement of anti-inflammatory cytokines including IL 10 and TGFbeta, markers of activation such as B lymphocyte stimulator (BLyS), and suppression of T cell responses. I will attempt to expand isolated Bregs and assess their ability to suppress T cell activation. I will also use a rat model of MPO-ANCA vasculitis to identify Bregs and assess their ability to control disease, using cell transfer experiments.