Oral Presentation 43rd Lorne Genome Conference 2022

Integrated single-cell genomics to map immune cell states and predict cellular etiology of autoimmune risk loci. (#9)

Hamish W King 1 2 , Kristen L Wells 3 , Zohar Shipony 3 , Arwa S Kathiria 3 , Lisa E Wagar 4 5 , Nara Orban 6 , Robson Capasso 7 , John C Riches 8 , Andrew J Clear 8 , Gary Warnes 9 , Caleb Lareau 3 , Mark M Davis 4 10 11 , Lars M Steinmetz 3 12 13 , Sarah A Teichmann 14 , William J Greenleaf 3 15 , Louisa K James 2
  1. Walter and Eliza Hall Institute, Parkville, VIC, Australia
  2. Centre for Immunobiology, Queen Mary University of London, London, United Kingdom
  3. Department of Genetics, Stanford University, Stanford, CA, USA
  4. Department of Microbiology and Immunology, Stanford University, Stanford, CA, USA
  5. Department of Physiology and Biophysics, University of California Irvine, Irvine, CA, USA
  6. Barts Health Ear, Nose and Throat Service, The Royal London Hospital, London, United Kingdom
  7. Department of Otolaryngology–Head and Neck Surgery, Stanford University School of Medicine, Stanford, CA, USA
  8. Centre for Haemato-Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
  9. Flow Cytometry Core Facility, Blizard Institute, Queen Mary University of London, London, United Kingdom
  10. Howard Hughes Medical Institute, Stanford University, Stanford, CA, USA
  11. Institute for Immunity, Transplantation and Infection, Stanford University, Stanford, CA, USA
  12. Stanford Genome Technology Center, Stanford, CA, USA
  13. Genome Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany
  14. Wellcome Sanger Institute, Cambridge, United Kingdom
  15. Chan–Zuckerberg Biohub, San Francisco, CA, USA

B cell-mediated immune responses and memory form in secondary lymphoid organs, such as the tonsils, lymph nodes or spleen and form a major arm of the adaptive immune system to fight and remember infections. During this process, B cells undergo affinity maturation in the germinal centre reaction before differentiation into memory or plasma cells. Dysfunction in the germinal centre can lead to either defective immune responses or contribute to autoimmune disease through the production of autoantibodies or ectopic germinal centre-like structures in non-lymphoid tissues. Many questions remain about the dynamic cellular states involved in normal and disease-related B cell maturation, including the gene regulatory networks that underlie key cell fate decisions and phenotypes. We have therefore generated a comprehensive roadmap of human B cell maturation in a model secondary lymphoid organ by defining the gene expression, antibody repertoires, and chromatin accessibility of diverse B cell states at single-cell resolution. We reconstruct gene expression and transcription factor dynamics during B cell activation to identify a novel pre-germinal centre state and use spatial transcriptomics to map this population in human tissue. Finally, we leverage our single cell transcriptomic and epigenomic maps to interpret potential regulatory impact of genetic variants implicated in autoimmunity. We find that many autoimmune-linked fine-mapped GWAS variants exhibit their greatest regulatory potential in germinal centre-associated cell populations, providing new insights into the cellular and genetic causes that may underpin autoimmune disease.