ePoster Presentation 49th Annual Scientific Meeting of the Australian and New Zealand Society for Immunology 2021

Delineating the role of IFN-I in the development of spontaneous germinal centres and autoantibody production. (#216)

Lisa Miosge 1 , Ayla M Lorenzo 1 , Yaoyuan Zhang 1 , Alex Joule 1 , Chris Goodnow 2 , Stephen Alexander 3 , Matthew Cook 1 4 , Si Ming Man 1 , Carola G Vinuesa 1 , Julia I Ellyard 1
  1. John Curtin School of Medical Research, Acton, 0200, Australia
  2. Garvan Institute of Medical Research, Sydney, NSW, Australia
  3. Department of Rheumatology, Sydney Children's Hospitals Network, Sydney, NSW, Australia
  4. Department of Immunology, The Canberra Hospital, Canberra, ACT, Australia

Systemic lupus erythematosus (SLE) is a heterogeneous autoimmune disease.  After anti-nuclear antibodies (ANAs), elevated levels of type-1 interferons (IFN-I) are one of the most prominent features of SLE. We and others have shown that mutations in genes such as TREX1 and IFIH1 result in overproduction of IFN-I, can cause monogenic forms of SLE1, as well as interferonopathies such as Aicardi-Goutieres Syndrome2. T1-IFN has also been shown to have important effects on survival of autoreactive B cells3. It is thus expected that excess IFN-I also drives the production of high-affinity class-switched autoantibodies in these patients through the dysregulation of germinal centres.  Indeed, spontaneous germinal centres (sptGC) are a known feature of many mouse models of lupus and this has been linked to production of IFN-I.  Here we use two autoimmune mouse models with monogenic mutations in Trex1 and Ifih1, to delineate the role of IFN-I in the production of sptGC and autoantibodies.  Analogous to human SLE patients, the loss-of-function Trex1 allele (Trex1LOF) and gain-of-function Ifih1 allele (Ifih1GOF) drive overproduction of IFN-I and development of autoimmunity. Yet, despite similar phenotypes with regard to T cell activation and autoimmune pathology, we found that Trex1LOFmice develop sptGC, but IfihiGOF mice do not, indicating that excessive IFN-I does not always lead to sptGC despite the production of class-switched antinuclear antibodies. Furthermore, removal of IFN-I signaling in Trex1LOF mice, through the deletion of the main IFN-I receptor IFNAR1, did not eliminate either sptGC or autoantibodies. However, removal of sptGC through Tlr7-deficiency did significantly reduce autoantibodies in Trex1LOFmice. Thus, our data using human-specific monogenic lupus models, suggests that IFN-I may not control all aspects of SLE disease. These findings have important implications for understanding the potential therapeutic benefits of monoclonal antibody therapies targeting excessive T1-IFN in SLE.

  1. 1. Ellyard, J. I. et al. Identification of a pathogenic variant in TREX1 in early-onset cerebral systemic lupus erythematosus by Whole-exome sequencing. Arthritis Rheumatol 66, 3382-3386, doi:10.1002/art.38824 (2014).
  2. 2. Alperin, J. M., Ortiz-Fernandez, L. & Sawalha, A. H. Monogenic Lupus: A Developing Paradigm of Disease. Front Immunol 9, 2496, doi:10.3389/fimmu.2018.02496 (2018).
  3. 3.Domeier, P. P. et al. B-Cell-Intrinsic Type 1 Interferon Signaling Is Crucial for Loss of Tolerance and the Development of Autoreactive B Cells. Cell Rep 24, 406-418, doi:10.1016/j.celrep.2018.06.046 (2018).