Science Bite - 3 min Oral Presentation (Students and ECRs only) Lorne Infection and Immunity 2020

The story of a rogue B cell clone in Hepatitis C virus-associated cryoglobulinemic vasculitis (#55)

Clara C Young 1 2 , Manu Singh 1 2 , Katherine J.L. Jackson 1 2 , Tim Peters 1 , Megan Faulks 1 , Joanne H Reed 1 2 , Matt Field 3 , André Minoche 1 , Money Gupta 4 , Rowena A Bull 4 , Fabio Luciani 4 , Robert Brink 1 2 , Dan Suan 1 2 , Chris C Goodnow 1 2
  1. Garvan Institute of Medical Research, Darlinghurst, NSW, Australia
  2. St Vincent’s Clinical School, Faculty of Medicine, UNSW, Sydney , NSW, Australia
  3. Australian Institute of Tropical Health and Medicine, James Cook University, Smithfield, Queensland, Australia
  4. Kirby Institute for Infection and Immunity, School of Medical Sciences, UNSW, Sydney , NSW, Australia

It remains unclear how autoantibody production occurs in patients with autoimmune disease despite self-tolerance mechanisms. Cryoglobulinemic vasculitis is an autoimmune pathology frequently associated with chronic hepatitis C virus (HCV) infection, whereby patients develop a precipitating cryoglobulin composed of monoclonal IgM rheumatoid factor bound to polyclonal IgG. Previous work by our lab has shown somatic variants associated with B cell lymphomas or leukemias can be found in B cells isolated from Sjögren's syndrome patients with cryoglobulinemic vasculitis. Using bulk and single cell next generation sequencing techniques, we have deeply analysed an expanded “rogue” B cell clone in a HCV patient with cryoglobulinemic vasculitis, to reveal similar findings. Whole genome sequencing has identified somatic gene variants specific to the rheumatoid factor cryoglobulin-producing B cell clone, which are absent from the polyclonal B cells of the patient. Certain somatic variants identified provide functional insight into how the rogue pathogenic autoantibody-producing B cell may be persisting. Furthermore, by reconstructing and expressing rogue B cell clone antibody sequences to measure precipitating capacity and specificity to IgG or HCV antigens, we have extrapolated a possible somatic hypermutation pathway taken by the rogue B cell clone leading to rheumatoid factor and cryoglobulin activity. Our findings related to this particular “rogue” B cell clone may have broader implications for autoantibody production in other autoimmune conditions.