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Spontaneous autoimmunity in mice that carry an IghV partial transgene: a required arginine in VHCDR3

Integrated Department of Immunology, National Jewish Health and University of Colorado, Denver, USA;

T Detanico

Integrated Department of Immunology, National Jewish Health and University of Colorado, Denver, USA; Faculdade de Biociencias, Instituto de Pesquisas Biomédicas, PUCRS, Porto Alegre, RS, Brazil;

D Smith

Integrated Department of Immunology, National Jewish Health and University of Colorado, Denver, USA

KSK Tung

Departments of Microbiology and Pathology, University of Virginia, Charlottesville, Virginia, USA

C Bonorino

Faculdade de Biociencias, Instituto de Pesquisas Biomédicas, PUCRS, Porto Alegre, RS, Brazil

LJ Wysocki

Integrated Department of Immunology, National Jewish Health and University of Colorado, Denver, USA wysockiL{at}njc.org

We describe a unique spontaneous mouse model of autoimmunity, which occurs on a non-autoimmune–prone SWR genetic background. In this model, SWR mice carry an IghV partial transgene (pTg) encoding only the heavy chain variable domain of an antibody directed against chromatin. Autoimmune disease in pTg mice was manifested by some of the features of systemic lupus erythematosus (SLE), including the presence of serum anti-nuclear antibodies, splenomegaly, skin lesions and a moderate degree of kidney pathology, in various combinations among individuals. Autoimmunity was observed in three independent transgenic lines, but not in three control lines carrying a nearly identical pTg, in which a VHCDR3 codon for Arg was replaced by one for Ser to ablate chromatin reactivity. Various features of disease were often but not always accompanied by anti-chromatin antibodies. Unexpectedly, the anti-chromatin antibodies detected in seropositive animals were not encoded by the pTg. These observations strongly implicate a role for the transgene product in disease initiation but not necessarily for end-state pathology, and they raise the possibility that autoreactive B cells may play a previously unappreciated role in initiating the development of systemic autoimmunity.

Key Words: autoantibodies • autoimmunity • partial transgene • systemic lupus erythematosus

Lupus, Vol. 18, No. 4, 299-308 (2009)
DOI: 10.1177/0961203308097480


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