SAT0158 IL-7 and IL-7 receptor blockade selectively inhibit TLR7-induced B cell activation in primary sjögren’s syndrome

Background Toll-like receptors (TLRs) have been implicated in several auto-immune diseases, especially those involved in the recognition of nucleic acids (viral, bacterial, and possibly self). In primary Sjögren’s syndrome (pSS) TLR7-induced B cell activation has been implicated in the immunopathology. An increased expression of TLR7 mRNA has been found in the parotid gland of pSS patients. In addition, TLR7 specifically recognizes ssRNA from viruses, and possibly self-ssRNA, with which Ro- and/or La-proteins form complexes, facilitating anti-SSA/SSB auto-antibody production, one of the hallmark disease parameters of pSS. Interestingly, EBV-transformed B cells have been shown to express the IL-7R and IL-7. Recently, we found increased levels of IL-7 in the minor salivary gland as well. Objectives To investigate the role of IL-7/IL-7 receptor-mediated immune activation in TLR7-induced B cell activation in pSS patients. Methods Isolated CD4 T cells and CD19 B cells from HC (n=7) and pSS patients (n=5) were co-cultured with and without a TLR7 agonist (TLR7A, Gardiquimod) in the presence or absence of CD14 monocytes/macrophages. Additionally, PBMCs (HC n=5, pSS n=8) were cultured with TLR7A with and without soluble human IL-7R (shuIL7R) and fully human anti-human IL-7 mAb. Proliferation of T cells and B cells was measured using 3H-thymidine incorporation and Ki67 expression (FACS analysis). Activation markers (CD19, HLA-DR, CD25) and intracellular IL-7 and IL-7Rα expression by B cells were measured by FACS analysis. Results TLR7A-increased proliferation of T and B cell co-cultures was associated with significant and selective increases in Ki67+ CD19 B cells (HC from 1.2±0.2% to 9.3±1.3%, p