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J Exp Med. 2010 Sep 27;207(10):2225-37. doi: 10.1084/jem.20092712. Epub 2010 Aug 30.

Somatic hypermutation as a generator of antinuclear antibodies in a murine model of systemic autoimmunity.

Author information

1
Integrated Department of Immunology, National Jewish Health and 2 University of Colorado, Denver, CO 80206, USA.

Abstract

Systemic lupus erythematosus (SLE) is characterized by high-avidity IgG antinuclear antibodies (ANAs) that are almost certainly products of T cell-dependent immune responses. Whether critical amino acids in the third complementarity-determining region (CDR3) of the ANA originate from V(D)J recombination or somatic hypermutation (SHM) is not known. We studied a mouse model of SLE in which all somatic mutations within ANA V regions, including those in CDR3, could be unequivocally identified. Mutation reversion analyses revealed that ANA arose predominantly from nonautoreactive B cells that diversified immunoglobulin genes via SHM. The resolution afforded by this model allowed us to demonstrate that one ANA clone was generated by SHM after a V(H) gene replacement event. Mutations producing arginine substitutions were frequent and arose largely (66%) from base changes in just two codons: AGC and AGT. These codons are abundant in the repertoires of mouse and human V genes. Our findings reveal the predominant role of SHM in the development of ANA and underscore the importance of self-tolerance checkpoints at the postmutational stage of B cell differentiation.

PMID:
20805563
PMCID:
PMC2947070
DOI:
10.1084/jem.20092712
[Indexed for MEDLINE]
Free PMC Article

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