W116 - Lymphoma Driver Mutations Drive Pathogenic B Cell Clones in Autoimmune Hcv-associated Cryoglobulinemic Vasculitis

Mandeep Singh – Garvan Institute of Medical Research, Sydney, Australia; Matt Field – Australian Institute of Tropical Health and Medicine, Australia; Shyam Ravishankar – Garvan Institute of Medical Research, Sydney, Australia; Katherine Jackson – Garvan Institute of Medical Research, Sydney, Australia; Money Gupta – The Kirby Institute, Sydney, Australia; Andrew Carr – St Vincent’s Clinical School, Sydney, Australia; Mark Danta – St Vincent’s Clinical School, Sydney, Australia; Greg Dore – St Vincent’s Clinical School, Sydney, Australia; Gail Matthews; Fabio Luciani – The Kirby Institute, Sydney, Australia; Joanne Reed – Garvan Institute for Medical Research, Sydney, Australia; Chris Goodnow – Garvan Institute of Medical Research, Sydney, Australia; Dan Suan – Garvan Institute of Medical Research, Sydney, Australia

Abstract Text: The pathogenesis of autoimmune disease remains unclear. It has been proposed that some aspects of autoimmune disease overlap with lymphoid cancer pathogenesis. The autoimmune syndrome, mixed cryoglobulinemia, and its more severe form, cryoglobulinemic vasculitis, almost exclusively arises secondary to hepatitis C virus (HCV) infection. HCV infection is associated with an increased risk of developing B cell lymphoma. Here, we interrogate the autoreactive pathogenic B cell clones in four patients with HCV-associated cryoglobulinemic vasculitis, for the presence of somatic gene lesions. Using a combination of whole genome sequencing and single cell genome amplification techniques, we reveal the pathogenic autoreactive B cell clones harbour somatic gene mutations (KLF2, TRAF3, NOTCH1) and chromosome aberrations (11q22-23 del, trisomy 12) recurrently detected in B cell lymphomas. The somatic gene lesions are predicted to cause hyperactivation of the NF-kB signalling pathway. The discovery of functional somatic mutations linked to hyperactivation of NF-kB signalling pathway, not only explains the capacity of the B cell clone to expand and persist in the patients even following clearance of HCV, but also demonstrates how the pathogenic B cell clones and their self-reactive precursors are able to evade B cell tolerance checkpoints. These findings provide evidence for a shared pathogenesis between autoimmunity and lymphoid cancer which may be relevant to the pathogenesis of other autoimmune diseases.