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Transforming mutations in the development of pathogenic B cell clones and autoantibodies*

Journal

IMMUNOLOGICAL REVIEWS
Volume 307, Issue 1, Pages 101-115

Publisher

WILEY
DOI: 10.1111/imr.13064

Keywords

autoantibodies; autoimmunity; B cells; gene rearrangement; somatic mutation

Categories

Funding

  1. National Health and Medical Research Council [1183619, 1142186]
  2. NSW Ministry of Health
  3. Rebecca L Cooper Medical Research Foundation
  4. National Health and Medical Research Council of Australia [1183619, 1142186] Funding Source: NHMRC

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Autoimmune diseases are characterized by the presence of serum autoantibodies, which can be pathogenic and cause severe manifestations and organ injury. The development of these autoantibodies is driven by various genetic and environmental factors, but the factors behind the development of pathogenic autoantibodies are not well understood. Recent advancements in single-cell technology have allowed for the analysis of rare B cell clones producing pathogenic autoantibodies, revealing genetic events and mutations that disrupt antibody quality control mechanisms and decrease autoantibody solubility. Understanding the molecular characteristics and tolerance checkpoints involved in the formation of these pathogenic autoantibodies will improve prognostication, enabling early treatment to prevent organ damage and B cell malignancy.
Autoimmune diseases are characterized by serum autoantibodies, some of which are pathogenic, causing severe manifestations and organ injury. 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-cell technology have enabled the deep analysis of rare B cell clones producing pathogenic autoantibodies responsible for vasculitis in patients with primary Sjogren'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.

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