Th148 - Type I Interferon-dependent and -independent TRIF Signaling Are Required for Autoantibody Generation in an Induced Model of Systemic Lupus Erythematosus

Rebecca Subang – Medicine – Research Institute of the McGill University Health Centre; Elena Lonina – Medicine – Research Institute of the McGill University Health Centre; Sylvie Lesage – Immunology-Oncology Division; Département de Microbiologie, Infectiologie et Immunologie – Maisonneuve-Rosemont Hospital Research Center; Université de Montréal; Salman Qureshi – Research Institute of the McGill University Heath Centre; McGill University; Emilie Charette – Research Institute of the McGill University Heath Centre; McGill University; Gregory Fonseca – Research Institute of the McGill University Heath Centre; McGill University; Jerrold Levine – Medicine – Jesse Brown Veterans Affairs Hospital; University of Illinois at Chicago; Joyce Rauch – Medicine – Research Institute of the McGill University Health Centre; McGill University

Abstract Text: Systemic lupus erythematosus (SLE) is an autoimmune condition characterized by the production of autoantibodies to cellular and nuclear self-antigens, with damage to multiple organs. Immunization with the SLE autoantigen β2-glycoprotein I (β2GPI) and TLR4 ligand lipopolysaccharide (LPS) induces a murine model of SLE characterized by the generation of autoantibodies to multiple SLE antigens. LPS induces both inflammatory cytokines and type I interferons (IFNs) by signaling through the adaptor proteins MyD88 and TRIF, respectively. We investigated the mechanisms of LPS-dependent signaling on the induction of murine SLE following β2GPI/LPS immunization. Immunization of mice deficient in MyD88 or TRIF with β2GPI/LPS revealed that LPS-dependent TRIF signaling preferentially promoted autoantibody production in this model, compared to MyD88 signaling. Furthermore, SLE-specific autoantibody production was induced by TLR3 or TLR4 agonists, in combination with β2GPI, but not by agonists of TRIF-independent TLRs. RNA-sequencing of dendritic cells and macrophages isolated from wildtype (WT) and TRIF-deficient mice immunized with β2GPI/LPS revealed differential expression of both type I IFN-dependent and -independent genes. Moreover, type I IFN receptor (IFNaR)-deficient mice immunized with β2GPI/LPS showed diminished autoantibody production compared to WT mice, but to a lesser extent than TRIF-deficient mice. We conclude that LPS-dependent TRIF signaling is required for the generation of autoantibody production in our induced SLE model, both through type I IFN-dependent and -independent effects.