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However, autoantibodies of the same antigenic reactivity are also present in the serum of asymptomatic people years before they develop any clinical signs of autoimmunity. Autoantibodies can arise during multiple stages of B cell development, and various genetic and environmental factors drive their production. However, what drives the development of pathogenic autoantibodies is poorly understood. Advances in single\u2010cell technology have enabled the deep analysis of rare B cell clones producing pathogenic autoantibodies responsible for vasculitis in patients with primary Sj\u00f6gren's syndrome complicated by mixed cryoglobulinaemia. These findings demonstrated a cascade of genetic events involving stereotypic immunoglobulin V(D)J recombination and transforming somatic mutations in lymphoma genes and V(D)J regions that disrupted antibody quality control mechanisms and decreased autoantibody solubility. Most studies consider V(D)J mutations that enhance autoantibody affinity to drive pathology; however, V(D)J mutations that increase autoantibody propensity to form insoluble complexes could be a major contributor to autoantibody pathogenicity. Defining the molecular characteristics of pathogenic autoantibodies and failed tolerance checkpoints driving their formation will improve prognostication, enabling early treatment to prevent escalating organ damage and B cell malignancy.<\/jats:p>","DOI":"10.1111\/imr.13064","type":"journal-article","created":{"date-parts":[[2022,1,10]],"date-time":"2022-01-10T04:10:35Z","timestamp":1641787835000},"page":"101-115","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":13,"title":["Transforming mutations in the development of pathogenic B cell clones and autoantibodies*"],"prefix":"10.1111","volume":"307","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-7585-7848","authenticated-orcid":false,"given":"Joanne H.","family":"Reed","sequence":"first","affiliation":[{"name":"Westmead Institute for Medical Research Centre for Immunology and Allergy Research  Westmead NSW Australia"},{"name":"Faculty of Medicine and Health School of Medical 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